Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
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May 20, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, Associate Editor of Circulation and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article is going to focus on trastuzumab-induced cardiac dysfunction in breast cancer patients. We will discuss with Stanford investigators their use of pluripotent stem cells that are differentiated to cardiomyocytes and subsequently exposed to toxins to determine an individual's susceptibility to cardio-toxicity from cancer treatment. But before we get to that, Carolyn, do you have a paper that you'd like to discuss?

Dr Carolyn Lam:                Well, the first paper deals with cardiac biomarkers and asks the questions, can these biomarkers be useful for the diagnosis and risk stratification of syncope?" Now, this paper is from Dr Mueller and colleagues from University of Hospital Basel in Switzerland. They evaluated the diagnostic and prognostic accuracy of BNP, NT-proBNP, high-sensitivity cardiac troponin T, and high-sensitivity cardiac troponin I concentrations, alone and against the ones of clinical assessments in more than 1,500 patients presented with syncope to the emergency department in a prospective, diagnostic multi-center study. Now, cardiac syncope was adjudicated in 234 or 15% of patients. What they found was that the diagnostic accuracy from cardiac syncope, as quantified by the area under curve, was 0.77 to 0.78 for all four biomarkers. That was superior to that of the syncope-specific diagnostic score, EGSYS.

                                                Now, combining the four biomarkers further improved diagnostic accuracy to an area under curve of 0.81. Furthermore, using the four biomarkers at cutoffs achieved predefined thresholds for sensitivity and specificity and allowed rule-in or rule-out of 30% of all patients. Finally, the biomarkers predicted adverse cardiac outcomes with moderate to good prognostic accuracy and better than some of the existing syncope risk-prediction scores.

Dr Greg Hundley:             Very interesting, Carolyn. Do you think we can now use this clinically? Should we be drawing these biomarkers on patients with syncope?

Dr Carolyn Lam:                These results really do imply that these biomarkers look like useful tools for the early rule-out and/or rule-in of cardiac syncope in the emergency department. After all, these biomarkers are readily available, inexpensive, and results of this study suggest that they have potential to simplify diagnosis and to risk stratify in challenging presentations. However, before embracing the concept of ordering cardiac biomarkers routinely for syncope presentation, we really need to read the editorial by Dr Sandhu and Sheldon, in which important perspectives are presented, such as considerations of the certainty of the diagnosis of syncope, the usefulness of the comparative scores, the timing of testing, the potential unintended adverse consequences of testing. These editorialists concluded that, although promising, further work is needed to determine how the use of cardiac biomarkers should be incorporated into a risk-stratification algorithm.

Dr Greg Hundley:             Wow, Carolyn. It sounds like we'd get a lot out of that particular editorial. I'm going to switch over and talk about NT-proBNP in patients with pulmonary hypertension. This is a paper from Dr Kelly Chin from UT Southwestern, and the study evaluated the utility of end terminal pro BNP level thresholds and assessing prognosis in pulmonary hypotension using the GRIPHON study. So GRIPHON is a global double blind, randomized placebo control event driven phase 3 study which assesses the safety and efficacy or a Prostacyclin agonist that promotes pulmonary arterial vasodilation.

                                                They performed the study in patients that were 18 to 75 years old with a diagnosis of idiopathic pulmonary hypertension, heritable hypertension or pulmonary hypertension associated with connective tissue disease, repaired congenital systemic pulmonary shunts, HIV infection, drug use or toxin exposure; and the diagnosis of pulmonary hypertension was confirmed by right heart catheterization and by a reduced 6-minute walk distance of 50 to 450 meters.

                                                Eligible patients were permitted to take their other therapies including Endothelin receptor agonists and phosphodiesterase type-5 inhibitors. The patients were categorized into low, medium and high in terminal BNP level subgroups according to two thresholds. First, by just the tertiles within the study overall and the secondly by the ESC guideline cutoff ranges.

Dr Carolyn Lam:                Nice, so what did they find Greg?

Dr Greg Hundley:             Well first of all both thresholds either the tertile one of the ESC in follow-up NT-proBNP categories were highly prognostic for future morbidity and mortality. And their time dependent analysis the risk of experience a morbidity or mortality even was 92% and 83% lower in the treated patients with a low and medium NT Pro BNP level. And 90% and 56% lower in placebo treated patients with low and medium NT-proBNP levels. So both, whether you're taking that drug of not, the NT-proBNP levels were prognostically valuable. More pronounced treatment benefit of selexipag was seen in the medium and low proBNP groups. There was a positive value for the interaction term.

Dr Carolyn Lam:                Wow, sounds like two really important findings.

Dr Greg Hundley:             Yes, exactly Carolyn. So first, NT-proBNP levels are highly prognostic for pulmonary arterial hypertension progression. And having NT-proBNP in the low range, by improving to or maintaining low NT-proBNP levels is a clinically relevant treatment goal for those with pulmonary artery hypertension. And of course as we described this was a very diverse well represented group of many different types of patients with pulmonary hypertension. Then second, while selexipag the study drug was beneficial in all NT-proBNP categories, the treatment effect was greater in those with low and medium categories versus the very high. Suggesting that earlier selexipag treatment may be of greater benefit. But very interesting biomarker study that follows up on yours Carolyn.

Dr Carolyn Lam:                Indeed!

Dr Greg Hundley:             Carolyn what about your next paper?

Dr Carolyn Lam:                Well I want to switch tracks now and talk about iron. And the question is, how does intravenous iron repletion augment exercise capacity in chronic heart failure? Even if hemoglobin doesn't change. So, first some background right, now, besides hemoglobin it's important to recognize that iron is an obligate component of the mitochondrial enzymes that generate cellular energy in the form of adenosine triphosphate and phosphocreatine. So dynamic phosphorous magnetic resonance spectroscopy is a noninvasive tool that can really quantify the in vivo muscle energetics by measuring the kinetics of phosphocreatine recovery after exertion. These authors use this technique, and these are Dr Okonko from King's College, London British Heart Foundation sender of excellence, school of cardiovascular medicine and sciences. The James Black Center in London and colleagues. And what they did was they tested the hypothesis that intravenous iron repletion in chronic heart failure would enhance skeletal muscle energetics as reflected by a shorter phosphocreatine recovery halftime on phosphorous magnetic resonance spectroscopy imagining of the skeletal muscles. And they looked at 40 patients with chronic heart failure with reduced deduction and iron deficiency in a randomized double blind placebo controlled ferric iron and heart failure trial.

Dr Greg Hundley:             So, what did they find?

Dr Carolyn Lam:                They found that a single total dose infusion of intravenous iron repleted iron stores and augmented skeletal muscle energetics at 2 weeks post infusion. Enhancements in the skeletal muscle energetics which implied better mitochondrial function were accompanies by improved symptoms despite no change in hemoglobin at 2 weeks. So, this trial really provides mechanistic support for iron repletion in patients with chronic heart failure and its very importantly discussed in an editorial by Peter van der Meer, Haye van der Wal, and Vojtech Melenovsky. And I really suggest that everybody read that.

Dr Greg Hundley:             Well, I'm going to talk a little bit about dietary omega-6 fatty acids and the incidence of cardiovascular disease and mortality. And this paper is from Matti Marklund from the Georgia Institute for Global Health and the University of New South Wales in Sydney, Australia. The study focuses on linoleic acid which is an omega-6 polyunsaturated fatty acid that we get from pumpkin seeds, flax seeds, walnuts, soybean oil, canola oil and grapeseed. It's been associated with a decrease in cardiovascular risk, but others have worried about an effect of consumption mainly the downstream production of arachidonic acid which can give rise to eicosanoids that are both pro inflammatory and pro thrombotic.

                                                And it's interesting Carolyn, several organizations suggest replacing saturated fat and carbohydrates with linoleic acid. So this study was really performed to address whether consumption of linoleic acid is associated with future cardiovascular events. In the study, investigators measured linoleic acid as well as arachidonic acid levels and from a global consortium across 30 perspective observational studies from 13 countries they performed multi variable adjusted associations of circulating an adipose tissue linoleic and arachidonic acid biomarkers with incident total cardiovascular disease and subtypes of cardiovascular disease including, coronary heart disease, ischemic stroke and cardiovascular mortality and this was all done as pre-specified analytic plan.

Dr Carolyn Lam:                Wow, so what did they find?

Dr Greg Hundley:             Well did I put you to sleep discussing all of that?

Dr Carolyn Lam:                No! You have to tell me what they found. I'm seriously so interested in this topic because being vegetarian I actually get my source of omega fatty acids exactly from these sources.

Dr Greg Hundley:             Okay, so Carolyn, higher levels of linoleic acid were associated with lower risk of total cardiovascular disease, ischemic stroke, cardiovascular mortality. While arachidonic acid was not associated with cardiovascular risks. And so, the clinical implications of the results support the potential benefits of main dietary omega- 6 fatty acid. That is linoleic acid for cardiovascular disease prevention. Now, while the trial is not randomized so we don't have definitive answers, the results do not support any theorized cardiovascular harms of consuming omega-6 fatty acids. And there is an excellent review on polyunsaturated versus saturated fat intake by Thomas Sanders from King's College, London as an editorial to this piece. So Carolyn I think we're safe right now in consuming linoleic acid. So how about a transition to our featured article and learn a little bit more about trastuzumab-induced cardiac dysfunction.

Dr Carolyn Lam:                Absolutely!

Dr Greg Hundley:             Great.

                                                Welcome everybody, we have a fantastic paper to discuss. We're going to review human induced pluripotent stem cell derived cardiomyocytes and how they can be used to identify individuals at risk of trastuzumab-induced cardiac dysfunction after treatment for breast cancer. We have today Nazish Sayed and also Dr Joseph Wu, both from Stanford University in California.

                                                Welcome gentlemen.

Dr Joseph Wu:                   Thank you for inviting us.

Dr Nazish Sayed:              Thank you.

Dr Greg Hundley:             Nazish tell us a little bit about what are these human induced pluripotent stem cells and then also describe your experiment and what were your results?

Dr Nazish Sayed:              So, induced pluripotent stem cells is about 10 years ago I knew technology where you can actually turn back the clock by you taking human fiber blast or blood cells and then you can test full reprogramming factors and turn back differentiated cells to pluripotent stem cells will mimic like catalytic stem cells. The catalytics include self-renewal, pluripotency and the most important that they can be differentiated to any cell type in the body. For example, cardiomyocytes or endothelial cells the neuron and kind of mimic these differentiated cells from the same individual from where the IPSCs were derived from.

                                                So, what we did in our study is we used this platform to derive these pluripotent stem cells from patients and then differentiated them into a cardiomyocyte to understand what would these human cardiomyocytes behave in a dish when treated with a Herceptin or trastuzumab and then kind of determine the underlying mechanism for this cardiac dysfunction. It seemed really difficult to model trastuzumab and use cardiac dysfunction as a heart which is the receptor for the trastuzumab is expressed only in humans.

                                                People have usually relied on animal model and for the first time what we did is we used these ideas of cardiomyocytes to model this dysfunction in a dish. Our results were pretty straightforward. We found that the IPSCs cardiomyocytes when treated with the chemotherapy agent showed cardiac dysfunction in the case of decrease contractility. The contraction velocity of these each individual cardiomyocytes is significantly reduced. More with this was also confirmed by having impaired calcium cycling which is very important for the contractility of these cardiomyocytes.

                                                But I think the most important thing which we determined from the study is that individuals who are treated with trastuzumab have a metabolic impairment in these cardiomyocytes which is convenient but however have a severe impact on this contractility and calcium handling in these cardiomyocytes. And that was one of the gist of these papers to figure out the metabolic impairment could be a target where we can improve this cardiac dysfunction in these patients.

Dr Greg Hundley:             And so, after you discovered this, I noticed you also did some work with AMPK activators and perhaps would reverse some of the dysfunction. Could you describe a little bit what are AMPK activators and then how did they reverse the dysfunction that you observed?

Dr Nazish Sayed:              In our study we characterized these IPS cardiomyocytes from these individuals and then we ran a whole sequencing of them after treatment where trastuzumab to see which of the pathways which could be down regulated or dysfunction when compared to the control patients which are not treated with trastuzumab. And one of the most significant pathways which we found was in PK pathways which was down regulated in the trastuzumab treated IPSC cardiomyocytes. So knowing that the AMPK activators are used for metabolic diseases, for example being diabetes and metabolic dysfunction, we thought that this same thing could be used in a dish where we can take these AMPK activators and simultaneously cotreat cardiomyocytes with Herceptin or trastuzumab to see if we can rescue the phenotype and indeed you can see in our paper we used 4 different AMPK activators with metformin which is a commonly used diabetic drug. Showing the best rescue for that trastuzumab induced cardiac dysfunction.

Dr Greg Hundley:             Very intriguing because it looks like you've been able to harvest cells from individuals and then pre-treat them, understand the mechanism of dysfunction, understand who's at risk of dysfunction and then offer therapeutic interventions to perhaps prevent that dysfunction in this patient population. Joe, turning to you now, this is really revolutionary technology it seems to me. Can you describe how long does this process take? Is this something that we see might come into clinical medicine soon?

Dr Joseph Wu:                   We're really excited about this technology that Nazish has described. I think as you know we've been working on this platform for the past 10+ years. In terms of the timeline, right now it takes us about a month to generate the induced pluripotent stem cells. It takes us another month to expand, propagate the IP itself. It takes us another month to generate the IPS cardiomyocytes. And it will take us probably another month to do all the phenotypic characterization in terms of using these IPS cardiomyocytes to expose them to various chemotherapy drugs and see how the chemotherapy drugs have an effect on these cardiomyocytes.

                                                So, I would say the total timeline is 12 months at this moment. Is it possible that the timeline could be crunched, could be shrunk over time? Yes that's possible, I think the technology is improving month by month, week by week because there are many different labs trying to work on this platform trying to improve the whole process. But right now one of the limitations that as you pointed out is this 4 month time period. And also the cost that's associated with this. But we're hopeful that over time that both the time, the costs can go down so that we can offer this type of platform to help patients diagnosed with cancer, find out what kind of chemotherapy is safe to use, what kind of chemotherapy is not safe to use.

Dr Greg Hundley:             So, we're working towards clinical applications but at this point in time it looks like a fantastic platform for understanding, diagnoses and understanding pathways that for patients particularly as they are treated for cancer will experience cardiovascular dysfunction. So, switching a little bit and asking a related question. Patients that receive trastuzumab often also receive doxorubicin. Especially the breast cancer patients. If you looked at this technology trying to understand, and certainly those more at risk for trastuzumab associated left ventricular dysfunction, are the patients that previously received doxorubicin. Have you and your group looked at patients that have also received doxorubicin and then went on to receive trastuzumab relative to those that received trastuzumab alone?

Dr Joseph Wu:                   I think for these two populations for this particular study, we tried to keep them clean. Meaning that we're looking mostly for trastuzumab treated patients, otherwise it's hard for us to piece out whether the toxicity was due to one medication or the other medication. But what you are asking is very important because as you pointed out many of these patients received both and I think for future studies we should be able to model both medications, meaning that take some IPS cardiomyocytes treated with doxorubicin, treated with Herceptin by itself and treated with both the medications.

                                                In previous studies we have studied using IPS cardiomyocytes the effects of doxorubicin induced cardiac toxicity. In just the assessment, doxorubicin is a very common effective chemotherapy for breast cancer medications and just like Herceptin, the clinicians struggled with the issue, as we cannot predict which patient will develop toxicity. And then granted the doxorubicin induced toxicity has a slight different mechanism compared to perception induced mild cardiac dysfunction that this Nazish had mentioned about. But these are kind of the studies that we're very excited because now for the first time we have a way to model this. Otherwise they alternative would be not possible, for example it would not be possible for us to biopsy breast cancer patients woman's heart to study the cells.

                                                Especially in the case of perception. The receptor that's being studied is not present in animal model cells. For example not present in mouse cardiomyocytes and therefore it would be very difficult to understand the mechanism and this is the reason why the patient specific and disease specific IPS cardiomyocytes become so useful.

Dr Greg Hundley:             Do you find another emerging therapy in this entire realm is the immunotherapies? Do you think this technology will be applied to determine susceptibility to immune mediated toxicity?

Dr Joseph Wu:                   This is a very good question as well Greg. We've been thinking about studying that and as you know, it's a more complicated system because it involves patients’ immune response, the myocardial, to inflammatory infiltrates that happens. So we have a couple projects going on. One is to study direct effect of the immunotherapy on the cardiomyocytes and then the second angle is to take patients who are in full myocarditis and collect their patients urine samples, blood samples and to see if we could expose these IPS cardiomyocytes to the patients urine samples to see what is the effect. For these IPS cardiomyocytes for future studies we're also trying to make it more complicated by generating not just the cardiomyocytes by itself, but generating what we call engineered heart tissues. In which it's a chunk of human heart muscles that would have the patients cardiomyocytes, patients fibroblast, patients endothelial cells and expose them to the patients serum.

                                                But that kind of study would take much longer period of time because the number of people who have these types of immunotherapy induced myocarditis it's relatively low compared to patients who have Herceptin or doxorubicin induced cardio toxicity. This is also part of the reason why we're very much interested in collaborating with big centers throughout the country like York Center to see if we could understand this process better as a team.

Dr Greg Hundley:             Excellent. I want to thank both of you for this really elegant discussion and perfect work moving forward. In summary, you've illustrated an ability to withdraw human pluripotent stem cells, differentiate them to cardiomyocytes and then perform tests on them to forecast susceptibility to various treatments used commonly for women with breast cancer. And in this study identifying mechanisms for trastuzumab toxicity. And then perhaps therapeutic interventions using again human cells which has a marked leap as you've identified over doing mouse studies, particularly for studying trastuzumab when the receptors the HER2 receptors in mirroring models differ substantially to those in human subjects.

Dr Joseph Wu:                   Thank you Greg. And we want to also express our thanks to our collaborators, our colleagues who contributed to the study and most importantly to the patients who helped us with these studies.

Dr Greg Hundley:             I want to thank both Nazish and Dr Wu from Stanford and Carolyn and I wish you the best for the coming week and we look forward to speaking with you again next week.

Dr Carolyn Lam:                This program is copyright American Heart Association 2019.


May 13, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, Associate Editor of Circulation from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam:                Are NOACs, or non-vitamin K antagonist oral anticoagulants, safe and efficacious in patients with extremely high or very low body weight? Very interesting paper and discussion coming right up. Greg, I hear that you've got a couple of papers you'd like to highlight first.

Dr Greg Hundley:             You bet, Carolyn. My two papers today both focus on ventricular dysrhythmia. The first one, from Yuki Komatsu from Tsukuba, Japan, researches the efficacy of catheter ablation of refractory ventricular fibrillation storm after myocardial infarction. VF storm attributed to focally triggered VF after MI is recognized as a distinctive, lethal, arrhythmogenic syndrome that differs from scar mediated monomorphic VT.

                                                This study investigated the acute and long-term outcomes of catheter ablation for the treatment of last resort in a large series of consecutive patients with post-MI VF storm refractory to medical therapies. In the study, investigators enrolled 110 patients averaging about sixty-five years in age. Ninety-two were men, and their average ejection fraction was approximately 31%. VF storm occurred in the acute phase of MI, about four and a half days after MI-onset, during the index hospitalization in about 39% of the patients. It was sub-acute (that is greater than 1 week later) in 44% of patients. It was remote (greater than 6 months later) in 17% of patients. And the focal triggers were found to originate from the scar border zone in 80% of the individuals.

Dr Carolyn Lam:                And what did the study show?

Dr Greg Hundley:             So Carolyn, during in hospital stay after ablation, VF storm subsided in 84% of patients and overall, 27% of in-hospital deaths occurred. The duration from the VF occurrence to the ablation procedure was associated with in-hospital mortality, with a P-value of 0.008. During follow-up after discharge from the hospital, only one patient developed recurrent VF storm. Of note though, 36% of the patients died, with a median survival of 2.2 years. And the long-term mortality was associated with a low EF (less than 30%), New York Heart Association class greater than 3 Heart Failure, a history of atrial fibrillation or chronic kidney disease.

                                                So in summary Carolyn, the results of this study show that in patients with MI presenting with focally-triggered VF storm, catheter ablation of the culprit triggers is life-saving and appears to be associated with short and long-term freedom from recurrent VF storm. The overall mortality for these patients is associated with the severity of their underlying cardiovascular disease, and those associated co-morbidities.

                                                Now my next paper is from one of our associate editors, Sami Viskin from Tel Aviv University. He's looking at a new form of polymorphic VT. Now as we think about polymorphic VT, I always think about the long QT interval syndromes associated with Torsades de Pointes. We have specific management strategies for those long QT syndromes, but Carolyn, there's a second category of polymorphic VT that's not related to QT prolongation. This second category involves patients without structural heart disease, who have genetic disorders like Brugada or patients that may have experienced hypothermia. There is also a third category of individuals with structural heart disease, during acute ST elevation MI.

                                                What Sami has discovered is there's now a fourth category of non-QT prolongation, which includes those with coronary artery disease but without evidence of ischemia.

Dr Carolyn Lam:                So how did they show or find this fourth category?

Dr Greg Hundley:             Well, this is a longitudinal cohort that he identified, and they basically followed forty-three individuals who developed polymorphic VT within days of an otherwise uncomplicated MI or coronary revascularization procedure. The in-hospital mortality was 17% with these patients with arrhythmic storm and the patients were treated with quinidine invariably survived to hospital discharge, just like the other categories of non-QT prolongation polymorphic VT.

                                                During long term follow-up of five and a half years, 16% of patients discharged without quinidine developed recurrent polymorphic VT and there were no recurrent arrhythmias in those individuals that were receiving quinidine therapy long term.

                                                So Carolyn, although quinidine therapy is usually considered contraindicated in patients with organic heart disease who develop ventricular arrhythmias, this therapy may be life-saving for patients with coronary disease developed arrhythmic storms due to polymorphic VT. Polymorphic VT storms may be a transient phenomenon. It's unclear for how long quinidine should be continued in these responsive patients.

Dr Carolyn Lam:                Wow, neat! Well, for my two papers I'm going to start off with a basic paper and, in fact, a quiz for you this time, Greg! So, what do cilia have to do with the heart? All right, you get to ask me, do you remember what cilia are?

Dr Greg Hundley:             Aren't cilia on prokaryotes? I mean, I think of bacteria.

Dr Carolyn Lam:                All right, let me set us straight. The primary cilium is a cellular organelle and it's formed by a protrusion of the plasma membrane that functions as a signaling platform in eukaryotic cells and is found in many cells including neurons, pre-adipocytes and kidney tubular cells, where they have been reported to be involved in a variety of cellular functions such as proliferation, differentiation, cell cycle regulation as well as mechano-chemical sensing of diverse stimuli.

                                                Now, the importance of these cilia is highlighted by the role in several diseases, known as ciliopathies. Polycystic kidney disease is one such disorder with, by the way, numerous cardiovascular manifestations. Whereas ciliated cells have been described in the developing heart, a role for primary cilia in the adult heart has not been reported. It was therefore the aim of these authors and those co-corresponding authors Dr Hill from UT Southwestern and Dr Lavandero from University of Chile, who aimed to identify cells in the adult heart harboring a primary cilium and to determine whether these primary cilia play a role in disease-related remodeling.

Dr Greg Hundley:             Carolyn, this is so interesting. I had no idea about these cilia. So what did they find?

Dr Carolyn Lam:                So, in a series of elegant experiments, these authors identified for the first-time primary cilia in mouse, rats, and human hearts, specifically and exclusively in cardiac fibroblasts. Now these ciliated fibroblasts were enriched in areas of myocardial injury. Transforming Growth Factor beta-1 signaling and SMAD3 activation were impaired in fibroblasts that were depleted of the primary cilium. Extra cellular matrix protein levels and contractile function were also impaired. And in vivo depletion of PC1 inactivated fibroblasts after myocardial infarction impaired the remodeling response.

Dr Greg Hundley:             So how do we use this clinically, and what does it mean for us?

Dr Carolyn Lam:                These findings point to a pivotal role of cilia and PC1 in disease related pathological cardiac remodeling and suggest that some cardiovascular manifestations of autosomal dominant polycystic kidney disease, for example, derive directly from myocardium autonomous abnormalities. The findings also uncover novel fibrosis regulators and raise the prospect that this pathway may emerge as a target with therapeutic relevance.

Dr Greg Hundley:             Wow, very interesting!

Dr Carolyn Lam:                Thanks! And the next paper is also very interesting, in dilated cardiomyopathy and providing insights in how specific viral function may be involved in the development of dilated cardiomyopathy. Looking at the Group B enteroviruses, which are a common cause of acute myocarditis and can be a precursor of chronic myocarditis and therefore dilated cardiomyopathy leading to heart transplantation. In fact, enterovirus-induced dilated cardiomyopathy represents a third of idiopathic dilated cardiomyopathy cases.

                                                So these authors, led by corresponding author Dr Andreoletti from University of Reims, Champagne-Ardenne and Dr Semler from University of California, performed deep sequencing of viral RNA from cardiac tissue from patients with enterovirus related end stage dilated cardiomyopathy and then trans-factored viral RNA clones, mimicking the viral genomes found in patient tissues into primary human cardiac cells to assess their replication activities and impact on cardiomyocyte function.

                                                They found that the major persistent viral forms are composed of B-type enteroviruses harboring 5' terminal deletion in their genomic RNAs. These viruses alone, or associated with full length populations of helper RNAs, could impair cardiomyocyte function by viral enterovirus proteinase 2A activities in these enterovirus-related dilated cardiomyopathy cases.

Dr Greg Hundley:             Very interesting, Carolyn. So what are the clinical implications of this viral infection of the heart?

Dr Carolyn Lam:                Well, the findings seem to imply that it would be important for us to develop specific inhibitors of enterovirus proteinase 2A activity that might prevent viral replication and inhibit the shut-off of host cell translation as well as the disruption of dystrophin.

                                                Furthermore, in early diagnosed enterovirus induced dilated cardiomyopathy, the use of such protease inhibitors could potentially decrease and stop the chronic pathological process of dilated cardiomyopathy and therefore reduce the need for heart transplantation in this end-stage. Very interesting, but requires more work.

                                                So, that wraps up our summaries Greg. Shall we move to our feature discussion?

Dr Greg Hundley:             Absolutely.

Dr Greg Hundley:             Today we have Renato Lopes from Duke University in Durham, North Carolina and Brian Olshansky, Professor Emeritus from Iowa now in clinical practice in Waterloo and Mason City, Iowa. We're going to talk about our non-vitamin K oral antagonists, or NOACs, safe and efficacious in patients in extremely high (greater than 120 kg) or extremely low (less than 60kg) of body weight.

                                                Renato, welcome to our podcast in Circulation on the Run. Can you give us a little overview of your study, why you performed it and what results did you experience?

Dr Renato Lopes:              The idea behind this study was to provide more data into the use of NOACs in these extreme body weight patients, where we don't have a lot of information. Some guidelines actually caution against the use of NOACs in patients with extreme body weight because of the lack of data.

                                                We had the opportunity to look at the Aristotle database, which was a large, randomized trial comparing apixaban versus warfarin for patients with atrial fibrillation, over 18 000 patients. We took advantage of this database to try to look at the extreme body weight and how those patients at weight more than 120 kg, more than 140 kg and less than 60 kg, performed in terms of the treatment effect of apixaban versus warfarin. This was the rational, to try to provide more data so people could gain additional confidence in using apixaban in clinical practice in those extreme body weight patients.

                                                What we showed was, in general the treatment effect of apixaban versus warfarin for the efficacy outcomes CHOKE, systemic embolism and all cause death and myocardial infarction was very consistent across the weight spectrum and preserved. Apixaban was superior to warfarin and this was consistent regardless of the weight category. For the low body weight patients less than 60 kg, we also found that apixaban results in terms if efficacy was preserved.

                                                So, going out to the bleeding and safety endpoints, apixaban was safer than warfarin across different spectrums of weight. Surprisingly, in patients less than 60 kg we saw an even greater relative risk reduction in bleeding, in patients treated with apixaban compared to warfarin. The main message was for efficacy, apixaban was better than warfarin - the same results as the Aristotle main trial. For bleeding and safety endpoints, we also saw the same results and consistent results with apixaban- in particular with patients below 60 kg, which is always a concern that people might have in clinical practice. It seems that apixaban was even safer with an even greater treatment effect.

Dr Greg Hundley:             Very nice. Can you tell us a little bit about some of the sites where you enrolled patients and did you identify any variation in age, sex or region specific factors? Were there any differences in your findings related to race?

Dr Renato Lopes:              That is a very interesting question because we know that these variables play an important role in body weight. We enrolled patients from thirty-nine countries in Aristotle, in over a thousand sites all over the world. Interestingly, I can tell you that the heaviest weight we had in our study was 205 kg, a patient from the United States. The lightest weight that we had was 39 kg, from the Philippines. You lose trading the variation that regions of the world can play out and how patients can perform. We haven't seen any major difference in these analogies. There were prior analogies that look at different BMIs, and we know that the treatment effect might be attenuated depending on race and sex. In this analogy, we did not find any significant difference according to race, region of the world or even sex.

Dr Greg Hundley:             Just getting back to your body weight measurement, you mentioned percentage of individuals were above 120 kg and briefly mentioned some were above 140 kg. What percentage of your study cohort was that extra-large size, above 140 kg? Do you think more work needs to be done in that area or do you think the results were sufficient for that very heavy body weight?

Dr Renato Lopes:              This is a very important question. If we look at the breakdown, we had about 11% of the entire trial in the low spectrum of weight, less than 60 kg in weight - almost 2000 patients. A good number of patients. In extreme weight more than 120, we have about 980 patients. That was 5.5% of the overall trial. When you look at greater than 140 kg, we had 258 patients, 1.4% of the overall trial population and about 25% of this category greater than 120.

                                                I think as we start getting greater than 140 kg, we had 258 patients. It is not a large number of patients. It is some information and it is good to have some data on these patients. Before that, we had no data on apixaban in this level of weight. What we are seeing is that above 140 kg, the death rate are very low. There is a trend to better bleeding endpoints and better bleeding profile with apixaban, similar to what we have seen in the entire spectrum of weight when we look at weight as a continuous variable. We also saw that trend in patients greater than 140 kg for bleeding. This is reassuring. I don't think we can say it is definitive, it is only 260 patients that we are talking about.

                                                It is reassuring that we now have data in patients more than 140 and up to 205 kg, and we didn't seem to see any major concern or any difference in the curves in terms of the direction of efficacy and safety of apixaban. For the majority of patients it is reassuring and gives us extra confidence that the dose we use in clinical practice five milligrams twice daily should also work in those heavy weight and the heaviest body weight patients.

Dr Greg Hundley:             Very good. Brian you've done an excellent editorial and I wonder if you could help us put this study in perspective with what we know about NOACs and managing patients with atrial fibrillation?

Dr Brian Olshansky:         It really is a fascinating study. Obesity is as growing problem for us here in the mid-west and probably throughout the world. It effects a variety of things including drug pharmakinetics, volume of distribution, drug clearance etc. So knowing how NOACs work at the extremes of body weight, either the massively obese or the vanishingly frail, it becomes important to understand the safety and efficacy of the use of NOACs in these individuals. There are guidelines that caution us against use of NOACs at extremes of body weight, particularly those patients who are over the 120 kg mark. The one point I would like to make is, at least here in the mid-west, 120 kg is becoming almost the norm. We are having people that are becomingly massively obese and this is really the question then in my mind, is what to do with those patients who are over 140 kg or even way more than that. This gets to points that I would like to make about some the issues we need to consider about this study and where we are with our understanding about the use of NOACs in the extremes of body weight.

                                                One thing to keep in mind is, in this analysis, this was a retrospective group analysis. That is one important point. We don't have prospective data that look at an entire large population, a very frail, a very low body weight population.

                                                Another issue is that weight is not a static measure. We only have assessment at the baseline. Variability in weight or body mass index may be important in terms of its relationship to the development of atrial fibrillation and sequelae. The other issue here to consider is that there are comorbidities that are associated with those who are at the extremes of body weight and there was a significant variation in this study in age composition, sex dominance, the region of enrollment, the presence of comorbidities between the different weight groups that could contribute to results we have seen. Those with low body weight had more comorbidities and a higher mean CHADSVASC score, and had the biggest difference between apixaban and warfarin.

                                                We have quite a bit to learn about how to understand these data, and when we consider the individuals who are over 140 kg, indeed there are concerns about the volume of distribution of a NOAC and its efficacy. We would like to rely on this data. The problem is that the number of individuals that are a part of this retrospective analysis at the very high body weight and very low body weights was a rather small number and so to project from that number, what we should do with all of our patients becomes somewhat of a concern.

                                                Although these are interesting and provocative data, what we really need is to have some well-designed large prospective randomized controlled trials that specifically address those individuals at the extremes of body weight because this is becoming more and more of a problem as time goes on. We are seeing more individuals that are at the extremes of body weight. While I have not specifically noticed a difference in my own clinical practice, what we need is a better understanding about the dosing of and potential risks and benefits of the NOACs for the extremes of body weight.

Dr Greg Hundley:             On behalf of Carolyn and myself, we really appreciate you listening. Have a great week. We look forward to seeing you next week.

Dr Carolyn Lam                  This program is Copyright American Heart Association 2019.


May 6, 2019


Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, Associate Editor as well, at Circulation, and Director of the Pauley Heart Center in Richmond, Virginia at BCU Health.

Dr Carolyn Lam:                Now, we've heard of the PIONEER heart failure trial and that is a sacubitril/valsartan in acute decompensated heart failure. A very important trial, but was powered on the surrogate outcomes. Now, in today's issue though, we're going to hear a little bit more about the clinical outcomes from the PIONEER heart failure trial, a very important paper, a very important discussion coming right up. Greg, what paper do you have to start us off?

Dr Greg Hundley:             Carolyn, I've got another favorite of our little discourse, your next Carolyn's Quiz. Except this time it's essay format, so it's open ended questions. And so here's my question to you. What paper addresses an important issue related to hookah inhalation. So Carolyn, do you know a little bit of the origins of hookah and then how does its use compare to e-cigarettes or conventional cigarettes?

Dr Carolyn Lam:                Oh, okay. Well at least the quiz wasn't asking if I smoke hookah. Okay, so hookah, that water pipe smoking pipe, fun stuff. I think, is it a Middle Eastern origin? And frankly I don't know of any data to say whether it is better or worse than cigarette smoking.

Dr Greg Hundley:             Yeah, you're exactly right. Hookah, it's a longstanding practice, primarily confined to men from the Middle East. But in the 1990s it was introduced with fruit flavored pre-packaged tobacco products and that ignited a sharp uptake of hookah smoking by young women and also men in the Middle East, and then a migration to our western culture. Now, believe it or not, in the United States and in the United Kingdom, hookah has a prevalence of 15% to 25% among university students. And today, twice as many secondary school children smoke hookah as they do cigarettes, and more adults have tried or currently use hookah than electronic cigarettes.

                                                So, what does this article discuss? Well, it focuses on hookah inhalation byproducts, because the charcoal traditionally is used to heat the hookah tobacco in the water pipe, hookah smoke delivers tobacco toxicants and nicotine plus charcoal combustion products, not only carbon rich nanoparticles and oxidants that may destroy nitric oxide and impair endothelial function, but also large amounts of carbon monoxide, a putative vasodilator molecule that will dilate the arteries independent of endothelial dysfunction.

                                                So, this study enrolled three groups of patients. First, there were 30 26-year-old hookah smokers. Second, there were 20 in which the flavored hookah tobacco product was heated electrically, not by the charcoal. And then finally, 15 age matched cigarette smokers who smoked one cigarette.

Dr Carolyn Lam:                Wow, what was the result?

Dr Greg Hundley:             Unfortunately, nicotine levels increased similarly with all types of smoking. Now, flow-mediated arterial dilation, a marker of endothelial function, did not become impaired after smoking charcoal heated hookah, but instead increased by about 43%. In contrast, flow-mediated arterial dilation decreased by 27% after smoking electrically heated hookah, compared to the decrease after cigarettes smoking. For hookah smokers, vasodilation increased 138% times more than in the other two groups. Therefore, the acute endothelial dysfunction was masked by those high levels of carbon monoxide that are generated from the charcoal. Remember, carbon monoxide is a very potent vasodilator.

                                                What do we take away from this, Carolyn? With respect to large artery endothelial function, smoking hookah is not as harmless as discussed by an excellent editorial by Naomi Hamburg from the Whitaker Cardiovascular Institute at Boston University School of Medicine.

Dr Carolyn Lam:                Oh wow.

Dr Greg Hundley:             You know, importantly, the carbon monoxide is blocking our ability to appreciate endothelial dysfunction with traditional measures. So Carolyn, what about your article?

Dr Carolyn Lam:                Going from smoking to exercise, this one looking at intensity of exercise that should be performed after heart transplantation. This is a study from Dr Nytrøen and colleagues from Oslo University Hospital in Norway, and they performed a multicenter prospective randomized controlled trial of 81 patients at a mean of 11 weeks only after a heart transplantation. And these patients were randomized to either nine months of high intensity training, which is a four by four minute intervals at 85% to 95% of peak effort, or to moderate intensity continuous training defined as 60% to 80% of peak effort. And the primary outcome was the effect of high versus moderate intensity exercise on the change in aerobic exercise capacity assessed as VO2 peak.

Dr Greg Hundley:             So, what did they find here?

Dr Carolyn Lam:                First, it's important to note that it is the first study to test this and to show that the effect of nine months of high intensity training in de novo recipients of heart transplants produced a clinically meaningful, significantly larger increase in peak VO2 and muscular exercise capacity compared to moderate intensity continuous training. Importantly, the study also showed that the approach was safe with high adherence and high completion rates. 96% of patients completed the study, during which time the exercise adherence for both groups was 81% and there were no serious exercise related adverse events.

Dr Greg Hundley:             Wow. So it looks like we've been hearing about that in training and athletes. Are there any caveats?

Dr Carolyn Lam:                Yeah, and that's an important question. High intensity training in this study required one to one interaction with physical therapists, and of course that's not feasible in most cardiac rehabilitation programs. It also requires motivated, medically stable patients who can maintain high exercise intensity ranges. So further research is really required to determine if these initial improvements at peak VO2 and muscular endurance persist in the long-term period post heart transplantation and, of course, whether they're associated with favorable clinical outcomes. All this is discussed in a beautiful editorial entitled "Can a Hit Result in a Home Run?" by Mark Haykowsky, Wesley Tucker, and Peter Brubaker.

Dr Greg Hundley:             Carolyn, that's fantastic. In my next study, I'm going to switch over and discuss diabetes and the age of diagnosis of type two diabetes and its association with cardiovascular mortality and risk findings from the Swedish National Diabetes Registry. The study was conducted between 1998 and 2012 and the analysis cohort comprised 318,083 patients with type two diabetes mellitus matched with just under 1.6 million controls. Participants were followed for total mortality, cardiovascular mortality, coronary heart disease, acute myocardial infarction, stroke, heart failure, and atrial fibrillation.

Dr Carolyn Lam:                Huge study. Important question. What did it show?

Dr Greg Hundley:             Over a median follow up of about five and a half years, patients with type two diabetes diagnosed under the age of 40 years had the highest excess risk for the most common cardiovascular related outcomes. All risk attenuated progressively with each increasing decade. By the time type two diabetes was diagnosed at an age greater than 80 years, adjusted hazard ratios for cardiovascular disease and non-cardiovascular mortality were all less than one. In addition, survival for those diagnosed beyond 80 years was the same as controls, whereas it was more than a decade less when type two diabetes was diagnosed in adolescence.

Dr Carolyn Lam:                Okay, so Greg, what does this mean for us clinically?

Dr Greg Hundley:             The observations of this study amplify support for preventing and delaying type two diabetes onset in younger individuals and raises questions as to diagnostic strategies, as to whether we should even screen or implement management strategies for those individuals that are diagnosed with diabetes beyond the age of 80 years.

Dr Carolyn Lam:                Interesting. Well, for my last paper, I have a basic science paper and this one really provides insights into endothelial dysfunction. It looks at
S-Adenosylhomocysteine, which is a precursor of homocysteine, and elevated levels of these are positively associated with the risk of cardiovascular disease and with development of atherosclerosis, but its role in endothelial dysfunction has been unclear. So authors Dr Ling from Sun Yat-sen University in Guangzhou, China and Dr Ke from Shenzhen Center of Disease Control and Prevention in Guangzhou, China, these co-corresponding authors and their colleagues performed a series of elegant mouse experiments and showed that the inhibition of S-Adenosylhomocysteine hydrolase resulted in elevated plasma levels of S-Adenosylhomocysteine, which then induced endothelial dysfunction via epigenetic upregulation of the p66Shc-mediated oxidative stress pathway.

                                                Furthermore, plasma S-Adenosylhomocysteine levels were positively associated with oxidative stress levels and inversely associated with flow-mediated dilation and methylation of p66Shc promoters in patients with coronary artery disease and healthy controls. So, this study really provides a novel molecular insight into mechanisms by which this molecule, S-Adenosylhomocysteine, may be associated with endothelial injury and contribute to the development of atherosclerosis. So that brings us to the end of our summaries, Greg. Let's move on to our feature discussion.

Dr Greg Hundley:             Welcome everyone to the second half of our presentation where we have an outstanding interview with David Morrow from Brigham and Women's Hospital and Dr Justin Ezekowitz from Edmonton to discuss a letter that we've received, "The clinical outcomes in patients with acute decompensated heart failure randomized to sacubitril/valsartan or enalapril in the PIONEER HF trial. David, can you remind us just a little bit about, first, your New England Journal study, and then how this letter adds to the prior findings?

Dr David Morrow:            I think it's first worthwhile to place a little bit of context in that paradigm heart failure trial, which was a preceding trial in patients with chronic heart failure, who were ambulatory patients, who had to be tolerating a stable dose of an ACE inhibitor or an ARB, and could not have had a current acute decompensation of their heart failure, were randomized to sacubitril/valsartan versus enalapril with a significant reduction in major clinical cardiac events with sacubitril/valsartan. And that finding from that trial has led to changes in guidelines and clinical practice for patients with chronic heart failure with reduced ejection fraction.

                                                But there were several important aspects that still left gaps for our clinical care, in that because of a run in period in that trial, so a period where patients had to tolerate sacubitril/valsartan, the stability of the patients that I just described, it often left practitioners in the position of caring for patients who might not meet those inclusion criteria, particularly those patients who are hospitalized where there is an opportunity, often, to update their care to be consistent with current standards and current guidelines. And so we designed the PIONEER heart failure trial with that in mind, to study specifically patients with acute decompensated heart failure, all patients with heart failure with reduced ejection fraction. And they were randomized within hospital initiation after an initial period of stabilization to either sacubitril/valsartan or enalapril in a double blind, double dummy design.

                                                The primary endpoint for the PIONEER heart failure trial was a biomarker, so NT-proBNP, and we saw that there was a significantly greater reduction in
NT-proBNP by four to eight weeks as an average endpoint, by 29% more with the sacubitril/valsartan versus enalapril. And we also saw that the adverse events, the tolerability of the two regimens was similar and the event rates did not differ in the sacubitril/valsartan group.

                                                And so that was the primary result of the trial that was published in the New England Journal of Medicine. We had, in addition, some exploratory clinical end points, one of which was a broad composite which included all-cause mortality, the need for an LVAD implantation, referral for transplantation, heart transplantation, as well as rehospitalization for heart failure. And so, what was new in the letter that we have published in Circulation, is that we specifically looked at the clinical end points and additional exploratory end points, looking at the harder composite of cardiovascular death and rehospitalization for heart failure. And we had particular interest in that because it's being used as a primary end point that was consistent with the paradigm heart failure trial that I described in chronic heart failure. That was really the reason for undertaking this additional analysis.

Dr Greg Hundley:             So how did you define rehospitalization for heart failure and what did you find?

Dr David Morrow:            Rehospitalization for heart failure, we actually used the same clinical endpoint committee as for the paradigm heart failure trial and used the same definition, which requires that patients had clinical evidence of heart failure, which could include both symptoms as well as biomarker values and evidence of congestion on physical exam. We needed graphic evidence of pulmonary edema. Together, they had to have a clinical presentation that was consistent with heart failure, and then also who have been hospitalized for the management of that decompensation.

                                                And so what we found overall was that there was a significant reduction in cardiovascular death or heart failure with the sacubitril/valsartan over the eight week double blind study period, such that it was a 42% reduction in that end point and an absolute 6% reduction in cardiovascular death or rehospitalization for heart failure with sacubitril/valsartan compared with enalapril.

Dr Greg Hundley:             And David, looking at these fantastic figures, for listeners, please take a look at this letter, it looks like the two groups separated early. Can you suggest a mechanism for why that might've occurred?

Dr David Morrow:            We agree that it does appear that the separation begins early on. We did not have sufficient statistical power to test individual hypotheses much earlier time points, but the relative risk reduction appears homogeneous over that period. And when we look specifically at 30 days, for example, the relative risk reductions are comparable. So we do think that observation you just made is correct and consistent.

                                                And I think that there's evidence of support for rather early effects on hemodynamic stress. So we have the primary end point with NT-proBNP where we saw that there was separation between the groups that was actually statistically significant on that continuous end point of a natriuretic peptide value already by one week of therapy, which was quite remarkable to us. We had planned as our primary end point the four to eight weeks period where we had expected, based on previous work, that there would likely be a reduction in this slightly different population. But in fact we saw those curves in NT-proBNP separate already by one week. We've also had subsequent work that we presented in abstract form looking at other biomarkers such as troponin and soluble SD2, so biomarkers of wall stress and myocardial injury, and also seeing reductions in those markers that appear also to occur early on.

Dr Carolyn Lam:                Justin, can we bring you into this conversation here right now? What do you think are the clinical implications of this particular research letter and then perhaps of PIONEER in general?

Dr Justin Ezekowitz:        Thanks Carolyn, and my compliments to Dr Morrow and the team for putting this together as a research letter because that's often a challenge to get to the core information from the study. And I would, again, draw the listeners to get a look at the figures that they put together and especially the way in which they separate early out. And we did ask to be cautious with statistical power about rehospitalization, but it's quite a driving factor for the overall end point and one that shouldn't be lost, because that has the biggest probably clinical implications, that the curves separate early between the groups on an ACE inhibitor versus to sacubitril/valsartan. And given they separate early, one of the clinical implications is, why wait? So why wait for when people have been outside the hospital to change the medication but instead use that as an opportunity when they're in front of you as a clinician to consider switching them over to a newer therapy and consider what they’ve been on from the majority of patients being on an ACE inhibitor or an ARB, but it is the right time when you have them in observation.

                                                The second observation I would make from this study is that although this was done in high quality sites and sites that know how to do clinical research, but also those who take care of patients that are on high quality medications, the baseline medication rate use wasn't perfect. So there's dual opportunity for looking at the baseline medications, which was MRAs and beta blockers, and use it as opportunity and an implication to use all the best medications. And in this case sacubitril/valsartan would be an opportunity.

                                                My final point would be, I think this study is critical from a clinician's perspective, as we've seen many biomarker-based studies where there's a reduction in the biomarker, but the clinical end point doesn't seem to change so NT-proBNP is great, but here is the judicated clinical endpoints. So for me, when I'm treating a patient, that means more to me than the lowering of a biomarker. We've seen other evidence where that doesn't always pan out, and so you are confident now that that is the case.

Dr Carolyn Lam:                Well put, Justin. And you had a question, didn't you, for David?

Dr Justin Ezekowitz:        Right. One of the questions I was trying to sort through, and we couldn't squeeze this fully into the research letter, was there were some patients who were randomized in the hospital but the overall PIONEER program allowed for up to 10 days, and when you look at the patients and when they were randomized and how they were cared for beginning of the hospital, end of the hostel, right after discharge, was there any difference that you saw across the spectrum of outcome?

Dr David Morrow:            Actually, the study drug was initiated in hospital for all patients. We did provide up to 10 days while in hospital for the outer limits of recruitment into this study because we recognized that some hospitalizations for acute decompensated heart failure are quite lengthy, and we wanted to give sites the opportunity to recruit patients who took longer to stabilize in this study than others. So it was starting from 24 hours after hospital presentation up to 10 days as a maximum, but all patients were initiated in hospital.

                                                The median turned out to be at 68 hours and at least three-quarters of patients were recruited and randomized within 98 hours. So the vast majority were early on. Overall, when we look at the consistency of the effects of the primary end points of the natriuretic peptide and a broader composite, we did not see any evidence of heterogeneity based on the timing of randomization relative to presentation. As you pointed out earlier, we have to recognize that the numbers do get smaller across that tier, particularly when we get out to the later window. Still. I would say that the primary results, almost in any trial you should always go by the primary result, and we did not see any heterogeneity to think that there was a different effect in those who were enrolled early or late.

Dr Carolyn Lam:                David, can I just chime in and say again, congratulations on this great work. Can I go back to one of the points that Justin made a bit earlier? This being a research letter, could you maybe share with the audience a bit, what's it like to write and be constrained to such few words and a single figure?

Dr David Morrow:            Well, as Dr Ezekowitz said, it does present a little bit of a challenge. You have to be very concise. We certainly were fortunate that we could leverage the primary publication for the majority of methods and other design elements that we didn't need to recapitulate. And so I think for, in particular, this type of research where there was something that we felt was quite important scientifically with potentially important clinical implications, but yet still was an additional exploratory end point that we could express concisely, the research letter was a very reasonable format to do that.

Dr Carolyn Lam:                I couldn't agree more. But Justin, how about from the editor's point of view? Could you share about the research letter?

Dr Justin Ezekowitz:        My compliments to Dr Morrow and his team, as I asked him a lot of questions that required both expanding on the things they had to say while constricting the number of words at the same time, and that's a huge challenge to get findings across. So they were able to meet that challenge. I think one of the key things was really honing down as to what the key messages are, as Dr Morrow just alluded to, you can refer to the main complication or a baseline trial publication for all the other details, but what were the core things that could be demonstrated in a publication that is of a limited number of words, tables, or figures. And I think that's the key is, what is the real hypothesis and question to be answered. And that's the way we focused on all the efforts. I did appreciate that it was not easy not to have a lengthy discussion. So we had a ... in the written discussion we have really just truncated this down to a few key sentences which summarize the overall study, so the reader could pick this up and know what the implications are without actually having to go into a lot of the detail that we've just been speaking about.

Dr Carolyn Lam:                Ah, I love it. And thank you so much for this conversation too. That helps us go under the hood a little bit. I'm sure everyone who's listening just wants to pick this up now because it's so concise, so beautiful to read, and just look at the figure.

                                                Thank you everyone for joining us today. Don't forget to tune in again next week to Circulation on the Run.

                                                This program is copyright American Heart Association 2019.
















Apr 29, 2019

Dr Carolyn Lam:                                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore.

Dr Greg Hundley:                             And I'm Greg Hundley, associate editor as well, at Circulation, and director of the Pauley Heart Center in Richmond, Virginia at VCU Health. Carolyn, this issue, we've got a super-exciting interaction to follow related to SGL2 inhibitors on 24-hour ambulatory blood pressure in African-Americans, something used to treat diabetes, and maybe a positive effect on blood pressure, but more to come on that. Now, Carolyn, you're also planning to discuss some results from another SGL2 study.

Dr Carolyn Lam:                                You bet. This time, I'm taking you to Japan for the results of the SACRA study which stands for SGLT2 Inhibitor and Angiotensin Receptor Blocker Combination Therapy in Patients with Diabetes and Uncontrolled Nocturnal Hypertension and this is from Dr Kario and colleagues from Tochigi in Japan. It's a multi-centered, double-blind parallel study of 132 non-obese older adults with type 2 diabetes and uncontrolled nocturnal hypertension, receiving stable antihypertensive therapy, including angiotensin receptor blockers, who were then randomized to 12 weeks' treatment with empagliflozin 10 milligrams once daily or placebo. Clinic blood pressure was performed at baseline in weeks four, eight and 12. Twenty-four hour ambulatory blood pressure monitoring was performed at baseline and week 12 and morning home blood pressure was determined for five days before each visit. The primary efficacy endpoint was changed from baseline in nighttime blood pressure.

Dr Greg Hundley:                             So, what did they find, Carolyn?

Dr Carolyn Lam:                                Well, empagliflozin significantly reduced nighttime systolic blood pressure versus the baseline. The reductions in daytime 24-hour morning, home, and clinic systolic blood pressure at 12 weeks with empagliflozin was also greater than placebo. Between group differences in body weight and glycosylated hemoglobin reductions were significant, but small and the changes in antihypertensive medication during the study also did not differ significantly between the groups.

Dr Greg Hundley:                             Very good. Well, I'm going to switch gears and talk also on the same theme of sugar and diabetes and evaluate the long-term consumption of sugar-sweetened and artificially-sweetened beverages and the risk of mortality in U.S. adults. This is a study by Vasanti Malik from the Harvard School of Public Health. Now, as you know, in epidemiologic studies, intake of sugar-sweetened beverages has been associated with weight gain, a higher risk of type 2 diabetes, coronary heart disease and stroke, but to date, few studies have examined the association between sugar-sweetened beverages and intake and mortality. All right, Carolyn, I'm going to give you a quiz now. Here's the first question.

Dr Carolyn Lam:                                What?

Dr Greg Hundley                               That's right, sugar-sweetened beverages are the single largest source of added sugar in the U.S. diet, true or false?

Dr Carolyn Lam:                                I'm going to guess true.

Dr Greg Hundley:                             Okay, so all those consumption of sugar-sweetened beverages in the United States has decreased in the past decade. National survey data show a slight rebound in consumption in recent years among adults in many age groups. With the average equivalent being, multiple choice, 2%, 6.5% or 10% of our total energy requirements?

Dr Carolyn Lam:                                Oh, my goodness. One of the higher ones. I'm just going to go in the middle, 6.5.

Dr Greg Hundley:                             Excellent, good choice, you're a good multiple-choice taker, 6.5%. So, among younger adults, sugar-sweetened beverages contributed. They're a little bit higher, 9.3% of the daily calories in men and 8.2% in women in the United States. Now, how about other parts of the world, particularly developing countries? The intake of sugar-sweetened beverages, is it dropping, is it flat or is it rising dramatically?

Dr Carolyn Lam:                                Sorry, Greg, but that one's too easy. It's definitely rising.

Dr Greg Hundley:                             Yup, you got that right.

Dr Carolyn Lam:                                I live in those other developing countries, so I've seen so.

Dr Greg Hundley:                             And it's really thought due to widespread urbanization and beverage marketing. So, now we've got an alternative, artificially-sweetened beverages. And they're often suggested as alternatives to sugar-sweetened beverages and intake levels have increased of these alternative sweeteners in the United States. So, next question. Are the artificially sweetened beverages a better alternative to sugar--sweetened beverages in regard to cardiovascular or all-cause mortality?

Dr Carolyn Lam:                                Yikes. Okay, so Greg I'm afraid to guess on this one because I have to admit I sometimes, with a sweet tooth, like to take these alternative beverages. I think you're going to be telling us.

Dr Greg Hundley:                             Well, we don't know. Most of the data in this area is from research and comes from associative analyses utilizing longitudinal cohorts and some studies suggest yes, some studies, no. For example, one in the elderly suggested artificially-sweetened beverages, but not sugar-sweetened beverages were associated with adverse events, but critiques indicated that finding may have related to reverse causation because the elderly patients were switching from sugar-sweetened to artificially-sweetened beverages. So, where are we now? Well this study, in our Journal, examined the associations between the consumption of sugar-sweetened beverages and artificially-sweetened beverages with the risk of total and cause-specific mortality among 37,716 men from the Health Professionals Follow-up Study between 1986 and 2014 and 80,647 women from the Nurse's Health Study from 1980 to 2014, who were free from chronic diseases.

Dr Carolyn Lam:                                Wow, that's a huge combined cohort. So, come on, what were the results?

Dr Greg Hundley:                             So, the researchers found after adjusting for major diet and lifestyle factors, consumption of sugar-sweetened beverages was associated with a higher risk of total mortality and cardiovascular mortality and cancer mortality and, thus, the results provide further support for the recommendations and policies to limit intake of sugar-sweetened beverages and to consume artificially-sweetened beverages in moderation did improve overall health. Now, what were the results from artificially-sweetened beverages? Well, they were associated with total and cardiovascular disease mortality in the highest intake category only. So, those consuming large amounts of those daily, but only in the cohort of women from the Nurse's Health Study, not from the men in the Health Professionals Follow-up Study. Artificially-sweetened beverages were not associated with cancer mortality in either cohort.

So, moving forward, the positive association between high intake of artificially-sweetened beverages and total and cardiovascular disease mortality observed among women requires more study and further confirmation and also, we might consider that even though artificially-sweetened beverages could be used to replace sugar-sweetened beverages among habitual sugar-sweetened beverage consumers, higher consumption of the artificially-sweetened beverages would probably be discouraged. Finally, policies and recommendations should continue to call for reductions and limits on sugar-sweetened beverages intake and also address alternative beverage offerings with an emphasis on our favorite, water.

Dr Carolyn Lam:                                Sweet, Greg! Or maybe not so sweet. Oh, goodness. All right, well my paper deals with related, but not related perhaps, but talking about ketone body, 3-hydroxybutyrate and the cardiovascular effects of treatment with this ketone body in chronic heart failure and this is from corresponding author, Dr Nielsen from Aarhus University Hospital in Denmark and his colleagues. Now, they performed a series of studies. In the first 16 chronic HFrEF patients were randomized in a crossover design to three hours' infusion of 3-hydroxybutyrate or placebo and monitored invasively with a Swan-Ganz catheter and studied with echocardiography and they found that infusion of 3-hydroxybutyrate increased cardiac output by two liters per minute or 40% with an absolute improvement in left ventricular ejection fraction of 8%, and the observed defects were accompanied by vasodilation with a resultant stable systemic and pulmonary blood pressure.

Now, in the second part of the study, they studied eight HFrEF patients examined at increasing infusion rates of 3-hydroxybutyrate and they found a dose response relationship with a significant increase in cardiac output. And, finally, they studied 10 HFrEF patients and 10 age-matched volunteers, randomized in a crossover design to a three hour infusion of 3-hydroxybutyrate or placebo and they looked this time at myocardial external energy efficiency and oxygen consumption using 11-carbon acetate PET and what they found was 3-hydroxybutyrate increased oxygen consumption without altering myocardial external energy efficiency. The response did not differ between HFrEF and age-matched volunteers.

Dr Greg Hundley:                             Wow, Carolyn, there was a lot of data in that study. So, what's your main take home?

Dr Carolyn Lam:                                In summary, 3-hydroxybutyrate, this ketone body, demonstrated dose-dependent beneficial cardiac and hemodynamic effects in patients with heart failure reduced ejection fraction without deteriorating mechano-energetic coupling and without causing any safety issues. And what's significant is that this opens the door to modulating circulating 3-hydroxybutyrate as a novel treatment option in patients with heart failure.

Dr Greg Hundley:                             Right, Carolyn, so I've got an interesting study from the world of basic science that's looking at the role of potassium channels as novel molecular targets and bradyarrhythmia’s and even, perhaps, in atrial fibrillation. This is from Yoshihiro Asano from Osaka University in Japan. So, the acetylcholine activated potassium channel is expressed in the sinus node, atrium, and atrioventricular node and contributes to heart rate slowing triggered by the parasympathetic nervous system. So the potassium, activated potassium channel is a heterotetramer of 2 inwardly rectifying potassium channel proteins encoded by two genes, KCNJ3 and KCNJ5, respectively.

Dr Carolyn Lam:                                Okay, so what did this study show?

Dr Greg Hundley:                             What it showed is a selective potassium acetylcholine channel blocker effectively inhibited a mutant potassium channel and up-regulated heart rate and bradyarrhythmias using a zebra fish model. And this is really interesting, Carolyn, because two conclusions are worth considering. First, future studies could determine the prevalence of bradyarrhythmias associated with dysfunctional mutation in this potassium channel. And, second, results raise the possibility that pharmacologic blockade of this channel might serve as a therapy for increasing heart rate and be especially beneficial for bradyarrhythmias in patients with gain of function mutations in the channel and, therefore, genetic testing for KCNJ3 and KCNJ5 in patients with bradyarrhythmias may provide a drug treatment option in lieu of an invasive surgical implantation of a pacemaker.

Dr Carolyn Lam:                                Fascinating! Thanks, Greg. What a great issue and now onto an even greater feature discussion.

Dr Greg Hundley:                             Welcome, everybody, to the second part of this interview. We've got a very exciting paper to discuss with you. Remember this is our backstage pass to Circulation and we've got today, Keith Ferdinand from Tulane University in Louisiana and our Associate Editor, our hypertensive expert, Dr Wanpen Vongpatanasin from the University of Texas Southwestern Medical School in Dallas. We're going to be discussing the anti-hyperglycemic and blood pressure effects of empagliflozin in African-Americans with type two diabetes and hypertension. Keith, we're going to start with you. What was your hypothesis for this study? Who's the study population? Review a little bit about your design and, importantly, what were your results?

Dr Keith Ferdinand:                         Well, my hypothesis was that one of the new classes of medications, the SGLT2 inhibitors, which have a mild diuretic effect and a mild natriuretic effect, may have benefits in self-described African-Americans in not only controlling glucose, but also controlling hypertension. These medicines are approved, of course, as medications for type 2 diabetes, but we had seen in some earlier trials that did not include self-defined African-Americans, that there may be a blood pressure effect. We know that diabetes is higher in blacks, almost twice that seen in the general population and, of course, hypertension and uncontrolled hypertension is disproportionate. So, here's a medication that may be even more beneficial in that population and we wanted to study it.

Dr Greg Hundley:                             And tell us a little bit about who was in the study and what was your design?

Dr Keith Ferdinand:                         The design was to be a placebo-controlled randomized trial using empagliflozin starting at 10 milligrams and force-titrating to 25 milligrams versus placebo on the background of conventional anti-hypertensive agents. Everyone was on one or more anti-hypertensive agents. We used the gold standard for blood pressure control with 24-hour ambulatory blood pressure and that was the means by which patients entered the study, although the primary endpoint was changed in hemoglobin A1c, we actually designed and powered the study to see if there would be a change in blood pressure. Additionally, we looked for changes in weight, losing calories with the effects of the SGLT2 inhibitors with glycosuria has translated in some preliminary trials to weight loss. So, this was a study looking at a population. Most of them had diabetes for approximately nine to 10 years, 59 years of age, definite hypertension, obesity, a high risk population, to see if a new class of medications would be beneficial.

Dr Greg Hundley:                             And what did you find?

Dr Keith Ferdinand:                         Fortunately, we did find an effect. It did lower the primary endpoint of a change in hemoglobin A1c, but remember it was powered also by blood pressure effect and fortunately, we did see that both with the ambulatory and clinic blood pressure, both at 12 weeks and 24 weeks. The clinic blood pressure was a trend, but the ambulatory blood pressure was positive at 12 weeks and both had a strong difference in terms of confidence intervals for blood pressure lowering. About five millimeters of mercury at 12 weeks and up eight millimeters of mercury at 24 weeks for the change in ambulatory blood pressure which, in a large population would translate into a significant blood pressure lowering, the hemoglobin A1c reduction was also significant. But, although that was the primary endpoint, my concern is as a cardiologist and cardiovascular specialist.

Dr Greg Hundley:                             And what dose did you select? Did you have to up-titrate this at all and, finally, were there any side effects?

Dr Keith Ferdinand:                         You know, with the SGLT2 inhibitors, you have an effect both in terms of glycosuria, some osmotic diuresis and some natriuresis, and with the loss of body weight. But the change in body weight really wasn't that much, about 1.2 kilos and the change in blood pressure was discordant with the change in body weight. So, we think that the effects in blood pressure may be from extended diuretic effect, but it may also be from effects on endothelial function that are outside those significantly related to diuresis, per se. Because you're urinating glucose, glycosuria, you would expect the potential for superficial infections, mycotic infections and that was seen. The rates were not prohibitive and not dissimilar to what's been seen in other studies. So, overall, the drug was well-tolerated. It did not have any significant adverse effects outside of a few mycotic infections, which are basically superficial fungal infections and that's been seen in other uses of the SGLT2 inhibitors, but nothing that I think would be unusually disturbing in this population.

Dr Greg Hundley:                             Outstanding. So, Wanpen, going to switch over to you and ask you to help us put this in the context of treating African-American men, women with hypertension. How do we think about using this new finding? How would we integrate it with other therapies that these individuals already might be taking?

Dr Wanpen Vongpatanasin:         Sure, so I think that this study is very intriguing and interesting that empagliflozin to me actually had more prominent benefit on lowering 24-hour blood pressure than the previous study that the true analysis showed the effects of 24-hour blood pressure is much less or almost half of four to five millimeters of mercury and that could be that this was not that significant in African-Americans and maybe this drug is particularly effective and, as you know, African-Americans tend to have more salt sensitive form of hypertension and I wonder if that could explain the results, but I think it's very encouraging because this drug class approved for treatment of diabetes and medication. African-American have higher blood pressures than other ethnic groups and having diabetes makes them prone to having more resistant hypertension. In this particular trial, almost 40% of the patients enrolled is already taking three or more antihypertensive medications, so adding this on top and having that benefit is as good as adding spironolactone, for example, and I didn't see from the manuscript, how many patients are taking spironolactone already, but I would be curious to see that, as well.

But I think that is something that physicians should think about and this drug is already FDA-approved for treating diabetes, so if you have a patient with difficult to control blood pressure and already needed something for diabetes, this could make a lot of sense to use it.

Dr Greg Hundley:                             Keith, do you have any thoughts on Wanpen's comment regarding the use of spironolactone in the study population?

Dr Keith Ferdinand:                         No, I don't have those specific data available at the time that we're speaking now, but that's certainly something that I will attempt to look at the database and get more information. But, I think Wanpen is absolutely right. If you look at some of the previous studies, for instance, EMPA-REG, the major outcomes trial that led to the indication of a decrease in cardiovascular death and heart failure, the blood pressure lowering wasn't that robust, maybe 4/2, but here we saw at week 24, 10 millimeters of mercury of blood pressure reduction and if you placebo subtract, which is what I mentioned in my first comments, you're talking about 8 to 8.5 millimeters of mercury reduction and that's a significant reduction, especially for ambulatory blood pressure measurement.

Dr Greg Hundley:                             Absolutely. So, I'm going to go with each of you separately, but taking this manuscript and this work that Keith, you've performed, we'll start with you. What do you think of the next steps in the research in this area, both from the perspective of using this family of agents in individuals with both diabetes and hypertension?

Dr Keith Ferdinand:                         What I would hope in the future is another outcome study is done with an SGLT2, any numbers of that class, that they particularly target enough African-Americans to see if this robust blood pressure reduction not only is found again, but also translates to decreased cardiovascular events. You know, NHLBI, for instance and ALLHAT, selectively over-represents African-Americans. They had 35% African-Americans in ALLHAT and the reason for that is you have a population that has a disproportionate degree of hypertension and a disproportionate degree of associated cardiovascular disease and renal disease, so you want to make sure that any medication that's been shown to be effective is effective in the higher risk population. So a future outcome study, regardless of whether they're renal-based or related to heart failure, I hope will target an increased population of blacks to see some of the robust reduction we have, translates in cardiovascular events.

My suspicion is that self-defined African-American versus a genetic factor, describes the phenotype of patients who tend to be more obese, have more salt sensitivity, perhaps subclinical kidney disease and will respond to a medication that has some diuretic natriuretic effects and effects with endothelial dysfunction and sympathetic discharge.

Dr Greg Hundley:                             Very good, well I heard sympathetic discharge. Wanpen, any comments there? That's your area.

Dr Wanpen Vongpatanasin:         I think that definitely needs to be studied. To my knowledge, there was only one small study that published that tried to measure sympathetic nerve activity directly, but unfortunately that study after a very short-term treatment for like four or five days, so I’m sure that there will be more studies to come and also hope that the future study will shed light on any particular markers with surrogate that will identify patients that will respond better, for example, PATHWAY-2 trials that were done to test the effects of spironolactone on resistant hypertension they found that the lower the reading, the more likely you can have better response to Aldactone and I wonder if this might apply to empagliflozin and be something else. I think the fact that the blood pressures continued to decline from the week 12 to week 24 is very, very interesting when the body weight effect doesn't necessarily go down much further. This really tells us there's something else beyond weight and perhaps glucose that would explain this.

Dr Greg Hundley:                             Very good. Well, I certainly want to thank you both for this outstanding discussion. Keith, we want to thank you for bringing this manuscript to Circulation and identifying this new application for this therapy in African-Americans. Wanpen, thank you also for your time and comments.

On behalf of Carolyn and myself, we really appreciate you listening. Have a great week and we look forward to seeing you next week.

Dr Carolyn Lam:                                This program is a copyright of American Heart Association 2019.


Apr 22, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, associate editor as well at Circulation, and director of the Poly Heart Center in Richmond, Virginia, at VCU Health. Well, I'm going to talk about anti-hyperglycemic agents and look at a very important meta-analysis.

Dr Carolyn Lam:                Those are the rage: GLP-1 receptor agonists and SGLT-2 inhibitors. But first, let's talk about psychosocial stress and cardiovascular health. So what is the joint impact of multiple stressors on racial or ethnic disparities in cardiovascular health?

                                                Well, this question was tackled by Dr Albert, from University of California San Francisco Center for the Study of Adversity and Cardiovascular Disease and her colleagues. They basically studied more than 25,000 women participating in the women's health study follow-up cohort, and examined the relationship between cumulative psychosocial stress and ideal cardiovascular health as defined by the American Heart Association Strategic 2020 Goals.

                                                As a reminder, this health metric includes smoking, BMI, physical activity, diet, blood pressure, total cholesterol and glucose, and higher levels indicate more ideal cardiovascular health and less cardiovascular risk.

                                                So, they found that both cumulative psychosocial stress and ideal cardiovascular health varied by race or ethnicity. Mean cumulative psychosocial stress scores were higher in Hispanic, Black, and Asian women compared to white women, even after adjusting for age, socioeconomic status and psychological status such as depression and anxiety. The mean ideal cardiovascular health scores remained worse in blacks and better in Asians compared to whites, despite taking into account socioeconomic factors and cumulative psychosocial stress.

Dr Greg Hundley:             So Carolyn, how should clinicians incorporate this information in what we do every day?

Dr Carolyn Lam:                Although the cumulative psychological stress and socioeconomic status did not fully explain the racial or ethnic differences in ideal cardiovascular health that we saw, clinicians should be informed by these data that psychosocial stressors are social determinants of health that have different prevalence according to race and ethnicity. I think that's what we need to learn. And of course these data support the need for additional work that addresses the joint impact of multiple social determinants of health on cardiovascular disease and in diverse populations.

Dr Greg Hundley:             Very good, Carolyn. That was really an interesting article. Well, I'm going to switch gears and talk about the role of red blood cells in promoting vascular calcification. My article is from Dimitrios Tziakas from the Department of Cardiology in Thrace, Alexandropoulos, in Greece.

                                                Now, the presence of extravasated erythrocytes in human atherosclerotic lesions was described several years ago, but little is known about a possible active role of red blood cells during these cardiovascular disease processes. Clinical studies suggest that intraplaque hemorrhage may be associated with the progression of coronary, carotid, and atherosclerotic lesions and degenerative calcific aortic valve stenosis. So, in the present study, the authors examined the contribution of erythrocytes to vascular and valvular lesion progression, focusing on the effects of red blood cells on the osteoblastic transdifferentiation of smooth muscle cells in calcification.

Dr Carolyn Lam:                Interesting. So, what did they find?

Dr Greg Hundley:             So, lysed erythrocytes, and in particular their membrane faction, enhanced human and murine arterial smooth muscle cell mineralization and vascular aortic ring calcification. Red blood cell membranes injected in the vascular regions of atherosclerotic-prone mice also promoted calcification and red blood cells were found to co-localize with osteoblast like cells in human atherosclerotic plaques, stenotic aortic valves, and abdominal aortic aneurysms. And so, the study demonstrated that intra plaque hemorrhage promotes atherosclerotic and valvular lesion calcification and membranes of extravasated lysed red blood cells appeared to play an important role in the process. The investigators also showed a mechanism, that nitric oxide derived from erythrocyte endothelial nitric oxides synthase is involved, at least in part, in mediating the effects of red blood cells on vascular calcification.

Dr Carolyn Lam:                Thanks, Greg. Now back to another, well, clinical paper with the next one asking, do mid-life biomarkers of heart and kidney damage associate with the level of and decline in physical capability with aging? Dr Kuh and colleagues from MRC Unit of Lifelong Health and Aging at University College London used data on 1,736 men and women from the oldest British birth cohort study. And, looked at their walking speed, chair rise speed, balance time, and grip strength. Assessed at ages 60 to 64 and 69 years. They tested the associations between Cystatin C, NT-proBNP, interleukin-6, and E-selectin all at ages 60 to 64 years with their performance at 69 years. And what they found was the lower levels of NT-proBNP in interleukin-6 in middle aged adults were independently associated with better physical capability up to nine years later. And all these associations were stronger than those observed for conventional risk factors: including lipids, blood pressure, and glycemia, and were not explained by the onset of cardio vascular and kidney disease or diabetes.

Dr Greg Hundley:             Carolyn, is this saying we should now measure these biomarkers in mid-life?

Dr Carolyn Lam:                Ah, before considering the use of NT-proBNP and IL-6 or interleukin-6 for risk stratification, we really do need further research to untangle whether these associations exist because the biomarkers are an integrated measure of accumulated exposures to stressors. Or, whether they are really capturing early an organ damage. Or, whether they are marking additional risk pathways. So, this and more is discussed in a great accompanying editorial entitled "Putting the Measurement of Physical Capacity in Older Adults in its Place". And that's by Dr Kritchevsky from Wake Forest School of Medicine.

Dr Greg Hundley:             That's a favorite of my heart, Caroline. The old institution Wake Forest. But, I'm going to switch now and tell you a little bit about plasma ceramides and this is an article from Wei Zhao from the Department of Epidemiology in Population Health at Albert Einstein College of Medicine in Bronx, New York. The study evaluates the role of ceramides and what are those? Well, they're a class of bio-active lipids composed of sphingosines and fatty acids. And are involved in the development of cardiovascular disease. Elevated circulating levels of ceramides have been shown to be associated with increased risk of cardiovascular events, cardiovascular death, and even so, after adjusting for other cardiovascular disease risk factors. Now, interestingly, ceramide metabolism has long been noted to be closely related to HIV infection. But, the relationship has not been fully understood. HIV infected cells may cause enhancement of sphingomyelin volume breakdown and accumulation of intercellular ceramides, whereas intercellular accumulation is associated with enhanced replication of HIV.

                                                So, what did this study do? They evaluated circulating levels of four ceramides species which have been investigated in previous studies of non-HIV populations. And were measured in 737 women and men, 520 HIV infected and 217 HIV uninfected from the Women's Intra-Agency HIV Study and the Multi-Center Aids Cohort Study. And they compared the relationships with the progression of carotid artery disease assessed by B-mode ultrasound over a seven year period.

Dr Carolyn Lam:                Interesting approach. So, what did they find?

Dr Greg Hundley:             Elevated ceramide levels were associated with anti-retroviral therapy use. Particularly, protease inhibitor use HIV infected individuals. All four ceramides were highly correlated with each other and significantly correlated with total cholesterol and LDL cholesterol. And of note, remember they were measuring four, but C16:0 and C24:1 ceramides rather that C22:0 and C24:0 ceramides were more closely correlated with specific modified activation and inflammation markers and, surface markers of CD4 t-cell activation. Elevated plasma levels of C16:0 and C24:1 ceramides were also associated with progression of carotid artery atherosclerosis. So, in summary, the results of this study provide new information on biological mechanisms that may involve the specific mono-site activation and inflammation beyond cardiovascular disease traditional risk factors like cholesterol levels. For the association between ceramides and CVD, particularly among individuals living with HIV infection.

Dr Carolyn Lam:                Fascinating. Thanks, Greg. Now that sets us up for beautifully for our featured discussion.

Dr Greg Hundley:             Welcome everyone, to our podcast. My name is Greg Hundley and we've got a very exciting paper for the second part of our program today. With us we have Dr Thomas Zelniker from Brigham and Women's Hospital. And then, also, a guest editor, Dr John McMurray from Glasgow, Scotland. We're going to be discussing a meta-analysis in type 2 diabetic patients. Thomas, can you tell us a little bit about the study population, your design, and what where the outcomes that you saw in this study.

Dr Thomas Zelniker:        As you know, the last half decade, members of two drug classes, GLP1 receptor agonists and SGLT2 inhibitors, so our goal was to provide clear context by comparing or contrasting the benefit of these two drug classes, and in particular to investigate the potential heterogeneity in the treatment site between patients with and without atherosclerotic cardiovascular disease. For that reason, we performed meta-analysis of all randomized partially controlled cardiovascular outcome trials of GLP-1 receptor antagonists and SGLT-2 inhibitors. We included data from more than 77,000 patients, nearly 43,000 patients coming from the five GLP-1 receptor antagonist trials and approximately 34,000 patients coming from the three SGLT-2 inhibitor trials. We tried to compare patients with those with known established atherosclerotic cardiovascular disease with those that have multiple risk factors for but no evident ASCVD. And as you can see, our interests included MACE, or major atherosclerotic cardiovascular events, and its individual components, MI, stroke and cardiovascular death. And then we looked at hospitalization for heart failure and progression of kidney disease. The progression of kidney disease was defined as one of the broad composites consisting of new onset of macroalbuminuria, worsening of eGFR, end-stage kidney disease, or death due to renal cause. And then we also had a more narrow kidney outcome which excluded macroalbuminuria.

Dr Greg Hundley:             Thomas, did you observe differences in the types of events between the two agents, as they would have impacted hospitalization for heart failure or the progression of renal disease?

Dr Thomas Zelniker:        Right. So foremost both trial analyses reduced the risk of MACE, major atherosclerotic events, but the reduction of MACE was actually confined to those patients with atherosclerotic cardiovascular disease. We saw a 40% reduction in patients with known ASCVD, where neither of these groups reduced the risk of MACE in patients with only multiple risk factors but without ASCVD. Now, in terms of the individual components of MACE, both trial analyses reduced the risk of myocardial infarction cardiovascular death but only GLP-1 receptor agonist reduced the risk of stroke. In contrast, as SGLT-2 inhibitors vastly reduced the risk of hospitalization with heart failure by more than 30%, where there was only a non-significant 7% relative risk reduction with GLP-1 receptor antagonist.

                                                GLP-1 receptor antagonists also reduced the broad kidney composite outcome. However, this effect was mainly driven by reduction macroalbuminuria. When excluding macroalbuminuria we found a non-significant relative risk reduction by 8% and this stands in contrast to a very robust relative risk reduction with SGLT-2 inhibitors of more than 45%.

Dr Greg Hundley:             Thomas, you mentioned there was a difference in benefit for those with existing cardiovascular disease versus no-known cardiovascular disease upfront. What do you think the reason for that might be, and then did you have the same number of patients in the non-cardiovascular disease group? Did you have enough events in that group? And finally, do you think we might need to follow that patient population a little bit longer in time, to see those events as they didn't have pre-existing cardiovascular disease?

Dr Thomas Zelniker:        These are fantastic points. I personally think it's biologically plausible that both drugs and receptors have the same benefit in both patient population to treatment effect may just require more time to become evident in patients with lower risk. You also mentioned a very good point, we had substantially more events in the patient cohort with ASCVD.

Dr Greg Hundley:             Very good. So John, we want to turn to you now. Can you help us put those results of this study in perspective? Can you put this into context for us with other published reports using these particular ages?

Dr John McMurray:         Certainly Greg, and I'd like to congratulate Thomas on what very important and very timely meta-analysis because, of course, what Thomas and his colleagues have done Greg, is to put all these studies together, to give us what meta-analysis does, which is much more power to look, for example, at components of composite outcomes, and we will in that way compare and contrast the differences and similarities between these two treatments. And as Thomas has mentioned, so interesting differences stand out but there are also some similarities that perhaps were not clear from the individual trials and I suppose the one that would perhaps stand out to me and might not have been realized by many of our readers, is myocardial infarction, that seems to be reduced to pretty much a similar extent by both GLP1 receptor antagonists and SGLT-2 inhibitors.

                                                I think there had perhaps been a view out there from the individual trials, that maybe GLP-1 receptor antagonists have more effect on atherosclerotic events and SGLT-2 inhibitors more effect on heart failure and renal events and to some extent that's true, both agents seem to reduce myocardial infarction to approximately the same extent. Which in itself is interesting, perhaps raises some mechanistic questions. I mean, the differences that stood out is stroke is reduced by GLP-1 receptor antagonists but not by SGLT-2 inhibitors and conversely heart failure which is the opposite, which is by SGLT-2 inhibitors, but not by GLP-1 receptor antagonists in this meta-analysis.

                                                So, I suppose, in summary what this tells us is that these drugs have complementary, perhaps additive cardiovascular benefits. Together, they potentially reduce the whole spectrum of the adverse cardiovascular events that occur in our patients with Type 2 diabetes, especially those who've got established cardiovascular disease.

Dr Greg Hundley:             And so, just a last question here, for both Thomas and John, if you're considering in your practice, you have a diabetic patient that's not on these, one of these agents, and they have existing cardiovascular disease, how do you go about considering the addition or the switch to this type of medicine, and what practices do you use to effect that change?

Dr Thomas Zelniker:        I guess, looking at patients, so we know that both drug classes have great benefits from MACE, right, but to people on antagonists having also reductions in stroke. So probably the associated risk is in the focus, I would probably rather go with the GLP-1 receptor antagonist. While looking at it from the heart failure perspective, or from the renal perspective, we see obviously bigger advantages attributed to inhibitors.

Dr Greg Hundley:             And John, how about you?

Dr John McMurray:         I would agree with Thomas' perspective, although I might add just a little caveat which is, of course, that the prevention of heart failure which is what, I think, the clear benefit of SGLT-2 inhibitors is, prevention of heart failure is different to the treatment of heart failure. So, patients at risk of heart failure sadly, an SGLT-2 inhibitor would make sense, but when it comes to patients with established heart failure event, of course we will get that answer because one of the great things about this recent incredible development of new therapies for diabetes, is that now there are now more studies underway including remarkable five trials in patients with different heart failure phenotypes, patients hospitalized, patients in the community, so we will learn a lot more about the use of these drugs, in particular cardiovascular populations.

Dr Greg Hundley:             Excellent. I want to thank both Thomas Zelniker from Brigham and Women's Hospital and John McMurray, guest editor from Glasgow, Scotland for helping us work through this just fantastic meta-analysis study pointing us in a new direction for utilizing medications to treat diabetes and those that we see every day, with cardiovascular disease.

                                                On behalf of Carolyn and myself, have a great week and we look forward to seeing you, next week.

Dr Carolyn Lam:                This program is copyright American Heart Association, 2019.


Apr 15, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, also associate editor of Circulation and director of the Poly Heart Center at BCU Health in Richmond. Carolyn, we've got a really exciting interview to follow our coffee chat and it's evaluating individuals with low complexity congenital heart disease. We often think of those with high complexity congenital heart disease and looking at their cardiovascular events. We're going to hear a little bit about low complexity congenital heart disease.

                                                Now you've got a paper you wanted to talk about first.

Dr Carolyn Lam:                Absolutely. You've got to hang on for that because I'm going to delve into chromatin architecture in heart failure, and it's in this paper from corresponding author Dr Foo from Genome Institute of Singapore.

                                                So, as background, the human genome actually folds in 3D to form thousands of chromatin loops within the nucleus encasing the genes and assists regulatory elements for accurate gene expression control. Now, these physical tethers of loops are anchored by the DNA binding protein CTCF, also known as the weaver of the genome and the cohesion ring complex. Now, the role of CTC in binding and changes in chromatin structure in heart failure are not well understood. Well, until today's paper.

                                                What the author said is they undertook an independent analysis of chromatin organization with mouse pressure overload model of myocardial stress or transverse aortic constriction, and a cardiomyocyte specific knockout of CTCF. So, interestingly, they found that the cardiac chromatin architectural in adult terminally differentiated cardiomyocytes was unchanged in pressure overload from transverse aortic constriction. Now this was completely unlike the CTCF knockout model where they verified that there was generation of vast genome-wide loss of genomic insulation and near complete abolition of the CTCF chromatin loops.

                                                Instead of chromatin rewiring on the scale of that knockout, the myocardial stress response appeared to proceed through enhancer H3K27 acetylation epigenetic changes and gene network co-regulation driven largely by fixed cardiac 3D chromatin architecture. In other words, a stable chromatin architecture really set the stage for accurate enhancer promoter interactions required for basal gene expression control and induction of the classical myocardial stress gene response.

Dr Greg Hundley:             So Carolyn, are there therapeutic implications here for this?

Dr Carolyn Lam:                Now of course, that was preclinical work, but it really opens the door to consider these epigenetic regulators that control disease expression changes and interacting gene sets in heart as potential future targets for novel heart failure therapy.

Dr Greg Hundley:             Very interesting. So, I'm going to review and switch gears a little bit and focus on diabetic cardiomyopathy and mitochondria associated endoplasmic reticulin membranes. And this paper is from Shengnan Wu from the Center for Molecular and Translational Medicine at Georgia State University here in the US in Atlanta, Georgia. So as we all know, mitochondria are essential for cellular energy production, but when they're damaged, they become a major source of reactive oxygen species and pro-apoptotic factors. In particular, increasing evidence suggests that mitochondrial dysfunction is a central event in diabetic cardiomyopathy.

                                                Well, the mitochondria and the endoplasmic reticulum are key players that regulate many cellular functions and their structural and functional interactions are essential for cellular homeostasis. The contact points, however, through which the endoplasmic reticulum communicates with mitochondria, they're known as mitochondria associated endoplasmic reticulum membranes, or MAMS. Importantly, MAMS play a pivotal role in calcium signaling, lipid transport, energy metabolism and cell survival, and they've been implicated in a variety of diseases, including Alzheimer's Disease, cancer, lysosomal storage diseases, diabetes, obesity induced mitochondrial dysfunction and other metabolic disorders.

                                                But the role of these MAMS in the initiation and progression of Diabetic Cardiomyopathy is really unknown. So now, FUNDC1 is a highly conserved protein that's exclusively localized to the mitochondria. And this group had previously demonstrated that FUNDC1 was essential for maintaining the structure of MAMS and ensuring appropriate calcium transfer from the endoplasmic reticulum to the mitochondria normal hearts. Moreover, cardiac specific deletion of FUNDC1 induced cardiac dysfunction by inhibiting MAM formation.

Dr Carolyn Lam:                Interesting. So that was their prior work? What did the current study show?

Dr Greg Hundley:             Right, so what the investigator showed in this study is that high glucose driven inactivation of AMP-activated protein kinase increased FUNDC1 stability, but resulted in aberrant MAM formation, impaired mitochondrial calcium increase, mitochondria dysfunction and then cardiac dysfunction. And additionally, AMP-K activation reverses Diabetic Cardiomyopathy by suppressing high glucose induced MAM formation, mitochondrial calcium increase and mitochondrial dysfunction.

                                                And interestingly, Metformin, an AMP-K activator, used exclusively for Type 2 Diabetes, might be effective in treating Diabetic Cardiomyopathy in individuals with Type 1 Diabetes. So a very interesting mechanistic study providing some information of how MAMS, mitochondrial function and endoplasmic reticulum could be important in understanding how to prevent Diabetic Cardiomyopathy.

Dr Carolyn Lam:                Indeed. And you know, that last note that you made on Type 1 Diabetes, also links very well with the next paper that I chose. Which really asks the question, in Type 1 Diabetes, what are the relative prognostic importance and optimal levels of risk factors for mortality and cardiovascular outcomes? And this comes from Dr Rawshani and colleagues from the Swedish National Diabetes register who studied more than 32,600 patients with Type 1 Diabetes in their national observational cohort study from the Swedish National Diabetes register, with a mean follow-up of 10.4 years and a mean duration of diabetes of 17.9 years.

                                                They found that the most important predictors for outcomes were HP-A1C, albuminuria, duration of diabetes, systolic blood pressure and low-density lipoprotein cholesterol, or LDL cholesterol. Now, the lower levels of HP-A1C, systolic blood pressure and LDL cholesterol than contemporary target levels were associated with lower risk for outcomes. Albuminuria was associated with a two to four times greater risk of cardiovascular disease and death. And each millimole increase of LDL cholesterol was associated with 35 to 50% higher risk for outcomes.

Dr Greg Hundley:             Boy, Carolyn, those are interesting results. So, what do we take away from this in clinical management of patients?

Dr Carolyn Lam:                The take home message is that in patients with Type 1 Diabetes, the strongest predictors for mortality and cardiovascular disease, with the exception of age, were mostly conventional and modifiable cardio-metabolic risk factors. And this in turn suggests that increased clinical focus on these risk factors, particularly in primary prevention, may result in the largest relative risk reduction for mortality and cardiovascular disease, even in Type 1 Diabetes. So, future clinical trials may be designed to test these findings.

Dr Greg Hundley:             Very good. Well, Carolyn, my next paper, I'm going to talk about five year outcomes after off-pump versus on-pump coronary artery bypass grafting in those over the age of 75 years. And this paper comes from Anno Diegeler from Bad Neustadt in Germany. From June of 2008 to September of 2011, they evaluated a total of 2,539 patients that were 75 years or older, who had been randomly assigned to undergo off-pump or on-pump coronary artery bypass grafting across 12 centers in Germany.

                                                And the primary outcome was all cause mortality at five years, and the secondary outcome included a composite of death, myocardial infarction and repeat revascularization. What did they show in this study? Well, after a median follow up of five years, the hazard ratio for off-pump versus on-pump coronary artery bypass grafting was 1.03, confidence interval 0.81 to 1.19, no difference. The composite outcome of death, myocardial infarction and repeat revascularization, the same. Hazard ratio 1.03, confidence interval 0.89 to 1.18, P-value 0.7.

                                                So, first take-home message, no difference if you had your surgery off-pump or on-pump, if you're over the age of 75. Now, another outcome related to incomplete revascularization. And what was striking I this study is whether you underwent on-pump or off-pump bypass, if you were incompletely revascularized, that was associated with both the primary as well as the secondary outcomes. So, in elderly patients, in summary, greater than or equal to 75 years, the five year survival rates as well as the combined outcome of death, MI and repeat revascularization, was similar for on-pump versus off-pump CABG. And incomplete revascularization was associated with a lower five year survival rate, irrespective of the type of surgery that was performed.

Dr Carolyn Lam:                Interesting. Beautifully summarized, Greg. Thank you.

Dr Greg Hundley:             Absolutely. And let's head on to that featured article.

                                                Well, welcome everyone to the second half of our program. We are very excited today to have Dr James Priest, from Stanford University School of Medicine. And also our associate editor Gerald Greil from University of Texas Southwestern School of Medicine in Dallas. And we're going to be discussing the article, Substantial Cardiovascular Morbidity in Adults with Lower Complexity Cardiovascular Disease.

                                                So, James, first could you tell us a little bit about what constitutes low complexity congenital heart disease? And then a little bit about your study population, your design, and the results that you found with your study?

Dr James Priest:                So, low complexity congenital heart disease really derives from definitions of congenital heart disease in adults that are grown up and have different complexity of lesions. And so high complexity congenital heart disease, you see things that, as people may remember, adult cardiologists may remember from their training. People remember from medical school, things like single ventricle disease, hypoplastic left heart, tetralogy of fallot, transposition of the great arteries. But, non-complex, so our low complexity disease, really constitutes a relatively simple malformation. Things like atrial septal defects, ventricular septal defects, patent ductus arteriosus. Things that are treatable with a single surgery.

                                                You close the hole, you ligate the vessels, you dilate the valve, and the patient is affectively cured. So relatively low complexity diseases that can be treated with typically, a single surgery or minimal interventions to restore completely, or essentially normal, cardiovascular physiology.

                                                So, the study was based upon a very large you know, volunteer data set, the UK Biobank. It comes from the United Kingdom where 500 thousand individuals enrolled, and from those individuals there is genetic information, medical histories dating back to the 1990s, self-reported history. A variety of functional and neuropsychiatric measures. And if you get a group of 500 thousand individuals from anywhere, there's going to be some congenital heart disease in there. And so, we looked to see what types of congenital heart disease were in there. And in fact, there was lower complexity individuals.

                                                And because I spent some time on the research side of things with my adult colleagues, the first thing we looked at were from the common adult cardiovascular outcomes, things people write about in Circulation all the time. Coronary artery disease, atrial fibrillation, heart failure. We know these things are problems in adults with complex cardiovascular disease, but nobody had really looked for the most part in adults with low complexity or non-complex disease. And we were surprised to see such high event rates for these common adult cardiovascular conditions.

Dr Greg Hundley:             So, what type of events did you appreciate in the population in follow up?

Dr James Priest:                So, we really appreciated about a two-fold rate of let's say, acute coronary syndrome relative to the general population. Up to almost 13 fold risk of atrial fibrillation and heart failure, relative to the general population. So, really substantial and very impactful event rates.

Dr Greg Hundley:             Very good. And so, just a couple points of clarification. Do you think that the events you observed, were they related to the congenital heart disease, per se? Or could it have been a result from the surgical procedure to treat that heart disease?

Dr James Priest:                So, that's a great question. I think, in some ways, that's the fundamental question that the paper leads to. So, we thought of it in two different ways. You know, one, were these events, and they're perioperative events, for individuals receiving some type of care for their congenital heart disease, during their adulthood? And we performed a sensitivity analysis where we basically looked at those events and then looked for events occurring within a year of adult interventions. And we saw no difference in those event rates. So, they weren't perioperative or postoperative events in adults receiving adult congenital heart disease care.

                                                The second part of the question is really more of an existential question in some ways. You know, is there some fundamental relationship between the care these people received as children? Or the genetic basis of congenital heart disease in the first place that is somehow put people at risk long term for adult cardiovascular disease, acquired adult cardiovascular disease? And I think there's indeed a lot of different ways to try and get at that question and explore that more, which we're currently working on.

Dr Greg Hundley:             So, Gerald, I wanted to turn over to you now and, in your practice that encompasses those that are young adults that have this low complexity congenital heart disease, how do you manage them now? And how might the results of this study suggest, potentially, a different management strategy?

Dr Gerald Greil:                 Usually these patients, they're kind of thought to be cured or only needed minimal follow up in the past. So, if you take a patient with a VSD, rarely during childhood, young adult or even kind of in 20s and 30s, you have any major difficulties. And as a pediatric cardiologist, you rarely experience any major follow up problems with these patients. I think, particularly in the US, and I work actually for more than 10 years in the UK, the problem in the US is how can you organize follow up in these patients?

                                                There're insurance issues, there're issues about moving into different areas, and since these patients were kind of labeled as being healthy and close to normal, they were lost for follow up, particularly in the US. I think this study raises some concerns, we should probably be more careful and cautious and follow these patients up kind of in a lifelong session. And take care of them. This is definitely something, which is a new finding, and what the cause is, how we are following up, that's the question. I guess it could be a good question for future studies.

Dr Greg Hundley:             You mentioned future studies. Specifically, what type of future studies do you think we need to perform next? This shows us that the events are occurring, are we ready yet for randomized trials to perform prevention? Do we need studies that have more frequent observation? What are your thoughts there? And I'll get your answer and then we'll come back to James and get his thoughts on the same question.

Dr Gerald Greil:                 Yeah, I think the major thing is we need close follow up of these patients. And it will be a combined effort between pediatric and specialized adult cardiologists, with a special interest in patients with congenital heart disease. Once again, coming back to it, a closer follow up is a little bit dependent on the medical system, which you have. If you take Canada and the UK, it may be easier in these patients are under close follow up. And this allows large multicenter studies, large data bases like UK Bio Bank are kind of exemplary. And we should try to get something similar within the US or in other countries.

                                                I think that's the lesson what we take from that, we need larger data bases, probably more granular than what we have right now. I mean, James probably can comment in a second about the shortcomings and what can be done better in the UK Bio Bank to allow more detailed conclusions than we have currently from his study.

Dr Greg Hundley:             James?

Dr James Priest:                I would agree with that. I think as a person who does not, clinically speaking, take care of adults with congenital heart disease, my colleagues and I, or I have the impression from my colleagues that for most of the time, in most of these patients in the Unites States adults who had VSD or ASD repair as a child, they were essentially said, oh, you're cured. And they perhaps had some follow up during childhood, but then were otherwise discharged to live the rest of their lives.

                                                And so, in many cases I'd say the first step before performing any studies is to simply identify who these patients are, and figure out you know, what their risk factors otherwise for cardiovascular disease might be. Now, that being said, I think that was one of the powerful things about the UK Bio Bank study is that there's a large population in which all these traditional cardiovascular risk factors you know, obesity, lipid levels, hypertension, smoking status, all these things were uniformly measured in both the individuals with congenital heart disease, the adults with congenital heart disease. And of course the control population.

                                                And so that allowed us to make some estimates about what proportion of disease was attributable to these traditional cardiovascular risk factors. And what was attributable to other factors related, potentially, to the congenital heart disease. But all those things being said, I think the first questions that I often to tend to receive about these studies from the pediatric cardiologists and the adult congenital heart disease doctors, reflects the sorts of data sets that we're used to looking at.

                                                Well, what sort of an intervention did this person have? Did they have a ventriculostomy? When did they receive their diagnosis and their repair? Details of the surgical care and the perioperative of course, are not available in this data set because it's not a particularly pediatric cardiology focused data set. It's a broad population based data set. And so the relationship specifically the details of their perioperative care and diagnosis are not able to be attained. And so we'll need larger data sets that include that information to fully start to develop those sorts of relationships over time.

Dr Greg Hundley:             So, we want to thank our lead author, Dr James Priest from Stanford University School of Medicine, and our associate editor, Gerald Greil from the University of Texas Southwestern Medical School in Dallas. And reviewing this very interesting article on lower complexity cardiovascular disease and its association with an increased risk of cardiovascular events. And thank you both so much for clarifying. It sounds like an opportunity to collect more data through registries, et cetera, that we may need to expand around the world.

                                                Thank you everyone for listening to Circulation on the Run. Remember that's your back stage pass to our journal. And we'll see you next week.


Apr 8, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, also associate editor from VCU Health Systems, the Poly Heart Center in Richmond, Virginia.

Dr Carolyn Lam:                So arrhythmogenic cardiomyopathy that will make most of us think of right ventricular disease and fatty infiltration of the muscle, but could arrhythmogenic cardiomyopathy really be a bi-ventricular disease? Well you've got to stay tuned to find out more in a fantastic interview coming right up after our little coffee chat. So Greg, what are your picks this week?

Dr Greg Hundley:             My first paper is from Chris Lim at NYU in New York. And it's looking at the relationship between Mediterranean diet, air pollution and cardiovascular events.

                                                So, it's unknown whether usual individual dietary patterns can modify the association between long-term air pollution exposure and health outcomes. And so, in this large cohort with detailed diet information at the individual level, they had 548000 individuals across six states and two cities within the U.S. and a follow up period of 17 years. And that occurred between 1995 and 2011. And they evaluated whether a Mediterranean Diet modified the association between long-term exposure to ambient air pollution and then cardiovascular disease and mortality risk. And so, the average exposures to parts per billion and nitric oxide air pollution that the residential census track level were measured, and the investigators found that for the particulate matter there were elevated significant associations with cardiovascular disease. So, a hazard ratio of 1.13, ischemic heart disease similar hazard ratio and cerebrovascular disease with also a similar hazard ratio.

                                                For the nitric oxide, there were also significant associations with cardiovascular disease, as well as ischemic heart disease. And then the analysis indicated that Mediterranean diet modified the relationships. Those with a higher Mediterranean diet score had significantly lower rates of air pollution related mortality. These results therefore indicate Carolyn, that Mediterranean diet reduce cardiovascular disease mortality related to long-term exposure to air pollutants in a large perspective, U.S. cohort. Can you believe increased consumption of foods rich in antioxidant compounds actually may aid in reducing the considerable disease burden associated with ambient air pollution?

Dr Carolyn Lam:                Oh wow. That is hugely interesting. Gosh, what do we do about this clinically now?

 Dr Greg Hundley:            Remember, first of all, this is an associate study, so we can't infer cause effect. And what we need next are some more independent studies from other cities around the world, prospective cohorts, examinations of clinical outcomes and randomize interventions. And so, I think the results add to a growing body of literature suggesting that dietary patterns may help reduce cardiovascular events in these high air pollution exposure areas. And how does this work? Well, potentially through augmenting antioxidants and reducing oxidative stress.

Dr Carolyn Lam:                That's really cool. So from one region, talking about air pollution to another region that often reports about air pollution and that's China. But this study from China is actually the largest registry study to evaluate sex related differences and hospital management and outcomes of patients with acute coronary syndrome in China.

                                                This is from corresponding author Dr Zhao from Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease. With colleagues of the improving care for cardiovascular disease in China, Acute Coronary Syndrome project, which is an ongoing nationwide registry of the American Heart Association and the Chinese Society of Cardiology. So, the authors use data from this project and evaluate at sex differences in the acute management, medical therapies for secondary prevention and in hospital mortality in more than 82000 patients admitted for acute coronary syndrome in 192 hospitals across China from 2014 to 2018.

Dr Greg Hundley:             What did they show in this study?

Dr Carolyn Lam:                They showed that women hospitalized for acute coronary syndrome in China less frequently received acute treatments and strategies for secondary prevention and had a higher in hospital mortality rate than men. Now the observed sex differences in this in hospital mortality were likely due to older age, worse clinical profiles and fewer evidence base acute treatments provided to women. And that's because the sex differences were no longer observed after adjustment for these clinical characteristics and acute treatments.

                                                What this all means though is specifically targeted quality improvement programs may be warranted to narrow these sex related disparities in patients with acute coronary syndrome in China.

 Dr Greg Hundley:            Very interesting. I'm going to take sort of the next paper and it's looking at a different aspect of acute myocardial infarction. And these papers from Yong Wang from the Division of Molecular and Translational Cardiology at Hannover Medical School in Hanover, Germany.

                                                Now as we know, the heart can undergo deleterious changes and left ventricular geometry and function during that vulnerable period before scar formation has stabilized the infarct area. And so inflammatory cell trafficking from hematopoietic organs like the spleen to sites of tissue injury is coordinated by chemokine chemokine receptor networks. Therapeutically modulating these chemokine chemokine receptor interactions may promote infarct healing by limiting excessive inflammation induced tissue damage or by enhancing the recruitment of angiogenic cell populations to the infarct or the wound. Inflammatory cell trafficking after a myocardial infarction is controlled by a CXC motif chemokine ligand 12 or CXCL12 and its receptor CXC motif chemokine receptor 4. CXC receptor 4 antagonists, mobilize inflammatory cells and promote infarct repair. But the cellular mechanisms are unclear.

                                                So, what do these investigators do? In mouse models, the investigators found that inflammatory cell trafficking between a hematopoietic organs and sites of tissue injury is controlled by CXCL12 and its receptor CXC receptor 4. And bolus injectives of a highly selected peptidic macrocycles CXC receptor 4 antagonist, enhanced tissue repair and functional recovery after re-perfused acute myocardial infarction in mice. And interestingly, the therapeutic effects require a dendritic cell priming and we're specifically mediated by t-regulator cells. Intermittent CXC R4 blockade mobilized the t-regulator cells from their splenic reservoir. Leading to their enhanced recruitment to the infarct region.

Dr Carolyn Lam:                So bring it home for us, Greg. What does this mean clinically for MI management in humans?

Dr Greg Hundley:             Right. Highlighting the translational potential. What we might infer is that CXC receptor 4 blockade reduces infarct volume and improved systolic function in a porcine close chest model of re-perfuse acute myocardial infarction.

                                                And so, the results of both the mouse experiments and this sort of translational model in pigs should stimulate further research into therapeutic potential of CXC R4 blockade after MI and in other acute conditions were excessive, innate or adaptive immune responses cause immunopathology.

Dr Carolyn Lam:                Fascinating. So from one preclinical paper to another, but this time focused on heart failure. And focus specifically on titin. Titin is this giant elastic protein that spans the half-sarcomere from the Z-disk to the M band, and it acts like a molecular spring and a mechanosensor that has been linked to striated muscle disease. Now the pathways that govern tight independent cardiac growth and contribute to disease are diverse and have been really difficult to dissect. And so corresponding author Dr Gotthardt, from Max Delbruck Center for Molecular Medicine and the German Center for Cardiovascular Research and his colleagues aimed to study titin deficiency versus titin dysfunction.

                                                And how they did that is they generated and compared striatum muscles specific knockouts with progressive postnatal loss of the complete titin protein. And that's by removing Exxon 2. Or an M-band truncation that eliminates the proper structure and integration, but retains all the other functional domains. So they then evaluated cardiac function, cardiomyocytes mechanics, and the molecular basis of the phenotype. Now, what they found was that progressive depletion of titin led to sarcomere disassembly an atrophy in striated muscle. And in the complete knockout, remaining titin molecules had increased strain resulting in mechanically induce trophic signaling and eventual dilated cardiomyopathy.

                                                On the other hand, the truncated titin helped maintain passive properties and thus reduced mechanically and do signaling. In other words, truncations versus loss of titin, differentially affected cardiac pathology with atrophy versus dilated cardiomyopathy respectively. And together, these findings really contribute to the molecular understanding of why titin mutations differentially affect cardiac growth and have implications importantly for genotype, phenotype relations that support a personalized approach to the diverse titinopathy.

Dr Greg Hundley:             Interesting, Carolyn. All this information on titin. So why is it clinically important?

Dr Carolyn Lam:                Well, first of all, tightened mutations are the most common genetic basis of heart disease and the findings are clinically relevant, as I said, for understanding the genotype phenotype relations at the Titin mutation. But understanding the integration of Titin based signaling and sarcomere biology could indeed help personalize diagnostics by improved clinical decisions and maybe identify suitable therapeutic targets for these titinopathy. But that of course requires much further work. Well that brings us to the end of our summaries. Let's go to our feature discussion.

 Dr Greg Hundley:            Welcome everyone to our second segment of our program. We're discussing an interesting paper today entitled Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy. And we want to welcome our coauthors Elijah Behr and Mary Sheppard from St George's University in London. And also, our own associate editor, Sami Viskin to discuss this paper. Mary, can you tell us a little bit about your study design here, the population and the hypothesis and some of your results?

Dr Mary Sheppard:          I am a cardiac pathologist of 20 years and I have a special interest in sudden death. Over this time, I've established a national pathology database, where pathologists throughout the country when they have a sudden death, which is likely cardiac and non-ischemic, they will send the heart or tissue blocks insides to me for my opinion concerning the death. We have as a result developed a large number, over 5200 cases which has now built up to 6000. It's the largest pathological series in the world.

                                                And I was also discovering the pathologists were either under or over diagnosing all types of cardiomyopathy but particularly ergogenic cardiomyopathy. And that is why with Chris Miles, our research fellow, we looked in detail at what I had diagnosed, or the pathologist as ergogenic cardiomyopathy and we actually honed are pathological diagnostic criteria for this very important entity. Establishing that left ventricular is five and ventricular and left and ventricular is the norm almost. That right or left ventricular is unusual by themselves and even in 20%, one in five, the heart can look macroscopically normal. So that histology is essential when you're making this diagnosis. You cannot make the diagnosis pathologically without histologically examining the heart.

Dr Greg Hundley:             Very good, Mary. And did you also examine some genetic markers in some of the subsets of the patients? And how did you decide who those individuals would be that received the genetic analysis?

Dr Mary Sheppard:          A small subset and I will hand over to Elijah Behr, my colleague concerning that.

Dr Elijah Behr:                   The genetic tissue is only available in a minority of cases. We've developed a pipeline now with the referring pathologists who are increasingly they're sending samples of spleen suitable for DNA extraction that allow us then to do a retrospective postmortem genetic testing or molecular autopsy. But unfortunately, in this particular series we only had a small proportion. I think there were roughly about 24 out of the 202 cases, so just over ten percent. And interestingly, while we didn't necessarily mirror the expected yield of genetic testing that is seen in clinical cases, where you may see about 40% carrying pathogenic variance. We certainly picked up some important pathogenic variance, particularly those that are often associated with highly penetrant and more severe disease. In particular TMEM43 and desmoplakin. These findings may reflect the small size of the sample, but it also may reflect where the greatest risk for sudden death from ergogenic cardiomyopathy lies.

Dr Greg Hundley:             Elijah, getting back to some of the patients that experienced the sudden death in the study population Mary was referring to, were there characteristics that were associated with the sudden death? For example, those that might be related to gender or activity?

Dr Elijah Behr:                   So the majority of the cases were male. The majority has never had prior symptoms. These were unheralded deaths. The majority did not have a family history and I think the majority were addressed, but those that were athletes, we're much more likely to have died during exertion. So as we found with ergogenic cardiomyopathy in general and exertion is a trigger to sudden death. The risk was higher and compared to the athletes in death during exertion was associated with being younger as well. I think exertion and sports clearly play a role in ergogenic cardiomyopathy. It didn't appear to play a role in whether there was left ventricular involvement or not, but certainly a role at more severe presentation.

 Dr Greg Hundley:            Maybe both Mary and Elijah answering this. You found histopathological evidence of fibrosis and fatty infiltration. How extensive was that? And do you think that could be identified with a test like maybe magnetic resonance imaging?

Dr Mary Sheppard:          Yes. Our diagnostic criteria which is illustrated in the addendum is that it was at least two blocks of tissue. We always look at 10 to 12 to 15 blocks of tissue from both right and left ventricle. And at least two of the blocks had to have fibrosis with fat in 20% of the area examined. We did not include inflammation because inflammation is, an important histological criterion in our experience. We were very precise about that because you need that much at least to make the diagnosis. A little bit of fibrosis or a little bit of fat is not sufficient by itself.

Dr Greg Hundley:             When you mention a block, for us clinically, how much myocardium would that be? For example, on an imaging test like an echo or an MRI scan.

Dr Mary Sheppard:          One to two centimeters squared.

Dr Greg Hundley:             So quite a bit.

Dr Elijah Behr:                   You're looking at probably around two to four millimeters of potential depth of fibrosis. And what we've seen clinically in LV involvement of MRI scans is miss two epicardial late enhancement. Now the question is whether our scans are sensitive enough to pick that up? Given the technology available or a sense to the histopathology and I think that's why maybe some of the clinical studies have tended to miss the true proportion of left ventricular involvement. Because of the relative subtlety of the fibrosis compared to the technological ability to discriminate it. I mean certainly when you look at our cases that were diagnosed previously with cardiomyopathy, either they were arrhythmogenic or dilated, many did have imaging findings if MRI was performed, that would indicate or suggest some left ventricular involvement. But as you know, the task force criteria for arrhythmogenic cardiomyopathy having very much right ventricular focus. An LV imaging findings and LV ECG findings are just not part of those at the moment.

Dr Greg Hundley:             Was there a particular location within the heart where there was a predilection toward the findings of fibrosis and fat?

Dr Mary Sheppard:          In the posterior basal wall particularly, transmural involves going from the epicardium to the sub endocardium and also the interior walls of the left ventricular were the predilection areas.

Dr Elijah Behr:                   I think that's what we see on our MRI scans as well. When you look at these patients, that posterior basal area, is the one that tends to light up the most.

Dr Mary Sheppard:          It is believed that increased stress in that area gives more damage because of the stretching away from the septum.

Dr Greg Hundley:             Very interesting. So Elijah, you had mentioned task force criteria. I want to shift to Sami now and ask, Sami, can you help us put this in perspective relative to the existing task force criteria and then the findings in this study? And how that could lead to subsequent changes down the road?

 Dr Sami Viskin:                 Okay, so it is difficult to place this in the context of the task force because mentioned by Elijah, the taskforce are focused on a disease that is believed to be in the right ventricle. And the study shows that many of the sudden death cases will involve the left ventricle. One of the most important messages of this paper is importance of her forensic examination. And importance of making it for anything examination in the center of expertise. We know of patients that will travel a thousand miles to undergo surgery or an ablation procedure, but families do not think that way when there is casualty or family dies. You may take a postmortem as a given, but in many countries, including my own, most cases of sudden death would not be followed by a post mortem and will not go into center of expertise. And you cannot overemphasize the importance of doing that because then you have to know what you are looking for in the remaining relatives is extremely important.

Dr Greg Hundley:             Very good. How about from the perspective as an electrophysiologist? Does this impact in any way how you might evaluate a younger person with syncope?

Dr Sami Viskin:                  Well, it is difficult to conclude from this paper about how to evaluate patients with syncope because most of the cases in this series don't have symptoms at all. But this paper calls to very interesting investigations by Mario del Mar and others in New York. Looking about the electrophysiology consequences of a disease like right ventricle are like a bit mechanical in [inaudible 00:21:58] The tissues becomes editing the disease, the electrical properties how the patients in brugada can cause malfunction of this sodium channel and create a disease that is more like brugada and dysplasia at the beginning. So, the entire correlation between a morphologic disease and the metrical disease and we used to think they are two different things. And now we see that we can actually put them together and you can go through stages where one disease is before an electrical disease and only at later stages it becomes a morphological evident disease.

 Dr Greg Hundley:            A fantastic discussion on pathologic findings. Sami making the point that certainly in cases for young individuals having a postmortem examination performed at centers that have expertise such as what Mary's described, can be very important. And then Elijah, helping us to understand with arrhythmogenic cardiomyopathy, number one, findings are not, we shouldn't just be thinking about the right ventricle in isolation, but also the left ventricle. Fibro fatty infiltration, particularly in the posterior basal wall could be an important thing to look for, for those that are performing the magnetic resonance imaging exams. And then lastly, many of the patients in the study like this, the first presentation was of sudden death. And we need to be cognizant that this condition could be prevalent in the population and not necessarily appreciated by some of our current task force guidelines and examinations. So, what an outstanding discussion. And I think for today, we want to thank our authors and our associate editor and wish everyone a great week.

                                                On behalf of Carolyn and myself, we look forward to seeing you next week. Thank you very much.

Dr Carolyn Lam:                This program is copyright American Heart Association 2019.


Apr 1, 2019

 Dr Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, also associate editor in Richmond, Virginia at VCU Health.

 Dr Carolyn Lam:               So, PCI or no PCI for chronic total occlusion. That is a perennial question, and we have the results of the decision CTO trial reported in this week's Journal. In fact, we're going to discuss it right after our little chat here.

                                                So, Greg, why don't you kick us off? What paper did you choose?

 Dr Greg Hundley:            Yeah, thanks so much Carolyn. My first paper is from Laura Benschop from the Department of Obstetrics and Gynecology at Erasmus Medical Center in Rotterdam, the Netherlands. It's going to focus on placental growth factor as an indicator of maternal cardiovascular risk after pregnancy.

                                                So, as we all know, pregnancy is accompanied by extensive maternal hemodynamic changes that allow for proper placental implantation, growth, profusion, and fetal development and this process requires a tight balance between pro-angiogenic factors like placental growth factor, and anti-angiogenic factors like soluble FMS like tyrosine kinase factors. So, in response to stress, the syncytiotrophoblast will decrease the production of placental growth factor and women with reduced placental growth factor and increased FLT-1, are more at risk of a complicated pregnancy. For example, like preeclampsia and spontaneous preterm birth.

                                                So, angiogenic placental growth factor concentrations can rise during pregnancy, peaking at the end of the mid-pregnancy. And low placental growth factor concentrations during pregnancy are associated with pregnancy complications with recognized later life cardiovascular risk. So here, the authors hypothesize that low placental growth factor concentrations, especially in mid pregnancy, identify not only a subset of women at risk for pregnancy complications, but also women with greater cardiovascular risk factor burden after pregnancy, regardless of their outcome.

                                                So, among 5,529 women, the authors computed gestational age adjusted and mid-pregnancy placental growth factor concentrations and pregnancy complications, like preeclampsia, small for gestational age, spontaneous preterm birth, was obtained from hospital registries.

 Dr Carolyn Lam:               Cool, and what did they find?

 Dr Greg Hundley:            So six years after pregnancy, the authors found that women with mid pregnancy low placental growth factors, in the lowest quartile, had larger aortic diameters, left atrial diameters, and LV mass, and a higher systolic blood pressure by an average of 2.3 millimeters of mercury. High mid-pregnancy placental growth factor concentrations were the opposite. They were associated with smaller aortic diameters, smaller left atrial diameters, lower LV mass by 3.9 grams, and lower systolic blood pressure. And these differences persisted after exclusion of women with complicated pregnancies.

                                                So, the results suggest that a woman's response to the cardiovascular changes of pregnancy, measured by pre-mid-pregnancy placental growth factor levels could provide insight into the path of physiological mechanisms leading to future cardiovascular disease in multiparous women.

 Dr Carolyn Lam:               Wow. That is really interesting. Well, the paper I chose really answers the question, are there racial differences in sudden cardiac death, and why? And this is from corresponding author Dr Guallar from Welch Center for Prevention, Epidemiology, and Clinical Research in Johns Hopkins Bloomberg School of Public Health and Colleagues.

                                                What they did is they compared the lifetime cumulative risk of sudden cardiac death among blacks and whites in the atherosclerosis risk in community study, or ARIC. They evaluated the risk factors that may explain racial differences in sudden cardiac death risk in this general population.

                                                What they found was that blacks had a much higher risk of sudden cardiac death in comparison with whites, with a sex adjusted hazards ratio of 2.12. Known factors explained 65% of the axis risk of sudden cardiac death in blacks compared to whites. The single most important factor explaining this difference was income, followed by education, hypertension, and diabetes. These racial differences were evident in both genders, but stronger in women than men.

 Dr Greg Hundley:            Hmm. So are there implications, and are there potential strategies that could help reduce this risk in African Americans?

 Dr Carolyn Lam:               Yeah, this is a really interesting study, and it really implies that efforts to reduce the sudden cardiac risk in blacks should perhaps focus on improving CPR outreach, medical care engagement in response to cardiac arrest, the quality of treatment in medical institutions in predominantly black neighborhoods, and factors such as that. Because remember the single most important factor explaining the difference was actually income and education.

 Dr Greg Hundley:            Oh, wow. Well, I'm going to switch gears a little bit here Carolyn, and we're going to talk about pulmonary hypertension. And this next paper is going to focus on pericytes. We'll learn a little bit about what pericytes are. So, the paper is from Vinicio de Jesus Perez, who's an assistant professor of medicine and pulmonary critical care at Stanford University Medical Center in California.

                                                What are pericytes? So, pericytes are specialized perivascular cells embedded in the basement membrane of blood vessels, where in conjunction with neighboring and endothelial cells, they support vessel maturation and stability. In the lung, pericytes are mostly found associated with small precapillary arteries, the capillaries, and then those post capillary venules. And it's thought that pericytes are responsible for regulation of vasomotor tone and structural support of these micro-vessels. When the vessels become muscularized, pulmonary vascular resistance increases, resulting in pulmonary artery hypertension.

                                                So recent studies have focused on pericytes in addition to pulmonary endothelial cells, smooth muscle cells, and fiberglass, but not much is known about the contribution of pulmonary pericytes to pulmonary arterial hypertension. Two genes are involved in Wnt planar cell polarity pathway that is responsible for coordinating complex cell movements during tissue morphogenesis. So, in this group, they have produced prior results that show that restoration of the Wnt planar cell polarity in pulmonary arterial hypertension, pericytes could partially restore recruitment to PNVECs and increase vessel stability.

 Dr Carolyn Lam:               Interesting, and so that was their past research, and what did the current paper show?

 Dr Greg Hundley:            Right. So Carolyn, what they found is that pulmonary microvascular endothelial cells isolated from pulmonary arterial hypertension patients, and endothelium from pulmonary arterial hypertension tissue have reduced expression of Wnt-5a. Healthy PMVECs produce and package Wnt-5a in the form of exosomes which regulate pericyte recruitment, motility, and polarity.

                                                And so, the overall implication is that promising therapeutic strategies that help can restore the Wnt/PCP, or planar cell polarity pathway, and endothelial pericyte communication could help prevent micro-vessel loss in patients with pulmonary artery hypertension.

 Dr Carolyn Lam:               Thanks, Greg. So, I'm going to take us to the cath lab for this next paper. And it's the results of the CANTIC study, which aimed to answer the question, does intravenous P2Y12 inhibitor Cangrelor have a role in bridging the gap in platelet inhibition in patients with STEMI undergoing primary PCI. And this is from corresponding author Dr Angiolillo from the University of Florida College of Medicine Jacksonville and Colleagues.

                                                Now, CANTIC was a prospective randomized double-blind placebo control parallel design investigation of the pharmacal dynamic effects of Cangrelor versus placebo in patients undergoing primary PCI, who were also treated with crushed Ticagrelor. So, after diagnostic angiography, patients were randomized to a blinded two-hour infusion of either Cangrelor or placebo. At the same time, 180 milligrams of crushed Ticagrelor was administered to both groups. Platelet reactivity was measured with Verify Now P2Y12 point of care testing, and with vasodilator-stimulated phosphoprotein, or VASP.

 Dr Greg Hundley:            So what did the trial show, Carolyn?

 Dr Carolyn Lam:               They found that addition of Cangrelor led to more prompt and potent platelet inhibitory effects, compared with crushed Ticagrelor alone in patients undergoing primary PCI. The significant differences were observed as early as five minutes post bolus administration, and persisted until the end of its two-hour infusion.

                                                Furthermore, after discontinuation of Cangrelor or the placebo infusion, there were no differences in levels of platelet reactivity between groups. And this importantly rules out a drug/drug interaction when Cangrelor and Ticagrelor are concomitantly administered. This lack of drug-drug interaction is important, as it supports a more versatile use of Ticagrelor with respect to timing of its administration in patients treated concurrently with Cangrelor.

                                                Overall, the results are reassuring and demonstrate reduced platelet reactivity, and no high on treatment platelet reactivity with Cangrelor in combination with Ticagrelor in primary PCI patients. Of course, the implications of these pharmacal dynamic findings really warrant investigation in an adequately powered clinical trial.

                                                And that brings us to the end of our summaries. Let's go to our featured discussion.

                                                So PCI, or no PCI for chronic total occlusion, that is a perennial question isn't it? Especially nowadays when procedural results for PCI and CTO have improved in recent years, and PCI strategies have moved towards more complete revascularization. Yet the evidence is clearly lagging behind for us to make decisions on this. And that's why we're so happy that our featured paper today is the DECISION-CTO trial from Korea, and so happy to have the first author, Dr Seung-Whan Lee from ASA Medical Center to tell us about this, as well as our associate editor, Dr Manos Brilakis from UT Southwestern.

                                                So Dr Lee, could you tell us about the DECISION-CTO trial?

Dr Seung-Whan Lee:       Yeah, in our trial our multicenter, randomized, noninferiority trial, PCI-eligible patients were assigned to receive either one of two strategies; PCI or no PCI or CTO. We did the option for PCI of the other. The primary endpoint as you know the composite outcome of deaths, myocardial infraction, stroke, or any revascularization. As related to quality of life was assessed up to three years. However, because of the slow recruitment, the trial was stopped before completion. We started 208 planned enrollments. For six years 834 patients there were randomly assigned to the CTO PCI versus no CTO PCI strategy.

                                                Among the patients assigned to the no CTO PCI strategy, nearly 20 percent of patient cross over to the CTO PCI. That is our big limitation, as you know. Anyways, the primary end point was assessed per year, and then, finally, we founded the per year risk of the major adverse cardiac events there’s no difference in contributor composite outcome, MI, revascularization, and stroke.

                                                However, in our trial, in some detail, in CTO PCI was success rate around 91 percent. However, complication is very low, .6 percent of patient is complication. Very surprisingly the coheir is up to the three, and no difference between CTO PCI versus no CTO PCI.  

                                                I think our main message is our patient is a relatively low-risk population, including the syntax score 20 and the score 22%. The majority of patient preserved LV function and single-vessel disease 25%. The relative low risk population CTO PCI versus no CTO PCI clinical outcome is no difference of the per year from the two groups.

                                                I think that our trial is make the reposition with the medical law in the CTO patient. That’s my summary.

Dr Carolyn Lam:                Thank you. Manos, could you maybe paint the background and let us know why this was so important for us to publish in Circulation? Why is it so difficult to do these trials?

 Dr Manos Brilakis:           This is the largest study on CTO PCI so congratulations on getting this accomplished. I know it was many years and a lot of effort.

                                                I think a couple of things on the background. As Dr Lee said as well, CTO PCI success rates have been improved, and now at experienced centers you can get 85 to 90 percent success fairly consistently.

                                                The complication rates are low. .5 to 3 percent is the average rate. We do have a tool right now. The procedure is mature, and it's time test in the randomized trials.

                                                The question has always been for CTO PCI, "How does it help?" Does it improve symptoms? Does it improve the heart outcomes? Myocardial Infarction?  This is what DECISION CTO was trying to answer.

                                                Couple of I think limitations that we should take into account when interpreting the results. The first one is that these were notations with an isolated CTO, but a significant proportion had also multi-vessel disease. They were enrolled before treating the other vessels, which were subsequently treated.

                                                Sometimes it's hard to know how much the residual ischemia or symptoms would be present after the other lesions were treated. That's one thing.

                                                The second is that there was a significant crossover for about 1 in 5 patients that randomized to medical therapy immediately crossed over to the CTO PCI group. And that always uses the power and creates difficulty in interpreting the results.

                                                In my mind, the question still remains, in low risk populations it's possible that CTO PCI doesn't improve symptoms, but the ones that were expected to improve, the heart outcomes dec-MI, would be the high-risk patients with significant ischemia. Ideally, studies in the future should actually look specifically at patients who have high ischemia, significant symptoms when looking at heart outcomes.

 Dr Carolyn Lam:               Dr Lee, I think you did mention as well in your manuscript that a viability test was not mandatory for patient enrollment. I mean, clearly it was such as work of labor enrolling such patients. If you put even more criteria it would have been impossible, I suppose. Do you have some thoughts there on maybe future studies?

Dr Seung-Whan Lee:       Yeah, as you know, the currently ongoing CTO PCI process medical treatment is nobel CTO and ischemia CTO is assessed at the reduction of the ischemia burden in CTO PCI. I think there maybe two studies that give us some answer for the low level of the CTO PCI for the reduction of the ischemia.

                                                So, I think the larger ischemic burden the patient is maybe high risk to make the however we don’t know exactly the cut off… ischemic burden in CTO patient. Usually instable angina any kind…coronary disease…3 years circulation showed more than 10 percent of ischemic burden is really predictive of future cardiac event. However, we don't know exactly the can be applied to CTO patient. We don't know exactly.

 Dr Manos Brilakis:           Can I ask Dr Lee a question regarding the study and his interpretation as well. Now the study was borrowed for hard end points dec MI. What his is perception, based on the DECISION CTO, and, of course, everything else in the literature and the CTO study with symptomatic benefit...Dr Lee, what is your conclusion about, or your kind of thoughts about, the effect of CTO PCI on improving symptoms, which is a more accepted indication for the procedure right now?

Dr Seung-Whan Lee:       As you know, the university trials symptom assessment was done after the no CTO PCI. However, our trial is a pragmatic trial, initial approach to the CTO vessel and the vessels that is patient.

                                                At this moment, I think the other vessel, other no CTO vessel intervention and OMT may improve the patient symptom and then CTO vessel is the intervention including the CI patient completely…improve the symptom status. However, analysis showed up to the 3 year, maybe no difference between two groups in the CTO PCI versus medical treatment.

                                                Our trials of the CTO PCI symptom, we don't exactly the role of the after no CTO PCI. We don't know exactly the CTO based symptom assessment was not done, because of the symptom assessment was done before the intervention.

                                                I think that our trials are more practical, because of the initial…multivessel… CTO. Our trials, maybe, completely vascularization including CTO and no CTO vessel revascularization without the CTO intervention. Sometimes the patient to complain of symptom multivessel with the CTO I think we can wait if we continue the patient symptom…

                                                However, in this trial showed CTO specific intervention trial, because of the symptom assessment was done after no CTO vessel intervention. There is some improvement of the… receptor treatment satisfaction of the angina stability. I think that the CTO intervention is maybe reserved for the symptom control after the medical treatment failure of patient.

                                                I fully agree the symptom control is possible with the CTO PCI.

 Dr Manos Brilakis:           Wonderful. Thank you. I think that's a critical differentiation that the DECISION CTO is not specific for CTO, but it's multi-vessel disease plus CTO. Thanks for clarifying. That's very important for the leaders and the entire community to understand that part.

                                                One more question, if it's okay. I know that in Asian countries bypass patients are relatively less. I think in the U.S. 50 percent. Any comment on that? I know people get less bypass in Asia than they do in the United States. How may that affect the interpretation of the DECISION CTO?

Dr Seung-Whan Lee:       Initially, I introduced my studies to our patients syntax score under 20. As you know, the U.S. Registry shows the syntax score more than I think the 20, and the tester score around 46. Quite different in population, because the risk factor is quite different. U.S. patient is hypertension and diabetic are more prevalent than the Asian patient. Bypass surgery is 40 percent in Asian patients. Bypass surgery is around 102 percent in CTO registry. Quite big difference of the base rank, risk factor, and morbidity.

                                                I cannot apply to U.S. population exactly the same ... Not same situation. We cannot apply directly to the U.S. population. I fully agree with your suggestion, though. Lowest population is maybe ... Our trial is maybe lowest population. We agree.

 Dr Carolyn Lam:               I'm just learning so much listening to both of your interventionists. What do you think are the take-home messages from this? Maybe, could I start with Dr Lee, and then give Manos the last word?

Dr Seung-Whan Lee:       CTO PCI critical outcome, it should be tested as a large random trial. Maybe Manos already mentioned about the high-risk population, because our population is the lowest population. However, in some large random trial with a high-risk population we have consider some random trial because they are not easy.

                                                Maybe not easy to test in high-risk population. However, you must do that, because of the two established CTO PCI law in the current practice.

 Dr Carolyn Lam:               Manos?

 Dr Manos Brilakis:           Yeah, I would agree with that. I think the main conclusion regarding the field of CTO PCI is that still right now, the key indication remains symptom improvement. We do have the trials at this point showing that you do CTO PCI in terms of improving mortality. However, CTO PCI is a tool. It's a revascularization tool. Patients who have severe, complex, coronary disease, multi-vessel disease, may be best served with bypass in the first place. Those who have multi-vessel disease that's less complex and don't have significant symptoms after fixing the non-CTO lesions, then they may not benefit from CTO PCI as well. But those who have CTO lesions and have significant symptoms, this is the population for which I think there is general agreement, and I the decision that CTO is good with that, that those patients could benefit from CTO intervention.

 Dr Carolyn Lam:               Thank you so much for sharing your insights.

                                                Thank you, listeners, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019.


Mar 25, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             I'm Greg Hundley, associated editor from the Pauley Heart Center at VCU Health Sciences in Richmond, Virginia.

Dr Carolyn Lam:                A big number of acute ischemic stroke patients receiving endovascular therapy in the United States are receiving this therapy only after inter-hospital transfer. What are the temporal transient outcomes following this inter-hospital transfer? Very important discussion coming right up with our featured paper. But for now, sit back, relax with us. We're going to discuss a couple of papers that we found were interesting in this week's journal.

Dr Greg Hundley:             Very good, so thanks Carolyn. I'll start off, and I'm going to talk a little bit about stress induced cardiomyopathy, and we also know it as takotsubo cardiomyopathy, looking at a paper from Dana Dawson from the University of Aberdeen in the United Kingdom. Takotsubo cardiomyopathy can result in a heart failure phenotype with a prognosis comparable to myocardial infarction.

                                                In this study, the investigators hypothesize that inflammation is central to the pathophysiology in natural history of takotsubo cardiomyopathy. They prospectively recruited 55 patients with takotsubo cardiomyopathy, and 51 age, sex, and comorbidity match control subjects.

                                                During the index event, and at five months of follow-up, the patients with takotsubo cardiomyopathy underwent a cardiac MRI study in which they looked at ultra-small, super paramagnetic particles of iron oxide, or USPIOs, enhancement for detection of inflammatory macrophages in the myocardium. What would the studies show? Patients with acute takotsubo cardiomyopathy had macrophage-mediated myocardial inflammation.

                                                They also demonstrated modulation of peripheral monocyte subsets and increased systemic pro-inflammatory cytokines. This systemic inflammation persisted for five months, and then at that five-month time point, the cardiac MRI evidence of the macrophage presence was diminished.

Dr Carolyn Lam:                Wow, Greg. So this is right up your wheelhouse, isn't it? Can you explain? What are the clinical implications of these MRI findings?

Dr Greg Hundley:             It was really interesting. For the first time, they've linked an ongoing inflammatory process using the USPIO contrast agent with MRI actually going on or operative in the heart, and they associate that with systemic markers in the circulation.

                                                They help us elucidate the mechanisms and the pathogenesis of takotsubo cardiomyopathy, and systemic and myocardial inflammation really may start to now serve as a therapeutic target for patients with acute takotsubo cardiomyopathy.

Dr Carolyn Lam:                Very interesting. From stress-induced cardiomyopathy to early onset myocardial infarction. The first paper I chose really answers the question, "What is the relative prevalence and clinical importance of monogenic mutations, that is, a single mutation that significantly increases risk, versus a polygenic score, which really measures the cumulative impact of many common variants, in early onset myocardial infarction?"

                                                The co-corresponding authors were Doctor Amit Khera and Sekar Kathiresan and both from Massachusetts General Hospital, and they performed deep coverage, whole genome sequencing of more than 2,000 patients from four racial subgroups hospitalized in the United States with early onset myocardial infarction defined as myocardial infarction before the age of 55 years, and compared this to 3,761 population base controls.

                                                What they found was that a monogenic mutation related to familial hypercholesterolemia was identified in 1.7% of the patients, and associated with a 3.8-fold increased odd of myocardial infarction. In comparison, the high polygenic score, which was composed of 6.6 million common DNA variants and defined as the top 5% of the control population distribution, now, that was identified in 10 times as many patients, so 17% of patients, and associated with a similar 3.7-fold increased odds of myocardial infarction.

Dr Greg Hundley:             Interesting. How do we apply this clinically, Carolyn?

Dr Carolyn Lam:                These findings really lay the scientific foundation for the systematic identification of individuals born with a substantially increased risk of myocardial infarction. The important point is both familial hypercholesterol mutations and a high polygenic score are associated with more than three-fold increased odds of an early onset myocardial infarction.

                                                However, the high polygenic score cannot be reliably identified on the basis of elevated LDL cholesterol, and yet has a 10-fold higher prevalence among patients presenting with early onset myocardial infarction. So very intriguing that both groups matter.

Dr Greg Hundley:             Very good. My next paper is from Adrian Hobbs at the London School of Medicine, and is looking at the role of endothelial C type natriuretic peptide as a critical regulator of angiogenesis and vascular remodeling. We know that a central pathway coordinating both neovascularization and ischemic extremities in PAD is driven by vascular endothelial growth factor or VEGF-A4.

                                                But preclinical studies and other large scale clinical trials have been disappointing because administering or using VEGF-A to promote angiogenesis or arteriogenesis in PAD really hasn't occurred. This group focused on endothelial-derived CMP. Why? Because it plays a fundamental role in regulating vascular homeostasis. It controls local blood flow and the resistance vasculature, and systemic blood pressure, and reduces the reactivity of leukocytes and platelets.

                                                So, what were the results? Clinical vascular ischemia was associated with reduced levels of CMP and it's cognate NPR-C. Moreover, genetic and pharmacological inhibition of CNP and NPR-C reduced the angiogenic potential of the pulmonary microvascular endothelial cells and the human umbilical vein endothelial, and it isolated vessels ex vivo.

                                                So, the study really defines a central pathophysiological role for endothelium-derived C type natriuretic peptide via activation of cognate natriuretic peptide receptor C in angiogenesis and in vascular remodeling. Moreover, the work demonstrates the therapeutic utility of pharmacologically targeting NPR-C to restore deficits in these processes following ischemia and injury.

Dr Carolyn Lam:                Interesting, from new mechanisms and targets to good, old, major risk factors for coronary heart disease. Back to the basics but in a really, I think, nicely done paper from Dr Pencina and colleagues from Duke Clinical Research Institute.

                                                Now, their objective in this next paper was to compare the associations of key, modifiable coronary heart disease risk factors with incident coronary heart disease events based on their prognostic performance, the attributable risk fractions and treatment benefits overall and by age.

                                                And so really aiming at quantifying the importance of these major, modifiable risk factors for coronary heart disease. What they did is they used pool participant level data from four observational cohort studies sponsored by the NHLBI, and they created a cohort of more than 22,600 individuals ages 45 to 84 years old who are initially free of cardiovascular disease.

                                                And these individuals were followed for 10 years from baseline evaluation and followed for incident coronary heart disease. They estimated that age, sex and race captured up to 80% of the prognostic performance of cardiovascular risk models. When we add either systolic blood pressure or non-HDL cholesterol, diabetes or smoking to model with the other risk factors, the prognostic performance, as measured by the C index, increased by only 0.004 to 0.013.

                                                However, if you look at it from the attributable risk and absolute risk reduction standpoint, lowering the systolic blood pressure of all individuals to less than 130, or lowering LDL cholesterol by 30% would be expected to lower a baseline, 10-year coronary heart disease risk of 10% to 7% and 8% respectively.

Dr Greg Hundley:             That's a lot of data, Carolyn. Help me synthesize all that.

Dr Carolyn Lam:                This is a take-home message. Although the individual modifiable risk factors contribute only modestly to the overall model prognostic performance, when we eliminate or control these risk factors, they would actually lead to a substantial reduction in total population coronary heart disease.

                                                That's because if we look at the attributable fraction and the absolute risk reductions, we see that they actually really matter. The take-home message too from Dr Pencina was that metrics used to judge the importance of these risk factors should therefore be tailored to the question being asked.

Dr Greg Hundley:             Very good. That was a very nice summary, Carolyn.

Dr Carolyn Lam:                Thanks. Let's move on now to our feature discussion, shall we?

Dr Greg Hundley:             Very good.

Dr Carolyn Lam:                Trials have established that endovascular thrombectomy dramatically reduces disability after acute ischemic stroke due to intracranial large vessel occlusion. In fact, guidelines almost immediately adopted endovascular thrombectomy as a standard of care. However, that has created some problems.

                                                The main one being that hospitals equipped to carry out this procedure are largely limited to tertiary centers in urban areas. This is, of course, important because that means that patients may need to be transferred from another center to receive such treatment.

                                                Today's feature paper discusses this very issue, a terribly important one, and I'm so pleased to have the author with us, Dr Shreyansh Shah from Duke University Medical Center. We have our editorialist, Dr James Grotta who's director of the Mobile Stroke Unit project at Memorial Herman Hospital.

                                                And we have an associate editor, Dr Graeme Hankey from University of Western Australia. So, such an important topic. I think Shrey, could you just jump right in and tell us what your study showed.

Dr Shreyansh Shah:         I'm very excited to present findings of our study, and as a Carolyn mentioned, this study is going to have a very important implication in our country here in US on the creation of systems of stroke. I think the findings are already applicable to other countries also where we are seeing endovascular care getting more and more used.

                                                As Carolyn was talking, endovascular treatment is very important and lifesaving measure. But unfortunately, it is not available at every hospital. Patients are often transferred across different hospital or institution before they can receive this endovascular care.

                                                What we did in our project was we looked at the data from the hospital that's participating in Get With The Guidelines®® Stroke, which is a quality improvement program here in US. It looked at the endovascular thrombectomy used especially in relation to inter-hospital transfer.

                                                What we found was big proportion of patients receiving endovascular care, up to about 43% to 45% of patients, were getting the care after transferring across different hospital. The outcomes in this patient were worse compared to the patient who were receiving endovascular care if they had come directly to the hospital.

                                                While there was no difference in mortality between these two groups, the endovascular care, after inter-hospital transfer, resulted in a higher rate of symptomatic ICH, patients are less likely to be discharged to home, which is the preferred outcome. And patient was also less likely to be able to ambulate independently prior to the hospital discharge.

                                                There was also delay in endovascular care initiation for patient who received this after inter-hospital transfer. I think this particular study highlights the magnitude of this problem, and that's why it's going to be important for people who are studying systems of care. The fact that about 45% of patient had to get inter-hospital transfer before endovascular care tells us that we still need to take significant steps in increasing access to this lifesaving therapy.

Dr Carolyn Lam:                Thank you and indeed James, I really love the editorial you wrote that accompanied this. I mean you highlighted its importance, and you also noted that what was unusual about the paper was that even after controlling for the delay in initiating endovascular thrombectomy, there was still worse outcomes in the patients who were transferred. Could you share some thoughts?

Dr James Grotta:              It is a very timely issue. Now that we have a very effective treatment, the big challenge we have is getting it to the patients as fast as possible. Right now, our system, as is pointed out, means shuffling patients from one hospital to another.

                                                I think that clearly with stroke treatment, any sort of stroke treatment, the faster we deliver it, the better. Other studies have shown that transferring patients is associated with a delay of treatment, and this study showed the same thing.

                                                There was a substantial delay in getting the patients treated if they required a transfer. And as you pointed out, however, this did not explain the entire or was not at least the entire explanation for the worst outcome. So, it is a little bit of a mystery.

                                                I do know from personal experience that transferring patients from hospital to hospital, it's not exactly a black hole, but you lose control of the patient when they're being transferred. These are patients who have large artery occlusions. That means they have their middle cerebral artery is blocked.

                                                And so, the area of brain that's affected is in a very tenuous shape. So, any drop-in oxygen concentration from breathing problems or of any drop-in blood pressure might further worsen the stroke. So, this could happen in transit. So, it's possible that in the process of transfer, these sorts of things happen.

                                                I do think that we do have to be a little bit careful in that by remembering that this was not a randomized comparison, so patients that were treated directly and those that were transferred were not randomized. And so, although they appear to be balanced in a lot of the important variables like their stroke severity, there may be other things that we can't account for that could explain some of the worst outcomes.

                                                I'd like to ask Dr Shah whether he identified any things in ... well, he and his co-authors think might have contributed to some of the worst outcomes.

 Dr Shreyansh Shah:        To answer Dr Grotta's question about what other factors may have played a role in the worst outcome that we saw in patients who were getting inter-hospital transfer, I think as we correctly pointed out, transferring this very sick patient is very tricky. As we know, the hemodynamic instability or variability plays an important role in outcomes of stroke patient.

                                                And it is very likely that during the transfer process, there is not adequate control of their blood pressure variability, their oxygen saturation, and this ends up affecting their brain leading to worst outcome. The other possibilities also, as Dr Grotta was explaining, this is not a randomized control trial.

                                                And although we balance for number of important factors that can affect stroke outcome, there might be a selection bias in transferring patient who are more sicker and also patients who received thrombolysis with TPA but did not improve, while the patient who were directly arriving to the hospitals and getting endovascular care, they received the TPA.

                                                It is possible that they started to improve and still received a thrombectomy at the same time. So that group may have been more favorable in that respect, which could have also played a role in better outcomes with patient who are directly arriving.

Dr Carolyn Lam:                Interesting. And, you know, with the mention of TPA, I really have to bring James back. I loved your mention about potential solution using mobile stroke units. And since you direct one of them, could you tell us what you meant there?

Dr James Grotta:              Yes, of course, I have to state at the outset that I have a little bit of a bias about mobile strokes, and so I do it every day. What a mobile stroke unit is, for those who don't know, it's basically taking the emergency department to the patient.

                                                It's an ambulance with a CT scanner on board and the ability to treat with TPA in the field. But in addition, it's also the CT scanner. We can do CT angio and identify large vessel occlusions on the mobile stroke unit, not to mention the fact that you have a vascular neurologist either in-person or by telemedicine examining the patient.

                                                So clinically, you can make the determination also much more accurately than any sort of pre-hospital stroke scale, whether the patient has a large artery occlusion. That way, you don't have to take the patient to the nearest hospital. You can bypass the nearest hospital, take them right to the thrombectomy center, therefore, avoiding the transfer process.

                                                We've been implementing this in Houston, and there are now about 30 mobile stroke units around the world. The innovation actually started in Germany by Dr Fassbender about a decade ago in Hamburg, Germany. We are conducting a randomized trial, comparing mobile stroke unit care to standard management to see how much better outcomes occur as a result of this faster treatment.

                                                We obviously can treat patients with TPA faster. For example, a similar study from the Get With The Guidelines® a few years ago showed that only 1% of patients treated with TPA in emergency departments get treated within the first hour after symptom onset simply because it takes an hour in the emergency room itself to do the evaluation of the patient and get them treated.

                                                Whereas on our mobile stroke unit, at least a third and probably 40% of the patients we're treating with TPA, we can get treated within that first hour where there may be an exponential better benefit. But we don't yet know really how much that translates to better benefit, and also, of course, mobile stroke units are more intensive in terms of the amount of facilities on board and costs.

                                                So, we need to look at the cost-effectiveness. If it produces only a marginal reduction in disability but costs a fortune, then it's not worth it. But in fact, in our experience, it's pretty practical. We can cover almost the entire City of Houston, which is the fourth largest city in the country, with one mobile stroke unit. When it's well-integrated, it requires careful integration with the fire department and other hospitals in the city.

 Dr Shreyansh Shah:        At those two conferences, I came across a very interesting talk from Dr Grotta's group about rendezvous with the EMS which allows extending their coverage area significantly. I think we definitely need more and more innovative solutions like this where we can identify patients by their origin, whether they have large vessel occlusion or not, and then triage them appropriately at the centers that can perform endovascular therapy. So as a result, we can provide them earlier therapy and hopefully, it will lead to better outcome.

Dr Carolyn Lam:                Thank you Shrey and James for these incredible insights. Now, Graeme, I want you to have the last word and reflections from down under.

Dr Graeme Hankey:        Firstly, just to congratulate Dr Shrey and colleagues on this terrific study that reports a contemporary United States experience, a very broad one across the country, really highlighting how since 2012, until a year ago, there's been a six-fold increase in the number of patients being transferred for endovascular therapy.

                                                And we're all experiencing that around the world. And moreover, since the DAWN trial and the DEFUSE trial were published just over a year ago, which is when this study stopped, there's been an expansion of the window from six hours out to 24 hours.

                                                So, in the last year, which this study doesn't cover, we've seen an exponential increase in the number of people being transferred from rural and remote areas who have had a stroke up to 24 hours ago being considered for endovascular therapy if their CT angiogram at the base hospital shows a large vessel occlusion.

                                                This is likely to be not only internally valid, but externally valid to all of us around the world. It reflects our experience of this avalanche of cases coming. And it's provided a lot of challenges for those who are trying to deliver the service at the tertiary referral center.

                                                And it highlights that nearly half of the cases who are having endovascular therapy are coming from external sites. As Jim has really highlighted in his editorial, it challenges us to reassess the current practice of inter-hospital transfer.

Dr Carolyn Lam:                Thank you so much for publishing this paper with us and the editorial. And listeners, don't forget to tune in again next week. This program is copyright American Heart Association, 2019.


Mar 18, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and it's editors. We're your co-hosts. I'm Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, also Associate Editor from the Pauley Heart Center in Richmond, Virginia, VCU Health Sciences.

Dr Carolyn Lam:                How well are we doing with guideline-directed stroke prevention therapy in atrial fibrillation? Well, there are going to be very important results that you need to hear about from Get With the Guidelines Atrial Fibrillation. That's our feature paper coming right up in a future discussion. But first, you've got Greg and I discussing really important papers that we've spotted in The Journal. Greg.

Dr Greg Hundley:             Absolutely, Carolyn. And my favorite kind of follows from that 'cause it's really about left atrial electromechanical remodeling following two years of high intensity exercise training in sedentary middle-aged adults, kind of like me. The studies from Ben Levine at University of Texas Southwestern Medical Center in Dallas. So, what he's driving at here are moderate-intensity exercises associated with a decrease in incidents of atrial fibrillation. However, extensive training in competitive athletes is associated with an increased atrial fibrillation risk.

                                                So, in this study, they're looking at the effects of 24 months of high-intensity exercise training on left atrial mechanical as well as electrical remodeling in sedentary, healthy, middle-aged adults. So, he had 61 individuals, their average age was 53.5 years, quite young, who were randomized to 10 months of exercise training followed by 14 months of maintenance exercise and some stretching or stretching and balance control. He also had another group of 14 master's athletes that were added for a comparison and he looked at three of the echocardiograms to assess left atrial and left ventricular volumes and also had signal average EKG's for filtered P-wave durations and atrial light potentials. He made assessments at baseline, so before everyone started, and 10 and 24 months.

Dr Carolyn Lam:                Hold on, hold on. Let's really understand here how much exercise were these sedentary middle-aged adults subjected to.

Dr Greg Hundley:             So, let's talk about that because that was very interesting because a lot of us are out there exercising. So briefly the way he started this, there was an initial phase that was comprised of six months of regressive training during which an increase in the frequency, the duration, and the intensity of exercise, including two high-intensity aerobic interval sessions per week that were prescribed to peak training load. The peak training load included five to six hours of exercise per week that included two interval sessions, at least one being an hour-long session, and then two 30-minute sessions.

                                                Once you got that peak training load, that was sustained for four months and then he made these 10-month measurements as part of his study design. Now following that phase, a 14-month sort of a continuation, all of the 24 months, a 14-month period of maintenance exercise was completed where the frequency of high-intensity intervals was reduced to once per week plus continuous training all the way to that 24-month time point. And during the maintenance phase, participants performed a total of about three hours a week of aerobic exercise.

Dr Carolyn Lam:                Well, don't keep us in suspense now. What did the study show?

Dr Greg Hundley:             So at the 24 month time point of high-intensity exercise, it led to a disproportionate dilation of the left atrium compared to the left ventricle. So, mechanical changes, but no electrical remodeling was seen. And interesting, and remember he had that comparison cohort with master's athletes. Those participants randomized exercise training demonstrated lower absolute left atrial and left ventricular volumes, but a similar left atrial to left ventricular ratio after 24 months of exercise training.

                                                So, what's going on here, if you're middle-aged or young, some of us like to think, and you start one of these aggressive training sessions, you do have some changes mechanically in the shaping of your left atrium and left ventricle, but they're concordant, but no electrical remodeling that was observed in this situation. So, how do those elite athletes develop atrial fibrillation in the electrical remodeling? Don't know. It may be they need a longer duration of exercise. Maybe they start at a different time point because these are relatively sedentary individuals, and maybe their training regimen is very different.

                                                So, more research is needed, but it was interesting that these middle-aged folks that start with this little bit more aggressive regimen really didn't develop the electrical remodeling. So, Carolyn, you've got a couple of papers that are sort of tied together.

Dr Carolyn Lam:                Indeed. A couple of papers centered on lipoprotein little A. Now, we know that lipoprotein little A levels predict the risk of myocardial infarction and this has been shown in populations of European ancestry, however there's very little data available in other ethnic groups. And so, this was addressed by Dr Paré from McMaster University and the Interheart Investigators who looked at more than 6000 cases of first myocardial infarction and more than 6800 controls, all from the Interheart study, and were stratified by ethnicity and included African, American, Chinese, European, Latin American, South Asian, and Southeast Asian ancestries.

                                                Lipoprotein little A concentration was measured in each participant, first using an SA that was insensitive to iso-form size and then iso-form size itself was also assessed by Western Blot in a subset of more than 4200 participants. So, what they found was that lipoprotein little A concentration and iso-form size varied markedly among the ethnic groups. Africans had the highest concentrations with the smallest iso-form size whereas Chinese had the lowest concentrations with the largest iso-form size.

                                                Furthermore, higher lipoprotein little A concentrations were associated with an increased risk of myocardial infarction and carried an especially high population burden in South Asians and Latin Americans. And a high concentration above 15 milligrams per deciliter was associated with significantly increased risk of myocardial infarction in all populations except Arabs and Africans. The iso-form size, on the other hand, was inversely associated with lipoprotein little A concentrations and did not significantly contribute to the risk.

Dr Greg Hundley:             So, Carolyn, how do we use this clinically? I mean, do we measure this in folks?

Dr Carolyn Lam:                Yeah. So, there are two take-home messages. I think one is about the monitoring or measuring and it supports a clinical use of the actual lipoprotein A concentration rather than iso-form size as a marker of myocardial infarction in this ethnically diverse population. But this is, other than Africans and Arabs where, remember that cut off did not seem to associate with a risk of MI's in these two ethnicities. The second take-home is that the effects of clinical interventions that reduce lipoprotein A should be investigated especially in South Asians and Latin Americans where the population attributable risk is really high. And that actually brings me to the second study.

                                                So, we've always been looking for intervention that can reduce lipoprotein A and this current paper is really interesting 'cause it talks about insights from the Fourier trial. So, we may finally have a therapy that can reduce it. Dr O'Donoghue from the TIMI study group and Brigham and Women's Hospital in Boston, Massachusetts and colleagues looked at the relationship between lipoprotein A levels, PCSK9 inhibition, and cardiovascular risk in the Fourier trial, which you remember is a randomized trial of Evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease.

                                                So, they found that patients with a higher concentration of lipoprotein little A were at increased risk of coronary events independent of the LDL concentration. And individuals with a higher baseline LP little A concentration tended to have a greater relative and absolute coronary risk reduction with Evolocumab and therefore a lower number needed to treat. It was as low as four T for individuals with a lipoprotein A above the median versus 105 number needed to treat for those at or below a lipoprotein A level below the median.

Dr Greg Hundley:             So should we start checking this in all our patients now, these lipoprotein little A levels?

Dr Carolyn Lam:                Yeah. So, this issue was discussed beautifully in a company editorial by Dr Thanassoulis from McGill University Health Center. And here he mentions that there remains tremendous clinical inertia honestly for the measurement of lipoprotein A in North America and in fact, worldwide. For this to be successful, we really need to be proactively screening our patients with myocardial infarction and stroke and especially those with premature events or a family history. And particular attention will need to be made on screening individuals with recurrent events despite adequate lipid or LDL lowering who frequently may still have high lipoprotein little A. It's encouraging to know that the most recent version of the US Lipid Guidelines has newly recommended LP little A measurements in select individuals as a risk enhancer and so this should further raise awareness of lipoprotein little A as a risk marker.

                                                Finally, the editorialist mentioned that common misconception that we have a lack of therapeutic options to lower high LP little A. Still, we need to remember that these individuals may obtain significant benefit from more aggressive lifestyle modifications. And now we have these results of this trial that suggest that PCSK9 may be one of the few drugs that can lower lipoprotein little A. And so, the editorialist actually ended with targeting therapy for lipoprotein A is around the corner and a test of this hypothesis is really imminent, so we should watch this space.

Dr Greg Hundley:             Yeah, so it sounds like another wonderment of PCSK9 inhibitors.

Dr Carolyn Lam:                Yeah.

Dr Greg Hundley:             Well Carolyn, let me jump in and finish our chat here talking about iron. This particular paper is from Dr Jean-Sébastien Silvestre from Paris, France, and he's looking at the iron regulator Hepcidin. So, we know that iron deficiency is frequent in patients with coronary artery disease and increases morbidity in those with high risk profiles such as those with diabetes and anemia and then conversely, excess iron is also detrimental to cardiac function. We see this with iron overload cardiomyopathies and as a major co-morbidity in patients with genetic hemochromatosis.

                                                So, among the multiple regulators of iron homeostasis is Hepcidin. It plays an instrumental role in fine-tuning systemic iron trafficking by modulating the transfer of dietary, recycled, and stored iron from intracellular compartments to extracellular fluids. Hepcidin is a catatonic peptide hormone. It's produced primarily by hepatocytes, but also, it's produced in macrophages. So, given the role of Hepcidin to locally regulate cardiac function and that inflammation guides cardiac remodeling after acute MI, the investigators hypothesized that inflammatory macrophages may control cardiac repair through a Hepcidin-dependent mechanism. And until now, the role of Hepcidin in some other cardiac diseases challenged by inflammation hasn't really been explored.

Dr Carolyn Lam:                Huh, interesting. So, what did they find?

Dr Greg Hundley:             Great question and let's lead to the main results of this study. The hormone Hepcidin, they found, was produced by a distinct sub-population of inflammatory cardiac macrophages residing in infarcted heart tissue and the deletion of Hepcidin in macrophages improved tissue remodeling and stimulated cardiomyocyte renewal in both, just as our wonderful basic science studies have, in both adult mice with myocardial infarction, neonatal animals with apical resection and also in human subjects. And so, this study provided novel insights into the complex roles of the immune response during cardiac repair following MI and suggests and deleterious role for the macrophage-derived Hepcidin in cardiac repair.

                                                Interesting, Carolyn. Another role for iron in acute MI and more research to come.

Dr Carolyn Lam:                Indeed. Well, thanks Greg. Let's move on to our feature discussion, shall we?

                                                For our feature discussion today, we are talking about the first results from the Get With the Guidelines atrial fibrillation. That is huge, and I have none other than the first author, Dr Jonathan Piccini from Duke Clinical Research Institute, as well as Dr William Lewis from Case Western Reserve University here to discuss these really important results, so listen up. I think to start with it is such an honor to have you with us, Bill. I mean, as Chair of the Get With the Guidelines atrial fibrillation work group, could you give us a background on how did this start? How far has it come?

Dr William Lewis:             The Get With the Guidelines program started in 2000. Greg Fonarow figured out that if we put in place mechanisms to improve adherence, that we could get people on appropriate therapies. In 2012, there was some focus on atrial fibrillation and I had been participating in the program since 2004 and I kept telling them that A-fib was a big, big problem. And in 2012, they said, "Let's do this," so we built this program to try to improve adherence in atrial fibrillation. Get With the Guidelines is a national, hospital-based, quality improvement program that improves adherence to guidelines over time and it has been very successful at doing that.

                                                So, by 2013 we were ready to start enrolling patients and we started getting patients in the database and we're now up to about 162 hospitals nationwide, in the United States, and we've enrolled about 75000 patients in the program. So, it's been very successful from that standpoint.

Dr Carolyn Lam:                Congratulation. And today we're actually going to be talking about that very question you asked. Adherence. How well are we adhering to guideline-directed stroke prevention therapy for atrial fibrillation? Jonathan, wanna share the key results?

Dr Jonathan Piccini:         I think you're getting exactly to the point of what was the rationale for this study and I think most individuals that are familiar with the field and atrial fibrillation and also clinicians across the world who are treating patients with atrial fibrillation know that most large reports, most nationwide studies have shown that adherence for oral anticoagulation to prevent stroke in patients with atrial fibrillation usually ranges in the 50, 60, 70 percent range at best. And there's been some notable publications in the past several years from nationwide registries that have shown rates as low as 50 percent or lower in high-risk patients. So, one of the main goals of the program, as Bill articulated, was to try and improve the use of oral anticoagulation in patients who had a guideline recommendation. So, patients who had a CHA2DS2-VASc score of two and higher with atrial fibrillation.

                                                And so, looking at over 30000 admissions between 2013 and 2017 and the guidelines A-fib program, we saw that just under 60 percent of patients who had known AF at the time of admission were on oral anticoagulation. And not surprisingly, the patients who were on oral anticoagulation had lower rates of stroke during their hospitalization. But the major finding from the program was that in this quality improvement program, the program was able to improve adherence to oral anticoagulation at discharge from 60 percent to admission all the way up to 93.5 percent in the overall cohort. And if you looked at results over time, adherence improved from 80 percent at discharge all the way to 96 percent and those improvements were sustained in follow up as well.

Dr Carolyn Lam:                Could you tell us, what do you think are the key elements that help this improvement? Is it just because there's a program and people know they're being watched? Is it that there was a change? I mean, when you say oral anticoagulants I bet you mean both Warfarin and the newer oral anticoagulants, so how much did that help? What do you think is the key ingredient here?

Dr Jonathan Piccini:         It was several things. Having visited several of these hospitals and spoken with them about the impact of the program, I think you can't emphasize enough that if you don't measure something, you can't really expect to improve it. So, just the fact that hospitals were having systematic data on their atrial fibrillation patients at discharge illustrating who was and who was not getting oral anticoagulation makes a big difference. Between the program itself and the conferences affiliated with the program and teaching sessions affiliated with the program, there's a heavy emphasis on education of the importance of guideline recommended treatments for atrial fibrillation, so that's a second component.

                                                And then there's an iterative relationship between the sites and the American Heart Association where improvements in the rates of oral anticoagulation are recognized and celebrated. And I think it's not any one thing, in my opinion. I think it's all of those things taken together. And again, Bill, who's been with the program since its inception probably has additional thoughts on that as well.

Dr Carolyn Lam:                Bill, did you expect such remarkable results?

Dr William Lewis:             No. I actually didn't expect 96, but in a previous study where we were looking at patients who had had a stroke in the stroke database, we were able to achieve 93 percent adherence. And so, 96 is remarkable and it's the highest number that's ever been seen in any A-fib program. I was going to mention about the idea of what makes the special sauce, if you will, and I think John put forth a number of items. I think, again, celebrating success, those kinds of things, but I think that docs, by their very nature, are very competitive and when you get a data report that says you're doing x percent and somebody else is doing y percent and their percentage is higher, you tend to get motivated to actually do better. And so, we provide these reports in the program to hospitals so that they can measure their success against other institutions.

Dr Carolyn Lam:                That's such a good idea. And, you know, I practice here in Asia and there aren't these very massive programs that are accepted in many places. So, what do you think is the generalizability of something like this?

Dr Jonathan Piccini:         That's such a critical question because a limitation is that these are hospitals that are saying voluntarily, "We want to commit to the program because we think quality care for atrial fibrillation patients is important." And so, you could argue that, well, these results really don't generalize to your run of the mill hospital in different parts of the world. And I think while that's a limitation, it's also a call for what the next steps are. So, having visited many of these hospitals, these are real hospitals of brick and mortar that face many of the same challenges other health systems and hospitals across the world do and I think the key message is that a hospital that implements these types of interventions is very likely to see the same improvement with their patients. And so, I think that's a very important message and a very positive message for patients all over the US and all over the world.

Dr William Lewis:             I agree. I think it's, not turn-key, it's much more generalizable than we had ever expected. So, community hospitals do this. The American Heart Association is using other Get With the Guidelines programs in China. I think that there is a lot that has to do with the support that's provided by the program and the tools that are made available to them to be able to make it so that you can recreate it in a hospital. I agree, it is more difficult in some hospitals than others.

Dr Carolyn Lam:                John, before we end, what are the take-home messages for clinicians listening out there?

Dr Jonathan Piccini:         I'd have two messages. The first message is that this study shows that with some assistance any healthcare system or hospital can achieve optimal adherence to these medications for their patients and thus in so doing achieve a significant benefit for the public health. And the second message I would have, which isn't necessarily specifically related to the paper, but I think it's equally important, that this is just the beginning for the American Heart Association and the Heart Rhythm Society Get With the Guidelines A-fib registry. Though stroke prevention is obviously just one of many different aspects of quality care for atrial fibrillation and so keep an eye out 'cause you'll be seeing a lot of studies coming out about how Get With the Guidelines A-fib is better informing care and treatment for atrial fibrillation across many different therapy domains, including catheter ablation and rate control and other interventions for rhythm control. And again, on behalf of all the co-authors and the American Heart Association, the Heart Rhythm Society sponsors, we really appreciate to have the opportunity to talk about the program.

Dr Carolyn Lam:                Thank you so much for sharing that with us.

                                                Audience, you heard it right here on Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019.


Mar 11, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health, in Richmond, Virginia.

Dr Carolyn Lam:                So Greg, are ARNI's now going to be used for functional, mitral regurgitation and heart failure? Well, we're going to be chatting all about that with our feature paper, coming right up after these summaries.

                                                Greg, you've got a biggie to start with, haven't you?

Dr Greg Hundley:             Oh yes, Carolyn, I'm really excited about this paper. The senior author Wanpen Vongpatanasin from University of Texas Southwestern Medical Center in Dallas and looking at high phosphate diets and their relationship to exercise intolerance. I really felt this was an exceptional study and combining that key that we have, for basic science papers and translation, where we're looking at data from both human and basic science, in both in a single manuscript.

                                                So, this study focuses on inorganic phosphates and they are present in 40-70 percent of the foods, really as a preservative enhancer, in western diets. We see it in colas, meats, dry food mixes, bakery products.

                                                For the human subject component of this study, the investigators examine the relationship between physical inactivity, assessed with ActiGraphs that were worn, and serum phosphate levels. They also obtained MRI measures of cardiac function and participants were recruited from the Dallas Heart Study too.

                                                In animals, they looked at the direct effects of dietary, inorganic phosphate on exercise capacity, oxygen uptake, serum non-esterified fatty acids, and glucose was measured during exercise treadmill tests in mice fed either high inorganic phosphate diets or normal in-organic phosphate diets. And they were on that for 12 weeks.

                                                To determine the direct effect of phosphate on muscle metabolism and expression of genes involved in fatty acid metabolism, additional studies in the differentiated myotubes were conducted after subjecting those cells to media with high or low phosphate conditions.

Dr Carolyn Lam:                So, what did the study show?

Dr Greg Hundley:             In the human part, among 1603 participants, higher serum in-organic phosphate was independently associated with reduced time spent in moderate to vigorous physical activity and increased sedentary time. And interestingly, there was no association between serum phosphate levels and left ventricular ejection fraction or volumes.

                                                In the animal studies, mechanistic insight was obtained. Compared to controlled diets, consumption of high phosphate diet for 12 weeks did not alter body weight or left ventricular function, thereby confirming what we saw in the human subjects, but reduced maximal oxygen uptake, treadmill duration, spontaneous locomotor activity, fat oxidation, fatty acid levels, and led to down-regulations of genes involved in fatty acid synthesis.

                                                So, the take-home on this is that the results of this study demonstrate a detrimental effect of dietary, phosphate excess on skeletal muscle, fatty acid metabolism, and exercise capacity, which is independent of obesity and cardiac contractile function.

                                                And as such, dietary in-organic phosphate may represent a novel and modifiable target to reduce physical inactivity associated with the western diet. I think, Carolyn, we're going to see a large number of epidemiologic studies that are going to really look at this as something we might be able to modify in our diet to help impact some of these sedentary lifestyles and the harmful cardiovascular effects that we find associated with that lifestyle.

Dr Carolyn Lam:                Yikes. Remind me again, so phosphates in colas, meats, dried food mixes, and bakery products and so on, the preservative. Wow, you're right; big paper.

Dr Greg Hundley:             It's amazing. It's in 40-70 percent of the food products here in the United States. So, wow. Something really striking. So Carolyn, how about one of the papers that you liked?

Dr Carolyn Lam:                Moving to related cardio metabolic disease, we know that patients with type 2 diabetes and prevalent atherosclerotic cardiovascular disease, there is a tenfold variation in future cardiovascular risk in these patients. The current paper actually analyzes data from EMPA-REG OUTCOME where the authors, led by David Fitchett from St. Michael's Hospital in Toronto, sought to investigate whether the beneficial effects of Empagliflozin, observed in the EMPA-REG OUTCOME trial, varied across the spectrum of baseline, cardiovascular risk.

                                                What they found was that in patients with type 2 diabetes and atherosclerotic cardiovascular disease, the relative reductions in risk of cardiovascular death, all-cause mortality, 3-point MACE, and heart failure hospitalizations with Empagliflozin versus placebo, were consistent in patients with and without a prior, myocardial infarction, with and without a prior stroke, and across sub-groups by the 10-point TIMI Risk Score for secondary prevention at baseline.

Dr Greg Hundley:             Does this suggest, Carolyn, that we use these inhibitors in all patients with type 2 diabetes?

Dr Carolyn Lam:                Remember the EMPA-REG OUTCOME; all patients had established atherosclerotic cardiovascular disease. This paper really adds to the understanding of the gradient of risk within these patients who had atherosclerotic cardiovascular disease and says Empagliflozin could be beneficial. But remember, there are patients with type 2 diabetes without established, cardiovascular disease and I think there's still equipoise in this primary prevention population.

Dr Greg Hundley:             That was great, Carolyn. Now I'm going to grab another sip of coffee and go onto my next paper.

Dr Carolyn Lam:                Sure, as long as it's not cola. No phosphates.

Dr Greg Hundley:             Right, thank you very much, Carolyn. I'm going to talk about screening for small and medium abdominal aortic aneurysms. This particular study comes from the surveillance of the National Health Service screening program by Dr Earnshaw. Basically, population screening for abdominal, aortic aneurysms has been shown to reduce AAA-related mortality by up to 50%. Most men who screen positive have a AAA below 5.5 centimeters in diameter, and that's really our current referral threshold for treatment. When they have smaller diameter aneurysms they're entered into an ultrasound surveillance program.

                                                In this study, the investigators looked and reviewed those that had small, 3-4.4 centimeter diameter aneurysms or medium ,4.5 up to 5.4 centimeter aneurysms, and they were followed. They were looking at the risk of rupture in these under surveillance.

                                                They had a total of 18,652 men and the risk of rupture overall per annum was 0.03% for men with small, abdominal aortic aneurysms and 0.28% for medium size. That was just below the threshold for the 5-5.4 centimeters, which was 0.4% over time. The risk of abdominal aortic aneurysm surveillance is below .5% per year and that is just below our current referral threshold for surgery, which is 5.5 centimeters.

                                                This is a study that really confirms, Carolyn, that the target mark or diameter that we've selected is appropriate.

Dr Carolyn Lam:                Nice. These just confirm the current guidelines?

Dr Greg Hundley:             Yeah, they do and Gil Upchurch from University of Florida, a surgeon, had a very nice editorial. The point he wants to make is yep, diameter of 5.5 is the threshold, but a couple key points. As patients are coming in for these visits, we need to continue to emphasize to them other factors related to growth of abdominal aortic aneurysms and their rupture. So, tobacco cessation, treatment of your lipids, management of your hypertension.

                                                The other point that he makes, is we really don't need to be operating on those individuals with an abdominal aortic aneurysm diameter of less than 5.5 centimeters. He makes an argument here that's in some countries with fee-for-service reimbursement, up to 30% of AAA repairs are for aneurysms less than this diameter of 5.5 centimeters. This over utilization of resources can add considerable costs to the healthcare system for managing this condition and is unlikely to increase the overall survival of these patients.

                                                A nice study confirming that what we're doing, really in terms of size and diameter, is correct, but also emphasizing this patient population often has a lot of other cardiovascular co-morbidities that we need to aggressively manage. How about your next paper?

Dr Carolyn Lam:                From one very clinically, applicable paper to another. This one answers the question, what's the optimal duration of emergency department and post-emergency department rhythm monitoring among patients with syncope. And the authors, led by Dr Thiruganasambandamoorthy and his colleagues from the Ottawa Hospital Research Institute, prospectively studied adults presenting within 24 hours of syncope at six emergency departments. They collected baseline characteristics, the time of syncope, the time of emergency department arrival, and the Canadian Syncope Risk Score, risk category. They followed subjects for 30 days and adjudicated the primary outcome, which was serious arrhythmic conditions and that includes arrhythmias or interventions for arrhythmias and unexplained death.

                                                Their results showed that the overall arrhythmia risk, and the risk after two hours of emergency department arrival from Canadian Syncope Risk Score, low-risk patients, was indeed very low. Similarly, the overall risk and after six hours of emergency department arrival for medium and high-risk patients was moderate and high, respectively. No low-risk patients suffered ventricular arrhythmia or unexplained death and most of the arrhythmias among the non-low-risk patients occurred within 15 days of the index syncope.

Dr Greg Hundley:             Carolyn, what's the take home message here?

Dr Carolyn Lam:                The results really support brief monitoring in the emergency department for two hours for Canadian Syncope Risk Score low-risk patients, and six hours for medium and high risk patients followed by selective admissions and the results also support a 15-day outpatient monitoring for medium-risk patients at a selected threshold and for all high-risk patients. So very practical advice.

Dr Greg Hundley:             Very good. Until next week, I'm going to watch out for phosphates.

Dr Carolyn Lam:                Indeed, and let's go on now to our featured discussion.

                                                For today's featured paper, we are discussing the results of the PRIME Study and that is Angiotensin Receptor Neprilysin Inhibitor, or ARNIs, for functional mitral regurgitation. A terribly interesting study. So pleased to have with us an author Dr Sung-Hee Shin from Inha University Medical center in Incheon, Korea as well as our associate editor Dr Victoria Delgado from University of Leiden in the Netherlands.

                                                Sung-Hee, what an interesting study. ARNI or Entresto for functional mitral regurgitation. Could you tell us what inspired this study and what did you find?

Dr Sung-Hee Shin:            Our study was the designed to tell if ARNI or functional mitral regurgitation because secondary functional mitral regurgitation was developed as a result of a reduced function. Guideline-directed medical therapy for heart failure would be a mainstay for a therapy.

                                                But despite use of the traditional drugs such as BETA blocker, ACE inhibitor or angiotensin receptor blockers, you know that the functional mitral regurgitation may be common and significant in the person having this functional mitral regurgitation would be related to increased morbidity and mortality.

                                                So, that trial showed that trans-catheter mitral valve repair effectively reduced the function mitral patient and resulted in lower rate of heart related mortality among patients with heart failure and function mitral regurgitation.

                                                In our blind trial, we also tried to tell whether an ARNI is more effective in improving function mitral regurgitation and randomly assigned 118 patients with heart failure and chronic secondary function mitral regurgitation lasting more than six months despite medical therapy and ejection fraction between 25% and 50% to receive either sacubitril/valsartan or valsartan in addition to standard medical therapy for heart failure.

                                                What happened with that change of mitral regurgitation after 12 months which was assessed by means of transthoracic area ways echo. What we observed was that transthoracic area as well as the volume of mitral regurgitation saw a decrease much more effective in the sacubitril/valsartan group than valsartan group.

                                                We also looked at the various other measures of the left ventricle remodeling and showed that the valsartan group had smaller left ventricle volume at 12 months and had a greater reduction of end-diastolic volume index.

                                                Also, among the completers ARNI, for the reduced left ventricle volume and the yearly time than the control group. So, what we think is that these factors might contribute to greater reduction of function mitral regurgitation in patients in the sacubitril/valsartan group.

                                                But our study was a mechanism study, but it was not designed to see outcomes. So further research and data would be necessary to check is this transthoracic echo end point can translate into better outcome in this population.

Dr Carolyn Lam:                Sung-Hee, this is just so interesting to have hypothesized this about functional mitral regurgitation. And not only that, I mean, to my mind, this is the largest echo-based studies of patients before and after Entresto that I can think of. It's nice to know, on top of knowing in paradigm that we can improve outcomes in heart failure reduced ejection fraction, that we now can look at the heart and see what happens in so many dimensions.

                                                So, congratulations.

                                                Victoria, were you surprised by these results? And do you agree with the mechanisms that Sung-Hee suggested?

Dr Victoria Delgado:        I think that this study is very important because in the field of functional mitral regurgitation, there is still a lack of consensus on how to treat these patients, which are very challenging.

                                                If the patient needs revascularization they will be referred for certain. But it still should be CBR mitral regurgitation and moderate and mile mitral regurgitation are not considered.

                                                I think that we discuss often which is the optimal medical therapy or the guidelines based medical therapy but it's not really consensus because the studies before have not been like this one. That large in order to answer a specifically that question.

                                                I think that this article brings an important message and brings more evidence to our field that there is not that much data. So, I think it's very important for that research, in particularly after the research of the co-op and the mitral trial where it seems that the selection of patients is very important in order to identify the patients that will really benefit from those therapies.

Dr Carolyn Lam:                That's such a good point. Going to that selection of patients, Sung-He, you mentioned very carefully the ejection fractions that you allowed up to 50% in these patients. Could you explain how you reasoned the selection of this patient cohort?

Dr Sung-Hee Shin:            The reason why we chose the patients we did, the range of ejection fraction condition, was that we thought the reversibility of the left ventricle mortality and function mitral regurgitation might be more pronounced in these patients.

                                                When we considered the fraction condition in mitral regurgitation with ejection fraction used under [inaudible 00:18:17] LV dysfunction, our inclusive criteria of ejection fraction between 25 to 50% might correspond to ejection fraction of 20 to 40% in patients with mitral regurgitation.

                                                We concluded that if a patient had ejection fraction less than 25% because the reversibility of mortality and function mitral regurgitation might be smaller when all the LV dilation is too extreme and advanced heart failure is already established.

                                                So, I just thing how it can be provided to the patient who have functional mitral regurgitation associated with too extreme LV dilation and LV ejection fraction too.

Dr Victoria Delgado:        I think, Carolyn, it's a very good point what she explained because we are used to select patients based on ejection fraction, in particularly patients with functional mitral regurgitation, ejection fraction is rather misleading because actually it's just a change of volume in the ventricles emptying in a low pressure chamber which is the left atrium.

                                                The moment that you correct that in mitral regurgitation sometimes then you face, or you see, the true ejection fraction of that ventricle. And if we wait too long, we may end up with ventricles that they don't have any more resource in order to improve ejection fraction after repair of the mitral valve.

                                                So, I think that this study is important to also realize that concept. That ejection fraction in patients with functional mitral regurgitation may not be the most accurate parameter to assess the function of that ventricle.

Dr Carolyn Lam:                Yeah. Exactly. And I thought that was a very clever part of the design. I'm glad you explained it and also so glad, Victoria, you invited the editorial by Dr Mullens, who also commented on that. So, just for the audience to understand that ejection fraction up to 50% was included and ejection fraction less than 25% was excluded.

                                                So also, again, very consistent to your prior point, Victoria.

                                                Could I ask you, I think Dr Mullens also spent quite some time talking about the potential mechanisms. What's your take of this Victoria? ARNI for functional regurgitation. How come?

Dr Victoria Delgado:        For me, I'm much more from the side of the imaging point of view. When we have patients with functional mitral regurgitation I always try to see which is the capability that that ventricle has to recover.

                                                Actually, first is always medical therapy, but we know that the [inaudible 00:20:59] only, for example, we just reduced the mitral regurgitation, but they don't really improve the function of that ventricle, while if you reduce the loading conditions of the ventricle in terms of blood pressure as well and favoring remodeling of the left ventricle, you can improve the condition of the mitral valve and reduce the mitral regurgitation.

                                                How valsartan plus sacubitril works differently than valsartan alone that I don't think that I have enough knowledge to explain why but it could be that in a way there is more effective with sacubitril on top of valsartan can improve the loading conditions of the ventricle and improve the, or facilitate, the reversing of morbidity of that ventricle, reducing the mitral regurgitation and that, by itself, could also lead to reversing morbidity.

                                                Like a little bit cardiac resynchronization we'd do, for example, in patients with an ejection fraction below 35% and based on the EEG you have the synchronous fraction of the papillary muscle or the walls of the ventricle which could lead to the mitral regurgitation at the moment that you resynchronize that mitral regurgitation can produce, you reduce part of the volume of the load of the ventricle and that can favor that reversing morbidity.

                                                So, I think that this study raises a lot of questions and I think that further research is needed in order to confirm or to know more how these treatments work.

Dr Carolyn Lam:                Goodness, that was so beautifully explained and in fact, many clues from Sung-Hee's study and the reversal of left ventricle end diastolic volume index greater with those treated with ARNI, the LA size and so on.

                                                But maybe I should ask you, Sung-Hee, in line with what Victoria said, what are the next steps? Do you already know what are the next studies that you're going to be looking at in PRIME?

Dr Sung-Hee Shin:            We're considering mark of monitoring such as NT pro-BNP or using auto imaging models such as echo and cardiac MRI to look at the change of mitral valve regurgitation in more detail.

                                                This kind of study might be very helpful in understanding [inaudible 00:23:15] ARNI in functional mitral patient.

Dr Carolyn Lam:                Yes, that's clever, too. And Victoria, before we end could you maybe give us some take home messages?

Dr Victoria Delgado:        I think that the take home message from this study is that when we have patients with functional mitral regurgitation, we need to think what we can offer to them. Not consider mitral regurgitation just as a base standard. That it's going to respond only to diuretics. No. We need to do something on that left ventricle to help it to improve the function and to avoid the progress to more reduced function.

                                                It's very important to understand the mechanism of the mitral regurgitation and to use the guidelines based medical therapy trying to go step by step in order to optimize the medication of that patient and later on, see all the potential treatments that are available right now such as cardiac synchronization therapy, which we should not forget, and then surgery if the patient needs catheterization and if the patient needs the benefit from mitral valve plasty or eventually, for example, trans catheter mitral valve therapies.

                                                But we should avoid that the patient goes further down into heart failure with very dilated ventricles and very poor function because then probably we may face a point of no return.

Dr Carolyn Lam:                Thank you so much, Victoria. Both you and Sung-Hee mentioned this is a mechanistic study. So many insights. But it's not saying that everybody with functional mitral regurgitation has to be treated this way now. It's calling for more work and it's certainly very, very important study.

                                                Thank you listeners, for listening today as well. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association, 2019.


Mar 4, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm doctor Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam:                Have you heard of long non-coding RNAs? Well, they are definitely the hot topic and our feature paper today discusses the first demonstration of the importance of a linked RNA in atherosclerotic lesions not just in mice but also in humans. You have to listen on, it's coming up right after our copy chat.

                                                Greg, what are your picks upon the journal this week?

Dr Greg Hundley:             The first paper I wanted to discuss comes from France, and it's basically looking at ambulance density and outcomes after out of hospital cardiac arrest from Florence Dumas from Hôpital Cochin in Paris, France. This manuscript addresses the geographic disparities and survivorship of out of hospital cardiac arrest and the relevance of the patients characteristics versus whether ambulances are equipped with those trained in basic or advanced cardiac life support. So, what they did they had nineteen neighborhoods in Paris, and the number of BLS trained versus ALS ambulances was collected, and the authors assessed that respective associations of socio-economic characteristics of the patient population and the ambulance resources of these neighborhoods and compared those with successful return of spontaneous circulation or risk as the primary end point and then survival of out of hospital discharge as the second end-point.

                                                So, they had 80754 non-traumatic out of hospital cardiac arrests across the Paris area. 42% at ROSK 9% head survival at discharge, and after accounting for the patient's socio-economic status, greater than one and a half advanced cardiac life support ambulances per neighborhood and greater than 4 basic cardiac support basic life support units per neighborhood were associated with ROSK, but only the 1.5 ALS units per neighborhood were associated with survival.

Dr Carolyn Lam:                Oh, interesting Greg. So does this we need more advanced life support units?

Dr Greg Hundley:             So, Paul Dorian from St. Micheal's Hospital in Toronto, Canada wrote an excellent editorial, and one point he made related to these ALS units is that it was really a very small 1.3 adjusted odd ratio for survival to hospital discharge, and it's important to note that although the increase in survival was associated with more ALS units, there were many other variables that were likely important and not recorded in this study. For example, including the time to collapse, to calling for EMS, the time from the call to the deployment of that ALS unit to the scene, the time from collapse to the defibrillation, the total "no flow time" sort of in quotation, which is the total duration of collapse until CPR is started and so I think one of the points in this observational study is there could've been many differences that would've associated with the findings, interesting findings how about one of the papers that you liked?

Dr Carolyn Lam:                So, the paper that I selected here is a first time that a targeted anti-inflammatory therapy has been shown to reduce hospitalization for heart failure and at-risk patients. So, you know that some clinical inflammation associates with an increased risk of heart failure and associates with the worst prognosis in patients with heart failure, and yet, so far, treatments specifically directed at reducing inflammation in patients with heart failure have not been shown to improve clinical outcomes. That's why today's paper is so special and it's from Dr Everett and colleagues from Brigham and Women's Hospital Harvard Medical School in Boston, and basically, the authors looked at CANTOS and tested the hypothesis that the interleukin -1β inhibitor can canakinumab would prevent heart failure hospitalizations and the composite of heart failure hospitalizations on heart failure related mortality in the CANTOS trial.

                                                Now, remember the CANTOS trial randomized more than 10 000 patients with a prior myocardial infarction and with high sensitivity C-reactive proteins at least two or greater, and they were randomized to canakinumab 50, 150, and 300 mg or placebos. Now, before randomization, these participated were asked if they had a history of heart failure and 22% said yes so the current paper actually looks at this stratification of patients who said they had heart failure, and during a meeting follow-up of 3.7 years, 385 patients had a new heart failure hospitalization event. Now, here's the key: the authors found a dose dependent reduction in the risk of hospitalization for heart failure as well as the composite of hospitalization for heart failure or heart failure related mortality among those allocated to Canakinumab.

Dr Greg Hundley:             So, how does this differ from prior attempts targeting inflammation and heart failure? I mean is this ready for prime time thing?

Dr Carolyn Lam:                So, we have to bear a few things in mind here you know. CANTOS was different from a previously published randomized controlled trials, which were basically neutral and that was like of infliximab and etanercept so the drug in CANTOS targets interleukin-1 beta whereas the prior ones targeted the TNF-alpha, and also very importantly, CANTOS did not specifically enroll patients with an established heart failure only. CANTOS patients had to have a history of myocardial infarction and there was no data on their ejection fraction or natriuretic peptides at the time of randomization nor at the time of heart failure hospitalization. So, by the way, we don't know whether there's a differentially effect on hep pef versus hep-ref. So, again difference from the heart failure focused trial previously that used an anti-inflammatory agents.

                                                The other thing: although there was a dose dependent reduction in the risk of hospitalization for heart failure no single dose of Canakinumab compared to the placebo had a statistically significant reduction in the risk of heart failure hospitalization. Only the trend was statistically significant so all in all, this was a pre-specified aim of CANTOS to look at heart failure, the data presented here should really be considered hypothesis generally, but really quite promising. And what about you Greg? What's your other paper?

Dr Greg Hundley:             We're going to switch gears a little bit and shift over to the Jackson heart study. The large longitudinal cohort from Jackson, Mississippi that's recruited to follow for cardiovascular events, and it's an area of the United States where we have some of the highest cardiovascular disease event rates really across the nation so this study focuses on sleep apnea and is the Jackson's heart sleep study. It's a sub-study of this larger Jackson's heart study that involves 913 patients, and the investigators were looking at the association between sleep apnea and blood pressure control among those of a Black race. So, Dayna Johnson of Emerald University is the first author on the paper. What's nice about this sub-study, this sleep sub-study is that there are objective measures using an in-home type III sleep apnea study. They had clinical blood pressure measurements and then anthropometry as opposed to questionnaire derived data that may have been performed in the larger cohort.

                                                And the study determined these associations between moderate or severe obstructed sleep apnea with controlled, uncontrolled and resistant hypertension. So the analytic sample of the individuals with hypertension was 664, and they had an average age of about 64 years. They were predominately women 69%, obese 58%, College-educated at 51%. Among the sample, about a quarter had obstructive sleep apnea, which was untreated and unrecognized in 94% of the participants. That's an interesting point, just right there.

                                                Overall, 48% of the participants had uncontrolled hypertension and 14% had resistant hypertension. So, multiple medications, often four and still unable to control the blood pressure. So the findings participants with moderate or severe obstructive sleep apnea had 2 times higher odds' ratio of resistant hypertension.

Dr Carolyn Lam:                Whoa Greg, that's a huge risk and very important finding. I mean if sleep apnea could be modifiable risk factor perhaps for very important issue among African Americans resistant hypertension. What do you think about clinical implication?

Dr Greg Hundley:             One of the things to be considering now is what are we going to do about that cause as you know CPAP is really the preferred treatment for resistant hypertension, but it's efficacy hasn't been really that well studied in African Americans and CPAP tolerance is low so this study highlights for us potentially new mechanisms for resistant hypertension, but we still got to be thinking about what would be our next therapeutic intervention for this particular patient population. And what about your next study?

Dr Carolyn Lam:                The next study is about Impella support for acute myocardial infarction complicated by cardiogenic shock. Now, we use it all the time, but did you know that to date, there is no large randomized study actually comparing the use of Impella to other contemporary cardiac support devices and medical treatment in stem related cardiogenic shock. So, Dirk Westermann and colleagues from University Heart Center in Hamburg tried to address this knowledge gap by using a multi-national database of patients with acute myocardial infarction complicated by cardiogenic shock and treated with the Impella device and compared in a matched fashion their outcomes to patients from the IABP Shock II trial, which you would recall is a randomized trial which demonstrated similar outcomes between IABP and medical treatment in myocardial infarction in cardiogenic shock.

                                                So, they looked at 237 matched-pairs so remember this was pairs from this registry of acute myocardial infarction with shock and using an Impella matched with IABP shock patients and what they found was that there was no significant difference in 30-day all-cause mortality. Instead, severe or life-threatening bleeding and peripheral vascular complications occurred significantly more often in the Impella group when they limited the analysis to the IABP treated group as controlled versus Impella that was still the same results.

Dr Greg Hundley:             So, Carolyn, there are trying to match patient population from two different studies and they may have confounders in there that we can't account for so why we not able to produce large randomized trials of Impella devices in studies of patients with acute myocardial infarction?

Dr Carolyn Lam:                The rate of acute myocardial infarction complicated by cardiogenic shock has really declined in the past decade. Furthermore, clinical signs of shock really appear in half to three quarter of cases several hours after hospital admission so making randomization before primary PCI of the AMI really very difficult. And finally, many interventional cardiologists believe that there's equipoise that has already been reached on the use of these cardiac assistive devices in patients with cardiogenic shock and this was from registry data, and so if interventionists believe this then they also believe its unethical to randomize these patients in trials. Still, I think that current study to date really causes us to pause and to acknowledge that we really need to evaluate this better and prospective randomize trials of Impella treatment are warranted.

                                                Let's now go to our featured discussion, shall we?

                                                For our featured paper discussion today, we are talking about a basic science paper, and we have none other than the best of the best Dr Charles Lowenstein, our associate editor from University of Rochester Medical Center joining us as well as the first author of a really fantastic paper on long non-coding RNA in a specific type involved in arthrosclerosis and plaque formation. This first author is Sebastian Creamer from Goethe University in Frankfurt.

                                                Charlie, could you start us off by telling us what is a long non-coding RNA? We've heard a lot about this in recent times. What's the big deal about them?

Dr Charlie Lowenstein:  So in the last decade, scientists have learned that your genome, your DNA inside you, every cell codes about 20,000 genes and those 20000 genes encode proteins, but there are another 20000 genes that encode RNA only, RNA that never turns into protein that leaves RNA are an amazing diversity of different kinds of RNA really short micro RNA, longer RNA that defends the host from viruses and long non-coding RNA that have a huge variety of effects regulating genes, turning genes on and off in proliferation and cell growth and inflammation so long non-coding RNAs are increasingly appreciated as an important part of the genome.

Dr Carolyn Lam:                What a perfect set up with that. Sebastian, could you tell us about your study please?

Dr Sebastian Creamer:   Our laboratory was interested in non-coding RNAs for some time and previously, we've found that this specific non-coding RNA MALAT1 regulates endothelial cell functions and because we were interested in analyzing this particular RNA in the disease setting it shows at a risk growth so it's because also we saw that when it's regulated by flow and end of previous cells and so we cross MALAT1 deficient mice to Apoe mice and set them on a high fat diet and analyzed and subtracted in both groups. And while we only saw a modest increase in plaque size in MALAT1 deficient mice, we could appreciate a higher amount of inflammatory cells in plaque of aortic roots in those mice, which let us hypothesize that inflammatory responses was appreciated and is a very important contributor to arthrosclerosis in MALAT1 deficient mice. And to test this, we decided to transplant MALAT1 deficient bone marrow in Apoe knockout mice with MALAT1 and interestingly, we saw that now plaques were significantly larger than compared to mice who received controlled MALAT1 white cell bone marrow, and also inflammatory cells were more prominent in those mice.

Dr Greg Hundley:             Sebastian, this is Greg Hundley. You also did some experiments in human subjects. Could you tell us a little bit about those too?

Dr Sebastian Creamer:   So, because we saw this interesting phenotype, we were very much interested if this also translates into the human setting. Luckily, we got a really nice collaboration receding in Stockholm access to high impact material from patients with arthrosclerosis and what we could see here that MALAT1 expression was down regulated in patients with arthrosclerosis and it also correlated with disease progression. Moreover, in another collaboration, we consolidated those findings with experiments, which showed that human cells have less MALAT1 compared to normal vasculature.

Dr Carolyn Lam:                It all sounds so sensible and logical and so on but let me just frame this for our audience. This is actually the first time that it's been demonstrated. The importance of long non-coding RNA in arthrosclerosis. Charlie, could you tell us a little bit about how significant these findings are?

Dr Charlie Lowenstein:  Sure. So, I'm really interested in the final figure in this paper because there are lots of interesting human data, showing that MALAT1 expressed more in normal than atherosclerotic arteries and also that MALAT1 expression is correlated with fewer major adverse cardiac events so the whole story is a very nice story saying that the expression of this anti-inflammatory link RNA not only has an effect in mice but it can be extended into the human field of arthrosclerosis and inflammation. It's particularly important because there's a lot of attention in the last decade that inflammation drives atherosclerosis, and in light of CANTO trial showing that anti-inflammatory therapy can actually decrease atherosclerosis and decrease cardiovascular events in humans. This is important cause it shows another pathway, which regulates inflammation. Not only in mice, but also in humans, and in the human atherosclerotic setting.

Dr Carolyn Lam:                Amazing. Sebastian, what are the next steps? How far are we away from clinical applications here? What are the next steps to get it in the clinic?

Dr Sebastian Creamer:   So, the very difficult thing is that MALAT1 is down-regulated in atherosclerosis and also therapeutic approaches is very difficult in such a complicated disease like atherosclerosis to actually increase the expression of such a long non-coding RNA. What we are currently working on is to decipher more than the clinical malade-1 is actually influencing atherosclerosis so we have lots of hints or some evidence that adhesion of inflammatory substances altered and the bone marrow activity, which is very important in atherosclerosis and also in other cardiovascular diseases like myocardial infarction is altered so we think that malade-1 might actually influence the resolution of inflammation and when it's lacking, inflammation can be resolved. So, we are now putting somewhat mechanistic studies and finally, we hope that we can find another downstream target like micron AB, we talked about in our paper, which we can directly target in the future.

Dr Charlie Lowenstein:  So, I agree with Sebastian. I think MALAT1 is going to turn out as one of those major link RNAs that controls inflammation possibly controlling the way in which the bone marrow reacts to systemic inflammation and produces cells and then have those cells home in on various inflammatory targets so I think this is an important observation that's going to have not only implications for atherosclerosis but also for other inflammatory diseases.

Dr Carolyn Lam:                Excellent. If you don't mind, I would love to switch tracks a little bit. We find it that very special and we can discuss basic papers with people who can explain it so well because we understand that there's so much work that goes in to these papers and so on. Charlie, could you take behind the scenes a little bit with the editors and tell us what is it that circulation looks for in basic science papers that makes us published?

Dr Charlie Lowenstein:  We get a lot of really good basic science papers, and it's a challenge for the associate editors, and the editors to figure out what's right for circulation and let me use this manuscript as a great example because this is a terrific paper. So, this paper is divided into four sections, and these sections are what we look for in any basic science paper that's going to reach an audience of clinicians who are interested in pathways and therapeutics so this paper has a section on mice. There's a gene in mice that's important then the paper delves into cells what's happening with cells and then a little bit of mechanisms and genes and proteins and then this paper takes the observation back into humans and shows that there's some human and clinical relevance so this is not only a great paper, but it is a classic example of what the associate editors are looking for in a basic science paper that's targeted towards clinicians.

Dr Charlie Lowenstein:  There's some in vivo work with mice, there's some mechanistic work then they take it back to the humans. Plus, of course like anything that comes into circulation, it's going to be novel, interesting and has some important relevance to human cardiovascular disease. This paper that we're discussing is a great example of a paper that we love to publish in a circulation and it's a real tribute to Dr Dimmeler and her team and to Sebastian that they put this paper together and submitted it to us.

Dr Carolyn Lam:                Thank you audience for joining Greg and I today. You've been listening to circulation on the run. Don't forget to tune in again next week.


Feb 25, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, associate editor and director of the Pauley Heart Center from VCU Health in Richmond, Virginia.

Dr Carolyn Lam:                So, Greg, are we any closer to the holy grail of safe ED discharge for acute heart failure based on a risk score? Well, we're going to be discussing that coming right up after Greg and I share about the papers that we'd like to discuss today. Lovely issue, isn't it?

Dr Greg Hundley:             Yup, and time to get your coffee and bring it up. My first paper, Carolyn, is from Michael Chu from London Health Sciences Center, and is really investigating the surgical management of thoracic aortic disease, and looking at the impact of gender or sex related differences. Sex related differences have not been thoroughly studied. This group looked at a total of 1653 patients, 30% were women, who underwent thoracic aortic surgery with hypothermic circulatory arrest between the years of 2002 and 2017 across Canada in 10 institutions.

                                                Well, women underwent less aortic root reconstruction, including aortic root replacement, Ross procedures, or valve sparing root operations. But, even with less invasive, the women experienced higher rates of mortality, 11% versus 7%, stroke, and that composite of the thoracic surgeons' adverse events. On multi variable analysis, female sex or women was an independent predictor of overall mortality, stroke, and those comorbidities.

Dr Carolyn Lam:                Greg, you know how much I love these papers, so I'm going to repeat that. You're saying the women received less ominous procedures and yet had worse outcomes, and this was independent of the clinical covariances, right?

Dr Greg Hundley:             Absolutely. Putting all this together, women underwent thoracic aortic surgery a little bit older, and with larger index aortic aneurysm size than men. Intraoperatively, women undergo fewer concomitant procedures, such as the aortic root repairs, and things that you just mentioned. But nevertheless, women experience significantly worse outcomes identified as an independent predictor of mortality, stroke, and that composite endpoint for mortality, morbidity, after multi variable analysis.

                                                What should we think about this? Well, sex specific considerations are important when considering thoracic aortic surgery and future research should focus on the development of a personalized approach to thoracic aortic surgery with respect to gender. For example, utilization of maybe lower size thresholds for women for aortic aneurysms should be considered, and for earlier interventions, and improved outcomes.

                                                Carolyn, tell me about one of your papers.

Dr Carolyn Lam:                All right, so I chose a paper looking at the stroke outcomes in the COMPASS trial. Now, let's remind everybody that the COMPASS trial, where patients with stable coronary artery disease or peripheral artery disease, and randomly assigned to receive aspirin 100 milligrams daily, rivaroxaban five milligrams twice daily, or the combination of rivaroxaban 2.5 milligrams twice daily plus aspirin. Patients requiring anticoagulation with a stroke within a month had a previous lacunar stroke or intracerebral hemorrhage were excluded.

                                                Now, in the current paper, and this is from Dr Sharma from Population Health Research Institute, and their colleagues, basically they looked at a detailed analysis of the stroke by type, predictors, and anti-thrombotic effects in the key subgroups. They found that the combination of low dose rivaroxaban and aspirin prevented stroke and disabling stroke better than aspirin in patients without atrial fibrillation and with stable vascular disease, and without an increasing risk of hemorrhagic stroke; which is really important. This effect was consistent across subgroups of baseline risk, and particularly marked in those with a history of previous stroke.

Dr Greg Hundley:             Carolyn, what about that rivaroxaban five milligrams twice daily alone?

Dr Carolyn Lam:                There was no significant difference in the occurrence of stroke in the rivaroxaban alone group compared with aspirin. But all of this simply says perhaps low dose rivaroxaban and aspirin may be a really important new anti-thrombotic option for primary and secondary stroke prevention in patients with clinical stable atherosclerosis.

Dr Greg Hundley:             Very interesting. I'm going to follow your lead and go into another sort of anticoagulant-related topic on iliofemoral deep vein thrombosis. This paper is by Suresh Vedantham from the Washington University of St. Louis.

                                                Let's talk about just what is the definition? This is a DVT that involves the iliac and/or the common femoral vein with or without involvement of additional veins. It basically obstructs the outflow of the veins. These patients are phenotypically distinct from patients with cath or femoral popliteal DVT because that totally obstructs flow, and they have more frequent recurrence of venous thromboembolic events, and more frequent post-thrombotic syndrome. Well, that's a horrible condition because of that obstruction, it leads to calf muscle dysfunction, edema, subcutaneous fibrosis, tissue hypoxia, and ulceration.

Dr Carolyn Lam:                Great background. What did this study show?

Dr Greg Hundley:             This is a sub-study of the ATTRACT trial. The ATTRACT trial basically is looking at anticoagulation plus perhaps mechanical intervention, or direct catheter directed thrombolysis therapy versus just anticoagulation alone. This sub-study is 391 patients with acute DVT involving just the iliac or the common femoral veins, and following these individuals for 24 months to compare short and long-term outcomes.

                                                What did the study show? Well, this interventional group did have a reduction in leg pain and swelling, and improvement in quality of life related to that lower extremity. But, no overall difference in overall quality of life, and very importantly, no difference in the occurrence of this post thrombotic syndrome.

Dr Carolyn Lam:                That's kind of disappointing. I understand that the ATTRACT study is not the first to look at this, though. That was in an editorial discussing this. Could you tell us about that?

Dr Greg Hundley:             Yeah, Carolyn. Jay Giri from University of Pennsylvania just had an incredible editorial. I think if you have an opportunity, listeners, to take a look at that, I highly recommend it. He reminded us of the CaVenT trial, which is basically performed as an open label randomized control trial of 209 patients across 20 hospitals in Norway.

                                                What was different in the CaVenT trial is that at 24 months of follow up, the intervention with thrombolysis and systemic anticoagulation improved iliofemoral patency. It reduced the incidence of this post thrombotic syndrome. In ATTRACT, in this sub-study, it was intravenous thrombolysis, systemic anticoagulation, and mechanical intervention on the vein versus in the other study from Norway, CaVenT, just the inter vein thrombolysis and the systemic anticoagulation.

                                                What Dr Giri points out is that maybe something related to intervention in that vein when you're stripping out thrombus, et cetera, are we damaging the veins in the vessel that prevents reflux, et cetera?

                                                I think really moving forward, you're going to have to personalize this decision in individual patients until we have more data on this subject.

Dr Carolyn Lam:                Great learning. I learned a lot from this next paper, too, because I actually chose a basic science paper. This is a paper that uncovers a new fine tuning factor that modulates myocardial infarction induced inflammation. That is a small GTPase called RhoE.

                                                In this study, Drs Chang from Texas A&M University College of Medicine, and Song from Fuwai Hospital in Beijing used three genetic mouse model lines. Those are the global knockout, the cardiomyocyte specific RhoE heterozygous mouse, and the cardiomyocyte specific RhoE over expression mouse. With this combination, they showed that RhoE deficiency causes excessive inflammatory response in infarct animal heart, resulting in enlarged heart, decreased contractility, and increased mortality. The mechanism is that RhoE binds to P65 and P50, which impedes their dimerization and blocks these two proteins from nuclear translocation. Now, over expression of cardiac RhoE inhibits NF-κB, restrains post MI inflammation, and improves cardiac function and survival.

                                                Importantly as you always say, Greg, there is human data. They found that the expression of RhoE was elevated in the infarct patient heart and that patients with a higher expression of RhoE exhibited a better prognosis and better cardiac function recovery.

Dr Greg Hundley:             Carolyn, tell me a little bit about the clinical significance of this.

Dr Carolyn Lam:                You just wanted to ask me a tough question. I can see it on your face. Basically, I think this is really exciting because RhoE may serve as a new potential biomarker for the assessment of myocardial infarction in patients, and manipulation of RhoE could be a potential therapeutic approach for MI. There.

Dr Greg Hundley:             Very good.

Dr Carolyn Lam:                That's all the time we have for our little discussion here. Now, let's go onto the feature paper. ...

                                                Over 80% of emergency department patients with acute heart failure are admitted to the hospital. Now, contrast this with the fact that over 80% of all emergency department visits result in discharge. So, why is that many other emergency department based cardiovascular disease processes like for acute coronary syndrome have evolved from high rates of admission to timely and safe discharge whereas decision making in acute heart failure has not experienced a similar evolution. Do we need perhaps a better acute heart failure prognostic score that's validated?

                                                Well, guess what? We're going to talk about this right now in our feature discussion, and a beautiful feature paper that we're so proud to have the corresponding author, Dr Douglas Lee from University of Toronto right here to discuss; along with the managing editor, Dr Justin Ezekowitz, who's associate editor from University of Alberta, and the editorialist, Dr Sean Collins from Vanderbilt University Medical Center. Welcome everyone, and Doug, please, could you just start by telling us about this great paper?

Dr Douglas Lee:                 We validated, and it's a tool, decision making tool, for acute heart failure patients in the emergency department. We, in this study, wanted to prospectively validate a decision making prognostic tool called the Emergency Heart Failure Mortality Risk Grade, or EHFMRG for short, to see how well it performed in the real world busy emergency department hospital setting.

                                                We studied just under 2,000 patients who came to emergency departments at multiple centers, and asked physicians to rate their prognostic estimation of what's going to happen to that patient in the next seven days. We compared that with the EHFMRG model, which predicts outcomes of seven days and 30 days. We were very careful to ask physicians to provide their prognostic estimates. This is their intuitive guesstimation of the risk of the patient before calculating the score because we didn't want the physicians to be influenced by the score.

                                                What we found was that when we looked at how well physicians' estimates performed, they actually performed quite well. The c-statistic for physician estimated risk was around .7, which is a reasonable discrimination. However, the physicians' estimates were not as good as the EHFMRG risk score, which had a C greater than .8. The mathematical model seemed to do better in terms of predicting what's going to happen to the patient than physicians' estimates.

                                                Interestingly, when we combined the physicians' estimates with the EHFMRG risk score, the c-statistic improved by another 1%, so there's some additive value of having both factors combined.

                                                The other interesting finding was that patients in the lowest risk groups had 0% mortality at seven days, and 0% mortality at 30 days. We may be able to identify, using the score, patients who have a very low risk of events in that seven to 30 day period after emergency department presentation.

Dr Carolyn Lam:                Thanks so much, Doug. I have to tell you, I am a fan of the EHFMRG score. In fact, we're trying to study how well it performs in our local situation even here in Singapore.

                                                Justin, you've been thinking a lot about this. I would love for you to share the reactions that we got when we discussed this among the editors.

Dr Justin Ezekowitz:        We had a lot of good discussion about this from a number of different aspects. First, it's an in-practice assessment, a physician-based risk assessment, as we survey hundreds of physicians in the ER, which is a busy environment, and get these types of information. That's a very unique piece of this study where, in addition to the just under 2,000 patients and collecting the other data in a robust way, this really does have a potential to contribute to the literature.

                                                A lot of the discussion was about how data rich this is, and that this is an area where unlike acute cardiovascular disease where there are good risk assessment tools and other therapies, it's a really need of a scoring system that was well validated, can be replicated, and both in clinical practice as well as in selective cohorts. Doug, my congrats to your and the other parts of the team that's helped put this together.

                                                One of the questions that came up when we were discussing it was the risk textiles and buckets were very important for people to think about the very low risk, as you mentioned, 0% all the way up through much higher percents for seven day mortality, but how discrepant the risk was of the physicians versus the mathematical model; and a very good reminder of the inaccuracy of sometimes our assessments of risk in practice, especially in acute care.

                                                I wonder if you could comment on what your fence was from the physicians who participated in the study, and then the data of those, the most striking findings of that piece about where physicians make judgements on risk in for that seven-day mortality. Just any comments you may have?

Dr Douglas Lee:                 We didn't know what to expect because there haven’t been many studies of this type before. What we found in our study was that physicians tended to overestimate the risk of lower risk patients. They thought bad things would happen to healthier patients, just to put it very simply. Physicians also underestimated the risk of the highest risk patients. They thought that the highest risk patients would do well.

                                                We were surprised about that finding, but also, we were not surprised in the fact that it seems to explain some of our earlier findings that in our earlier work, we found that low risk patients are hospitalized, and we think it's probably that physicians are admitting those patients because they want to ensure that they're making a safe decision; and no harm will fall in the patient. Maybe physicians are erring on the side of admitting those patients, even though they know they're a little bit low risk.

                                                At the other extreme, physicians underestimated risk in the highest risk patients. We think it might explain the observation that we made previously that sometimes high risk patients are discharged home, and they die at home after discharge. That may be because patients who look well to physicians, I think there's great value in the clinical experience of a seasoned physician looking at a patient and knowing that, that patient is sick or not sick. But in certain cases, patients may look relatively well, but their numbers would indicate that they're actually higher risk. I think it's that group where we found they're higher risk, but physicians thought that they were healthier than they were. It seems physicians' estimations really have great value, but it seems that they can be improved.

Dr Carolyn Lam:                Sean, you discussed this beautifully in your editorial. Share with us your thoughts, and especially thoughts on the question you posed: are we any closer to the holy grail of safe emergency department discharge based on acute heart failure risk rules?

Dr Sean Collins:                 Doug, kudos to you. Nearly 2,000 patients, nine different hospitals, prospective data collection, as Justin said. I don't think this can be overstated. From a data cleaning perspective, this is truly a labor of love, and to get this done, congratulations to you and your team.

                                                I think the most interesting part of this is this exact disconnect of patients look well who are high risk, and patients may look a little bit unwell who may be low risk, ironically. That's where a risk tool is much needed, as Carolyn said in her introduction to sort of change the dynamic of 80 to 90% of patients are admitted to the hospital. If we even chipped away at 10 to 15% to able to be discharged, it would be a huge win for partly for management for an emergency department perspective.

                                                I think that the importantly, the next steps will be now looking at implementing this in some sort of a randomized manner, somewhat like what you did with asking physicians gestalt about what their level of risk is, but really finding out how does a physician gestalt when it comes to nuance and heart failure. A relative amount of congestion, even when the tool says the patient may be low risk, can they go home? I think that will be the crucial next step to find out how much does this augment and/or detract from physician decision making? We have a long way to go, as Carolyn said. It's just the complete opposite at almost every other disease process, including chest pain, from a discharge perspective. Even a little bit improvement would be great, so I'm looking forward to seeing the next steps, and I'm wondering what your thoughts are about the next steps, Doug.

Dr Douglas Lee:                 There's actually great value in physicians' clinical judgment. It's been, I think relatively understudied. I'm hopeful that future studies where decision tools or prognostic tools are validated, we can see more potentially, more comparisons with clinicians because we don't have a real great understanding, I think, of how doctors think, especially in an acute setting. More research in this area, I think would be really helpful, especially as we ... As more and more clinical decision tools being published, it would be great to see how well they hold up against good clinician judgment.

                                                In terms of next steps and implementation, when we talk to our emergency colleagues, they have brought up an issue about it's great that patients are low risk, and that we could potentially discharge them from hospital; but where is the receptor to take that patient and to care for that patient once they've left the hospital? Are they going to get good care once they leave the hospital? Are there structures in place?

                                                We're now embarking on testing this in the clinical trial where we will be comparing two strategies. The first strategy will be using the risk score at a hospital-wide level, and then discharging home patients who are in the lower risk categories, and having them follow up, and receive their care in a rapid ambulatory follow up clinic within two to three days after discharge from the emergency. This will be compared to the control, which is not using the risk score, and having usual follow up care. This trial is called the Comparison of Outcomes and Access to Heart Failure Trial, or the COAHFT trial. It is currently ongoing.

Dr Sean Collins:                 Great point, Doug. As Carolyn suggested with chest pain and heart failure as the interesting dichotomy is that unlike chest pain, when we safely rule somebody out and send them home, we're sort of done with that acute episode. Heart failure, it doesn't end. We've found that they're safe enough to go home, but now they need great collaboration and outpatient support with their heart failure provider, which may be as equally heavy lift as externally validating the EHFMRG score. You bring up a great point, which is we need to have outpatient follow up and collaboration for this to be successful. Thanks.

Dr Carolyn Lam:                Awesome comments, guys. Could I switch tracks a bit and maybe just ask Justin to round up by sharing? Circulation, we get a lot of papers about risk scores and so on. There's a bit of fatigue, I think, about scores in all kinds of things. Now, could you maybe tell us, Justin, what makes us look at a paper twice, and in fact, feature this one with a good editorial? I mean it's clearly very clinically applicable. Could you share some thoughts there?

Dr Justin Ezekowitz:        Yes, that's a great point. The things that make a risk score like this kind of elevated into kind of a circulation level of manuscript is A) the data quality has to be excellent. There has to be lots of completeness of data, but also capture of elements that we think are quite important. Two, the data science about how it's analyzed and put together, and interpreted, it has to be to the bar that we feel would be robust, and be able ... if somebody could repeat it and replicate it without an obvious challenge to the quality.

                                                The third, I think is the clinical applicability. It's okay to write a data model and come up with all these great risk scores, but if they haven't been thought through about how either a patient will be seeing this, or clinicians behave, or the environment that it has to be deployed in that, that isn't necessarily going to be something that is going to be implemented. Then, the question is: why would somebody do the study in the first place?

                                                Now, it's okay if somebody's forward thinking and saying, 'Look, EMRs are coming, or other EHRs around, so this could be implemented if there was enough impetuous and it's a good enough quality.' That's actually okay, but in the reverse where if you try to implement a model that is too complex, and it's in a hand-off to the environment, it just won't work. We just want to make sure people have thought that next knowledge translation and dissemination approach through.

                                                The final part is things that have a very local impact are, that are very unique to the environment they're in, such as it only would work in your hometown or your own country because of some environment, that's okay. But under that, the much more global focus that, that is, it could be picked up and trans located to any major city, providence, state, or country, because vis vises are global. Those things have a much greater impact because the circulation leadership is global. The patients are global. The clinicians who care for them are also global. People are all looking for very similar situations and can adapt to their own environments.

Dr Carolyn Lam:                Awesome, Justin. I don't think any of us could have said it better. Those are the reasons that we're so grateful that you publish with us, Doug. Thank you so much, Sean, for your excellent editorial, too.

                                                Thank you, listeners, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019.


Feb 18, 2019

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. And I am so privileged to be joined by Senior Associate Editors whom I respect and admire so much. And they are Dr Biykem Bozkurt from Baylor College of Medicine and Dr Sana Al-Khatib from Duke University. And we have three woman discussing the Go Red for Women issue. Yes!

                                The current issue is the third Go Red for Women issue and boy, is it a bonanza issue. It tackles a wide spectrum of topics relating to cardiovascular disease in women, including prevention, risk stratification, myocardial infarction, pregnancy, heart failure, cardiac arrest, sudden cardiac death, and in so many wonderful formats; from original papers to systematic reviews, state-of-the-art papers, in-depth reviews, a research letter, and even frame of reference papers.

                                So, let’s get digging into this issue, shall we? And Biykem, we could start with you because I'd like to start with three original papers that really set the scene. The first discussed temporal changes and the very contemporary data from 2001 to 2016, describing cardiovascular risk factors and their treatment. And then the second focuses on young females with acute myocardial infarction. And the third on older women. Could you take us through these papers Biykem?

Dr Biykem Bozkurt:         Lets first start looking at the sex differences through the Anne Haines Survey which enrolled more than 35000 patients. And they examined the trend all the way back from 2000 to 2016. Now the good news is the improvement in hypertension diabetes hyperlipidemia in woman were similar to men. So that's the good news. But BMI increased more in women than in men and overall, the ability to control blood pressure and diabetes hyperlipidemia appear to be a little bit better for women than in men.

                                But the concerning trend becomes apparent when we look at another paper that examined the twenty-year trend in young adults. Now, the first message is, and this is important for both genders, the proportion of the hospitalizations that are attributable to young patients, and young patients are defined as ages between 35 and 54 in this study, and this study was from Erik, increased from 1995 to 2014. So young patients appear to be having more in life compared to before, compared to 1990s and the 2000s. And that was actually partly due to the increasing prevalence of comorbidities, such as hypertension diabetes among young patients.

                                Now, interestingly among young patients, young women presenting with [inaudible] had a lower likelihood of receiving guideline directed therapy which, of course, sound familiar to our audience because we have the disparities of lower treatments and lower access to care in women with MI presentation compared to men. And unfortunately, again this will sound like the former news, the pre-hospital mortality was quite high in young women and has declined less in young women, compared to men.

                                So, the Erik study highlights the disparity for young women compared to young men. And then we have to recognize that most young patients in my hospitalization attributed to young patients is increasing. So this is probably a population that we need to be aware of. Regarding the older patients, there is a publication from the Opach Study looking at the sedentary behavior and cardiovascular disease in older women. And they looked at more than 5500 patients aged between 63 and all the way up until 97. And they looked at sedentary time and they looked at the duration of sedentary time all the way over eleven hours in some of the patients. And of course the higher the sedentary time was, the worse the cardiovascular disease risk was amongst the older women. So now we are recognizing that among older women, the post-menopausal or elderly women, the risk of cardiovascular disease rises with sedentary lifestyle.

                                And I think these three papers highlight the overall trend that we tend to see, maybe, better emphasis for comorbidity control. But at the same time we are now starting to recognize that in younger patients, especially in younger women the risk of MI is on the rise. And in older women, activity and remaining active and not having too much sedentary time are important to prevent cardiovascular disease.

Dr Carolyn Lam: Oh, Biykem, thank you for framing that so beautifully. So some good news, some bad news, and certainly some things we should be looking out for. You know, in another patient group that we always need to touch on when we talk about the Go Red for Women issue is pregnant women, or post-pregnancy. Could you comment, perhaps, on the systematic review that we have?

Dr Biykem Bozkurt: This is a very comprehensive, systematic review looking at the cardiovascular disease morbidity and mortality in women with a history of pregnancy complications. And they provide detailed systematic review and method analysis. It's becoming more apparent that the spectrum of cardiovascular disease ranges all the way from preeclampsia to arrythmia to pericardial myopathy. And we're recognizing this continuum both in the peripartum period, at the same time as the future risk. So those with preeclampsia and premature birth and delivery are associated with lifetime risk of cardiovascular disease. So, I think this paper is providing the right overview and a very comprehensive meta-analysis recognizing that pregnancy led to complications and morbidity and mortality in women.

Dr Carolyn Lam: Indeed. And it does just add so nicely to this issue, you know? Letting us know that we should watch out for the young women. We should watch out for the sedentary older women. And we should watch out for women with a history of pregnancy complications. But let’s switch tracks now. Sana, there was an amazing autopsy paper, actually, relating to sudden death in women. And as well as another original paper focusing on out of hospital cardiac arrest that is really very interesting. Would you like to tell us about those two?

Dr Sana Al-Khatib: Oh absolutely. I would love to. As someone who has devoted her life to the study of sudden cardiac death and you know, identifying factors, prevention. I really like that the paper looking at the risk of cardiac death in women and men. This study, Carolyn, was conducting in Finland, and the aim of the study was to determine autopsy findings and causes of death among women in a large population of sudden cardiac death.

                                They also were able to classify some EKG characteristics in men and women cardiac death victims. That really added helpful information. To do that, they systematically collected clinical and autopsy data from sudden cardiac death victims in Northern Finland between 1998 and 2017. So they actually had data on close to 5870 SCD victims. The findings were very interesting because they found that victims were significantly older than that. You know, so when they provided the median age it was 70 years for women versus 63 for men. So that was a significant difference there. And when they looked at the most frequently identified cause of death, they found that it was ischemic heart disease in both factions. Seventy two percent in women verses seventy six percent among men. And what was really striking about this was that the seventy two percent presence among women was higher than what had been reported in other theories.

                                They also reported that women were more likely to have lung ischemic cause of sudden cardiac death than men. It commented on the fact that primary myocardiac fibrosis was more likely to be found in woman victims rather than in men. And then they were able to identify some EKG factors stating that, in general, women were more likely to have a prior normal EKG than men. But that it increased the marker for sudden cardiac death with the presence of MDH with the polarization changes that were more commonly seen in women.

                                So, I thought that the findings were really interesting. They sure to be advance the field.

Dr Carolyn Lam: I couldn't agree more. Sex differences in sudden cardiac death. I don't think many people could tell you they knew much about it at all before this paper. And what about at a hospital cardiac arrest?

Dr Sana Al-Khatib: So, the other paper, which was really interesting, was a study that really looked at the public perception on why women receive less bystander CPR than men in out of hospital cardiac arrest. And this was an observation that was made a long time ago, Carolyn. So what's interesting for these investigators to be able to shed some light on this observation. What they did was they conducted a national survey of members of the public. And they were able to get 548 people to respond. Not a very high response rate, but pretty good for getting qualitative research studies. About fifty percent of the responders were women, so it was important to note that. And there was a good geographic distribution of the people; this was done in the U.S. And after they corrected their data, and they analyzed their data, the major thing emerged in terms of why the public perceived that women received less bystander CPR. The findings were really interesting.

                                The first finding was that people were concerned about being accused of sexual assault if they were to do CPR on the woman, which was interesting. Some actually were concerned that women were too weak or too frail. If they were to ever do CPR, might they cause any bone fractures, any injuries to the woman because they're more fragile, so to speak, than men. And their last theme was misperceptions about women in medical distress. What that meant was they felt that, well, you know, are women actually victims of sudden cardiac death? Yes, definitely, women can have sudden cardiac arrest and some people said, "Well, sometimes women can be overly dramatic and so maybe those presentations were not real presentations of sudden cardiac arrest," which I thought was really interesting.

                                I felt these were really interesting insights into why women don't receive CPR as much as men, and hopefully future interventions can be targeting these misconceptions or these concerns that the public has about doing CPR on women.

Dr Carolyn Lam: Isn't that so intriguing. The misconception that women are either too shy, too frail, or too dramatic. Oh my goodness. Anyway, that was all the original papers, which were fantastic. But I have to admit that one of the things that I love most about the Go Red for Women issues is that it talks about women in cardiology. And Biykem, you've always been such a huge mentor to me. And what I love about this issue is that there are a few papers, aren't there, that actually focus on the importance of this mentorship. Could you tell us about that?

Dr Biykem Bozkurt: It's a very important concept that I think is underlying a few papers in our issue. The first one is women in cardiology and perhaps the lack of increase in the representation of women in cardiology. Even though women make up about half of our medical graduates, among practicing cardiologists women comprise less than about twelve to fifteen percent of the population. That perhaps disparity hasn't changed in the last two decades. We tend to sometimes compare our profession to the surgical field, and I think gender inequality appears to be a little bit similar to general surgery and orthopedic.

                                But the paper by Ziman underlines the following: Even though our gender inequality is similar to the surgical field, to look at the temporal trends there has been a significant rise in female representation in general surgery. And actually, among medical trainees, about one third of the medical trainees, not fifty percent like us, one third of the medical trainees are in surgical fields after they go to medical school. But the female representation has been steadily increasing in the surgical fields; about three-fold out of cardiology. Whereas female representation cardiology has the main slot, so the surgical fields are doing a better job in either welcoming, supporting, and mentoring their female trainees than the cardiology field.

                                This is an important concept for us to recognize, and usually the disparity reasons are perceived to be gender and lifestyle and/or personal preferences. That doesn't appear to be the case. Perhaps the better role models and better mentorship could eliminate this disparity and this is underlined in the Olmein Mein paper by Ziman.

                                Another paper by Sharon Hunt also underlines this concept. She portrays the woman needed in cardiac transplantation from a historical and personal perspective, and underlines the following: We tend to have a large number of woman leaders in advance heart failure and cardiac transplantation. And part of this may be attributed to the fact that women have been part of the fabric, part of the readership, part of the group that has developed the field and has been practicing. And thus, there has not been a nation or incorporation of the women in the field. And thus, since they've been involved in the practice from the beginning, they have been seen as a natural partner. Even though cardiac transplantation is quite demanding, requires bedside presence, and hours which are usually used as a reason for women not to go into certain fields, such as interventional. In transplant, we don't seem to have that much disparity for women. Women tend to select this field on one of the reasons in Sharon Hunt's piece is identified as being part of the team from the beginning, and having good role models and mentors.

                                And finally, there is a research letter that identifies if the corresponding author is a female author. There is a large representation of co-authors. This is a very interesting finding by Ouyang stating that even though the female to male senior authorship rates have not been different over the years, if the senior author or the corresponding author is a female there tends to be a higher number of co-authors. This may suggest that female corresponding authors are able to mentor or include their partners or team members. Or vice versa, female co-authors may feel more invited and incorporated as a team. So, this paper also underlines that women in leadership positions connected to cardiology may serve as positive role models to recruit and retain talented junior female investigators.

Dr Carolyn Lam: Ah, indeed, indeed, indeed. So many topics that come close to my own heart. But Sana, among the numerous other papers here, we have two state of the art papers, two in-depth reviews, there are three frame of reference papers. Which one, or ones, stood out to you?

Dr San Al-Khatib: One important paper, Carolyn, you certainly mentioned is an online paper that was titled "Why are Young Black Women as High Risk for Cardiovascular Disease". I personally like this paper a lot because it highlights such an important issue that has great impact on public health. And sometimes the population of young black women may go unrecognized in terms of their risk of cardiovascular disease and what have you. So really the On My Mind paper tackles what are these things that are driving the worsening cardiovascular disease trends in this patient population. And what can we do about it? And they talk about how the awareness of heart disease and the leading cause of death among these women is actually more among black patients. And so, they talk about the need to really implement multi-level strategies to try to address this, raise awareness, identify disparities in care. They even also call for really investing in black women scientists.

                                And so, this was such a really good paper and I'm sure that the readers will enjoy it as much as I have.

Dr Carolyn Lam: Oh, thank you so much for that, Sana. That really, really makes for such a rich issue with such a lot of different papers. We're running out of time, so we don't even have the opportunity to really discuss, but I want to mention these so that the listeners will look out for them. Beyond the papers we've already discussed, we have state-of-the-art papers on cardiovascular care in women veterans and the management of cardiovascular disease in women with breast cancer. We even have two in-depth reviews. One on sex differences in advance heart failure therapies and a second on the role of breast arterial calcification in cardiovascular risk stratification in women. And finally, there's a research letter on the size of thoracic aortic aneurysms in women. So many papers, such a beautiful, beautiful issue. I just want to thank you both Sana and Biykem for leading this beautiful Go Red for Women issue.

                                Thank you, listeners, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                This program is copyright American Heart Association 2019.


Feb 11, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Dr Greg Hundley, director of the Pauley Heart Center from VCU Health in Richmond, Virginia.

Dr Carolyn Lam:                Is income volatility a new cardiovascular risk factor? You have to stay tuned to hear all about that. But for now, join Greg and I over a nice little coffee chat, because we're picking up the journal right here and I'm going to tell you about our two top picks this week. Greg, you go.

Dr Greg Hundley:             Well my top picks, Carolyn, is really pertaining to senescence and senescent cardiomyocytes. Remember that? Senescence is a situation where there's a mismatch between energy demand and supply and so that facilitates the cells transitioning toward failure. They lose their ability to function. In other parts of the body, they lose their ability to divide.

                                                And these investigators assessed altered calcium transfer from sarcoplasmic reticulum to the mitochondria, because that's being casually linked to the pathophysiology of aging in heart failure. Because the advanced glycation end products or AGEs accumulate through life, the authors thought that maybe this intracellular glycation would be occurring in aged cardiomyocytes and their impact on the sarcoplasmic reticulum and mitochondria. So, their study, they investigated both mice and humans and the found that ryanodine receptor glycation was associated with more pronounced calcium leak in mice and also interfibrillar mitochondria directly exposed to sarcoplasmic calcium release from aging mice had increased calcium content, compared to those with younger ones.

                                                Now we're starting to implicate a mechanism by where senescence could be important in these mice. But of course, in Circulation in these wonderful basic science papers that we have, they also cover a translational human component. And what these group found is that there were higher levels of advanced glycation end products and reduced glyoxalase 1 activity present in left atrial appendages, from those patients that underwent surgery greater than 75-years-of-age, compared to individuals that were younger. And also, elderly patients exhibited hyper glycation and increased mitochondrial calcium content that was associated with reduced myocardial aerobic capacity due to less respiring mitochondria.

Dr Carolyn Lam:                Wow Greg, that was a huge summary and how nice to link aging or senescence with AGE or advanced glycation end products. Seriously, that was new to me. Okay look, bring it home. What are the clinical implications?

Dr Greg Hundley:             What these investigators have done is now identified a previously unknown pathophysiological mechanism that may facilitate the transition from healthy, towards failing cardiomyocytes and the implication is that if you could disrupt that process, maybe you could halt the aging of cardiomyocytes. You got to be careful though I think with senescence, just as we know from the general literature. Senescence is a defense mechanism in cancer therapy, but it's a protagonist if you will, in aging. More to come in this field, but very exciting research.

                                                So Carolyn, tell me about your first paper.

Dr Carolyn Lam:                Happily, Greg. I'm going to take us to the cath lab and talk about functional assessment of epicardial coronary artery disease. This paper from Dr Koo and colleagues of Seoul National University Hospital, is the first to validate the physiological relevance and prognostic implication of all available novel resting pressure derived indices of coronary stenosis. This includes indices like resting full cycle ratio or RFR and diastolic pressure ratio or DPR, and they compared this to instantaneous wave free ratio or IFR and fractional flow ratio or FFR.

                                                What they looked at was more than a thousand vessels in 435 patients and showed that all the resting ... Just the resting. Not hyperemic but resting pressure divide indices, closely correlated with each other and showed excellent agreement and the same discriminatory ability for no FFR. All the indices also showed a similar pattern of changes to different anatomical and hemodynamic stenosis severity, regardless of the target vessels and importantly showed similar diagnostic performance for myocardial ischemia, defined by gold standard PET derived CFR and hyperemic myocardial blood flow.

                                                And finally, they showed that all these indices showed significant association with the two year vessel oriented composite clinical outcomes.

Dr Greg Hundley:             So, do we still need to do adenosine infusions in the cath lab?

Dr Carolyn Lam:                That's exactly what they're trying to drive at, because the major advantage of these resting indices, for example RFR over IFR, is that IFR doesn't require identification of a specific landmark or a specific time point during diastole. They may be simpler to perform and this first study showing their physiologic relevance and prognostic implication may enhance adoption of invasive physiologic assessment in daily clinical practice, which we know is important and a clinical benefit.

Dr Greg Hundley:             Excellent. I tell you, it would sure save time if we could use indices like that.

                                                Let me tell you about my next paper. This is from Renato Lopes, from Duke University Medical Center, in Durham. Also, one of your affiliates. In all of our cardiovascular/metabolic clinical trials today, cardiovascular death is a very important outcome. But what happens when, in doing a study like that and you have an undetermined cause of death, the US Food & Drug Administration Guidance indicates that deaths due to undetermined causes should be rare in well-run clinical trials.

                                                And so what this group did is they looked at 127,049 enrolled participants from nine trials and they looked at how deaths were adjudicated. And across nine clinical cardiovascular trials, in different therapeutic areas, the proportions of deaths adjudicated as related to undetermined cause ranged from 7-to-22% and overall, had an average of 16%. Interestingly, in multi-variable analysis, death due to undetermined cause, was associated with the therapeutic area and the year of publication of the study, and then also several patient factors including: gender, age, the region of enrollment, and time from enrollment to death.

Dr Carolyn Lam:                Gosh, this is so enlightening. Greg, having been on CECs and struggle with the adjudication, I really like this paper as well. But please, tell us all, why should we be concerned about this?

Dr Greg Hundley:             Great question, Carolyn. First we might think about, if you're reading a study, the proportion of deaths due to undetermined cause should really fall within this range. And have a mean of maybe 16%. Second, what if there are higher rates due to undetermined cause? Well, that may indicate there are issues with the trial quality. And then finally, researchers, whenever they're doing a study, should really report on the proportion of deaths where cause was unable to be determined.

                                                And there was a great editorialist, David Morrow, from Brigham and Women's Hospital, and really pointed out, you've got a couple factors here that lead to why there's undetermined cause of death. Maybe the documents are missing, or you're in a clinical situation where a subject lives alone, found dead, there's no autopsy. Uncertain duration. Sometimes there are limits on the study personnel; their ability to actually go out and acquire the data so that the team, like what you're on, can actually adjudicate the information. And a point that's made is really ... He used the word, doggedness, but with which he consistently worked toward and tried to get those medical records and pursue them, because that is very important.

                                                When we think, well what's the importance of a study like this? It's valuable to those that perform studies, because as we're working with our study coordinators, we need to make that information known to them. If we don't collect the exact cause of death in these important cardiovascular interventional studies, we may end up with an improper result. And also, for the investigative team. A really important study I think, providing guidance for the first time now about what we should expect in undetermined cause of death, when we're looking at cardiovascular trials.

Dr Carolyn Lam:                Indeed, and from talking about doing the trials to talking about a very important trial, I want to take you to The Partner 2 Trials and talk about the cost-effectiveness of Transcatheter Aortic Valve Replacement, or TAVR, compared to surgical aortic valve replacement, in patients at intermediate surgical risk.

                                                Now we already know that TAVR is cost-effective, although not cost-saving. But cost-effective compared to surgical aortic valve replacement in those at high surgical risk. But this paper refers to intermediate surgical risk. And the analysis is from Dr Cohen and colleagues from Saint Luke's Mid-America Heart Institute, and it's an analysis of the Partner 2A Randomized Trial and the SAPIEN 3 Intermediate Risk Registry.

                                                In summary, they found that TAVR was projected to lower total costs by $8,000.00 to $10,000.00. And to increase quality adjusted survival by 0.15 to 0.27 years, compared to surgical aortic valve replacement over a lifetime horizon.

Dr Greg Hundley:             Wow! Carolyn, I've got two questions for you. First of all, how does TAVR save those costs? And number two, was this true for everyone? Were there any caveats or special subgroups that this was really applied to?

Dr Carolyn Lam:                The cost savings in a TAVR cohort looked like they were driven by both a shorter length of stay during the index hospitalization, as well, as less resource utilization during follow-up. And that would be in the form of fewer hospital days, as well as fewer rehabilitation and skilled nursing facility days.

                                                As for the caveats, you see that the authors did acknowledge that the long-term durability of the valves involved like the SAPIEN XT and the SAPIEN 3 valves is still unknown, and so lifetime costs associated with TAVR, may be higher than we assumed, owing to the need of more frequent repeat valve procedures for example.

                                                Now if though, the long-term data demonstrate comparable late mortality with TAVR, and the surgical aortic valve replacement, these findings are really significant, because they suggest that TAVR may become the preferred treatment strategy for patient populations. Not only based on clinical outcomes, but even based on economic considerations.

Dr Greg Hundley:             It looks like that long-term information is going to be really critical here, so we'll look for more in this area.

Dr Carolyn Lam:                For sure. Wish we could keep chatting, but I think we need to move to the featured discussion.

Dr Greg Hundley:             And now to the very fun segment of our discussion this week at Circulation on the Run. This is Greg Hundley, from VCU Health. Director of The Pauley Heart Center. And today we have a fantastic paper from Adina Zeki Al Hazzouri from Miami, transitioning to Columbia University. And also, our Associate Editor, Dharam Kumbhani from the University of Texas, Southwestern.

                                                Today's paper, Adina is going to discuss is, Associations of Income Volatility with Incident Cardiovascular Disease and All-Cause Mortality in a US Cohort. And what she's done is worked with the Coronary Artery Risk Development in Young Adult Study, we also know that as, CARDIA. And it's really a prospective cohort conducted in urban centers, in Birmingham, Alabama, Chicago, Illinois, Minneapolis, Minnesota, and Oakland, California. The goal here was to asses a block of individuals, younger, aged 23-35 years, identified in the time window of 1990-to-2005 and then followed subsequently to look at income volatility.

                                                Adina, we're so excited to have you here. And can you tell us a little bit more about your study.

Dr Adina Zeki Al Hazzouri: Sure, the motivation for the study is the fact that we know that income volatility is on the rise. And what I mean by, income volatility, is the sudden and unpredictable change in income. And in the health researcher, we actually do not know as much, what is the effect or the influence of income volatility on health outcomes, and it is really common, most of us do experience these sudden or unpredictable changes in income. Whether they're little dips or little jumps in income. So they are really common, and I think it's really important to try to understand what would be their effect on health outcomes.

                                                We were really interested in specifically understanding their effect on all-cause mortality and incidents of cardiovascular disease events, so we took advantage of an ongoing perspective cohort study. The cardio study that you just mentioned. And what is really nice about this study is they were really relatively young back in 1990 when we first had the measure of income. They were between ages 23-and-35. And they were followed for over 20-years, so we had repeatedly over 10-years, or 15-years, repeated measures of income. And then we were able then to look in the subsequent 10-years for incident events, cardiovascular events and all-cause mortality, and what is also interesting in this study is that these individuals, given that their age range, so that they are in the peak of their working years, which makes it even more interesting in terms of applicability and inference of those findings that we're making in this study.

                                                We looked at, as I said, income volatility and we defined it basically as what is the standard deviation of these percent changes in income that you experience between the different visits in the study, which were on average, five years apart. And once we defined that, then we looked at it with outcome and what we really found was that those who experienced high volatility had around a two-fold increased risk of cardiovascular disease, as well as all-cause mortality.

                                                We also looked at another measure of income volatility which is the number of income drops, so how many times you've dropped significantly, which we defined as a drop of more than 25%. And that is lower than your average income throughout the study period. And we found similar results.

Dr Greg Hundley:             Adina, what could be the cause of this? What do you think as an investigative group, is the mechanism behind this finding?

Dr Adina Zeki Al Hazzouri: There could be various mechanisms playing roles here. Stress is obviously one of the important mechanisms. If you think about the instability of income, that instability in income could result in daily stresses, maybe inability to pay for bills. Also, that resulting in inflammation in all the stress pathway.

                                                Also, you could think potentially having this instability could also maybe hinder access to care, maybe coping mechanisms related to stress could alter adherence to treatment. Whether maybe someone has to take daily medications, having those dips or changes, sudden changes in income, could alter your adherence to those medications and then subsequently influence your risk for cardiovascular disease.

                                                Also, you could think access to health insurance. The social support, though it's not very well evidenced, but maybe if you've had always stable income, or low income, you're more likely to have more resilience. However, when you have these unpredictable changes, or sudden changes in income, you may not have that coping mechanism or support ready for you to deal with those sudden changes.

                                                These are some of the pathways that we think of that could potentially be playing a key role here.

Dr Greg Hundley:             Very good. Now let's turn to Dharam, our Associate Editor, from University Texas, Southwestern. Dharam, boy, surprising findings. A young cohort. I mean, they were 23-to-35 and in the next 10-years of their life they start to experience hard cardiovascular events. I mean, fatal and non-fatal myocardial infarction, and also, all-cause mortality. How do you put this in perspective, related to the workforce, and what do you think this means for this young population moving forward?

Dr Dharam Kumbhani:   At the outset we obviously want to congratulate Adina and her group, for this really, very interesting study in cardiovascular EPY and broadly intersects in health economics and health policy, as well for obvious reasons.

                                                Very interesting construct as you pointed out and what does this mean for younger subjects who experience these income volatility very early in their life. I think, just like any other EPY study, I think the perspective is helpful, because although the hazard ratio for these income volatility is two or higher, the absolute incidents rates are, again putting that in perspective is important, and so the absolute incident rates for example is somewhere between two-to-five, per 1,000 persons. So overall that impact, that's just helpful to understand what effects this would have.

                                                Hopefully, that helps. But obviously, very interesting analysis and brings up a lot of questions. I think one thing I may add to what was just mentioned is ... And this was highlighted very nicely by the editorialist, Dr Spatz, and her colleague from Yale. About how this is globally in the financial toxicity space, and there are a number of these indicators that are now being carefully studied like in this study, such as wealth shock and as I said, financial toxicity. And how they actually have an impact on cardiovascular outcomes.

                                                One of the feelings when you read a paper like this or when you read studies like this, and in fact this was one of our initial concerns as well, is to what extent you may have a component, or significant component of reverse causality. Your, "Patients who are sicker in some way," or have those culpabilities, be the ones that have these events is their relationship with other socio-economic indicators such as employment and how that would affect income volatility as well.

                                                I think the authors have done a really terrific job responding to that. And again, it shows an association obviously we know that, that doesn't imply that it's cause[owed], but it's a very interesting association. And that it's helpful to speculate both on the mechanisms, which were just outlined, and also what this means from a health policy standpoint. What that would mean for researchers in the cardiology community, or policy makers, things like that. So I think this is a very nice analysis and definitely brings up a lot of discussion points.

Dr Greg Hundley:             And a very important paper on multiple fronts. One, we've identified an issue in young, healthy individuals that could significantly contribute to adverse cardiovascular events. And then number two, I really liked your point on how this could impact public health policy, and maybe even how we need to think about reducing stress and how we design aspects of the workforce moving forward, so individuals don't suffer from these conditions.

                                                I want to thank, Adina Zeki Al Hazzouri, from Columbia. And our Associate Editor, Dharam Kumbhani, for these excellent comments. We look forward to seeing you next week.

Dr Carolyn Lam:                This program is copyright, American Heart Association, 2019.


Feb 4, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, from National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, associate editor for circulation from VCU Health Systems in Richmond, Virginia.

Dr Carolyn Lam:                What does cardiac autoimmunity, glycemic control, and cardiovascular disease risk and Type I diabetes have in common? Well, you've got to wait for our feature discussion. This one's such a hot one, don't you agree, Greg? We could hardly finish talking.

Dr Greg Hundley:             Absolutely, and Myra, you're just going to love listening to her.

Dr Carolyn Lam:                Yep, but stay tuned. First, we're going to discuss a couple of papers each. Greg.

Dr Greg Hundley:             Thanks Carolyn. So, the first paper I've got is from Professor Van Rein at Leiden University Medical Center. And basically he's getting at the issue of bleeding in patients with atrial fibrillation. So this is a retrospective cohort that evaluates different anticoagulation strategies for atrial fibrillation. They examined 272,315 patients that had a median age of 75 years and followed them longitudinally over time. These individuals experience 31,459 major bleeding events, and what he did is he evaluated whether they were not taking anticoagulant therapy, whether they were on a vitamin K antagonist, a DOAC, antiplatelet therapies, and then all combinations of the above, including single, double and triple therapy.

                                                What he observed is relative to taking a vitamin K antagonist alone. The hazard ratios range from 1.13 to 3.73 in those that were receiving dual antiplatelet therapy of vitamin K antagonist plus antiplatelet therapy, a DOAC plus antiplatelet therapy, and then of course triple therapy, which had that highest hazard ratio.

Dr Carolyn Lam:                But were there particular combinations within these groups that had particularly high bleeding risk?

Dr Greg Hundley:             Well, yeah, Carolyn. As we might expect, triple therapy was the worst, but those that were receiving triple therapy, there were two subgroups that were particularly susceptible to having a bleeding episode. First, those that were greater than 90 years of age, and second, those that had CHADS-VASc 2 scores greater than six. Of course, these are very complicated patients, often particularly that latter group. So there are clinical implications. I mean, clearly, this isn't a randomized trial, but what we should take away from this is that if we have one of those two patient groups, age greater than 90, CHADS-VASc score greater than six, that we ought to minimize the time that those individuals are on that triple therapy.

Dr Carolyn Lam:                Talk about and bleeding, I've got a paper, and it's on the performance of the ABC scores for assessing the risk of stroke and systemic embolism or bleeding in patients with atrial fibrillation. This is a study that actually looked at the performance of these scores in an external cohort, which actually hasn't really been done. Now, as a reminder, the ABC score is actually the age biomarker clinical history stroke score, which helps to estimate the risk of stroke or systemic embolism. The ABC bleeding risk score incorporates biomarkers along with the clinical variables to estimate the risk of bleeding.

                                                All of these were tested in the ENGAGE AF-TIMI 48 trial, which was that multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS-VASc 2 score of two and above. Now, this was from Dr Morrow and the TIMI study group in the Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts. Basically what they found was that the ABC stroke and ABC bleeding risk scores performed well in stratifying the risk for stroke or systemic embolic events or major bleeding in this multinational trial.

                                                Compared to the CHADS-VASc score, the ABC stroke score provided both correct upward and downward reclassification of the stroke systemic embolism risk. Compared with the HAS-BLED score, the ABC bleeding score resulted in a predominantly correct downward reclassification of the bleeding risk.

Dr Greg Hundley:             So, this new ABC score, do we integrate it with HAS-BLED? Do we integrate it with CHADS-VASc 2? How do we use this clinically?

Dr Carolyn Lam:                So first of all, there are some important remaining unanswered questions, and this was really nicely discussed in an accompanying editorial by Dr Hylek from Boston University School of Medicine. Among this, first of all, the ABC scores need to be validated in patients outside of a clinical trial. Remember, this was a clinical trial cohort. Then there are questions about the timing of measurements of the score, the different settings, hospital and otherwise. Do these scores perform equally well across different vascular beds and in diverse patient populations at the same thresholds used?

                                                So, all these things still need to be addressed. And really, in Dr Hylek's words, the work has just begun.

Dr Greg Hundley:             This is an issue with the theme that might be bleeding, and I'm going to talk about a study from Professor Huisman from Leiden University again, and this is the RE-VERSE AD study. Again, patients that are receiving dabigatran and that may have a GI bleed or patients that are on this therapy and unexpectedly need an emergent surgical procedure, this investigative team evaluated the utility of idarucizumab on reversing that anticoagulant dabigatran. So what did they do? They administered 2.5 milligrams of idarucizumab twice separated by 15 minutes.

                                                And again, the study population was uncontrolled GI bleeding or those in need of an emergent procedure. The types of GI bleeds that were involved in this study, a third were upper GI bleeds, a third lower, and then a third, it was either unknown, or there was a mixture of both upper GI or lower GI bleeding. So how do we know that dabigatran is effective? We use a DTT time, and 98% of those with an elevated diluted thrombin time had that reduced after receiving these two twin 2.5 milligram doses at a time point of four hours after administration.

Dr Carolyn Lam:                Okay, but were there any complications?

Dr Greg Hundley:             Yeah, there were. So first of all, something to think about is that this is a high-risk group. In this study, 14.6% of the cohort actually later died either from the bleeding or what have you. Then another thing we need to be thinking about is when we reversed this anticoagulant, do patients experience thrombotic events? So what this group reported is 4.4% did within 30 days. What were those? Myocardial infarction, deep venous thrombosis, and subsequent PE. Then also at the 30-day time point, one patient experienced an ischemic event.

                                                Another question is once you've administered this, you've gone through the procedure. You stopped the GI bleeding, or you've had the surgery. In this particular study, 66% of those individuals had restarted their DOAC. Those events occurred on top of that. So, interesting information. Looking at administration of idarucizumab, and we'll be using this I think frequently as DOACs are used more frequently in the population, particularly dabigatran, so some important data in guiding us on what we might expect when we administer this therapy.

Dr Carolyn Lam:                I think going back to atrial fibrillation though, this is my other selected paper, and it's actually results from the GARFIELD-AF Registry. It's from Dr Bassand from University of Besançon in France, and colleagues, and basically, they looked at the early risks of death, stroke, systemic embolism and major bleeding in patients with newly diagnosed atrial fibrillation in the GARFIELD-AF Registry. They basically found that the rates of all three major clinical events was significantly higher during the first month than in the subsequent period set following up to 12 months.

                                                The leading causes of early death were heart failure, sudden death, acute coronary syndromes, infection or sepsis, and respiratory failure.

Dr Greg Hundley:             So, what's the take-home message here?

Dr Carolyn Lam:                This is observational, so the key thing to understand here, it's a registry. It's observational. We can't really tell chicken from egg with regards to its newly diagnosed AF verses events, which comes first, which causes what. But nonetheless, the increased hazards of an early event and especially cardiovascular mortality in these newly diagnosed AF patients really point to the importance of comprehensive care for such patients and really should alert physicians to detect warning signs of possible early mortality in these newly diagnosed patients.

Dr Greg Hundley:             Very good, Carolyn.

Dr Carolyn Lam:                I think that wraps it up. Let's hop to our feature discussion, shall we? I'm so super excited about today's feature paper because it may explain that strong link between hyperglycemia and cardiovascular disease in type one diabetes and all by revealing a potential novel pathway that may have been hiding in plain sight. And yes, I'm stealing the words of editorialists and our associate editor, Dr Naveed Sattar from University of Glasgow, and we're all so pleased to have with us the corresponding author of today's feature paper, Dr Myra Lipes from Joslin Diabetes Center in Boston, Massachusetts. Myra, start us off by telling us a little bit about your study please.

Dr Myra Lipes:                   Sure. So we were interested in examining the role of whether chronic hyperglycemia could trigger cardiac autoimmunity in type one diabetes, because chronic hyperglycemia is associated with subclinical myocardial damage, and we had actually previously observed just unexpectedly in a young adult cohort that ... Actually from Italy, where unexpectedly, we noticed that patients with the poorest glycemic control expressed cardiac antibodies. There's a lot of interesting people who are autoimmune-proned may overreact to injury of certain tissues.

                                                So, type one diabetes, it's a classical autoimmune disorder. So we examined, really tested this hypothesis, in stored samples from the DCCT/EDIC study, and this is a very landmark study where patients were randomized to tight glycemic control, intensive glycemic control. Then another group had just conventional control, and this was done over an average of six and a half years. So during this time, the samples were stored. Every year samples were stored from participants, and this was quite a rich data set that is publicly available. So we studied the development of autoimmunity in two groups that had very distinct separations of the A1C level.

                                                We specifically excluded people who developed kidney disease or cardiovascular disease events during the study. So this is a cohort that had relatively recent onset type one diabetes. They're relatively healthy, and again, groups were matched with cardiovascular risk factors at the beginning and the end of this DCCT period. And of course with our studies, we've also looked genetically because your HLA immune response genes can influence susceptibility to autoimmunity.

                                                These patients were actually matched in HLA genotypes. So what we found was that patients with poor glycemic control, there was expression over time. You could see a time course relationship between expression of antibodies over time on the levels of the antibodies that were different in the two A1C groups. The number of antibodies were different in that with the high group expressing more antibodies, more different types of antibodies. These are antibodies ... might say antibodies as like proteins in the blood, and they're actually directed against parts of the myocytes, the myofibrillar complex, and a major target is cardiac myosin heavy chain.

                                                We saw the different parts of the myosin heavy chain retarded, and the presence of two or more antibodies, different types of antibodies, different regions of the myosin to different isoforms. Also, we saw antibodies, the troponin, troponin I. So the number of antibodies with different ... with almost a complete absence of antibodies in a tightly controlled group. I might mention the A1C average was 6.5%, so this is a very tightly controlled group whereas the poorly controlled group is at the opposite extreme, the average A1C during DCCT. The mean updated A1C was about 10%.

                                                So, it was a very clean group, two different groups, and we could see that the number of the types, the number over time, very different in the two groups. In fact the profiles of these antibodies were almost very similar to patients with Chagas cardiomyopathy. That was our positive control group. Chagas cardiomyopathy is possibility to be a form of chronic myocarditis directed against cardiac myosin. So the profiles are almost indistinguishable. So on one hand, you have relatively healthy patients with type one before glycemic control, and that was very unexpected that this would look pretty similar.

                                                But very interestingly, and I might say unexpectedly, we saw ... It was very clear that the people with the highest titers of antibody and the most different types of antibodies, particularly two or more, were subsequently ... We noticed that those patients were at high risk for developing CVD events. And that's while the number of events was slow, we noticed that all the patients, some 60%, had two or more antibodies and developed cardiovascular events. Perhaps one more striking example is a single patient in the study could die of cardiovascular death, had a positivity for all five antibodies at highest titer.

                                                Then we looked at coronary calcification just to measure subclinical atherosclerosis. We noticed that the same numbers, two or more, and also the same antibody specificities that were the highest predictors of CVD events were also predictive of coronary ... had detectable coronary calcification. In addition, we looked at the levels trying to find mechanistically what could explain the link between cardiac autoimmunity and an increased risk for atherosclerosis. We looked at CRP, high sensitivity CRP levels.

                                                Again, these were measured about a decade after the antibody samples were obtained, and we saw that the positivity for multiple antibodies was also associated with markedly elevated ... subsequently elevated high sensitivity CRP levels with levels of six versus something like 1.4 in a group with one or less antibody. So these were very intriguing findings, suggesting a role for autoimmune pathways as a susceptibility to cardiovascular disease in type one diabetes.

Dr Greg Hundley:             Myra, that was absolutely incredible description of the study and all the particulars of the findings. I wonder if I could ask both you and Naveed, where do you see the next steps moving forward with this research in the future? Number one. And number two, is this in any way can be used to segregate patients that may need, for example, really aggressive glucose control with an insulin pump or something of that nature?

Naveed Sattar:                  I think we left this study as beautifully described as you see by Dr Lipes. I think the context ... We looked at this from editorial perspective ... is that most people don't realize if you have a middle-aged person with type one, their hazard ratio for cardiovascular risk is about somewhere between four to six fold for men and women respectively, which is much higher than type two. It's often thought that it's the area under the curve for hyperglycemia. But what this paper throws up is actually maybe there's another pathway, which we just didn't understand that this wasn't a permanent autoimmunity closing subclinical myocardial disease and inflammations.

                                                But potentially, for me though, there's a saying in British that one swallow does not make a summer. So, it would be nice for other groups to replicate this. I think the findings are, as they stand in isolation, fantastically well done. But it would be lovely if other groups had accessible samples, and I knew of several groups that have up towards tens of thousands of samples, maybe even not 10,000. Certainly 10,000 or so plus or minus samples for type and prospective outcomes to potentially validate the findings and extend them.

                                                And really, if the antibodies do help protect people at higher risk in a meaningful way and improve beyond what we can already do, then you're right. Absolutely. If we can pick up early people who are going to have substantially higher risk, you would want to potentially improve glycemic control, potentially pumps, CGM, closed-loop systems or more intensive statins or lower blood pressure targets or other types of antihyperglycemic agents, which seem to be being tested in type one as well. So that's really one example.

                                                And for me, the other thing would be really nice is to pull up any inflammation. Is this high systemic inflammation? Is it IL-6 level? Is it something else? What about troponin and BNP levels, et cetera. I'd be interested to hear what Dr Lipes thinks and how do you think to take it forward as well.

Dr Myra Lipes:                   So, this is something Dr Sattar said and I completely agree. Actually, right now, we're looking at the DCCT cohort as a whole for already. It's relatively small compared to the population-based studies. But there's 1,400 patients, and the subjects had CMR studies that were published in Circulation. So we're going to actually study next whether we see CMR evidence of systolic dysfunction and looking at the broader DCCT cohort. So, those studies are underway. But of course the ultimate test would be looking at if there were samples available from the Swedish NDRs, Scottish registry.

                                                I think it's something that's not often done prospectively. So that would be incredibly exciting, and that's the important thing. I'd say with type one diabetes, for screening for type one diabetes, the use of autoantibodies and particularly two or more different types of islet autoantibodies, and this is just putting things in a broader context, is the entry criteria for type one diabetes prevention trials and something cardiologists wouldn't be aware of but this particular thing. So in decades, people, researchers, in the field has spent decades optimizing islet antibody assays.

                                                So by analogy, it would be really important to standardize assays so that they can be done in Sweden and Scotland and so that other groups could confirm this, and I'm confident that this could be done, since the setting up of our assays was really built on the experience of people of developing standardized assays and rigorous cutoff points for antibody positivity. So it would be really important to work internationally to try to tap into this.

Dr Carolyn Lam:                Oh, my goodness. Myra, Naveed, these are such insightful comments. I think as Greg said earlier, I think we could go on forever discussing this paper, but I'm so sorry. Our time is up. Before we go though, I must point all readers to look at figure five of this marvelous paper. It puts together the whole schema of how autoantibodies can play a role both in myocardial and atherosclerotic cardiovascular disease and type one diabetes.

                                                Thank you so much. Greg and I loved having you. Listeners, don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019.


Jan 28, 2019

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts of Circulation on the Run. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I am Greg Hundley, also associate editor from VCU Health Systems in Richmond, Virginia.

Dr Carolyn Lam:                So, have you ever wondered in patients with atrial fibrillation and stable coronary artery disease beyond a year of coronary stenting, can you safely just continue on oral anticoagulation without antiplatelet therapy? Well, if you've ever wondered that ... I sure have. I'm sure you have too, Greg. Our feature paper this week does discuss this, so you have to stay tuned. But for now, Greg, what are your picks from this week's issue?

Dr Greg Hundley:             I've got a couple to discuss. The first is Patrick Hsieh from Taipei, Taiwan, and really is evaluating the gut microbiota and how that affects cardiac repair after myocardial infarction. I mean, who would've thought to chase an idea like this? But what this investigative team did is they had mice, so this was a basic science experiment, and they treated them seven days prior to ligation of their left anterior descending artery that would induce a myocardial infarction. They treated them seven days prior with ampicillin, metronidazole, neomycin, and vancomycin. What were they trying to do? Totally obliterate any bacterial load within their GI system. Then, they ligated that coronary artery, and at 21 days, they looked at histopathologically what was happening.

                                                And you know what they found? Those where they wiped out the bacterial load, they had increased cardiovascular events. And importantly, myocardial rupture was very high in this group of mice. Also those mice, they had reduced heart rate, and mechanistically what had occurred is there was a reduction in our immune monocytes that were trying to infiltrate the peri-infarct. They weren't there. They were not in those peri-infarct zones. And so, the thought here is that removal of the favorable microbiota in the gut can actually be harmful in the setting of myocardial infarction.

Dr Carolyn Lam:                Fascinating. So, microbiome as our pals. But wait a minute. I mean, how can you say it's from elimination of the microbiome versus some kind of effect of the antibiotics itself?

Dr Greg Hundley:             Yeah, that's a great question, Carolyn. The way they did this is they took another group of animals, and they supplemented them with lactobacillus probiotic, like the stuff we get in the grocery store. And those animals, they did not suffer any of the adverse cardiovascular effects. So, it really points to an important role of our gut microbiota. You know, and what do they do? They basically ferment these carbohydrates that we ingest, and produce short chain fatty acids that are a substrate for these mononuclear cells to help infiltrate those infarct zones. So, really exciting basic science question that this group examined.

Dr Carolyn Lam:                I love that you picked a basic science paper, and I love that you made even me understand it so well. Okay, but what I have is a clinical trial. So, it's the REDUCE-MVI trial, which is the first randomized trial comparing maintenance treatment with ticagrelor or prasugrel after a primary PCI. So, this is from Dr van Royen and colleagues. They're from Radboud University Medical Center in the Netherlands. Basically, they figured that despite successful restoration of epicardial vessel patency with primary PCI, coronary microvascular injury does occur in a large proportion of STEMI patients, and of course, adversely affects outcomes. Now, ticagrelor has been reported to increase plasma adenosine levels, which may have a protective effect on the microcirculation. So, the authors randomize 110 STEMI patients following revascularization to maintenance therapy with ticagrelor versus prasugrel, with the primary outcome being microvascular injury at one month as determined by the index of microcirculatory resistance in the infarct related artery.

                                                What they found was that there was no difference in the extent of microvascular injury and in the extent of infarct size by cardiac MRI at one month after the primary PCI. The attributed pleiotropic benefits of ticagrelor through the adenosine metabolism pathway actually could not be confirmed in the STEMI population, as plasma adenosine levels were actually not increased in the patients treated with ticagrelor.

Dr Greg Hundley:             So, what does this mean for the use of adenosine and its role?

Dr Carolyn Lam:                I suppose you're also asking, you know, is the adenosine hypothesis really out here? This is a study that really suggests we have to question it, but there are some limitations that we perhaps should keep in mind when we think about this. So first, before primary PCI, all patients were loaded with ticagrelor because this was standard of care in the participating centers. That, of course, could have modified microvascular injury already at the index event. Now, a second important thing is that the study may have been underpowered. There was a greater than anticipated variability in that primary outcome of index on microcirculatory resistance.

                                                The relatively low rates of risk factors, the small infarct size, the preserved ejection fraction could all have influenced this IMR values, as well as the potential effects of the pharmacological intervention. And furthermore, the natural recovery of microvascular dysfunction over time may have diluted the positive effects. And of course, selection bias is inevitable in a trial. And so, you know, although this really questions the adenosine hypothesis, there are still caveats to these results.

Dr Greg Hundley:             Very good. So, Carolyn, I've got another study to sort of go over, and this is from Dan Modin from the University of Copenhagen. And it's really addressing this issue. We all in the fall, do we all get our flu shots? And could that be helpful in patients with heart failure? You know, the ACC, the AHA, and the ESC all suggest flu shots, but there's actually no guideline to recommend. So, what did these investigators do? They looked in Denmark, and from the period of January of 2003 to June of 2015, they identified 134,048 subjects. And they looked at the vaccination status for those with a diagnosis of heart failure that were greater than 18 years in age. 55% percent of these were men. And then, they also looked at ICD-10 codes for cardiovascular events.

                                                Now, they examine the dates of when you had your vaccination, how frequently, what were your comorbidities cardiovascular-wise, medication use, etc. And what they observed is that those individuals that had more than one vaccination ... So, basically annual vaccinations for a three year period, they had an 18% reduction in all death, and a 19% reduction in cardiovascular death.

Dr Carolyn Lam:                So, is this all heart failure patients? Are there specific subgroups that we should be targeting?

Dr Greg Hundley:             At our institution, they really get on us. If we don't have our flu shots in September, I mean, they threaten to withhold everything, or maybe October. Well, interesting that you asked that question. Those individuals that had flu shots in the September to October window did much better than those individuals that had their vaccination November, December, or actually later in January. And the second group that benefited were the individuals that actually had annual vaccinations. So, if periodically you say, "Oh, I'm going to get it this year, but then I'm not going to get it two years from now." Not so good. It was those individuals that had those vaccinations annually.

Dr Carolyn Lam:                You know, Greg, it's making me question too, because here I am in a tropical island. We actually don't have seasons. So, what does that mean for us? That's one thing. And then, do we need even randomized trials now?

Dr Greg Hundley:             Yeah, I think you're right there, Carolyn, because first of all, you know the investigators targeted this because 50% of heart failure exacerbations are actually triggered by some sort of respiratory infection. So, that was kind of the thought behind this. But we do have to be careful about looking at this longitudinal data and making predictions or developing guidelines. A couple of reasons why. It could be that those that come in for annual vaccinations at the time points, well, maybe they also come in for more frequent heart failure visits with their doctor. So, it's not cause and effect.

                                                And in fact, there was another study, Get with the Guidelines heart failure study, and it actually showed no association. So, more work really needs to be done in this area. And just to point out quickly, there is a current randomized trial going on called Invested, and it's looking at different types of vaccinations, trivalent versus quadrivalent. They're underway in those with heart failure. And so, there's a lot more work in this area. But it was interesting getting it that old "get your flu shot," and it looks like at least longitudinally in cohort studies could be beneficial. And if you are going to do it, do it every year and get that September, October. So, Carolyn, what about your next paper?

Dr Carolyn Lam:                So, Greg, my second paper is another trial. It's the radio sound hypertension trial, this time focusing on renal denervation. In fact, it's the first trial to compare three different techniques and technologies for catheter-based renal denervation. It's from Dr Lurz from Heart Center Leipzig in Germany. And what they did is, they randomized 120 patients with resistant hypertension to three arms. Either one, radiofrequency, renal denervation of the main renal arteries. Two, radiofrequency renal denervation of the main renal arteries and the side branches and accessories. Or three, an endovascular ultrasound-based renal denervation of the main renal artery. The primary endpoint was change in systolic daytime ambulatory blood pressure at three months. In the end, endovascular ultrasound-based renal denervation was the winner over radiofrequency ablation of the main arteries, with or without ablation of the side branches.

Dr Greg Hundley:             Carolyn, does this mean that renal denervation is coming back? Are we going to actually start thinking about this as a viable option to treat those with longstanding hypertension?

Dr Carolyn Lam:                Greg, this was exactly addressed by an editorialist, Dr Ram from UT Southwestern and Apollo Hospitals and Apollo Medical College in India. Beautiful editorial. Basically, even with the publication of these new data, it is difficult to predict whether renal denervation is firmly back on track. You see, some caveats should be mentioned, including that in this trial, only patients with large renal arteries were chosen for this study. And patient enrollment was rather selective.

                                                For example, out of 1,884 patients screened, only 120 patients met the inclusion criteria. And then, importantly, in a few patients, the reduction in systolic blood pressure was really impressive, close to 40 millimeters mercury. But the majority of responders had a more modest effect, and in about 30%, there was no change in blood pressure.

                                                So, one of the ultimate things we need to learn to do is to identify the so-called hyper-responders from the non-responders. So, lots more work needs to be done in renal denervation.

                                                That brings us to a close of our little chat. Can't wait for our feature discussion coming right up.

                                                Our feature paper today deals with a very important topic in a very frequently encountered group of patients. And they're the ones with concomitant stable coronary artery disease and atrial fibrillation. You see, these are patients at high risk of both ischemic and bleeding events, and therefore, it's critical to identify the right antithrombotic regimen with the optimal benefit ratio, since this is going to be lifelong therapy. Now, interestingly, despite recommendations in the guidelines and consensus documents, there has been no randomized controlled trial evaluating oral anticoagulation with and without antiplatelet therapy in patients with atrial fibrillation and stable coronary artery disease beyond one year of coronary stenting. I mean, Greg, I didn't even realize that we didn't have a randomized control trial. Did you?

Dr Greg Hundley:             Absolutely, Carolyn. And, you know, this is an important issue, because we have a lot of patients coming to the cath lab that have atrial fibrillation, and what is going to be the recommended anticoagulant and antiplatelet combination? And so, it's really time for a randomized trial.

Dr Carolyn Lam:                I know, and luckily for us, that's exactly what this issue's feature paper does. And I'm so pleased to welcome to the show Dr Satoshi Shizuta from Kyoto University Graduate School of Medicine, Japan, as well as associate editor Dr Shinya Goto from Tokai University in Japan. We're so proud to be publishing the OAC-ALONE trial, even though we understand it was a difficult trial. Tell us, what were the results?

Dr Satoshi Shizuta:           As you know, the results were somewhat inconclusive because of pretty much a combination of patient enrollment. Initially, we scheduled to enroll 2,000 patients during 12 months, but patient enrollment speed was extremely slow, much slower than expected. So, we extended the patient enrollment period from 12 months to 38 months. But finally, we could only enroll 696 patients, about one-third of the initially planned patients. The result was around 50% rate of primary end point during 2.5 years of follow up. And the hazard ratio of [inaudible 00:15:01] strategy, as compared with OAC plus APT was 1.16 with a 95 confidence interval of 0.79 to 1.72.

                                                So, in conclusion, our study failed to establish no inferiority of OAC-ALONE to combination therapy of OAC plus antiplatelet therapy in patients with AF and stable coronary artery disease beyond one year after stenting in terms of primary endpoint of death, MI, or stroke. So, this study was underpowered and inconclusive. So, future larger studies require to establish the optimal antithrombotic regimen in this same patient population.

Dr Carolyn Lam:                Thanks so much. Shinya, you've been thinking about this, too, and the performance of such a difficult trial. Did you have anything to add or to ask?

Dr Shinya Goto:                So, first of all, I would to congratulate Satoshi and the group. They have completed a very interesting randomizing trial. As Greg mentioned, there is two kind of patient who lead to coronary artery disease and atrial fibrillation, especially after, you know, one year after stenting. So, taking a look at coronary artery disease with atrial fibrillation, we don't have the established standard of care yet. So, Satoshi know, it is a long-time study. So, I understand the rich colored nature of the patient in this kind of trial. So, what is the most difficult point increased to encourage the patient in this long-term trial?

Dr Satoshi Shizuta:           We think that difficulty reflects substantial reluctance of most cardiologists to withdraw antiplatelet therapy, single antiplatelet therapy from stented patients, even the patients treated with oral anticoagulation for atrial fibrillation. So, that is the most important point.

Dr Shinya Goto:                You have already showed in this paper myocardial infarction recurrence of stents thrombosis. Not a huge problem in this kind of patient population, you know? Stroke is a bigger problem, mortality, not including cardiovascular is also the problem. So, you have suggested, you have a strong kind of mind, is it? And single antiplatelet therapy necessary after stenting. Your results are underpowered but still suggest how always you know would be enough in stable CAD patients with atrial fibrillation.

                                                I would congratulate you again.

Dr Satoshi Shizuta:           Thank you.

Dr Greg Hundley:             Satoshi, I have a quick question. So, in the randomization process, how can you achieve the physicians managing the patients to administer the anticoagulant therapy to guideline levels, particularly when they are also prescribed antiplatelet therapy? I noticed that in the editorial on this manuscript that was a concern, and suggesting that in future studies that the therapy really be defined, and not so much open label administration at the discretion of the prescribing physician. What are your thoughts on that?

Dr Satoshi Shizuta:           I agree with you, but in this kind of study, randomizing whether or not to withdraw a drug is very difficult to conduct. Financial support is limited, and in such situation, double blind placebo controlled trial is very difficult to conduct. As you know, several years ago, a loose trial was published in the Lancet. And also in the loose trial, the study design was open level, and also in the PCI and [inaudible 00:19:48], I think the study design was not blinded but open. In this paper figure two, our control level was set as a dependent based on the Japanese guidelines. In the Japanese guidelines, target IR was set as 1.6 to 2.6, a little bit lower than Western golden standard for elderly patients older than 50 years. And same 2.0 to 3.0 in patients younger than 70 years.

                                                And in that criteria, as you can see, if you get 2A of paper, the therapeutic range was extremely high. 76% in the OAC-ALONE group, and also 73% in the OAC plus APD group. We can clearly understand that the intensity of oral anticoagulation was different between the two groups. Most of the OAC-ALONE group, OAC was controlled with ionine level higher than 2.0. On the other hand, in the OAC plus APD group, the ionine level was mostly controlled between 1.6 to 2.2 or .5 or so. So, this is a great big limitation of the study. But even in this limitation, the bleeding events, there was numerical excess in the OAC plus APD group. And, regarding the TEMI major bleeding, there was a trend toward increased major bleeding in the OAC plus APD group. If the intensity of OAC was the same, of course, I am convinced that even in this underpowered sample five, the major bleeding will be statistically higher in the OAC plus APD group.

Dr Carolyn Lam:                Thank you so much Satoshi for really taking us under the hood, and showing us all the myriad of considerations that occurred to perform this trial.

                                                This is Greg and Carolyn. Thank you for joining us on Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019.


Jan 21, 2019

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. We're your co-hosts of Circulation on the Run and if you don't know what this show is about, well, you have to listen to the previous episodes in January please.

                                I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Greg Hundley:   I'm Greg Hundley from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: So Greg, before we pick up our coffees and begin discussing a couple of the paper, let's just tell everyone that this feature paper, they have to listen to because it is the results of the cardiac amyloidosis section, or sub-set of the APOLLO study. Have to listen to this one. But how about the other papers in today's issue Greg?

Greg Hundley:   Right Carolyn, the first one I'm going to start with is from Alexander Fanaroff at Duke University and the DCRI. And basically, this particular paper was looking at the procedural volume and how that might affect outcomes with those that are performing PCI. So they divided the cohort into those individuals that had less than 50 PCIs per year, 50 to 100 and then greater than 100 PCIs per year. So, this is looking at our national cardiovascular data registry within the United States, and of course, as you know, that's linked to Medicare claims data for those that are over 65 years in age. So they had 723,644 PCIs performed by 8,936 operators. And the surprise in this study was that those low volume operators, less than 50 PCIs per year had a one year rate of 15.9% of MACE as opposed to those that were high volume operators that had 16.9% MACE rates. That was significant at a P value of .004.

Dr Carolyn Lam: Wait a minute, this seems different from prior reports. Are you saying that those with low volume operators actually had lower mortality?

Greg Hundley:   Yeah, exactly. And you've pointed out something, cause previously what's been shown is that high volume operators have lower 30 day and in-hospital mortality rates. And that was actually confirmed in this study. But out of a year it was really the low volume operators in unadjusted results had lower rates of all MACE.

                                A very nice editorial by Dharam Kumbhani from UT Southwestern points out that high volume operators do tend to take on more serious cases, those with higher numbers of cardiovascular risk factors. And so, when they did adjustments and accounted for all those risk factors, actually the event rates were the same. Still though, they're the same. And so what could be going on? And the editorialist and also the authors of the paper point out, "Hey, maybe we shouldn't just be focusing on PCI volume per operator, but other quality metrics to look at outcomes. And so this really builds in to the whole quality discussion. Adherence to therapy with the patients in your health care system. What about operator longevity? An operator that may have been doing this for 10 years but has a lower volume, maybe that could come into play. So future studies I think, certainly all over the world in this field, this paper's going to direct us to focus more on other quality issues and not just procedural volume.

Dr Carolyn Lam: So, quality versus quantity. Interesting.

                                Well switching gears to a paper that I thought was nice, it is from Dr Lubitz from Massachusetts General Hospital in Boston and colleagues, and they sought to answer the question of whether refining a phenotypic classification of heart failure would facilitate genetic discovery. So, to do that, they defined all cause heart failure among almost 500,000 participants in the UK bio-bank and performed a GWAS study and then later refined the heart failure phenotype by classifying individuals with left ventricular dysfunction but without coronary artery disease as having nonischemic cardiomyopathy and then repeated the GWAS. And basically they found that the GWAS in the all cause heart failure yielded multiple genetic signals for known heart failure risk factors, such as coronary artery disease and atrial fibrillation.

                                However, after refining the heart failure phenotype to a nonischemic cardiomyopathy sub-set, this enhanced the detection of genetic loci associated with dilated cardiomyopathy, which appeared to operate independent of the traditional heart failure risk factors. So that was pretty interesting.

Greg Hundley:   So where do we go from here with that Carolyn? I mean, what is this telling us and how are we going to move forward with this information?

Dr Carolyn Lam: I think the clinical implications are first that common genetic variants associated with both clinical and sub-clinical heart failure, because they looked at left ventricular dysfunction, these genetic variants may be leveraged to improve heart failure risk prediction and prevention. But obviously future studies are warranted to investigate the prognostic and therapeutic implications of these findings.

Greg Hundley:   Very good. Well I'm going to take us back into the cath lab again and we're going to address fractional flow reserve. And remember, typically, we get fractional flow reserve measures using guide wires, and that's kind of a tough thing to do sometimes in terms of adding links to the procedure, etc. So what these investigators did, they had 10 centers in the United States, Europe and Israel. And this was William Fearon from Stanford University who did this study. And they looked at 301 subjects and they had 319 evaluable vessels. Now what did they compare? They looked at guide wire derived fractional flow reserve versus angiographic derived. Simply, just when you're doing the injections, looking at how quickly that contrast flows down the coronary arteries.

                                And so, in this study the mean fractional flow reserve value was 0.81 and 43% of the vessels they studied had an FFR less than or equal to that magic number of 0.8. Interestingly, the angiographic obtained FFR measures were 94% sensitive and 91% specific for identifying the guide wire derived FFR. That's really incredible. And importantly, the accuracy of this contrast measure was 87% for FFR values between 0.75 and 0.85, that magical threshold.

Dr Carolyn Lam: Well that is impressive, suggesting that we don't need guide wires. I mean, is that true for all patients? All vessels?

Greg Hundley:   Right, so that's sort of the kick here, this is really interesting new data but let's look at the patients that they studied. First of all, they were relatively stable I would say. They had either angina or maybe even unstable angina and non-ST elevation MIs. But no ST elevation MIs. The average stenosis by angiography that they looked at was about 63% and then, very importantly, you have to look at the exclusion criteria. So things that, other conditions within the heart that are going to impact FFR were excluded. So, all their patients had an EF greater than 45%. Nobody had a CABG. Nobody had a chronic total occlusion. Nobody had a heart transplant, aortic stenosis, no heart valve surgery, no left main. It couldn't have had a recent stent within 12 months. It couldn't have had severe diffused disease, no collaterals, no in-stent thrombosis or stenosis. So this technique I think could be useful when you've got that patient perhaps with stable angina, single vessel disease, stenosis severity of 50 to 60% and none of these other conditions, preserved EF etc. But for many of the patients that we send to the cath lab, this technique, we still need a little bit more development. We don't know its utility. You've got another paper?

Dr Carolyn Lam: I've got another few papers because I'm going to drag you out of the cath lab right now and into the ICU. And we're talking about cardiogenic shock and it's really nice that we have these three papers in today's issue. One's an original paper and two are On my Mind articles. Now the original paper talks about the randomized shock cool trial. This is from Dr Thiele from the heart center Leipzig in University Hospital in Germany. And it is an un-blinded, randomized trial of 40 patients with cardiogenic shock undergoing primary percutaneous coronary intervention. And without a classical indication from mild therapeutic hypothermia, but randomized one-to-one to mild therapeutic hypothermia for 24 hours versus control. And basically the mild therapeutic hypothermia did not show a substantial beneficial effect on the primary outcome of cardiac power index at 24 hours or on any other of the hemodynamic parameters. And there was also no difference in the short and long term outcomes. So a neutral trial.

                                But taking a step back and just talking about these patients with cardiogenic shock and all the different ways that we have now to keep them alive, I really want to highlight these two On My Mind papers. One is by Drs Gill, Grunau and MacRedmond from University of British Columbia. And they really talk about the need to define limits for extracorporeal cardiopulmonary resuscitation. In a very similar vein, Drs Mulaikal, Nakagawa and Prager from Columbia University also wrote a beautiful piece on ECMO, ECMO as a bridge to no recovery. And when is enough enough? So really, really interesting conversations and discussions regarding what is death, when do we have to put a time limit perhaps to these therapies? And yet not limit the potential life-saving effects of these. I really strongly encourage our listeners to read these papers and also to stay tuned because coming right up, a very important paper on the APOLLO study in our feature discussion.

                                For today's feature paper we're discussing the results of a sub-study of the APOLLO study. Now this deals with cardiac amyloidosis, a super, super hot subject. And we have super, super hot guests today on the show. The first our corresponding author, doctor Scott Solomon from Brigham and Women's Hospital as well as our associate editor doctor Justin Ezekowitz. Welcome both, and let's just plunge straight into it. So Scott, tell us, tell us about this APOLLO sub-study.

Scott Solomon: APOLLO is a study of patients with hereditary transthyretin amyloidosis and, as you know, that hereditary transthyretin amyloidosis is an inherited disease caused by mutations of the transthyretin gene and these mutations cause the transthyretin protein to misfold and then accumulate as amyloid fibrils which go to the nerves and go to the heart. And we know that this can cause severe polyneuropathy and cardiomyopathy, partly depending on which mutation the patients have. And we, as cardiologists, are aware that when amyloid infiltrates the heart it can increase cardiac wall thickness, it can cause increase in chamber stiffness, it can result in severe diastolic dysfunction and these patients, often with cardiac involvement of amyloid, have a really markedly reduced life-span and really poor quality of life.

                                The APOLLO study was a study of a new agent that is designed to reduce transthyretin, it's a transthyretin knock-down agent. It's basically an RNAi therapeutic, it basically is a small, interfering RNA that basically blocks the production of transthyretin and this is one of several approaches that are currently being considered for amyloid disease. And APOLLO is primarily designed as a study to look at neuropathy. The primary end-point was a neurologic scale to look at neuropathy, but it was also designed to secondarily look at some cardiac end-points, especially in the patients who were felt to have cardiac involvement.

Dr Carolyn Lam: Cool. And so your current paper deals with that cardiac amyloidosis sub-set, but it was pre-specified, it was planned, right?

Scott Solomon: Yeah, it was a pre-specified sub-group. In fact, what we did is we actually did echocardiograms on everybody in the study and then defined a pre-specified cardiac sub-population that was comprised of patients who had a very high likelihood of having cardiac amyloid involvement, and so this was patients who had a baseline left ventricular wall thickness of 13mm or greater and no history of either aortic valve disease or hypertension. And so this was a group that we thought most likely had evidence of cardiac involvement. And just so it's clear, we did echocardiography on everybody in the study and in this paper we reported in both everybody and in the pre-specified cardiac sub-population. So we looked a number of things in these patients including various measures of cardiac structure function including wall thickness, left ventricular mass, ejection fraction, cardiac output, atrial size, volumes and myocardial strain which, as you know, has been particularly useful in assessment of patients with amyloidosis. And we also looked at reduction or improvement in Anti-proBNP which, as you know, is a very good measure of the severity of heart failure in patients.

                                And so, of the 225 patients who enrolled overall in the APOLLO study, 126 were part of this pre-specified cardiac sub-population. And in this group of patients, we've observed a reduction in left ventricular wall thickness of about a millimeter. And this was statistically significant in the patients who were treated with patisiran compared with placebo. We also saw an improvement in global longitudinal strain and improvement of cardiac output and an increase of left ventricular end-diastolic volume. In this case an increase in end-diastolic volume is actually a good thing because these patients often start out with smaller end-diastolic volumes because of the increased wall thickness. Those improvements in echocardiography were really paralleled by dramatic improvements in Anti-proBNP and we started out with patients with abnormal Anti-proBNPs in the range of about 800. These were significantly reduced, highly significantly reduced with a P value of about seven times 10 to minus eighth at both nine and 18 months, so pretty dramatic relative reduction in Anti-proBNP in the patisiran group compared to placebo.

Dr Carolyn Lam: Super exciting, and it really adds to mounting evidence isn't it? That we're sort of reaching a really effective treatment for these patients and who knows how common they are. But Justin, you've been thinking a lot about this, what are your thoughts?

Justin Ezekowitz: This is a terrific paper, and this is a groundbreaking therapy. Scott, this really has something for everybody, for example functional Anti-proBNP and echocardiographic measures of improvement and also less deterioration which I think is also holding it in its tracks. The question is, if you have 126 patients in the cardiac sub-group, whether or not this is really prime for clinical integration, as to start using this therapy broadly or do we need to really broaden the scope and do larger outcome studies with this therapy for these patients, recognizing some of the gaps in any clinical trial design and implementation. So what are your thoughts on that?

Scott Solomon: First of all, it's important to remember that the APOLLO study was designed primarily to look at the neurologic outcomes, not the cardiac outcomes. The cardiac outcomes were technically considered exploratory and, in fact, although really pretty impressive in this group, this wasn't really how the study was designed. And so the current indication for this particular therapy. Patisiran is for the improvement in the neurologic outcomes, not for the cardiac. So I think that there will need to be additional studies that will look more specifically at the cardiac effects, although I think these are among the most impressive findings we've seen with any agent that is interfering with transthyretin. And just to put this in context, there are a variety of ways in which amyloid can be affected and one of the other approaches to this disease has been not to reduce the production of transthyretin but to stabilize transthyretin.

                                And you may be aware of the ATTRACT trial which was presented at ESC and published in the New England Journal, which was actually an outcomes trial in patients with cardiomyopathy secondary amyloid and they used a drug which is a TTR stabilizer and showed a significant reduction in cardiac events and mortality. And I think that in the context of that study, this is extremely exciting as well because it says that there are multiple potential approaches to affecting transthyretin and potentially improving outcomes in patients with cardiac amyloidosis. There are other approaches that also are being tested. In fact, another therapy that works in a similar way to patisiran is atersin which is an agulo nucleotide anti-sense molecule. And so, I think that it's such an exciting time now in this field because there almost certainly will be several different approaches to transthyretin amyloidosis.

                                So, I think, Justin, to succinctly answer your question I don't think we're quite ready yet with patisiran but stay tuned because there will be more trials for sure. The other thing that we have to realize is that this study was done in mutant or hereditary amyloidosis but there's a very broad group of patients out there with wild type amyloidosis and there's no reason to think that a therapy like this won't work there as well. So that has to be tested too.

Justin Ezekowitz: I think, Scott, that's a true way to put it. I think one of the other questions is the substantial difference between the trials and sub-groups of the trial between the three major therapies you just described about wild type versus hereditary. It does make you wonder if either one individual therapy or a combination of the therapies might give the right way to precisely manage these individuals according to their phenotype, neurologic status or cardiac status.

So, I maybe just want to draw you on one other point which is that you used global longitudinal strain as one of your outcomes and it sounds like, and from all the data we've seen, it looks like GLS will be the way to go for earlier phase two and other types of studies. What are your thoughts based on experience?

Scott Solomon: Well in general I'm a big fan of global longitudinal strain because I think it is, in many respects, more robust than our standard measures of cardiac function like ejection fraction, it's not volume dependent the way ejection fraction is. In particular in amyloid heart disease, as you know, global longitudinal strain can be quite abnormal and, interestingly, it can be quite abnormal in a very specific pattern. And patients with amyloid is typically sparing at the apex, so the apical strain is relatively normal compared to the strain at the base of the heart. And this is kind of interesting and we've certainly been looking at this as well in amyloid heart disease but I agree that this global longitudinal strain as a measure of potential benefit for a therapy has a lot of potential.

Dr Carolyn Lam: You know, that's just so amazing. I just have one last question for both of you. Where do you think the field is going? Do you think it's going to be a race to treatment or a race to diagnosis? I shudder to think of the number of cases we're missing, what do you think Justin?

Justin Ezekowitz: Carolyn you just brought up a great point which is, one is our diagnostics need to improve and be broadly applicable and implementable in any health care system, so I think that race has to speed up and become more cost-effective and efficient to know who indeed we need to screen closer. That's point number one but number two is the therapies ... the race has to be focused around what will be the best way to treat patients rather than the cost-effectiveness initially, but then once we identify the three or four different agents that work with different groups and how you can combine them, then the consideration has to be how we can apply these more broadly to the groups that really haven't had a therapy that has had a meaningful impact trajectory.

Dr Carolyn Lam: Scott, what do you think?

Scott Solomon: Well I would add that one of the most exciting things I think in this area, Carolyn, and this is going to interest you I think because of your own interests, is that there's probably a lot of amyloid out there that we don't know about. Especially in these patients that we're currently calling heart failure with preserved ejection fraction. There's some data from Mayo clinic and from groups in Europe suggesting that 15 to 20% of patients with HFpEF, might actually have wild type transthyretin amyloid. And that means that we've got to get better at making this diagnosis, especially where our suspicions are high. Because we might all of sudden have a targeted therapy for some of these patients, so I think that's one area where things are really exciting. And then with respect to which of these therapies is going to be beneficial, I mean I think that we're still in the early stages, it's very possible as Justin said that even a combination of TTR stabilizers and knock-down agents are going to provide the best benefit. But I think we're going to see a lot of very interesting studies in the next several years in this field. It's really great to have a potential molecular target, and targeted therapy for a type of cardiomyopathy and I think this is one of the really few areas where we have that as this point. So I'm extremely excited.

Dr Carolyn Lam: Thank you so much for publishing your paper with us in Circulation.

                                Well audience you heard it right here on Circulation on the Run. Don't forget to tune in again next week.

                                This program is copyright American Heart Association 2019.


Jan 14, 2019

Dr Carolyn Lam:                Hello. We're here at the American Heart Association meeting in Chicago where circulation has 19 simultaneous publications this year. And that is a huge increase from six in the past to 19, all thanks to the man next to me.

                                                But first, let me introduce myself. I'm Dr Carolyn Lam. I'm associate editor from the National Heart Center and Duke National University of Singapore. I'm the voice you hear on 'Circulation On the Run'.

                                                I'm so pleased to be here in person today with Dr Dharam Kumbhani. He's associate editor from UT Southwestern and he also leads the simultaneous publications for this journal. So big applause for this amazing bonanza this year.

Dr Dharam Kumbhani:   Thank you.

Dr Carolyn Lam:                Next to him, we have Dr Sana Al-Khatib and she's from the Duke University. And finally, Dr Gabriel Steg from University of Paris. Wow! Okay, we've got 19 papers to chat about. No, I'm just kidding. We're going to talk and focus on the seven simultaneous publications that were late-breaking science.

                                                Why don't you start us off, Dharam. We will first start with the interventional trials, and there were three of them. I'd love you to chat about the first of them, but even before that, maybe, tell us what it's like to get a simultaneous publication. Because I think people underestimate the amount of work it takes to do that.

Dr Dharam Kumbhani:   Thanks a lot, Carolyn. I think under Joe's leadership the whole space of simultaneous publications in late paying clinical science has really been a big endeavor for him and for the journal. We just have an amazing team that's able to work on this in very quick order. So, for the viewers, I think it's a very involved process, but it's a very gratifying process.

                                                We work very closely among the associate editors, the senior editors, and then the circ staff, and we have very rapid turnaround time. So we owe a lot of gratitude to our reviewers who frequently will turn these reviews in within 48 hours. Our goal has been that we respond back with a decision usually within five to seven days. So it's been very gratifying.

                                                Then it moves onto the next set of revisions, et cetera. But even among the papers that we are unable to accept for circulation, it's just a quick turnaround time for the authors so they haven't lost as much time and can potentially look elsewhere.

                                                It's been a really gratifying process. It's been a great, great team effort. I appreciate everything you said, but really I don't deserve all that credit. It's been a great team effort.

Dr Carolyn Lam:                No, it's been rumored there's a lot of lost sleep on your end, so thank you, thank you Dharam for this. And maybe you could open with the ISAR-TEST 4, that's been [crosstalk 00:02:47].

Dr Dharam Kumbhani:   Yeah, well thank you. I think we had some really interesting interventional trials and Dr Steg will discuss a couple of them as well.

                                                ISAR-TEST 4 was a very interesting trial. It is one of the first 10 trials that gets to the 10-year mark, so this is just the 10-year follow-up results of that. It was about a 2500 patient trial. It was done in Germany, multiple centers. Really they were trying to assess the space that they were trying to ... Or the knowledge gap that they were trying to fill was the durability of the bioabsorbable polymer stents.

                                                Specifically, they were looking at a bioabsorbable polymer sirolimus-eluting stent, the Yukon stent, and then they compared that with durable polymer stents including Xience or the everolimus-eluting stent and then Cypher, which is no longer available in the U.S., but that's a permanent polymer sirolimus-eluting stent.

                                                The primary results were published and presented a long time ago. There was really MACE events at one year and it showed non-inferiority for this bioabsorbable polymer stent back then. So, then they had, incredibly, 83% of the cohort that they were able to follow-up out of 10 years. And what they showed is that ... I don't want to necessarily get into the numbers and the details as much, but what they showed is that this bioabsorbable polymer sirolimus-eluting stent tended to have similar outcomes to Xience, which we accept as state of the art current generation stent, permanent polymer. And it did better than the Cypher stent, both in terms of MACE events and stent thrombosis.

                                                So suggesting that, the big advance in the field for this is ... This is a long-term follow-up of the stent. It suggests that outcomes may be similar in this patient population. Although only 12% were really enrolled with an MI in this patient population. Most of them were stable or less sick ACS patients. And they show fairly good outcomes out of 10 years, comparable to Xience and better than Cypher.

                                                I think it was interesting. Gabriel, what is your take [crosstalk 00:04:57].

Dr Gabriel Steg:                I think it's important. There's been a tremendous interest in international community on trying to tease out which are the best types of stents and beyond brands, try to understand the type of stent, the coating, the drug that you put on it, whether the polymer is durable or not durable. I think these types of fairly well done, large randomized trials with long term flow are critical.

                                                A lot of the focus in the interventional community originally was on lumen size, late loss, angiographic parameters short term. And now the field has matured, and we've moved to clinical outcomes, patient-oriented outcomes, long term follow-up. And it's important because we've learned from long term trials such as PROTECT that the result at one year may not predict what happens at five years, and sometimes you have surprises.

                                                So, it's really important. We owe it to our patients because these are irretrievable devices. Once you've implanted them, they are there. We talked about Cypher being out of the market, but there are more than a million patients who walk every day on this plant with a Cypher in their coronary artery, so we better know what the long-term follow-up is.

Dr Dharam Kumbhani:   Yeah, that's a great point.

Dr Carolyn Lam:                Wow. And then thanks also for the discussion that allows me, as a noninterventionist, to realize ... It's hard to keep track of what's happening with all the different types of stents and polymers and so on. But could you then summarize for the field, does that mean that these biodegradable ones are now ... Do I sound ignorant when I say that? That they are now really in the game. Is that what it does?

Dr Dharam Kumbhani:   This whole bioabsorbable field, there are nuances. So this really is testing a bioabsorbable polymer where -

Dr Carolyn Lam:                Oh!

Dr Dharam Kumbhani:   So, with every stent you have a stent, you have the polymer, and then you have the drug.

Dr Carolyn Lam:                Thank you.

Dr Dharam Kumbhani:   And so, the polymer and the drug go away, and then you're left behind with a bare metal stent. And that's this Yukon stent.

Dr Carolyn Lam:                Got it.

Dr Dharam Kumbhani:   The one that has been in the press a lot more is the bioabsorbable scaffold where the stent and the polymer and the drug, everything in theory should be gone at a certain period of time. So this is ... It's an important distinction though. Because I know that it's very confusion when you just say bioabsorbable and it's unclear if you're talking about the polymer or you're talking about the stent, itself. But this really was a bioabsorbable polymer issue, so you're left behind with a bare metal stent at the end of it.

Dr Carolyn Lam:                Got it, crystal clear, and thank you. That's cool. That's super.

Dr Sana Al-Khatib:            I agree, for an electrophysiologist too.

Dr Carolyn Lam:                But now, let's go into the AMI field. There were two trials that really spoke to acute management patients coming in with an AMI and with cardiogenic shock, for example. Gabriel, could you tell us a little bit about the IABP-SHOCK II trial, as well as the really talked about a door-to-unload IMPELLA Trial.

Dr Gabriel Steg:                The IABP II trial is a randomized trial looking at the benefit, or lack thereof, of intraaortic balloon pump in patients with cardiogenic shock and acute MI. It's been standard practice since the '60s to offer IABP pumping to patients with cardiogenic shocks and AMI.

                                                So, literally more than a million patients have been implanted with IABP, but the reality is when we look at the randomized trial evidence of benefit there was none. They were very small trials, inconclusive, underpowered. Professor Thiele from Germany and his colleagues deserve enormous credit for having had the courage to really do what needed to be done. A proper randomized controlled trial, of course open label.

                                                And what they found in IABP II, which they already reported a few years ago, was that there was no acute benefit of IABP on survival short term, or for that matter on many of the secondary clinical outcomes looked at in this trial. They subsequently reported one year mortality.

                                                What they did here is they gathered follow-up on almost all of the cohort at more than six years. And they found that the long term survival is identical for patients who received an IABP and those who did not. So I think this nails the issue. But there's another thing we learn. The mortality at six years is staggering, it's close to 60%. And although a large fraction of the patients die in the first 30 days, you still have an additional 10% of patients who die between the first year and six years.

                                                So there still remains a very sick patient population for whom we need to investigate new strategies. I don't think it's going to be necessarily mechanical. We have to think of all of the strategies we do to prevent and mitigate cardiogenic shock to build up. And that's gets us to the second trial that I'll talk to you about in a minute.

Dr Sana Al-Khatib:            I have a quick question about this. Did they provide any information about modes of death in these patients?

Dr Gabriel Steg:                Yes. They did capture information about that. Off the top of my head, I'm unable to provide information, but yes they did capture that. The German system allowed them to retrieve information about causes of death and it's a closed system. It's a national trial, so they were able to get enormous follow-up.

Dr Sana Al-Khatib:            Because this information can help us inform what interventions are needed next.

Dr Gabriel Steg:                Yes. That's really important.

Dr Dharam Kumbhani:   To your point about ... You use a very interesting word, the last nail. That's actually how Dr Hochman addressed her editorial. She wrote a really nice editorial-

Dr Gabriel Steg:                The leading expert in the field.

Dr Dharam Kumbhani:   And so, I'm interested in your thoughts. The use of balloon pumps for shock, there's a discrepancy between the American guidelines and the European guidelines. Last year the European guidelines were updated. It is really such a practice changing guideline in that it now lists routine use of balloon pumps in cardiogenic shock-

Dr Gabriel Steg:                Class III.

Dr Dharam Kumbhani:   -as a class III indication. Going through training, that was all you had when someone came in with shock, you would throw in a balloon pump. So that's really quite a practice changing event.

Dr Gabriel Steg:                Yeah. These investigators are embarking on new studies with ECMO and I think it's going to be fascinating to see whether ECMO, which also gets increasingly used worldwide, whether there is evidence to acutely support or not whether this is useful. I think they are doing the proper thing. They are doing the right thing, randomized trials. And we could commend them because these are really difficult trials.

Dr Carolyn Lam:                Absolutely.

Dr Gabriel Steg:                In the acute MI setting, shock patients, ECMO, IABP, that's really difficult. They are brave investigators, they are good investigators, and I think they provided the community with a clear answer.

Dr Carolyn Lam:                And exactly the kind of papers that we like publishing at circulation, isn't it? Now what about the door-to-unload?

Dr Gabriel Steg:                That is actually a good segue with door-to-unload because if we can't properly treat shock once it's there, can we do something to prevent shock? Can we do something to preserve myocardium? One of the experimental findings that is very clear is that if you unload experimental myocardial infarction, if you unload the left ventricle you reduce infarct size.

Dr Gabriel Steg:                So, investigators have been trying to translate this experimental finding into the clinical arena using the Impella device. There's enormous interest, particularly in North America for Impella use in acute MI patients with larger infarcts with the idea that if you can unload the left ventricle, you might be able to mitigate the extent of the myocardial infarction, and therefore avoid cardiogenic shock and probably improve prognosis.

                                                Although this is a very attractive theoretical concept, it still deserves to be tested. And so, if you want to test it you have to unload the ventricle as soon as possible, ideally before reperfusion, which means that you're going to have to delay reperfusion for the time of implanting the device and unloading the ventricle. And so what the investigators did in this trial is to study whether delaying proposedly by 30 minutes reperfusion, to unload the ventricle for 30 minutes prior to reperfusion, was feasible and reasonably safe.

                                                It's a small trial. It's really a pilot trial. By no means does it test the proof of concept of the device or the theoretical issue, but it shows that it's feasible. There doesn't seem to be a massive increase in total time to reperfusion because just by change the group that was not delayed had a longer time to PCI, so eventually things are sort of evening out.

                                                They looked at MRI size of infarcts at follow-up. There was no obvious difference, but of course it could still be tied to errors. We're not totally sure about this, but it certainly paves the way for doing a proper proof of concept randomized trial, testing unloading versus no unloading with a true control group. And I think that's what investigators are looking forward, but I understand there's immense interest for this concept in international community, particularly in the United States and I'm quite curious to see what this future trial will look like and what the results will be.

Dr Carolyn Lam:                Yeah, indeed. Gabriel, I noticed you were very careful to frame it, to say what the trial was trying to address and what it wasn't. And there's been quite a bit of buzz after that.

                                                Do you agree with everything Gabriel has said and what have you heard?

Dr Dharam Kumbhani:   I think he was incredibly eloquent in outlining the premise of the trial and what it really showed. I think the one thing that ... And this was brought up in the very nice editorial by Dr Patel from Duke as well, is it would've been really nice to have a control arm which didn't have any unloading. Because these are not patients with shock, that just directly had primary PCI. And then comparing infarct size.

                                                So, I think that was one of the pieces of information that would've been helpful to then put this in perspective. When you have an infarct size of 8% or 10%, how does that compare in the same patient population in their testing? You're absolutely right about the need to do difficult trials like this, where a lot of times it's just assumed to be true and is embraced in clinical practice.

                                                As I gave the example about the balloon pump earlier, where as a Fellow you saw someone in shock and your reflex was to put in a balloon pump. And so, I think testing these very difficult patient scenarios, as well as just in terms of trial execution, it's amazing to have two trials on that.

Dr Gabriel Steg:                If I may come back to this?

Dr Carolyn Lam:                Yes.

Dr Gabriel Steg:                It's funny because we've been using the IABP for years, thinking this is what we should do in shock. Now our German colleagues have proven that IABP doesn't work. So a lot of investigators have reverted, saying "Well, we should use Impella." But where is the evidence showing that Impella is beneficial?

Dr Dharam Kumbhani:   That's right.

Dr Carolyn Lam:                That's right.

Dr Gabriel Steg:                We have none, so I think that's a trial that deserves to be done.

Dr Dharam Kumbhani:   And ECMO. Yeah, exactly.

Dr Carolyn Lam:                Yeah, ECMO. Exactly. And, you know, going back to door-to-unload, it's important to prove safety in order to go to the next step, which is exactly how you frame-

Dr Gabriel Steg:                I think it shouldn't be over interpreted.

Dr Carolyn Lam:                That's how it should be, exactly, received by the community. So that's great. Now let's switch gears a bit.

                                                Sana, in EP world, the EP guided noninvasive radio ablation of VT. Fascinating stuff. What are your thoughts?

Dr Sana Al-Khatib:            I absolutely agree, definitely. This was a phase two study that the authors did. They enrolled 19 patients, so it was a small study, but it was really helpful. Remember, there's a major clinical need there. These are patients who have an ICD, who have recurring ventricular tachycardia, that have been treated with at least one antiarrhythmic medication, at least one catheter ablation procedure, and then what do you do with those patients? This is actually a clinical scenario that comes up frequently and we absolutely need to be looking for more therapies for those patients.

                                                So that's what that study was about, trying to explore new ways to treat these patients. To be able to do it noninvasively, I think is fascinating. That's what ... They enrolled these patients. Patients had to have failed these treatments, antiarrhythmic medications, prior catheter ablation, and they underwent noninvasive imaging to really localize the source of the ventricular tachycardia, where it's coming from, and then they subjected them to stereotactic body radiotherapy to ablate those sources of ventricular tachycardia.

                                                And, of course, the results were fascinating because they showed on the effectiveness side that this seemed to be very effective because if you look at the reduction in the burden of ventricular tachycardia, and a couple of their patients actually had significant PVCs and PVC induced cardiomyopathy, there was a significant reduction in the rates of these arrhythmias in these patients with this intervention, which was great to see.

                                                In fact, to be specific, about 94% of these patients, so 18 out of the 19, had significant benefit. And in about 89% of the patients there was more than 75% reduction in the arrhythmia. So these are actually really interesting findings, especially in a patient population where we really don't have other options. Now of course you're going to ask me about the safety. What are the safety concerns?

                                                Of course, this was a primary endpoint for the authors. They did look at safety up to 90 days and they found that there were two significant adverse events that occurred in those 90 days. One was heart failure and one was pericarditis. The concern, of course, with radiation is what else can we expect especially if you follow the patients longer? So certainly we need more data. The authors acknowledged that beautifully and I think their intent is to launch a multi-center randomized clinical trial. I don't know if it will be randomized, but at least a multi-center clinical trial to see if they can replicate those findings. So that was very interesting to see.

Dr Carolyn Lam:                Yeah it was. Thanks, that was really exciting.

                                                So, some exciting trials in my world of cardiometabolic disease too, and I want to highlight two. The CARMELINA trial and the CAMELLIA-TIMI 61.

                                                First the CARMELINA trial. This was a secondary analysis of CARMELINA and this was ... CARMELINA, if I can remind everyone, is a cardiovascular outcomes trial, randomizing about 7000 patients with type 2 diabetes and atherosclerotic cardiovascular disease, and/or chronic kidney disease. Randomizing them to the DPP-4 inhibitor linagliptin 5 mg a day versus placebo, following up for a median of about two years.

                                                We know that type 2 diabetic patients are at risk of heart failure and there's always been a bit of a question mark when it comes to DPP-4 inhibitors and their risk for heart failure. And so this secondary analysis looks specifically at the hospitalization for heart failure and related events in CARMELINA. The important thing is that all these were prospectively centrally adjudicated events, and this was a pre-specified post hoc analysis.

                                                And the summary of it all is that linagliptin was not associated with an increased risk of hospitalization for heart failure or the composite of cardiovascular death in hospitalization or the related outcomes. Importantly, the authors did also sensitivity analyses and interaction analyses to show that the results were consistent whether or not patients had a history of heart failure, which was in 27% of patients, regardless of the baseline ejection fraction that was measured within a year of starting the drug, and also regardless of renal function. So EGFR or urinary albumin to creatinine ratio.

                                                This is really important because this trial adds to the growing perhaps understanding of DPP-4 inhibitor heart failure risk. The whole question mark actually came with SAVOR TIMI and that was saxagliptin. But since then there's been three other trials that have showed no heart failure risk. EXAMINE, TECOS, and now CARMELINA. So, an important addition and I think it should reassure us.

                                                And then from diabetes and heart failure risk, which is always very hot, but now obesity. The CAMELLIA-TIMI 61 trial looked at renal outcomes in this trial. Now what was this trial? It was actually testing lorcaserin, and that is a selective serotonin 2C receptor agonist, in about 12,000 obese or overweight patients.

                                                Basically, the primary results showed that it did not increase any ... It met it's CV safety outcomes with weight loss and so on. But this time they looked at renal outcomes. Because obesity has been known to be associated with hyperfiltration of the kidneys, you get albuminuria and it's apparently worsening of kidney disease. So what we need to know is pharmacological weight loss going to be associated with improved renal outcomes?

                                                And basically, that is what CAMELLIA-TIMIA 61 showed. Their renal outcomes were new or persistent albuminuria and then the standard doubling of EGFR or end-stage renal failure, renal transplant or renal death. And that was improved by lorcaserin. Along with that, there was the anticipated reduction in weight, HbA1c, and BP. It does look like, from these late breaking results that we have another tool in our toolbox.

Dr Sana Al-Khatib:            And for the clinicians out there, which patients should they be thinking to use this medication in? What kind of obesity are we talking about? At what point do you introduce that?

Dr Carolyn Lam:                This is common garden, just defined by BMI that was above 27. And I don't think they're saying to use it in patients with renal dysfunction, but to sort of say to look and see whether weight loss also associates with renal function improvement, and it does. It's reassuring.

Dr Sana Al-Khatib:            Yeah, okay.

Dr Carolyn Lam:                And then ... Okay, let's round up with that last trial. A very interesting one because it's pragmatic mobile health and wellness. Tell us.

Dr Dharam Kumbhani:   It's really a monumental effort. This is ... I'll be brief, but it's really a phenomenal trial from an epi standpoint and implementation standpoint. This is from India. It was coordinated by the Center for Chronic Disease Control and the Public Health Foundation of India where, as everyone knows, India is now the diabetes capital of the world and chronic diseases have very quickly overtaken other infectious causes as the number one cause of mortality and morbidity.

                                                This was a big undertaking, really collaboration from three continents, but it was a community based plus a randomized trial. They had 40 community health centers and what they were trying to see is primarily for hypertension and diabetes. That if you implemented a structure and typically using this mWELLCARE tool, which is basically an electronic medical records storage facility and then it also has inbuilt clinical decision support.

                                                And really for hypertension and diabetes management, but also, they had tobacco and alcohol screening, abuse screening, and also for depression. So what they really wanted to do ... A very ingenious endeavor and they try to see if doing this systematically on a clustered randomized fashion if that would actually influence patient outcome. They had a little over 3000 patients and they followed them for 12 months.

                                                Unfortunately, the trial, itself, as far as the primary endpoint, which was change in systolic blood pressure and hemoglobin A1c, they had pretty significant reductions in both arms, about 12 to 13 millimeters, which is amazing from a population health standpoint, in both arms not statistically significant, and in hemoglobin A1c also by 0.5% in both arms.

                                                Just suggesting that having this more frequent interactions with the medical health system, itself, was driving a lot of this benefit. So although the trial, itself, was negative for the primary endpoint, I think it's a huge step forward for the management of chronic disease epidemiology and burden in developing countries.

Dr Gabriel Steg:                Neutral.

Dr Carolyn Lam:                Ah, true.

Dr Dharam Kumbhani:   Fair point.

Dr Carolyn Lam:                We've discussed this whole array of seven trials and they are difficult trials. I mean, talk about another difficult type of trial to do, cluster randomized pragmatic trial. It's amazing the breadth of simultaneous publications we've had this year. Thanks again to everyone for introducing this and thank you for joining us today.


Jan 7, 2019

Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Caroline Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Greg Hundley:                   And I'm Greg Hundley, Professor at the Pauley Heart Center of Virginia Commonwealth University Health Sciences in Richmond, Virginia.

Dr Carolyn Lam:                In case you guys missed us last week, this is how our new podcast is gonna work. Greg and I are going to invite you for coffee with us, almost with a journal in hand, and we're gonna chat about the week's issue, highlighting two original papers each, that we thought were awesome. And don't you worry, the feature discussion is still there, authors will join us for a feature discussion right after our coffee.

                                                And for this week, the feature paper speaks about the MOMENTUM 3 trial, and talks about the important analysis of stroke outcomes in this trial. But before that, I think Greg, you've got a couple of papers don't you?

Greg Hundley:                   Absolutely Carolyn. So the whole issue, I think we're gonna pick out several stroke papers, really a stroke theme. The first paper is Ankit Maheshwari. He looked at the utility of P-wave morphology on the 12-lead electrocardiogram, to help predict ischemic stroke in patients with atrial fibrillation.

                                                Now, how did he do this? Basically, they looked at a large cohort of individuals from the ARIC study, and these were patients that developed atrial fibrillation. And electrocardiograms had been recorded prior to their Afib episode.

                                                So, what were they looking for in P-wave morphology? Well, they were looking for changes in Lead three. They were looking for changes in V1. They were also looking for extension of that P-wave. So a prolonged duration. And what they observed, is that that abnormal P-wave, could forecast abnormal atrial remodeling, that might be an indicator of future stroke.

Dr Carolyn Lam:                Huh, interesting. But is it really reproducible? Did they validate it somehow?

Greg Hundley:                   Yeah, so that's great Carolyn. You know, in papers like this, you like to take a finding in one large cohort, but then you've got to reproduce it. So they went to the MESA Study. Remember now, Mesa are individuals without cardiovascular disease. ARIC are patients with cardiovascular disease. And the finding was reproducible in MESA. Also, what the authors did, is they looked at the relevance of this EKG finding to our existing CHADS-VASc2 scoring system.

                                                And what was really smart by these investigators, is that if you added the information from the abnormal P-wave morphology to the CHADS-VASc2 score, you could forecast stroke. Now you say, well CHADS-VASc2 is already pretty reliable, but what about those patients that have a CHADS-VASc score of one right? We're always kind of wondering, do we anticoagulate them? Do we give them aspirin, et cetera. Well if the P-wave morphology was abnormal and they were at higher risk for stroke, that could sway you as a clinician, to go ahead and prescribe anticoagulation for that group of patients.

                                                And something very simple, just from the 12-lead EKG before the patients went into atrial fibrillation. You've got a paper that also is sort of focusing on stroke. You want to tell us about that?

Dr Carolyn Lam:                Yeah, one big data to another big data series. This time, it's Get With The Guidelines Stroke series, and this paper is from Dr Menon from University of Calgary in Canada. Where they described the door to treatment times for endovascular therapy in acute stroke. What is that? Well that's a time interval from when the patient arrives in the emergency department or the door, to the first pass of the treatment initiation and endovascular therapy. And basically they found that the median door to first pass time was 130 minutes. Only 3% of patients achieved a door to first pass time of less than 60 minutes.

                                                In multivariable analyses, older age arrival during nonregular hours and a history of diabetes, were all associated with the longer door to first pass time. And finally, among hospitals with an annual endovascular therapy case volume of 40 or less, every five unit increase in that volume was associated with a 3% reduction in this door to first pass time.

Greg Hundley:                   It sounds like that could be really useful information for stroke centers, you know, that are managing these patients acutely. How do you think these results are going to impact that Carolyn?

Dr Carolyn Lam:                Great question. So first thing is, I think it provides some benchmark times for this in hospital workflow, and it obviously shows areas of improvement. For example, improving workflow during nonregular hours, or increasing the experience of a center, and basically emphasizes the point that efforts on streamlining workflow and saving time, need to continue so that the full potential of endovascular therapy is realized.

Greg Hundley:                   Oh wow, that's outstanding. I'm gonna transition sort of to a basic science paper, also trying to help manage patients with stroke. This one is looking at the safety of all of the dehydrogenased right stem cells. Well, what the world is that. In animals, what has been shown previously, is this particular cells type, that's harvested from your bone marrow, can be infused into the carotid artery, and those animals experience smaller neurologic deficits after stroke. And so with that encouraging result in animals, these investigators sought to test the efficacy of this type of therapy, well not really the efficacy, but the safety of this type of approach in those patients that have sustained actually quite a large stroke.

                                                You had to have a relatively large neurologic deficit to qualify for this study. And just quickly, the way this works is these cells enter up through the bloodstream and they modulate inflammation. By modulating inflammation, that facilitates healing in the stroke patient.

Dr Carolyn Lam:                Yeah, but wow. I mean bone marrow, biopsy and isolating the cells and so on. How is the study done?

Greg Hundley:                   So, the key here is you've had your stroke, you're still in the hospital with a large neurologic deficit. And so day 11 to 17, you undergo a bone marrow biopsy. Then the cells are purified, and they're reinfused into your carotid artery by the way.

                                                And so, what was the study trying to do? Well, it was actually looking at the safety off all this. And what would the concern be? You're infusing these cells into the carotid artery. They go into the cerebral microcirculation, and those that are working in this field, are concerned is that going to promote more emboli? Is that going to promote thrombus? Extend the size of the infarct in the brain, et cetera?

                                                So, the investigators performed MRI's and neurologic exams. And what they found is the neurologic findings in the patients really didn't change, so there was no benefit. But the study wasn't set up to look for a benefit. And there were four patients that had a little bit of an enlargement of the stroke observed on MRI. So, a lot more to come in this basic science realm, but it's interesting to see investigators thinking about this in a whole different way, where we're harvesting one cell type from your body, and then infusing it up into the brain to sort of help rescue the situation.

Dr Carolyn Lam:                Well, another paper dealing with stroke. This time, a Mendelian randomization study to explore whether genetically determined circulating levels of cytokines and growth factors, may be associated with stroke. And this was done in the mega stroke GWA data set and validated in the UK biobank, and it’s by Dr Dichgans and colleagues from the university hospital, Ludwig Maximilian University of Munich. They basically found, that a genetic predisposition to higher circulating levels of monocyte chemoattractant protein one, was associated with a higher risk of stroke. The associations also found for the etiology of the stroke subtypes, and especially for large artery stroke and cardioembolic stroke. In fact the genetically determined levels of this monocyte chemoattractant protein one, was also associated with higher risk of the related phenotypes of coronary artery disease and myocardial infarction.

Greg Hundley:                   So, how do you bring this to practice in the clinic Carolyn?

Dr Carolyn Lam:                So, this is still some steps away, but I do think that it very nicely supports the idea that inflammation as part of the pathogenesis of stroke, and of course additional work is needed to determine whether targeting the specific monocyte chemoattractant protein one, or it's downstream effectors, may be a meaningful strategy to lower stroke risk. So, terribly interesting.

Greg Hundley:                   Yeah, you know it sounds like hitting inflammation or targeting that, is a real theme here from the basic science group. Well this is great Carolyn.

                                                And now, I guess we'll transition over to our feature article.

Dr Carolyn Lam:                Absolutely. So, we're here to discuss the long-term results of the MOMENTUM 3 Trial, and that was a randomized controlled trial of the HeartMate 3 versus the Heartmate II left ventricular assist device. And this time, with a focus on stroke. The outcomes that's just so important to our patients. Greg and I are incredibly pleased to have with us, the authors, Dr Mandeep Mehra from Brigham and Women's Hospital, as well as our senior associate editor, Dr Biykem Bozkurt, to discuss this paper.

                                                Mandeep, perhaps just set the scene by telling us what this secondary analysis found?

Dr Mandeep Mehra:       This analysis is really focused on the issue of stroke, as you pointed out. I'd like to just lace into context what this is important. Ever since the advent of left ventricular assist device therapy from the 80s and early 90s, to now, one of the major Achilles' heels, whether we have used pulsatile flow devices or non-pulsatile flow devices, has been the very constant occurrence of a high incidence of stroke, beyond the stroke rates were predominantly as compared to ischemic strokes. Then with the newer devices, we actually saw a reversal, where we began to see more ischemic strokes as opposed to hemorrhagic strokes, almost an equal parts at this time point.

                                                And this has been one of the critical reasons why we have not been able to expand the therapy beyond the very, very sick patient.

Greg Hundley:                   Very nice. And another particular in the results here is, you didn't really see a difference in stroke rates, either hemorrhagic or ischemic strokes early, but you did start to see a difference after 180 days. Why do you think that's the case?

Dr Mandeep Mehra:       That's a great point Greg. We really saw no difference in the first 30 days. When we analyzed this data, we divided it into a perioperative, a first 30-day time point. Then, we looked at the short-term time point up to 180 days or six months, and then beyond that to the two year end point. What became very clear is that most of the gains that we saw in the stroke rate, began to appear after the first 30 days, did not quite reach statistical significance at six months, but really the differences became heavily pronounced after six months, all the way out to two years.

                                                So, first point that I would make Greg, is that we did see differences beyond 30 days, it's just that they didn't reach conventional statistical significance. The second thing is, the more important point that you make, asking why that was the case. We actually think that the reason behind that, is that the first three months or so after that implant, really is a period of chaos in these patients, where the hemocompatibility, which is essentially the interface between the device as well as the patient, is attempting to be established. And it's very similar in a way as we see in heart transplantation Greg, where the real challenge in heart transplantation is between rejection and infection.

                                                And in the case of left ventricular assist device is the challenges between bleeding and thrombosis. It turns out that three months, whether it be transplantation or whether it be left ventricular assist devices, seems to be this period of chaos and adjustment, during which the patient and the device are starting to get to know each other.

                                                And this is why we think that most of the gains occurred after this period of chaos was overcome.

Greg Hundley:                   No, it's really interesting that after accounting or adjusting for all the anticoagulant drugs, antiplatelet drugs, even the other medical therapies that were applied, you found these results. I mean, maybe also bring in Biykem here to answer the question, what is this machine doing that's providing such a benefit?

Dr Biykem Bozkurt:         The two-year results being quite impressive for the HeartMate 3 are truly encouraging. Because I think we truly see a concordance benefit beyond 180 days, especially the nondisabling strokes, giving the hope to the providers that we can further perhaps enhance the field by focusing on optimization of anticoagulation strategies, prevention of atrial fibrillation, and maybe even consider our algorithms or pathways for stroke. Because, in this protocol, even though the stroke management was not standardized, and I'm sure that the data will not yield that information as to which centers were able to approach the stroke management in a perhaps evidence based approach, the sobering facts are regardless of the device, at two years, approximately half of the patients died. Even the non-disabling stroke patients had increased mortality compared to no-stroke patients.

                                                And if you examine evidence-based approaches, only one-third of the hemorrhagic stroke patients had reversal of anticoagulation, and a very small percentage ... actually, none of the patients had device intervention for the ischemic stroke. That raises the question of yes at two years the HeartMate 3 results are very promising. But, can we further even advance the field by doing evidence based standardized pathway driven stroke treatment approaches.

                                                The other very interesting finding from this trial is, in ENDURANCE trial, which was another trial with centrifugal device, HVAD device, there was an association of the stroke rates with inadequate control of blood pressure and anticoagulation, which was not noted in this trial. Maybe Mandeep can comment on do we truly have the adequate power to be able to infer whether blood pressure control and/or appropriate anticoagulation management strategies will matter?

Dr Mandeep Mehra:       Biykem you've said it really well, and I'd like to just make some additional points with respect to the question. So, first of all Greg you're absolutely correct, that we tried to search for anything that would predict this reduction in stroke with the HeartMate 3, and it turned out that all we were left with is the device itself. So, it really begs the question, what is it about the device or it's interface that may have resulted in this.

                                                And of course, some of what I'm about to tell you will be speculation, but it may actually carry some water. So, for example, the HeartMate 3 is very unique in one other aspect, and that is that, even though it's a small profile device, it's engineering principles are such that it allows for very wide blood flow pathways. And in fact, despite its small profile, the blood flow pathways allow for 20 times more red blood cells to travel through the primary and secondary pathway, than other devices.

                                                What it means is that as blood is going through this device, it is exposed to very low sheer stress. And in return, the benefit that we see very clearly with this device in a very, very important way, is the fact that we see almost no denovo pump thrombosis developing with this device. Certainly, if the device doesn't carry some small quad risks in it, that cause problems with the device, it's probably also not causing the production of smaller non-device malfunction producing thrombi, which may with other devices, actually develop and cause strokes.

                                                So, we think that particular engineering enhancement, may play a very important role in reducing this stroke rate that we have observed.

                                                The second very important point that Biykem brought up, is this notion about the management of ... whether it be with anticoagulants or with blood pressure management. And for a moment let's dwell on the blood pressure issue. One of the striking things with the other centrifugal device, the HVAD device, is that the ENDURANCE Trial showed a significantly higher stroke rate with that device. And in fact, in a subsequent study, the ENDURANCE Supplemental Trial, when blood pressure was tightly, tightly controlled in the device, there appeared to be a small signal in reduction in strokes, although it still did not meet the non-inferiority endpoint, compared to the HeartMate II in the second supplementary trial that was done with that device.

                                                So, what's unique about this? Well, we can very clearly say maybe we just didn't have enough ability to show a difference in this particular trial, we didn't analyze it the right way, because we didn't have a blood pressure intervention or low or higher permissive blood pressures in this trial. But I would say that there's one other issue that I think may have played a very important role in this, and that is the HeartMate 3 is intrinsically developed with a fixed pulse algorithm. And in fact, the HeartMate 3 has a capacity where the magnetically levitated rotor upregulates itself and then downregulates itself every two seconds, and creates an internal pulsatility.

                                                Now, engineers developed that pulsatility to really decrease stasis, so that the pump wouldn't thrombose. But we often see that it provides sufficient peripheral pulsatility, not to the pulse pressures that we would normally like to see, but certainly to some degree, where the vasculature can perceive or transduce some degree of pulsatility. Why that may be important is, that it may actually allow for preservation of baroreceptor function in these patients, which tends to be lost in continuous flow pumps.

                                                And how important that is for blood pressure regulation and its vascular effect, may be something that needs to be looked at into the future. But it's certainly a very, very intriguing issue for us to examine.

Dr Biykem Bozkurt:         Mandeep, one final question or comment. Do want to comment on the stroke rates of HeartMate II compared to former trials. Because that comes as a common query as to why in MOMENTUM 3 the stroke rate in HeartMate II, appear to be higher than the former trials.

Dr Mandeep Mehra:       So very quickly, I'll tell you they're not. So, if you look at the 2009 randomized trials, randomized patients with a HeartMate II versus the HeartMate XVE trial, the two-year stroke rates with the HeartMate II in that trial were 19%, exactly what we observed at two years in this trial.

                                                Other trials have shown exactly that same number. The only trial in which there appeared to be a difference in those numbers, was in the ENDURANCE Trial, where the two-year rate of any stroke was 12%, and was a little lower in the HeartMate II than what we observed. However, I will caution you that if someone dies before having a stroke, then they die without a stroke. And so, stroke can sometimes we underestimated if the population that is enrolled, such as a transplant ineligible population at very high risk, is dying more often than having the chance of a stroke.

                                                So, I actually do not think at all that there was any difference whatsoever compared to prior trials. And even when you look at the ENDURANCE Supplement Trial, which is probably the most contemporary comparison of HeartMate II stroke rates, with MOMENTUM 3, the ENDURANCE Supplement Trial was only a one year trial, and the stroke rates even at one year were right on target with what we observed at the HeartMate II group in MOMENTUM 3. So, frankly that criticism is probably an unfounded criticism.

Dr Biykem Bozkurt:         Thank you.

Dr Carolyn Lam:                Wow, thank you Mandeep and Biykem, for really helping us go under the hood with this paper. I'm heart failure trained as well, but I learned so much, I'm sure our listeners did as well, and I'm sure you agree too Greg.

                                                Thank you so much for joining us today. Don't forget to tune in again next week.

                                                This program is Copyright American Heart Association 2019.


Dec 31, 2018

Dr Carolyn Lam:                                Welcome to Circulation on the run, your weekly podcast summary and back stage pass to the journal and its editors, and welcome to a whole new podcast format in 2019. Ha-ha, I bet that surprised you. Well guess what? This new format promises more interaction, more discussion and a whole lot more fun, and that's because to begin with, you don't have to listen to me talk to myself half the time anymore. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore, and I am simply delighted that Santa gave me a partner on this podcast, and co-hosted with me, and my gift is none other than Dr Greg Hundley, associate editor from the Pauley Heart Center, at Virginia Commonwealth University Health Sciences. Welcome Greg.

Dr Gregory Hundley:                       Thank you so much Carolyn. How exciting is it to start this new year with this exciting format, where we'll take several of the key manuscripts from Circulation and discuss them? Picking five each time, and as you've alluded to, we're not going to get rid of that favorite format, where we take a select paper and interview and work with the authors.

Dr Carolyn Lam:                                Exactly. In fact, maybe I could liken it to welcoming everyone to join us over a cup of coffee, each week, with the journal in the hand and we're just going to discuss it, and never forgetting that feature paper with the authors, and this week's paper is huge. I love it. We're actually going to be talking about blood pressure control in the barber shop. But before then, here's the articles that we've chosen to discuss. So Greg, you got your coffee ready? Shall we start?

Dr Gregory Hundley:                       Absolutely Carolyn, and let's get going first with Gorav Ailwadi, from University of Virginia, his paper evaluating the utility of MitraClips in those with secondary mitral regurgitation. This is really a follow-up from the EVEREST study. It's not a randomized trial, but it's a longitudinal look over time, at 616 patients. Interestingly, those individuals that had class three or four heart failure, that had the MitraClip, the left ventricular volumes got smaller in a year, the hazard ratio for events became less. The magnitude of mitral regurgitation went from 4+ down to 2+. Exciting findings.

Dr Carolyn Lam:                                Interesting, but you know Greg, these all sound so positive. Why is it so different in the Mitra FR study?


Dr Gregory Hundley:                       Absolutely Carolyn. So, as you know, Mitra FR, that was a randomized trial. So, this study doesn't compare, the EVEREST study in this issue, doesn't compare with conventional medical therapy, that's number one, and Mitra FR did. Also, the Mitra FR patients were a little bit sicker. The ejection fraction really was 15 to 40 percent, and in the EVEREST study, much higher, average 45 percent. In fact, many had a normal EF. So it really raises a lot of questions as to whether or not this finding will hold up in future randomized trials, which we'll be looking to see the results.

Dr Carolyn Lam:                                Indeed, and it was really nicely discussing the accompanying editorial wasn't it, which I really enjoyed. Well, the paper I picked out Greg is from Dr Gatzoulis from The Royal Brompton Hospital, and it's actually the MAESTRO trial. Now, MAESTRO is a randomized control trial of the endothelin receptor antagonist macitentan in patients with Eisenmenger syndrome. Short and long of it, macitentan did not show superiority over placebo on the primary endpoint of change in baseline to week 16 in exercise capacity. And there was also no relevant trends observed for the secondary endpoints.

                                                                However, among the exploratory endpoints, macitentan did reduce Nt-proBNP in the main cohort, and improved pulmonary vascular resistant index, and exercise capacity, in a hemodynamic sub-study. Importantly also, there were no specific safety concerns with macitentan.

Dr Gregory Hundley:                       Sounds really interesting, Carolyn. But how did this compare with prior studies that have really focused on endothelin?

Dr Carolyn Lam:                                Great question. So, MAESTRO's only the second randomized control trial of an endothelin receptor antagonist in Eisenmenger Syndrome. BREATHE-5 was the first, and this used a different endothelin receptor antagonist that was bosentan, also in Eisenmenger Syndrome, and actually found that bosentan reduced pulmonary vascular resistance as its primary efficacy endpoint, without worsening systemic pulse of symmetry.

                                                                So, very different trials in terms of endpoints, as you can hear, but also importantly, different populations that were enrolled. MAESTRO enrolled a more heterogeneous population with more complex forms of Eisenmenger, including patients with Down syndrome, had a broader WHO functional class inclusion, and allowed the use of pre-existing therapies such as PDE5 inhibitors.


Dr Gregory Hundley:                       That's really spectacular, Carolyn. Very interesting findings for something that these vasoconstrictors, vasodilators, often very harmful. Switching over, I've got sort of another paper that is also working on vasodilation, but comes really from the world of basic science. And it's from Ingrid Fleming from Goethe University in Frankfurt, Germany, examining how does hydrogen sulfide, a common gas that we have in the environment, it smells terrible, we worry about sulfuric acid and acid rain, but how does this promote vasodilation in the system?

                                                                And so, in this basic science study, they unlocked sort of a key that this hydrogen sulfide is produced by cystathionine gamma-lyase, CSE. And why is that important, and what does it do? Well, production of H2S by CSE goes and inhibits human antigen R, or HuR, that regulates cellular proliferation and growth. And so, basically these authors have unlocked a mechanism by which hydrogen sulfide can be protective.

                                                                So, what's interesting Carolyn is that patients can have elevated levels of L-cysteine, increased expression of CSE, so you've got the components and the manufacturer of H2S, but they still have low arterial levels.

Dr Carolyn Lam:                                 Hm. So, how can this be addressed then? How can we raise that H2S?

Dr Gregory Hundley:                       That's what's so clever that the investigators found out, Carolyn. They found a slow-release oral active drug, a sulfide donor called sodium polysulthionate, H2R, or sulfhydration, and can inhibit atherosclerosis development or progression when these levels are low.

Dr Carolyn Lam:                                Indeed. sodium polysulthionate. Awesome, Greg! That is so cool. Honestly I just loved your explanation of that. Okay. Well, I've got another paper to share. And this is from Dr Bress and colleagues from University of Utah School of Medicine. And this one is really interesting because these authors estimated the number of cardiovascular disease events that could be prevented, and the treatment-related serious adverse events that could occur over ten years, if U.S. adults with hypertension were achieving the 2017 ACC/AHA guideline recommended BP goals, compared to their current blood pressure levels, as well as compared to achieving the older 2003 JNC7 goals, or the older 2014 JNC8 goals.

                                                                Now, basically they found that achieving and maintaining the 2017 guideline blood pressure goals over ten years could prevent three million cardiovascular disease events, a greater number of events prevented compared to prior guidelines, but this could also lead to 3.3 million more treatment-related serious adverse events.

Dr Gregory Hundley:                       So, Carolyn, hasn't a main concern of this type of work been that these new guidelines over-extend the reach of our treatment?

Dr Carolyn Lam:                                That's a real concern that I've also heard. The lower blood pressure thresholds used to define hypertension in the 2017 guidelines could indeed lead to more diagnoses. However, this paper helped because remember that the recommendation for anti-hypertensive drug treatment in patients with the pre-treatment blood pressure of 130-139 systolic, or 80-89 diastolic, was limited to those at high cardiovascular disease risk. So not everyone, but only those at high cardiovascular disease risk.

                                                                And so, treatment under the 2017 guidelines, by these data, would lead to more health gains, while only extending treatment to 5.4% more adults with hypertension compared to JNC7. So, this paper really modeled these things out with important contemporary U.S. adult populations using a national representative, a sample of U.S. adults, and NHANES, as well as REGARDS, and they also used estimates of benefit from the recent large meta-analysis of 42 blood pressure-lowering trials.

                                                                So, important data that I think are going to be reassuring to a lot of people managing these patients. Well Greg, that really brings us to the end of our little chat. Now, let's move to our future discussion, shall we?

                                                                Could cutting blood pressure in a barber shop be the long-term solution to hypertension in African-American men? Well, the future paper of this first issue in 2019 really talks about it. Greg and I are so delighted to have with us the authors of the paper, Dr Ciantel Blyler, and Dr Florian Rader from Cedars-Sinai Medical Center, as well as our associate editor, Dr Wanpen Vongpatanasin.

                                                                So, Ciantel, can you just perhaps start by telling us what you found.

Dr Ciantel Blyler:                               So, what we're talking about today are the 12-month results as a follow-up to our 6-month results that we published earlier this year. So, we took 319 African-American men in Los Angeles County, and randomized them to two groups. One group saw a clinical pharmacist who worked with them to reduce their blood pressure, and the other group just worked with their barber to talk about blood pressure, and encourage usual follow-up.

                                                                And, as we saw at the 6-month mark, blood pressure really improved in the group that was able to work with the clinical pharmacist. So, we saw an almost 29 mm Hg drop in the intervention group, as compared to only 7 mm Hg in the control group.

Dr Gregory Hundley:                       Ciantel, Florian, that is really exciting results. What is a collaborative practice arrangement, and how did you affect that in Los Angeles?

Dr Ciantel Blyler:                               So, collaborative practice is actually widespread in the United States. California is one particular state that is kind of ahead of the curve with respect to collaborative practice between pharmacists and physicians. But what it essentially allows a pharmacist to do is to prescribe, monitor, and adjust medications underneath a physician's supervision. So, a document is drawn up, medications are selected, and an algorithm so to speak is put together so that a pharmacist can treat a patient independently of a physician needing to be there.

Dr Greg Hundley:                             Very nice. And did you find in the pharmacist-led group that these patients were taking a different anti-hypertensive regimen, or were they more compliant? What do you think was the reason for the discrepancy in this magnificent blood pressure drop in this group of hypertensive men?

Dr Florian Rader:                              So clearly, there were a lot of differences between the two groups. First of all, we had a protocol with our favorite blood pressure medications that we use clinically here in the hypertension center at Cedars-Sinai. Essentially it is long-acting calcium channel blocker, specifically Amlodipine, longer-acting angiotensin receptor blockers, or ACE inhibitors, and a third line, usually a thiazide diuretic, and also a longer-acting one, not the usual Hydrochlorothiazide, but specifically Indapamide that we used for this research study.

Dr Greg Hundley:                             And do you think that there was more compliance in this pharmacist-led group?

Dr Florian Rader:                              One would expect that. First of all, I think that seeing the clinical pharmacist, more frequently being reminded of taking the medications, having feedback by actually seeing the blood pressure numbers in the barber shop, I think would help. But then, in addition, we choose these medications not only because they affect it, but also because they're easy to take. They're once-a-day medications with very high continuation rates in larger studies, so they're just easier to take than other medications that are oftentimes prescribed.

Dr Greg Hundley:                             It sounds like also, there might have been a trust factor. Because you're seeing the same person over and over in a very nice environment. Was that a factor?


Dr Ciantel Blyler:                               Absolutely. I think there's a different level of trust that's established when you meet somebody on their own turf. So I think the fact that we met men in barber shops where they felt comfortable, where many of them had been going to the same barber for over a decade, it made all the difference in terms of establishing a rapport, and gaining their trust with respect to having them take medications. So, I think that was a huge part of why we saw increased adherence, and really sort of a commitment to the program.

Dr Greg Hundley:                             And we certainly recognize how harmful hypertension is in individuals of Black race. How does this group in Los Angeles translate to perhaps other Black men in the United States? Particularly, for example, in the South.

Dr Ciantel Blyler:                               I think the program could translate really anywhere. I think what makes it so tailored to African-American men is this notion of going into a barber shop, which is a very important place in the Black community. So, again, sort of going back to what I said earlier, most of these men had been seeing the same barber as frequently as almost every two weeks for over a decade. So, it really helps increase the frequency with which we could interact with the men, and it helped with continued follow-up and adherence to the program.

                                                                With respect to the area of the country again, I think it translates.

Dr Carolyn Lam:                                I've got a follow-up question to that, if you don't mind. So, I'm here listening all the way from Singapore, and I'm just so impressed, and frankly just enamored by this study. And wondering what is the barber shop to my local Chinese guy? I'm actually wondering if it's the kafei dian and that stands for coffee shop, and I'm also wondering what about the women? Wanpen, do you have any insights that you want to share?

Dr Wanpen Vongpatanasin:         I believe that even Dr Victor had thought about the beauty shops, that is a barber shop study in parallel, and this could very well work very well. Who knows, we could be going to massage parlor, anywhere, that when we feel relaxed and be ourselves, we go out our way, out of our regular activity, and it could really be a neat idea. And for a study, I'm not sure I could do something out of the box. I would say it must have been successful as this approach, and partly it could be because of the additional pharmacists engage likely. So, I think this is a perfect combination.

Dr Greg Hundley:                             Wanpen, you had mentioned Ron Victor. Maybe Ciantel, Florian, and Wanpen, you used to work with him. What did Ron mean to this study? Ron Victor unfortunately passed away this past Fall.

Dr Florian Rader:                              Ron hired me almost seven years ago now straight out of fellowship. He was personally my mentor. He taught me all the tricks when it comes to the work of the management of hypertension, so personally I owe him a lot. Regarding the study, he's been thinking about this for a long time, this approach to hypertension management. He's tried it in Dallas. It worked partially, but not very well because he didn't have a pharmacist, and he didn't have somebody that made it their goal to lower blood pressure no matter what.

                                                                And in this study, we had somebody like that, the clinical pharmacist. So, Ron Victor has thought about this for a long time, has done a lot of analysis of the Dallas hypertension study, and figured out why it didn't work out in Dallas, and really cooked up a recipe for this trial, and the results speak for themselves.

Dr Greg Hundley:                             Wanpen, do you have anything to add about Ron? I think he was your mentor as well.

Dr Wanpen Vongpatanasin:         Absolutely. I trained with him actually from the internship until fellowship, and I owe my career to him. And actually, I see this idea stemming from the Dallas heart study when he did the survey, and realized that if you just wait for patients to show up in the clinic, that you're not going to get anywhere, because African Americans have higher blood pressure at a younger age, and are more susceptible for target organ damage. And as we all know, by the time many presented with, they already have end-stage kidney disease or cardiovascular disease by the time first presentation. So, to avoid it, we have to go into much earlier, not wait until they come to the healthcare facility, and I'm glad to see that this idea is really becoming widely successful more than anyone can imagine.

Dr Carolyn Lam:                                What a beautiful tribute. What a poignant note. Thank you, all of you, for your great input, and for publishing this amazing paper with us at Circulation!

                                                                Thank you, listeners, for joining us today on Circulation on the Run with Greg Huntley and me. Thank you, and don't forget to tune in again next week.

                                                                This program is copyright American Heart Association 2019.


Dec 24, 2018

Dr Amit Khera:                  Welcome to Circulation on the Run, your weekly summary and backstage pass to the journal. I'm Dr Amit Khera, associate editor and digital strategies editor from UT Southwestern Medical Center in Dallas. And I have the privilege of standing in for Dr Carolyn Lam, your usual weekly podcast host. Today we have a special treat. It is our semiannual fellows and training FIT podcast. And the additional part of this treat is we have three very special FITs today. These are our assistant editors for social media for Circulation. And really I want to introduce you just a moment, but I want to thank these three for their hard work and efforts. It really is them that helped bring our social media to life. And importantly for us, we really have a commitment to enhancing fellow education involving fellows in our editorial process and really making sure that the journal is appealing to fellows in training. So we really rely on these three to help us understand what best resonates and what is most helpful for fellows in training. So without further ado, Jainy Savla from UT Southwestern. Welcome Jainy.

Jainy Savla:                         Thanks for having me on the podcast today.

Dr Amit Khera:                  And we have Daniel Ambinder from Johns Hopkins University. Hi Dan.

Daniel Ambinder:             Hey Amit. Thanks for having me on the podcast today.

Dr Amit Khera:                  Absolutely. And finally we have Jeff Hsu from UCLA. Hi Jeff.

Jeff Hsu:                               Hi Amit and hi everyone. Very glad to be here.

Dr Amit Khera:                  Well, Jainy, I'm going to start with you. You've been with us on the social media side the longest. I think it's maybe almost a year or a bit more that you've been working on these efforts. And again, very much appreciate all of your hard work and insight. Tell us a bit about yourself.

Jainy Savla:                         So I'm currently a research fellow at UT Southwestern. So I completed my general cardiology training and I've been doing some extra research training in one of our basic science labs there.

Dr Amit Khera:                  So not surprisingly with your background, do you select an article? So we've asked them each to select one article as they've been working through the social media side and see all of our articles come through. Each to select one that they found was interesting and perhaps summarize for us what it included and what appealed to them. So Jainy, tell us a little bit about the article you chose and why you chose it.

Jainy Savla:                         So, I chose one of the articles that was published in April of 2018 from the Molkentin team lab. And this is a basic science article that focused on which types of cells contribute to heart regeneration. They hadn't thought that there was cardiac progenitor cell that could contribute to the development of new cardiomyocytes. And more recent data has shown that maybe that's not quite the case. So what this study did was used a lot of fancy lineage tracing models to try to figure out which types of cells we're actually contributing to the development of new cardiomyocytes. So importantly, what came from this was that one of their models, they were able to delete two transcription factors that are necessary for cardiomyocytes to develop from these progenitor cells. But they found that when they did that, they even got a higher number of cardiomyocytes that formed. And then what they were able to show in this paper was that actually comes from fusion of leukocytes to cardiomyocytes. And then interestingly, they found a role for one of these transcription factors and the development of endothelial cells. So that was kind of a new, not known function of one of these genes that was previously thought to be just contributory to cardiac development.

Dr Amit Khera:                  It's really a fascinating article when you think about it. Most of the science we publish are people bringing to light new discoveries and certainly there was a component of that here. But in many ways, it was kind of a different article where there had been this a prevailing thought about these c kit positive cells and here they're actually had gone through, refuted what people had thought was happening with these in this de novo cardiomyocyte formation. So you'll see that very often where people's articles or work is headed out to sort of maybe refute or set right what's happening in the literature in the field. Can you comment on that as to that type of article and how that appealed to you in this study?

Jainy Savla:                         That is interesting because previously it has meant that these cells can be used as a therapeutic option in human patients. But some of them were recent data showed that perhaps the new cardiomyocytes weren't actually coming from these cells, but it was hard to say. So the nice part about this paper was really they used a lot of important lineage tracing models to really show where these cells are coming from. And it helped clarify some of the, I guess, more confusing science that had been in the field since there were a few papers that showed these cells were contributary and then a few papers that have shown that maybe they weren't. So I think that's really helpful, particularly when you're talking about things that could be potentially used as therapeutic agents in human. And also the interesting thing is that while these cells themselves may not be useful to perhaps harvest and give to someone, you could potentially alter these cells and then they produce cells that fuse with cardiomyocytes. Or could you use this a different way? So I thought that was also interesting about this article.

Dr Amit Khera:                  Great points in it. It does remind us again that in our enthusiasm for rushing things to clinical practices in some things in this field, the importance of rigorous basic science to really understand the molecular underpinnings. And as you mentioned, there's some new insights here that could be used for clinical therapeutic purposes in the future. So definitely an interesting article and glad you enjoyed it and brought it to our attention. I'm going to ask you a bit of a different question. You again have been working with this in the social media side for longer. You've seen this now for some time about the different articles that come through. I know you and I've had several conversations about our different platforms, Twitter or Facebook, and how they're different and how we engage with them and how we engage with the audience. Can you tell us a little bit just reflecting now on your time and working with social media from a journal perspective, kind of what you've learned? What are some interesting observations over this year?

Jainy Savla:                         Definitely one interesting observation is just that their general usage of these social media platforms has increased significantly since I've started doing this. And you can see this with when we get articles that are accepted, how many authors have Twitter handles that they'd like to be tagged in some of these posts. And that's just gone up significantly since I've started doing this. And that also changes sort of what the comments we get on some of the posts and the back and forth discussions that we're seeing on these platforms. And then the second thing I found really interesting over time is that the way people use Facebook is really different from the way people use Twitter. And you can follow the discussions that people have linked to our posts a little bit better on Facebook. And then on Twitter, there's also a lot of similar discussions about these posts. But they kind of manifest in different ways and it's really interesting to see how that plays out.

Dr Amit Khera:                  I think those are fantastic points. And from a fellow's perspective, how do you think fellows are engaging with social media now compared to maybe, I don't know, when you started your training a few years back. What have you seen in a positive light?

Jainy Savla:                         I mean in general, there are more fellows on Twitter now than when I was a first-year fellow. Even myself, I've got my Twitter account when I was in fellowship. I didn't have one prior to that. I mean it's interesting because people are able to showcase their work a little bit better I think with these types of handles whereas before maybe you wouldn't know that even one of your own co fellows had published something. So it's kind of nice to see people use that kind of as a networking tool in some ways or to showcase some of their own work, which is something that when I was a first year and I didn't have a Twitter handle and there weren't as many fellows on Twitter, I didn't really notice some of the work that's being done by some of my colleagues at my level.

Dr Amit Khera:                  Those are great points and I'll stoplight some of the things you just said talking about it being a way for fellows to really showcase their work, to help with networking and in some ways, it's sort of the great equalizer. So I think it's really a valuable platform specifically for fellows. Well thank you Jainy. I'm going to move on to Daniel and hear a little bit from Daniel. Tell us a bit about yourself.

Daniel Ambinder:             I'm currently a second year cardiology fellow at John's Hopkins Hospital and I plan on doing interventional and structural cardiology in the future.

Dr Amit Khera:                  Great and certainly a lively and growing field and so many exciting things happening. Well, it's interesting you chose an article today that is more of a clinical article and obviously quite different than the last one we heard, but equally as interesting. Tell us a little about the article you've chose and why you chose it.

Daniel Ambinder:             I was very excited about this article that was published in Circulation back in July 2018. So, it's by Dr Borlaug and Reddy on how to diagnose HFpEF and what they did was they took patients with clinical dyspnea and they used invasive human dynamics to kind of assess whether or not they had HFpEF. And by doing so they were able to generate a list of clinical and eco based guidance to help us kind of identify patients with heart failure with preserved ejection fraction. So they came up with this amazing little table which was featured in Circulation and on Circulation twitter, where they have a chart that basically goes through several clinical variables including weight and hypertensiveness, atrial fibrillation, pulmonary hypertension, being elderly. And filling pressure is based on echo cardiographic information. And by that they were able to generate a score and give you a probability of if your patient has HFpEF or not.

                                                And the reason why I really enjoyed reading this article and also posting this article was because going through internal medicine and not being so fundamentally aware of echo and kind of what goes into understanding left ventricular filling pressures, it was challenging to make a diagnosis of heart failure with preserved ejection fraction. Do you just basically say, "My patient has lower extremity swelling but normal EF? They have heart failure with preserved ejection fraction and [inaudible 00:09:32] on the [inaudible 00:09:33]. And so I thought that this would be really helpful to the medical community at large. And in fact, shortly after we posted it, I saw that our cardiology console fellow is actually utilizing this exact table to help one of the medicine teams manage a patient with lower extremity swelling and come to the diagnosis of heart failure with preserved ejection fraction. So that is why I chose this article for today.

Dr Amit Khera:                  That's a great article and I thought you summarized it very well. And it is a field. HFpEF you'd see a lot of articles in Circulation on this topic. We have many people that are interested from an editor’s level but also from a society level. This is a huge problem, but we know very, very little. And I'm sure you know that as well and this was a wonderful tool. Just shows you're sort of the beauty and simplicity. Although if you read it, the message were pretty rigorous and they had a lot of great work that they did to develop it. But I love that the H2 HFpEF, how they basically came up with it h for heavy and the f from fibrillation. So I thought that was incredibly creative and a very simplistic but useful score. So, you said your, tell us about yourself. Have you used the H2 of the HFpEF score yet?

Daniel Ambinder:             Absolutely. I use it in clinic on a daily basis. And I actually pull up the Tweet in my office and show the patients why I think that they have heart failure preserved ejection fraction, especially since many of my patients start to get really nervous when you start talking about heart failure. But then they don't understand that they have a normal functioning heart. They can't really put those two together. And so going through this chart and going through the etiology, or at least what we know about heart failure with preserved ejection fraction, turns out to be quite helpful.

Dr Amit Khera:                  And the basis of this study goes back to hemodynamics. This obviously is a cohort where they had done invasive hemodynamics to essentially diagnosed HFpEF based on pressure. So as you, as someone who's going interventional and structural where we are really seeing kind of the rebirth or refocus on hemodynamics again, tell me a little bit like what you're learning in terms of hemodynamics and how you think that importance in today's practice of cardiovascular medicine.

Daniel Ambinder:             One of my passions is spending as much time as I possibly can in the cardiac ICU. And we're fortunate to meet many different patients that come in with very different kinds of cardiogenic shock for other hemodynamic compromise from other types of shock. And I have found it extremely helpful to think about either using a virtual Swan or by actually getting the measurements with a PA catheter to kind of identify where the break in the system is to hopefully provide our patients with the ability to turn them around in a fast manner before they develop metabolic compromise from prolonged hypoperfusion.

Dr Amit Khera:                  Great summary of how you're using hemodynamics and the training. And I'm going to pivot. The last question for you is when we first met I think several months back and we're communicating about your interest in social media, one thing that was really interesting and fascinating was the great work you're doing on Twitter on your own account where you essentially, if I think you told me this right, you sit on your iPhone and basically in this matter of a very few minutes would construct cases and teaching points on Twitter. So tell me a little bit about that, about using Twitter for medical education and learning cardiology and cases. And I know you're passionate about that. So tell us a little bit more about that.

Daniel Ambinder:             Back in May, last year, I had been in my first year of cardiology fellowship. And I was really kind of obsessed with grabbing as much imaging and cases as I could to construct them into teaching stories to share these important stories that I encounter with other people. And so also share the aha moments that I have when I'm learning from my mentors about a new clinical condition or even a clinical condition that I've encountered many times. We never thought about any unique way. And so I was putting these all together and developing somewhat of a library of cases. But I would share them with the residents that I was working with at the time. And then Dr Erin Michos was one of my mentors at Hopkins. She's an echocardiographer and she kind of exposed me to the Twitter community where you're really able to just start reaching out to different people and share the same insights that I had saved on my drive on my computer. And so I started constructing these cases, putting that together and developing them and then associating them with like a few bullet pointed tidbits of pearls that I can put on Twitter. And I quickly realized what an amazing community Twitter have to offer in terms of cardiology and in terms of the medical education community at large.

                                                At first, I realized you can't put out content and not expect to participate in a conversation. It has to be two ways. You have to really engage with others and others will engage with you. And then just a couple months later, it's really grown that you can post a case, post the teaching pearl and in about 24 hours it can be viewed thousands and thousands of times, really internationally. And generates just so much great conversation. So it's been really a tremendous way to communicate with the world, especially within the cardiovascular world.

Dr Amit Khera:                  Well thanks. I think there's so much learning that can happen and I think the work you're doing with cases and with others. And I know when I've gone on Twitter, even in just two minutes you can see really fascinating things and learn a lot. So keep up the good work and appreciate your efforts there. I'm going to switch gears and finally finished with Jeff Hsu from UCLA. Jeff, tell us a bit about yourself.

Jeff Hsu:                               I'm a fellow at UCLA. So I actually finished my general cardiology fellowship pretty recently and now I'm a research fellow in the STAR program here. I'm also enrolled in the PhD program at UCLA in the Department of Physiology and planning to defend in the next few months. So right now, very stressed out about that. Starting in July, I'll be starting advanced fellowship in advanced heart failure and transplant here at UCLA.

                                                Well excellent and best of luck to you in your PhD defense. Now you also chose a very interesting article that again, all of yours are a bit different. So tell us a little about the article you chose and why you chose it.

                                                When I chose this article, I was really excited by a few weeks ago. It was published in the December 4th issue of Circulation called Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human Induced Pluripotent Stem Cells. So this came out of the lab of Joe Wu at Stanford and the co first authors is Ning Ma, Joe Zhang and Ilanit Itzhaki. But I think the beauty of this article is that it really addressed this frustrating clinical scenario in question that we often encounter nowadays in this era of genome sequencing. And now that we're sequencing a lot more people, since the cost of sequencing has come down a lot, we were finding a lot of these mutations that we don't know what to do with, so I think Dr Wu's lab really try to address this question using the disease model with the cardiomyopathy. So, leveraging Dr Wu's expertise in using human induced pluripotent stem cells or iPSCs, they found a patient who is actually healthy but apparently had this mutation in this gene called MYL3 or myosin light chain 3. And so this patient had a variance of uncertain significance in this gene.

                                                Now, notably, this patient, again had no clinical phenotype, was very healthy and the patient's family members over three generations were all healthy too. But had this mutation that based on in silico analyses was thought to be likely pathogenic. So using cells from this patient that they reprogrammed into cardiomyocyte, they tested various properties of these cells from the same patient to see whether or not they thought this mutation is actually a pathogenic mutation. So again, using these reprogrammed cardiomyocytes, they tested a variety of things including gene expression, sarcomere structure, and cell contractility, action potentials, and the handling of calcium. And they saw that even with this mutation, there were no abnormal findings in vitro in their system.

                                                Now just to prove that their cell culture system and this in vitro model of testing the pathogenicity of certain mutations actually works, they actually took cells from a patient who did have the clinical phenotype as a result of a known mutation that causes hypertrophic cardiomyopathy. And found that when testing those cells in vitro, they did demonstrate abnormal phenotypes in all the parameters I mentioned before. So I thought this is really exciting. I thought this is a great way to address, potentially answer whether or not we think these variants of uncertain significance that we often encounter are indeed pathogenic because we are often just left in this situation where we don't know what to do with this information. But this potentially at least is a proof of concept for this protocol where we can finally take advantage of the ability to take cells from our patient and actually test them in the lab to see whether or not either various treatments work or whether or not these mutations that actually will results in pathology down the line. So I thought overall this was a great paper that was a great summary of how we can take the bedside to the bench actually. And I'm just really looking forward to the future where we can maybe then bring it back to the bedside.

Dr Amit Khera:                  Well thanks. I think that's an excellent choice and a great summary. And this article really hit all of the kind of timely and cutting-edge topics in the era genomic medicine and precision medicine have really kind of individualized treatments. And when we get stuck, these VUSes, these are a nightmare. And also this is sort of proof of concept for extending this to other treatments and other ways to test drugs and therapies. I've heard Joe, we talk about this before and use the word disease in the dishes. He did I think in the article itself and it's exactly that. I mean the potential here is profound. I'll pivot this into the next question for you. For our roles, one thing we do is we interact a lot with media and I interact a lot with them to help translate, I guess, the articles that we have to things that would be able to be digestible for media and for lay individuals. It was interesting because it's hard for us to do that with basic science and most of the time we have some difficulty in translating that. But this one translated pretty well and I think we had done some various press releases and things because it really showed the potential of modern medicine and kind of the excitement of it.

                                                But that gets to the question I have for you, something we have discussed as well, your interest in basic science and some of the challenges of taking basic science articles and digesting them down to a couple hundred-word tweet. Even as beautiful as all the pictures are, and in this article I think there's six figures, but each panel is 10 pictures or 10 figures by themselves. And how do we digest basic science articles down to make them really appeal to people on social media and help people understand that may not be in the fields or in basic science that are clinicians, if you will. I know you've thought about that a little bit. Tell me a little bit about your thoughts on that.

Jeff Hsu:                               Jainy, Dan and I have this challenge on a weekly basis, figuring out how to summarize great articles such as this one into a short tweet. And I think that is a big challenge particularly for basic science articles on social media to make it appeal to a broader audience because the audience you're seeing on Twitter and Facebook, again, they're not just basic scientists. If you want to catch people's attention, you need to find a way to really understand the big picture of the question you're answering in your basic science research. So I think that is a challenge. You're challenged to make your science appealing to a broader audience. But I think again, that's one of the advantages of social media is that you can appeal to a larger audience and have a wide range of people engage with your research and understand your research. So it is something that we work on is to try to pick out the figure that best represents the science that was done in these basic science articles.

                                                It can be quite challenging because a lot of times one picture won't do it justice. So it's tough to distill a full article in one picture. It is helpful when some articles do have a summary, a graphic or figure where they typically reserve their last figure for either a cartoon or some type of schematic that really explains either the mechanism or pathway that they explored in their article. So what we've found is that these articles that do have some of these illustrations or summary figures, they seem to engage a larger audience on Twitter and social media. So personally I find it more appealing when I do see these summary figures. So if there is one recommendation, I would have the basic science researchers, especially trainees is in this age of social media, try to come up with an illustration or summary figure for your research. I think it helps you figure out what is truly important with the research that you've done and helps you communicate this research to a broader audience. And I've seen a lot of people take advantage of a graphic designers to really help them illustrate their research. And I found that to be very effective in articles I've read on social media.

Dr Amit Khera:                  Thanks Jeff. That's a great point and great suggestion. And certainly these days the most effective communicators are those they can translate their complex science into easily digestible bites and can think of ways to portray them in ways that sort of summarize, like you said, be it summary figures or otherwise. And it's a challenge and also talent. And you all are certainly perfecting that. Well, I think we've had an excellent conversation. I have to tell you, I'm so excited to get the chance to spotlight you all. You do excellent work each day. Every week you're working hard and coming up with great ideas and suggestions and we really value having your input as fellows and training and as a colleague.

                                                Thank you for joining us today on our FIT podcast. Amit Khera standing in for Carolyn Lam. We look forward to seeing you for our next edition of Circulation on the Run. This program is copyright American Heart Association 2018.


Dec 17, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

                                                In today's feature discussion, we will be doing a deep dive into the LEADER trial results, looking at new results of liraglutide and its effects in patients with type two diabetes, with or without a history of myocardial infarction or stroke. All of that coming right up after these summaries.

                                                In today's issue, five groups of investigators in two original basic research articles and three research letters tackled the same biological question, and all reached the same conclusion that cells in the heart expressing the SCA-1 cell surface antigen do not become cardiomyocytes to any meaningful degree, and instead become endothelial cells. Among the original basic papers, first author Dr Vagnozzi, corresponding author Dr Molkentin from Howard Hughes Medical Institute and Cincinnati Children's Hospital Medical Center, and their colleagues use the inducible recombinase method and generated a constitutive recombinase at the SCA-1 locus. They found that cardiac resident SCA-1 positive cells were not significant contributors to cardiomyocyte renewal in vivo. Instead, SCA-1 positive cells generated cardiac vasculature throughout development, during aging, and following injury with trivial contribution to the cardiomyocyte population.

                                                In the second paper from co-first authors, Drs Zhang and Sultana, with corresponding author Dr Cai from Indiana University School of Medicine and colleagues, these authors engineered a series of genetically altered mice to identify and track SCA-1 positive cells in the heart, and found that SCA-1 positive cells were purely of the endothelial lineage. Together with three research letters, these five papers add to the growing body of evidence that in adult mammals, our new cardiomyocytes arise from preexisting cardiomyocytes and rarely, if at all, from adult cardiac stem cells.

                                                Could metformin be cardioprotective in patients with type one diabetes? Co-first authors Drs Bjornstad and Schafer, corresponding author Dr Nadeau from University of Colorado School of Medicine, and their colleagues hypothesized that adolescents with type one diabetes have impaired vascular function, and that metformin may improve insulin resistance and vascular dysfunction.

                                                To test this hypothesis, they studied 48 adolescents with type one diabetes and 24 non-diabetic controls using MRI of the ascending and descending aorta, as well as assessment of carotid intima-medial thickness by ultrasound, brachial distance ability by DynaPulse, fat and lean mass by DXA, fasting labs following overnight glycemic control, and insulin sensitivity by hyperinsulinemic euglycemic clamp. The adolescents with type one diabetes were randomized one as to one to three months of 2000 milligrams metformin or placebo daily, after which the baseline measures were repeated.

                                                The authors detected early signs of cardiovascular disease with MRI in these adolescents with type one diabetes compared to controls. They further found that three months of metformin therapy improved insulin sensitivity as assessed by gold standard hyperinsulinemic euglycemic clamp, both in normal weight and obese adolescents with type one diabetes. Moreover, metformin improved carotid intima-medial thickness and aortic wall shear stress and stiffness. Thus, metformin may hold promise as a cardioprotective intervention in type one diabetes.

                                                What are the clinical genetic and environmental determinants of varicose vein formation? Co-first authors Drs Fukaya and Flores, corresponding author Dr Leeper from Stanford University, and colleagues applied machine learning to agnostically search for risk factors of varicose veins in nearly half a million individuals in the UK bio bank. They found that greater height appeared as a novel predictor of varicose vein disease in machine learning analyses, and was independently associated in multi-variable adjusted Cox regression. Using Mendelian randomization, they demonstrated that greater height had a causal role in varicose vein development. A genome-wide association study identified 30 new genome-wide significant loci, identifying pathways involved in vascular development, and skeletal/limb biology, and discovering a strong genetic correlation between varicose veins and deep vein thrombosis. The knowledge greatly expands our understanding of disease pathophysiology, and may help future improvements in the management of varicose veins and their associated complications.

                                                The final original paper describes the effect of glucagon-like peptide-1 receptor agonist liraglutide on cardiovascular events, and all-cause mortality in patients with type two diabetes and chronic kidney disease. First and corresponding author Dr Mann from Friedrich Alexander University of Erlangen in Germany and their colleagues performed a post hoc analysis of the LEADER trial comparing the liraglutide's treatment effects in patients with and without kidney disease.

                                                As a reminder, LEADER was designed to recruit a subgroup of at least 660 patients with an estimated glomerular filtration rate, or eGFR, less than 60, approximately 220 patients with severe renal impairment, eGFR less than 30, and at least 440 patients with moderate renal impairment with an eGFR of 30 to 60. The authors found that the liraglutide reduced the risk of major adverse cardiovascular events, and all-cause mortality compared with placebo in patients with chronic kidney disease defined as an eGFR less than 60, and also in patients with albuminuria defined as a urinary albumin to creatinine ratio above 30.

                                                The overall risk of adverse events did not differ between the liraglutide and placebo treated patients either with or without chronic kidney disease in the LEADER trial. In summary, these results show that liraglutide added to standard of care reduced the risk of major cardiovascular events and all-cause mortality in patients with type two diabetes and chronic kidney disease. Furthermore, these results appear to apply across the chronic kidney disease spectrum that was enrolled.

                                                And that brings us to the end of our summaries. Now for this week's feature discussion.

                                                Cardiovascular outcome trials have transformed the world of treating patients with diabetes. And for our feature discussion today, we're going to be talking about a new analysis from a very important trial, the LEADER trial of GLP-1 receptor agonists, and that's the liraglutide. I'm very proud to have the corresponding author of this paper with us, Dr Subodh Verma, and he's from St Michael's Hospital and University of Toronto, and our senior associate editor, Dr Gabriel Steg, from University of Paris. Actually, Gabriel, I'm actually going to start with you for once because I recall perhaps something you may have written about cardiovascular outcome trials.

Dr Gabriel Steg:                Yeah, it's really funny. I'll try to take it graciously. You know, I wrote a frame of reference in Circulation a few years ago, wondering whether we were doing good by doing all these large outcome trials for safety with new anti-diabetic drugs, because there had been not one but two, three, four, five, six trials that were essentially neutral, enrolling more than 107 patients and participants at the expense of millions of dollars, and not much came out of it. And this was published in circulation. I was very happy until the next trial comes up, and this is EMPA-REG. And the next one is LEADER. And we have two trials that literally transform our vision of anti-diabetic agents as major agents for cardiovascular prevention. The trial we're going to discuss today, which you wrote about, is one of these trials. And I think I have to revisit my own writings and probably eat my hat.

Dr Carolyn Lam:                So indeed, that's a great segue. Thank you, Gabriel. And Subodh, tell us then, what did you look at this time in LEADER? And maybe start by saying a little bit about LEADER, and the rationale for doing this particular sub analysis.

Dr Subodh Verma:           Right. So, as Dr Steg mentioned, these were FDA-mandated studies to look at safety and potential efficacy of newer antihyperglycemic agents. The entire premise was that cardiologists and cardiovascular specialists were not really getting that excited about antihyperglycemic therapies in people with diabetes, because there was no data that they did much. And as Dr Steg mentioned, even the data leading up to some of these trials were disappointing, suggesting that they're safe, but they neither reduce nor increase events.

                                                So, I think EMPA-REG and LEADER really changed the calculus in many ways of how we look at cardiovascular risk reduction with antihyperglycemic agents. LEADER was a trial that was 9,340 patients. These are patients that were at high cardiovascular risk, but unlike EMPA-REG that only enrolled people with prior to ischemic cardiovascular events ICAD, PAD, and CVD, LEADER took a position of enriching the population with this spectrum of patients with cardiovascular disease and risk factors.

                                                So, some were in so-called high risk primary prevention who had not had established ASCVD, but had multiple risk factors such as uncontrolled hypertension or chronic kidney disease. Some had evidence of ASCVD, but had not had a prior myocardial infarction. And some, in fact, had had a prior MI stroke or PAD. So, it was a broad population of patients that was enrolled. And the primary result, again, for the primary outcome of MACE, demonstrated a significant reduction in favor of liraglutide versus placebo. And then for the individual components of that primary outcome, they were all statistically significant, or at least went in the right direction. Importantly, CV death was reduced by 22% with liraglutide versus placebo.

                                                I would like to emphasize that in this day and age, and Dr Steg has nicely set the stage, we have started thinking about how do we think about cardiovascular phenotypes of patients. You know, is a drug more likely to reduce heart failure? More likely to reduce ischemic events? And with LEADER, we found that in fact the trial actually reduced mostly ischemic events, and was really not that beneficial on heart failure related outcomes.

                                                So, that was the broad positive outcome from LEADER. They've led to guideline changes worldwide that patients with diabetes should be prioritized to receive an agent that has shown benefit, particularly if they have cardiovascular disease. And one of those agents was empagliflozin. The other was liraglutide. But, secondary prevention is a pretty crowded space, and not everybody can get everything, and not everybody should get everything, and not everybody can afford everything. So, I think leaders like the two of you here are often thinking about, how do you risk-stratify these populations, and how do we start thinking about people who are at greater risk, people who can actually derive benefit? And I think that's the smart and thoughtful way of doing this. And is there a certain threshold at which point the therapy loses its ability to reduce cardiovascular events, at least in the short term?

                                                So, in that theme, in that vein, what we looked at here was an analysis of people in LEADER who truly had a prior ischemic event. And the work that Dr Steg and others have done in REACH registries, etc. clearly establish that that's a population of patients, type two diabetes and a prior ischemic event. You don't really need many more calculators beyond that. That's the highest risk population. And then, the next level is really type two diabetes with a ASCVD. And we know that from REACH as well, that that's the next level of risk. And then, what about people who have type two diabetes just by itself? Which certainly are much higher risk than people who don't have diabetes, but we didn't have a non-diabetic group to compare to.

                                                And what we find is that the higher the baseline risk defined by this, the greater is the absolute risk reduction. The P value is consistent for ... You know, this is non-significant for heterogeneity. but specifically, people with a prior ischemic event derive benefit. People without a prior ischemic event who've had ASCVD derive significant benefit. But, in fact, we found that the curves were almost superimposable for people who did not have prior ASCVD. And that's not to say the GLP-1 receptor agonists should not be used in diabetes in the absence of cardiovascular disease, because they're great glucose lowering agents. They cause hypoglycemia, they cause weight loss. And potentially, within longer exposure times, cardiovascular benefit may actually emerge. And we've heard data from Dr Gerstein's study called Rewind that is positive, that will be presented next year. Harmony Outcomes was a study that was presented recently that also showed a benefit. So, whether in the primary prevention group we see a benefit in the future remains to be seen.

Dr Carolyn Lam:                Oh, that's a great, great summary. But Subodh, you know, it's become a bit of what do we define as a primary and secondary prevention anymore, you know? And the patient that already got type two diabetes. Now, in this paper, it's very nice. As you said, has a history of myocardial infarction and stroke. And maybe I could just clarify to the audience, you couldn't just pick up the primary paper and see that because the way the inclusion exclusion criteria were designed in LEADER, you can't just pick up the sub-groups. So, this specific analysis, so carefully and wonderfully done, was absolutely needed. But then you know, what do you think? What's primary and what's secondary prevention anymore?

Dr Gabriel Steg:                Well, I want to commend the authors for doing the careful stratification of diabetic patients they've done in the paper, and particularly for pointing out that it's one thing to have had an event where you actually ruptured a plaque and had a traumatic event. And it's very different from merely having plaque in one of your carotids or your arteries, and which is, of course, in turn very different from the majority of diabetic patients who have neither an event, nor diagnosed plaque or established plaque. And when we think about preventing cardiovascular and diabetes, we have to remember that the outer circle, the broader circle of diabetic patients who haven't had disease is the largest component.

Dr Subodh Verma:           True.

Dr Gabriel Steg:                And these are the patients whom we treat every day with the hope of eventually keeping them from harm, safe from harm, or with therapies that are new and potentially beneficial. And I think your research very clearly shows that there's a gradient of benefit. The sicker the patient, the greater the benefit in preventing MACE. And as long as you get to more healthier phenotypes of diabetes, then there is less of a benefit. Which doesn't mean that we shouldn't use these agents. As you point out, they're very convenient and effective agents for glucose control. But then, their cardiovascular benefits are more uncertain. And I think this is the key message from this analysis, and it's a great analysis.

Dr Subodh Verma:           Thank you. I appreciate that. I totally agree that for the doctor in the trenches, particularly the cardiologist who's just trying to get their feet wet with antihyperglycemic therapy, you know? Cardiologists will embrace PCSK9 inhibitors and rivaroxaban at low dose, and maybe a new way of doing surgery or putting an LVAD. But it's very hard to get their attention when it comes to antihyperglycemic therapy. So, defining for them the population that matters the most, where the greatest risk and risk reduction can be achieved, I think is quite important from a clinical standpoint. And I think most cardiologists will agree that type two diabetes and a prior ischemic event is a high-risk population. Type two diabetes in a prior ASCVD is a high-risk population, and the magnitude of CV death reduction here is something meaningful for them to pay attention to.

Dr Carolyn Lam:                Yeah, indeed. That's what I love best about this paper. It's actually asking the question the way a cardiologist would, exactly like you had both put. So, what do you think is the next step now? Do you think we need to look at this primary prevention type two diabetics with no established cardiovascular disease? Do we really need to? Is it that we need a method analysis, which you can talk about? Or, is it that we need longer follow up? Or, what next?

Dr Subodh Verma:           I think that first of all, we have to get rid of the terminology, and maybe as a heart surgeon, I can be a little bit provocative and just say it. I wrote an editorial to the Declare Study that was just published yesterday in The Lancet called "Pumps, Pipes, and Filter: Do SGLT2 inhibitors cover it all?" Then I made a strong statement there that this nomenclature of primary and secondary really is artificial because it only captures ischemic risk, and does not capture risk of heart failure or renal disease. So, in a patient, as you've asked, Carolyn, who has type two diabetes, whose renal function is 54 or GFR is 55, who's not had a prior MI ... Is that patient primary prevention? Maybe from an ischemic standpoint, but he's clearly secondary prevention from a renal standpoint.

Dr Subodh Verma:           So, I think we need to just think about all disease as a spectrum, and not as an artificial cutoff that, if you've had an ischemic event, suddenly the world changes for you there. Because, that gradient I think is probably what we need to somehow appreciate as to where that risk lies. The patient who's 40 who's had no risk factors, you know? The Rashami paper from the New England Journal that looks at risk factor control and diabetes make a very compelling story that if you control your five risk factors, you actually don't have an excess risk of cardiovascular events in diabetes, at least from MACE. The story is whether anybody can have those five risk factors controlled. But, early on in diabetes, with diabetes duration not being that significant, with risk factors not being that significant, I think maybe that's not the population to go after. But certainly, waiting for ASCVD to develop and then start therapy is also not the right way of doing it, so ...

Dr Carolyn Lam:                Interesting. I really wonder what new guidelines are gonna show. Gabriel, any other perspective?

Dr Gabriel Steg:                Well, first of all, I love the editorial. I thought the title was fantastic, and you summarize here what we need to think about when we think about diabetes; not solely the pipes. As an interventional cardiologist, I'm very interested in the pipes.

Dr Subodh Verma:           Me, too.

Dr Gabriel Steg:                Not solely the pump, but also the filter. And there's more than the heart and vessels in the complications of diabetes. So I thought it was a great, great title. My view is that we still need to remember that if we take the lifetime perspective, a healthy youngster with type one diabetes, a relatively healthy patient in his fifties with type two diabetes, their probability of dying from cardiovascular disease is enormous. Even though risk calculators will give them a relatively low probability over the 5 year or 10 year term, eventually that's what's gonna get them. And therefore, we still have progress to make. We are fortunate to have lived an incredible period in the past few years where we've had emergence of new risk preventive therapies in diabetes. That's incredible. It's an epiphany. But, it's not over. We need more information, more trials in other populations. We need to look at renal function and heart failure. So, it's a great time to be doing clinical trials in diabetes.

Dr Subodh Verma:           Right.

Dr Carolyn Lam:                And indeed, a great time to be publishing in circulation. We've been really doing a lot of publications in the cardiovascular outcome trials in diabetes here.

Dr Subodh Verma:           And it's being noticed. There's no doubt about it.

Dr Carolyn Lam:                I hope so. And, maybe a time for a new frame of reference, because what you just said was diametrically sort of in contrast.

Dr Subodh Verma:           I would emphasize one more point, and that is, you know in atherosclerosis, the dominant mechanism has been LDL, right? And Dr Steg here is changing the landscape of that with Odyssey Outcomes and many other strategies. But again, in Circulation, Dr Bhatt, and I, along with the LEADER investigators, recently presented and published a paper showing that liraglutide's benefit is seen independent of LDL cholesterol, and all the way down to people with LDLs of below .5. So, the point is that this mechanism of benefit of GLP-1 seems to be complimentary to LDL lowering. And therefore, I think it offers great hope that you can actually reduce the ischemic burden in diabetes, not just by ultra-low LDL, but by potentially additional mechanisms as well.

Dr Carolyn Lam:                Absolutely. And then now, because I have to have the last word here on this show, let's not forget heart failure outcomes in diabetes. I think it's underestimated. I think it's really important. Okay, and with that, thank you gentlemen for joining me today.

                                                You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association, 2018.


Dec 10, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. What are the long-term effects of oxygen therapy in patients with suspected acute myocardial infarction? Well, to find out, stay tuned for our discussion of our feature paper this week, coming right up after these summaries.

                                                The first two original papers demonstrate that, similar to neonatal mice, one day old and two-day old neonatal pigs are capable of mounting a cardiac regenerative response following myocardial infarction, which is characterized by restoration of contractile function, cardiomyocyte replenishment, and minimal fibrosis. Now, interestingly, this regenerative capacity is lost after the first two days of life.

                                                The first paper is from co-corresponding authors, Drs Yeh and Cook from National Heart Research Institute of Singapore and National Heart Center, Singapore, and the second from co-corresponding, authors Drs Zhang and Zhu from the University of Alabama at Birmingham.

                                                These authors report collectively that proliferation of preexisting cardiomyocytes appear to be the primary source of cardiomyocyte replenishment in neonatal pigs with markers of cardiomyocyte mitosis, sarcomere disassembly, and cytokinesis elevated following injury in the one day and two-day old hearts, but not at later time points.

                                                Furthermore, cardiomyocyte DNA synthesis was increased following neonatal pig myocardial infarction. Cardiomyocyte proliferation significantly decreased after this two-day window, which was associated with a marked reduction in telomerase activity.

                                                Heart failure with preserved ejection fraction may look different in the young compared to that in the elderly. First author, Dr Jasper Tromp, corresponding author, myself, Carolyn Lam from the National Heart Center, Singapore and Duke National University of Singapore, and our colleagues from the Asian Heart Failure Registry studied more than 1,200 patients with HEF PEF from 11 Asian regions and found that 37% of our Asian HEF PEF population was under 65 years of age. Younger age was associated with male preponderance, a higher prevalence of obesity, and less renal impairment, atrial fibrillation, and hypertension. Left ventricular filling pressures and the prevalence of left ventricular hypertrophy was similar in the very young of less than 55 years and elderly HEF PEF of more than 75 years of age.

                                                Compared to age matched controls from the community without heart failure, the very young HEF PEF patients had a three-fold higher death rate and twice the prevalence of left ventricular hypertrophy. Thus, young and very young patients with HEF PEF display similar adverse cardiac remodeling as their older counterparts, but very poor outcomes compared to controls without heart failure.

                                                Obesity may be a major driver of HEF PEF in a high proportion of HEF PEF in the young and very young.

                                                How important is hospitalization for heart failure as a complication of diabetes? In the next paper from first and corresponding author, Dr McAllister from University of Glasgow, the authors examined the incidents and case fatality of heart failure hospitalizations in the entire population age 30 years and older resident in Scotland during 2004 to 2013.

                                                Over the 10-year period of study, among 3.25 million people, the coot incidence rates of heart failure hospitalization were 2.4 per thousand-person years for those without diabetes, 12.4 for those with type two diabetes, and 5.6 for those with type one diabetes. Heart failure incidents had fallen over time for people with and without diabetes, but remained around two times higher in people with diabetes than those without diabetes. Heart failure case fatality was higher in people with type one diabetes. Duration of diabetes and glycated hemoglobin was associated with increased risk of heart failure in type one and type two diabetes. Thus, clinicians should be aware of the importance of heart failure and diabetes, especially in type one diabetes where this is under appreciated.

                                                What are epigenetic mechanisms contributing to ischemia reperfusion injury? Co-first authors Dr Yu, Yang, and Zhang, co-corresponding authors, Dr Xu from Nanjing Medical University, Dr Sun from Fudan University, and Dr Ge from Fudan University, and their colleagues evaluated the potential role of megakaryocytic leukemia one, or MKL 1, as a bridge linking epigenetic activation of NAD pH oxidases, or NOX, to reactive oxygen species production and cardiac ischemia reperfusion injury in mice. They found that genetic deletion of pharmaceutical inhibition of MKL 1 attenuated cardiac ischemia reperfusion injury in mice. MKL 1 levels were elevated in macrophages, but not in cardiomyocytes in vivo, following cardiac ischemia reperfusion injury.

                                                MKL 1 recruited the histone acetyltransferase, MOF, to activate NOX transcription in macrophages. Pharmaceutical inhibition of MOF attenuated cardiac ischemia reperfusion injury in mice, and pharmaceutical inhibition of NOX one or four attenuated cardiac ischemia reperfusion injury as well.

                                                These findings provide a novel link between MKL 1-mediated epigenetic regulation of gene expression in macrophages and ischemic heart disease. This opens the door to small molecule compounds targeting the MKL 1 MOF NOX access as a novel therapeutic strategy against ischemic heart disease.

                                                Is the time from last hospitalization for heart failure to placement of a primary prevention ICD associated with patient outcomes? First and corresponding author Dr Ambrosy from the Permanente Medical Group in San Francisco performed a post hoc analysis of Medicare beneficiaries enrolled in the national Cardiovascular Data Registries implantable cardioverter defibrillator, or ICD registry, all with a known diagnosis of heart failure and an ejection fraction of less than 35%, undergoing a new ICD placement for primary prevention.

                                                They found that older patients, currently or recently hospitalized for heart failure, undergoing initial ICD placement for primary prevention, experienced a higher rate of periprocedural complications and were at increased risk of death compared to those receiving an ICD without recent heart failure hospitalization. Additional prospective real world pragmatic comparative effectiveness studies should be conducted to define the optimal timing of ICD placement.

                                                The final original paper presents result of the VERDICT trial, a large scale randomized controlled trial evaluating the value of very early invasive strategy conducted within 12 hours of diagnosis on long term clinical outcomes in patients with non-SD elevation acute coronary syndrome. First and corresponding author Dr Kofoed from University of Copenhagen and colleagues studied 2,147 patients who were randomized and found that an invasive strategy performed within 4.7 hours after diagnosis was not associated with improved outcomes, compared to an invasive strategy conducted within two to three days.

                                                However, in the pre-specified subgroup of patients with a GRACE risk score of more than 140, a very early invasive treatment strategy did appear to improve outcomes, compared to a standard invasive treatment strategy. And that wraps it up for our summaries. Now, for our feature discussion.

                                                For our feature discussion today, we are talking about oxygen therapy for patients with suspected acute myocardial infarction. Something that seems so benign, something we've taken for granted, and yet now we now question since the Detox AMI trial. Well, for today's feature paper, we have a follow-up of this trial, and I'm so pleased to have actually our associate editor, but also author of this paper, Dr Stefan James from Uppsala Clinical Research Center, and the guest editor for this paper, Dr David Morrow, who's from Brigham Women's Hospital and Harvard Medical School. So, thank you both for being here.

                                                Stefan, could I just ask you to start by taking us back. How was Detox AMI first conceived? What made you even question oxygen therapy? And then, perhaps then, tell us about what this new paper adds.

Dr Stefan James:              I think that's so interesting because I think we all learned in medical school that for myocardial infarction, you should always deliver oxygen. That's sort of the first choice. And the other sort of first choice that we learned was morphine. Some of the other important things that we learned was to give not only oxygen but morphine, and nitroglycerin, and perhaps aspirin. And by those four, only aspirin is really the agent that has been proven beneficial to patients.

                                                But we thought for many years actually about this oxygen hypothesis, or we were interested in trying to understand, is it really helpful to give patients oxygen? Or are we in fact harming patients? Because there is, as you may know, there is a metanalysis performed long ago with small trials on the fibrinolysis era that showed actually a threefold increased risk of dying in those patients who had received oxygen in randomized various small trials, and their animal experience actually suggesting that oxygen is also hazardous. You don't think about that so often, but it's really an agent that constricts arteries, and so as the arteries close by a clot in myocardial infarction, there is no way the oxygen that you breathe in your nose can reach the suffering myocardium. It actually contracts the arteries, and may make the infarct larger than it would be otherwise.

Dr Carolyn Lam:                I love that explanation. Alright, so what did you find in the current analysis of longer term results?

Dr Stefan James:              So, we performed this, the main oxygen trial that we call Detox. We built it upon our national registries, and so we decided to include not only MI patients, but patients who were suspected of MI, in order to be able to enroll patients before the diagnosis was clear. We didn't want to wait for troponins, so we enrolled patients in the ambulances, in the emergency departments, in the cath labs, or in the wards, patients who had suspected myocardial infarction.

                                                Most of them, eventually, did have myocardial infarction, but a proportion did not have myocardial infarction. They had other diseases that resembles MI and have breathing problems. And we selected the cut point of 90%. We said if they are below 90%, they're hypoxic, and it would be unethical to withdraw oxygen, if you were hypoxic. So, we sort of arbitrarily selected the cut point of 90%. And then, we randomized patients to receive oxygen or do not receive oxygen.

                                                We considered to do double blind, but in order to do a double blind, you need to provide air on a mask. And air is not available in ambulances or in the emergency department. We cannot put a mask without anything in it because then it will feel more difficult to breathe. So, we had actually oxygen versus nothing, and we enrolled all patients coming to the cath labs, and emergency departments, and ambulances in Sweden. And thanks to the infrastructure that we have built on the national registries, we were able to enroll these to conduct this large trial, larger than any other trial, 6,600 patients.

                                                In the main study, we found no benefit, and fortunately, no harm of providing oxygen for our primary end point, which was all caused death. But we realized that we were little bit underpowered actually to really clearly rule out that there was any benefit on the primary endpoints. And so, we said, we probably need a longer follow-up, and we probably also need other important measures such as heart failure. Because we thought that oxygen may, if it works, it may reduce the infarct size and may result in a lower risk of heart failure in the long-term. We don't believe that we will reduce the risk of re-MI because we're not interfering with atherosclerosis or plaque ruptures, but we may interfere with the development of heart failure.

                                                So, in this particular paper, we said, longer follow up in order for patients to possibly develop heart failure and increase their risk of heart failure hospitalizations. So, in this paper, we used as a primary endpoint of this analysis, death or hospitalization for heart failure, post MI. And with this way of calculating events, we are more sure that we are not underpowered for this evaluation.

Dr Carolyn Lam:                Right. And the results?

Dr Stefan James:              The results were completely neutral. There was no benefit at all in any sub group. It doesn't matter if you were ST elevation MI, or no ST elevation MI, or no MI, or high risk prior MI, prior heart failure, respiratory disease, there is no benefits and no harm, which is good. And those results are supported by our findings on troponin levels. So, we checked troponins repeatedly. I shouldn't say top troponin, but the highest measured, we did not find any difference between the two groups in Troponin elevations. And we did not find any difference in LVEF and in Echo performed during the initial hospitalization.

                                                So, I think both of those results support the primary endpoint of death and repeat hospitalization for heart failure.

Dr Carolyn Lam:                So David, you've thought a lot about this, and also framed it so nicely when we were just talking a little bit earlier. What do you think is the real significance of this paper on so many levels?

Dr David Morrow:            Yeah, I think there are many levels. I think it's such important work because it takes something that we are still doing in many hospitals every day for patients and is difficult to study because it's become part of standard of care, as Dr James pointed out, and so the authors are to be congratulated for being able to study this intervention. And I think in additionally because it is a therapy that's not associated with high cost, has been part of our care for so long, it's not one where there is the support for a large type of randomized trials. So, the ability to perform this with relatively low costs by nesting it in a registry is important, not only for this particular test, but also as a model for future research of so many interventions that we make right now where they started in a time where our threshold for a need for data was much less.

Dr Carolyn Lam:                Yeah. Indeed. That's wonderfully put. I am also really struck. It's the importance of the message, but also especially about how you do a pragmatic registry-based randomized trial. The ability of Sweden to do this, it's just rock the world, right? Because we really need solutions like that for our clinical trial world, which has to be sustainable somehow. Could you maybe take us behind the scenes a little bit? I mean you did already in your description. I didn't realize there were so many considerations when you're planning this, but how easy or difficult is it to do a trial like this?

Dr Stefan James:              We call the entity RRCT. We call it registry based randomized trial, but being aware that there is no strict definition of what is a registry based randomized trial. So, sometimes for some simple interventions like strategies, we can use only the registry for collection of baseline variables, procedure variables, and also outcomes. The registry can really do everything. The only thing we need to add is a randomization, so then we just program into the registry, which is used live in front of the patients.

                                                So, when I enter a patient in the registry, the personal identification number collects me to the population registry that supports directly back to me name and gender of the patient, and then I enter all the baseline characteristics anyway in the registry. And then, there is a question that comes up that screens my patients. So, the system proposes to me to randomize patients who are eligible because I programmed the inclusion/exclusion criteria. So, it proposes to every doctor in the country, this is a patient that is eligible potentially for this trial and just click randomize, and that's the trial. Everything is completed by that. No extra tests, no visits, no follow up, no telephone calls.

                                                That's the basic, very simple format that can only be used for a strategy, like a device or a strategy. But many of the questions we have in medicine are really regarding strategies. How long should you treat? How often do you need to come back? Sort of strategies. Then, when we've tried to expand this to pharmaceutical agents, and oxygen was the first pharmaceutical agent that we wanted to try. You may not consider oxygen as a pharmaceutical agent, but it is in fact. But it's not manufactured by any companies, and we are still, in this trial, wanted to keep all-cause mortality as the primary end point because that's very reliable. That's indisputable, and in our country it's absolutely 100% correct. If they registered dead, they are dead. There's no question.

                                                The next level we did in the validate was a true pharmaceutical agent manufactured by a company, [byobatterin seprin 00:18:31]. A little bit more complex because you need to be careful about making sure that the patients are receiving the pharmaceutical agent in the right manner, in the right time point. We need to be a little bit careful about collection of side effects, and complications, and so on, but it also worked very well in that trial. If they validated, we did actually adjudicate events because in the primary end point we had it where it was more complex primary endpoint, including myocardial infarction. If you include myocardial infarction or bleeding events, that needs to be defined in a certain way according to protocol. You need to adjudicate. If you really need to rely on the outcome assessment.

                                                We're not trying to take this type of study to the next level, to use it for typical oral pharmaceutical agents. Our largest trial now running is the spirit HFPF lactone versus no treatment in patients with HFPF. And again, this is a pharmaceutical agent that is a very inexpensive. There's no company that would sponsor such a trial, but we think it's a really important question. There's so many patients that suffer from HFPF, and in order to do that trial, it has to be simple and inexpensive.

                                                So, that's running. We hope to be successful. There are, of course, many challenges. Like any other trial, it's difficult to write a protocol. You have to be very dedicated and detailed for any trial. So backstage, this is not easier than any other trial, but for the investigator, it is much easier. That's the reason we have succeeded to reach out to every hospital in the country, and every physician seeing these patients are investigators. And many of them have never done any trials before. They have no experience with research, but still they should be able to randomize and do the trials because it seems to be so easy for them and for the patients. That's the whole idea.

Dr Carolyn Lam:                Yeah. I'm just enamored by the whole concept, and of course, a lot of people I think are wishing that we could institute that in all countries as well. Trust me, a lot of conversation has occurred about that in Singapore, for example, where population based capture is possible. But, as you said, it's not that easy. It's got to be well thought out. Protocols still have to well thought out. Investigators still need to be trained, and so on.

Dr Stefan James:              We want the investigators to feel that it's easy, that it's attractive to participate. Not for money, just because it's so easy and so interesting to be part of such an experiment.

Dr David Morrow:            I think testing some of those therapies that are commonplace that they're used to, and our nature of practice is this is the perfect type of setting than more complicated interventions where you may need to train the investigators more in order how to implement to them, and apply the therapy correctly. That's the new trend, is ... I think the key issue is that in order to reliably test things where mortality is not the acceptable outcome that you could power adequately for, it's really the endpoint collection in the safety collection, and because of the robust medical record systems you have, you're able to do that. And we're so far from being able to do that reliably in the United States right now that it's not possible to do that. Unless we have specific well-constructed registries, which we do in some areas. I think we're learning, and hopefully we'll get there, but we're far behind [crosstalk 00:21:55].

Dr Stefan James:              [crosstalk 00:21:55] Yeah, but even-

Dr David Morrow:            [crosstalk 00:21:57] Nationals-

Dr Stefan James:              Even if you're not able to do a registry based, I think we all should consider in all trials to do it as easy as possible and really try to ask ourselves, what is the most important reason we're doing this trial? Sometimes we need to collect a lot of extra information because we need to understand the mechanisms or the side effects. If that's the case, I don't think at this trial methodology is not suitable. You shouldn't perform it that way. It needs to be the more traditional, more conservative, more expensive and burdensome way, but for many therapies, a more simple approach, more pragmatic approach is preferable.

Dr Carolyn Lam:                Well, thanks again for diving into that because it gives us a real, to me at least, even greater appreciation for this paper when you understand the amount of work that's gone into it. But may I just end by saying, what do you think is the take home message for clinicians now? David, for example, you started by saying everyone's still doing it? I fully agree.

Dr David Morrow:            Yeah. I think it's a very simple message, and that we know that oxygen is not effective in patients who have an oxygen saturation above 90%. And there's really no rationale to use it.

Dr Carolyn Lam:                Perfect. Has this been put in practice in Sweden already?

Dr Stefan James:              It has been. One of the virtues of running these registries is that we can also check the adherence to the results, so we can check that this is not used anymore.

Dr David Morrow:            And since the investigators are your entire country, they all learned actually from participation in these trials.

Dr Stefan James:              Exactly. Exactly.

Dr David Morrow:            There's more of an investment in it already.

Dr Carolyn Lam:                That's amazing. So, thank you again for sharing. Thank you for publishing this in circulation and for helping us to do that.

                                                You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright the American Heart Association in 2018.


Dec 3, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

                                                Our featured paper this week reports the five-year clinical outcomes and valve durability in the largest available cohort to date of consecutive high-risk patients undergoing transcatheter aortic valve replacement. You must listen up for this discussion, coming right up after these summaries.

                                                The first original paper describes a personalized risk assessment platform that promotes the implementation of precision medicine by helping us with the evaluation of a genomic variant of uncertain significance. A genomic variant of uncertain significance is a rare or novel variant for which disease pathogenicity has not been conclusively demonstrated or excluded and thus cannot be definitively annotated. These variants therefore pose critical challenges to the clinical interpretation and risk assessment. New methods are therefore urgently needed to better characterize their pathogenicity.

                                                Co-first authors, Dr Ma, Zhang, and Itzhaki, corresponding author Dr Wu from Stanford University School of Medicine and colleagues recruited a healthy, asymptomatic individual lacking cardiac disease clinical history and carrying hypertrophic cardiomyopathy associated genetic variant in the sarcomeric gene, MYL3, which has been reported by ClinVar database to be likely pathogenic.

                                                Human-induced pluripotent stem cells or IPSCs were derived from the heterozygous carrier, and their genome was edited using CRISPR/Cas9 genome editing to generate karyo-specific IPSCs. Extensive essays, including measurements of gene expression, sarcomere structure, cell size, contractility, action potentials, and calcium handling were performed on the isogenic IPSC-derived cardiomyocytes, and together, the platform was shown to elucidate both benign and pathogenic hypertrophic cardiomyopathy-functional phenotypes.

                                                Thus, this paper demonstrates for the first time the unique potential of combining IPSC-based disease modeling and CRISPR/Cas9 genome editing technology as a personalized risk assessment platform for determining the pathogenicity of a variant of unknown significance for hypertrophic cardiomyopathy in a patient-specific manner.

                                                Transcatheter aortic valve replacement is increasingly being used for the treatment of severe aortic valve stenosis in patients at intermediate risk for surgical aortic valve replacement. The next paper provides real world data comparing indications and clinical outcomes of patients at intermediate surgical risk undergoing isolated transcatheter vs. surgical aortic valve replacement.

                                                Co-first and corresponding others, Dr Werner and Zahn from Clinical Ludwigshafen in Germany compared clinical characteristics and outcomes of more than 7,600 patients with intermediate surgical risk who underwent isolated transcatheter or conventional surgical aortic valve replacement within the prospective all-comers, German aortic valve registry between 2012 and 2014.

                                                Multi-variable analyses reveal that factors that were associated with performing transcatheter instead of surgical aortic valve replacement included advanced age, coronary artery disease, New York Heart Association class three or four, pulmonary hypertension, prior cardiac decompensation, and elective procedure, arterial occlusive disease, no diabetes mellitus, and a smaller aortic valve area.

                                                Unadjusted in-hospital mortality rates were equal for transcatheter and surgical aortic valve replacement, whereas unadjusted one-year mortality was significantly higher in patients with transcatheter aortic valve replacement. After propensity score matching, the difference in one-year mortality was no longer significant. Thus, this large registry analysis suggests that both transcatheter and surgical aortic valve replacement are reasonable treatment options in a real world population with aortic stenosis and intermediate surgical risk.

                                                The next paper demonstrates a key role of vascular endothelial growth factor receptor 1 in hemorrhagic telangiectasia type 2. Now, this is an inherited genetic disorder where haplo-insufficiency of the activin receptor-like kinase 1 gene, ACVRL1, results in blood vessels that are prone to respond to angiogenic stimuli, leading to the development of telangiectatic lesions that can bleed.

                                                First author, Dr Thalgott, corresponding author, Dr Lebrin from Leiden University Medical Center and colleagues used ACVRL mutant mice and found that vascular endothelial growth factor, or VEGF receptor 1 levels were reduced, causing increased VEGF receptor 2 signaling that promoted sprouting angiogenesis, correcting the abnormal VEGF gradient, by expressing membranal-soluble VEGF receptor 1 in embryonic stem cells or blocking VEGF receptor 2 with antibodies in mutant mice, normalized the phenotype both in vitro and in vivo.

                                                Importantly, VEGF receptor 1 was reduced in the blood and skin blood vessels of patients with hemorrhagic telangiectasia type 2 compared with H match controls, demonstrating an important role of VEGF receptor 1 in these patients and explaining why their blood vessels might respond abnormally to angiogenic signals. These findings support the use of anti-VEGF therapy in hemorrhagic telangiectasia type 2.

                                                The next study suggests that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart disease following acute rheumatic fever. First author, Dr Kim, corresponding author, Dr Wicks from Walter and Eliza Hall Institute of Medical Research and University of Melbourne and their colleagues analyzed the immune response to group A streptococcus in peripheral blood mononuclear cells from an Australian Aboriginal acute rheumatic fever cohort by a combination of multiplex cytokine array, flow cytometric analysis, and global gene expression analysis by RNA sequencing.

                                                They then tested the widely used immunomodulatory drug, hydroxychloroquine for its effects on this response. They found that group A streptococcus activated persistent IL-1 beta production and selective expansion of a specific group of T helper 1 cells that produce GMCSF. Furthermore, hydroxychloroquine limited the expansion of these group A streptococcus-activated, GMCSF-producing T helper cells in vitro.

                                                Gene transcriptional profiling of peripheral blood mononuclear cells from patients with acute rheumatic fever showed dynamic changes at different stages of disease. Given the safety profile of hydroxychloroquine and its clinical pedigree in treating autoimmune diseases such as rheumatoid arthritis where GMCSF plays a pivotal role, the authors therefore proposed that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart fever following acute rheumatic fever.

                                                The next paper identifies a new anchoring B genetic variant in unrelated Han Chinese probands with ventricular tachycardia. In this paper from co-first authors, Dr Zhu, Wang and Hu, co-corresponding authors, Dr Hong from Second Affiliated Hospital of Nanjing University, Dr Mohler from Ohio State University Wexner Medical Center and colleagues, the authors identified the first anchoring B variant, Q1283H, localized to the ZU5C region in a proband with recurrent ventricular tachycardia.

                                                Knocking mice with this variant showed an increased susceptibility to arrhythmias associated with abnormal calcium dynamics. The variant was associated with loss of protein phosphatase 2A activity, increased phosphorylation of ryanodine receptor, exaggerated delayed after depolarization-mediated trigger activity, and arrhythmogenesis. Furthermore, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias, representing potential therapies for anchoring B variant-associated arrhythmias.

                                                Does variability in metabolic parameters affect health outcomes? First author, Dr Kim, corresponding author, Dr Lee from Seoul Saint Mary's Hospital College of Medicine and Catholic University of Korea and their colleagues used nationally representative data from the Korean National Health Insurance system, consisting of more than 6.7 million people who are free of diabetes, hypertension, or dyslipidemia and who underwent three or more health examinations from 2005 to 2012 and were followed to the end of 2015.

                                                Variability and fasting blood glucose and total cholesterol, systolic blood pressure and body mass index was measured using the coefficient of variation, standard of deviation, variability independent of the mean, and average real variability. They found that a high variability in fasting glucose and cholesterol, systolic blood pressure and body mass index was associated with a higher risk for all-cause mortality, myocardial infarction, and stroke. Variabilities in several metabolic parameters had additive associations with the risk of mortality and cardiovascular outcomes in the general population.

                                                These findings suggest that treatment strategies to reduce fluctuations in metabolic parameters may be considered another goal to prevent adverse health outcomes.

                                                How much exercise over a lifetime is necessary to preserve efficient ventricular arterial coupling? First author Dr Hieda, corresponding author Dr Levine from Texas Health Presbyterian Hospital Dallas and University of Texas Southwestern Medical Center and colleagues studied 102 seniors and grouped them based on their 25 years of exercise training history. The dynamic Starling mechanism was estimated by transfer function gain between beat-by-beat changes in diastolic pulmonary artery pressure and stroke volume index.

                                                They found that there was a graded dose-dependent improvement in ventricular arterial coupling with increasing amounts of lifelong regular exercise in healthy older individuals. Their data suggested that the optimal does of lifelong endurance exercise to preserve ventricular arterial coupling with age appeared to be at least four to five sessions per week. The sufficient lifelong endurance exercise was effective for maintaining the normal dynamic Starling mechanism, left ventricular compliance, and arterial compliance with aging, all of which may lead to favorable effect on cardiovascular stiffness or function.

                                                And that brings us to the end of our summaries this week. Now, for our feature discussion.

                                                Transcatheter aortic valve replacement is taking over the interventional world. It's really rapidly growing, and we're increasingly using it for the treatment of aortic stenosis. It was initially used for inoperable and high-risk patients but now is indicated even in the treatment of intermediate-risk patient, and even low-risk patients are being enrolled into current trials.

                                                So, with TAVR being used for low- and intermediate-risk patients, the longer-term results of this treatment involved your abilities becoming more and more important. Well, gratefully, we have today's feature paper, and it describes the five-year clinical outcomes and valve durability of the FRANCE-2 Registry.

                                                I'm so pleased to have with us the corresponding author, Dr Martine Gilard from University Hospital of Brest in France, we have our editorialist, Dr Anita Asgar from Montreal Heart Institute, and we have our associate editor, Dr Dharam Kumbhani from UT Southwestern.

                                                Martine, congratulations on this largest cohort of high-risk patients and long-term outcomes. Could you please tell us what you found?

Dr Martine Gilard:            Yes, and I'll just quote, actually, to have a follow-up of five years. We have 1,200 patients arrive at five years after rotation of TAVI. Each patient was a high-risk patient because it was at the beginning of each treatment, and in this time, it's only the high-risk patient was implanted with TAVI, and actually, we can follow this 1,200 patients, 50% of these patients of these patients have an echography because when we analyze these patients, we have an echography at five years, and the patients who have not echography at five years, the only difference is the age.

                                                It's very old patient. It's very difficult to make this echography on this patient to come back in our center, so it's why there is not all the patient who have an echography at five years.

                                                But our patients who have an echography, we can see that it's a very, very good result at five years. There is always the same area, just after before, of the valve. There is the same gradient. There is not a sign of deterioration.

                                                As you know, we have some guidelines published last year about how we asked to define deterioration of the valve, surgical or TAVI, and if we apply this new recommendation, we saw that in this largest cohort, at five years, there is only 13% of patient who have some sign of deterioration, and of these patients, we never need to make another valve in valve because the deterioration was not so important, and patient leave with this valve like that. There is no necessity to make a new valve in valve, so at five years of this very high-risk patient treated by TAVI, there is no necessity to implant a second valve because the valve deterioration. It's a very, very important message.

Dr Carolyn Lam:                Thank you, Martine. Indeed, an important message. And Anita, you wrote a beautiful editorial about it. First, could I ask you to frame the issue? I mean, is there any reason we would expect the durability to be any different from a surgical replacement?

Dr Anita Asgar:                  I think that's a great question, Carolyn, and I congratulate again Martine and her team for doing a fantastic job to add some very important results to the clinical literature on TAVI. Five years is relatively early to see structural valve deterioration, so in a sense, it's not surprising, and we would consider this sort of medium-term follow-up rather than really long-term durability, but very reassuring that in a high-risk population of patients, that TAVR performs very well in this population of patients and as mentioned, is very low to the dynamic structural valve deterioration.

                                                One question I have for Martine is, as you mentioned, there was only about 12% that had some evidence of structural valve deterioration hemodynamically, but this didn't result in another procedure, and I wonder if you could explain a little bit about that, whether it's the hemodynamic dynamic value, and yet there's a clinical indication for re-intervention. How do you incorporate the two?

Dr Martine Gilard:            It's actually hemodynamic deterioration, there is some form of regurgitation. However, there is no need or clinical indication to make another intervention. So, if you compare this research to the bioprostheses surgical paths, the only one who have, at five years, no need to make a re-intervention appearing rotated, which is a valve, a surgical valve we have a longer bioprostheses surgical path.

                                                So, if we compare this best bioprostheses surgical valve, we have sustained results at five years. At five years, we have no need to make a re-intervention because the deterioration was not so important or as needed for clinical evidence as a need to make a new intervention.

Dr Anita Asgar:                  So, there were some increased rates of heart failure in those patients with structural valve deterioration in your paper, and I know that in the paper you did mention that this is not an adjudicated outcome, and there wasn't a VARC definition for heart failure, but what's your interpretation of increasing heart failure events in these patients with structural valve deterioration?

Dr Martine Gilard:            We have no real definition about that. We know that there is another registry. We say that there is an increasing of heart failure, and during the follow-up, and the result of this heart failure increase in mortality. There is an increasing of heart failure, but the number of these patients, there is more. So I don't know if this due to because patient is a high-risk patient, or it's because of the TAVI, but it's very difficult actually to have a real explanation about that.

Dr Carolyn Lam:                Thanks, Anita and Martin. Dharam, could you share some of the thoughts and the discussions that were going on behind the scenes with the editors when we saw this paper?

Dr Dharam Kumbhani:   Professor Gilard, this was a really excellent paper. We really appreciated you sending it to us, and I think for us, the fact that this was a very large cohort, the largest published cohort that has gotten to five years in a TAVR population, in a multicenter study, and having very good follow-up up to five years, with these patients is always this competing hazard that you want to know what the valve is doing at five years from an echocardiographic and hemodynamic perspective, but there's such a high competing hazard of death, just given the population that you're enrolling, and still, you had one of the largest echo follow-ups on these patients, so we want to congratulate you on the study and really a monumental endeavor, and so really great, great work there.

                                                And I think this is, exactly some of the questions that I think we had and I'm sure that the audience would have as well, I guess the one other question I have, and it's not really a question about your paper. So the median Euro score is 21 in this study, approximately 21, so that's obviously gonna, consistent with the patients that are being enrolled at that time between 2007 and 2012, which were predominantly high-risk and inoperable patients. Can you talk to us a little bit about the landscape of, how is TAVR practice in France as a society or from the regulatory standpoint, what are the benchmarks that you have achieve as you move towards low-risk now? Because intermediate-risk, I'm assuming is a [inaudible 00:20:16], so could you talk to us a little bit about the landscape there?

Dr Martine Gilard:            Yes. In France, it's difficult because we have the authority to follow, not immediately, the ESC recommendations, so actually in France, we are allowed to implant only patients with high risk, patients with complication of surgery, and actually just since one year, patients with automatic risk, but we have no authorization to implant patient with low risk.

                                                However, the most important fact is the heart team, and if they write. Because we need to have something written, and if they write, if they explain that it's necessary to implant a patient at low risk because of some point while not including the risk score or it's very difficult to explain, for example, frailty or something, we can implant a patient with low risk.

                                                But normally actually, it is only for complication or high risk and for intermediate risk like the recommendation of the ESC.

                                                So the rate of implantation in France increased because we implant only 2,000 people per year, but actually, in 2017, we have implanted 10,200 patient, and this year, we think that we implant 12,800 patients, so as the number of patients increase, the number of patients who have a very high risk decrease because there is a futile indication, and we have a lot of futile indication, so we doesn't implant patient while too high-risk, and we select the most majority of patient implanted in France was high-risk but also intermediate-risk.

Dr Dharam Kumbhani:   So, you think you're implanting more intermediate, like that is a bigger population that is getting TAVIs right now in France?

Dr Martine Gilard:            Yes, exactly.

Dr Carolyn Lam:                How about perspectives from Montreal? What do you think the implications of this findings from today's paper in relation to the types of patients that you might perform this in now?

Dr Anita Asgar:                  For us, this is exceptionally reassuring, and as Martine has said, I mean, we have transitioned as well away from that very inoperable cohort C type of patient to more your higher-risk patient or intermediate, and to be honest, everyone over the age of 80 in Canada essentially is getting a TAVR.

Dr Carolyn Lam:                Oh, wow.

Dr Anita Asgar:                  Because regardless of their risk, and we've been very aggressive with that because trying to get patients back to an appropriate quality of life is very important, and to seeing this very reassuring data is telling us that, as she has already mentioned, we have reached the standard, at least in midterm follow-up as the gold standard of surgical valve replacement, and so structural valve deterioration is not as big a concern.

                                                I think we still however need longer-term data when we're looking at lower-risk patients, and lower-risk patients, let's remember, are not 60-year-olds. They're the 75-year-old, perhaps. But we're still gonna need some more data, but it's very reassuring, and patients are asking for it and are really advocating on their behalf to have a less invasive approach, and I think we can say now with more certainty that we know after five years, your chance of structural valve deterioration is actually quite low, and so I think that's very helpful from our point of view.

Dr Carolyn Lam:                I love that, Anita, and it's so consistent with the title of your editorial, "Closing in on the Finish Line". Love it, love it, and recommend all listeners pick it up and have a good read. Dharam, I want to leave the last words to you. What do you think are the implications of this paper?

Dr Dharam Kumbhani:   Well, I think that, as Anita said, this is very encouraging results that, in this kind of extreme and high-risk patient cohort, that there appear to be no medium- to long-term signals of structural valve degeneration, that the biggest hazard from this procedure is all upfront, and after that, it's pretty much, it's as we have seen with surgery, that after that, the actuarial rates come back to what you would expect.

                                                If they didn't have aortic stenosis and then they would die from whatever causes they had. Now obviously, that wasn't tested, but it seems like looking at the curves, that that seems like what's going on, so I think they've done a great service to our TAVR community in terms of showing us these results in very large, multicenter cohorts from France.

Dr Carolyn Lam:                Thank you so much for joining us today. Thank you, listeners. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association, 2018.


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