Circulation on the Run

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Apr 24, 2017

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 feature paper this week really adds to our understanding of the cause/effect relationship between obesity and heart failure, this time by comparing the effects of gastric bypass surgery versus intensive lifetime treatment on heart failure risk. Before we talk about that, though, let me give you your summary of this week's journal.

                                                The first paper brings us one step closer to understanding cardiac recovery in response to mechanical unloading by left ventricular assist devices and it does this by showing that this process may involve the transverse tubular system, which is a micro structural feature of ventricular cardiomyocytes important for contractility and consisting of tubular invaginations of the sarcolemma predominantly located at the Z-lines of sarcomeres. This transverse tubular system is crucial for efficient excitation contraction coupling by bringing L-type calcium channels in the sarcolemma in proximity to clusters of ryanodine receptors in the sarcoplasmic reticulum.

                                                In the current study by co-corresponding authors, Dr. Seidel and Drakos and Sachse from University of Utah, the authors studied left ventricular biopsies obtained from five donors and 26 patients with chronic heart failure undergoing implantation of left ventricular assist devices or LVAD's. They used three dimensional confocal microscopy and computational image analysis to assess the transverse tubular system's structure, density, and distance of ryanodine receptor clusters to the sarcolemma.

                                                They found that the majority of heart failure myocytes showed remarkable transverse tubular system remodeling, particular sheet-like invaginations of the sarcolemma, which is previously unknown phenotype. This sheet-like transverse tubular system remodeling led to increased distances of ryanodine receptors to the sarcolemma causing heterogeneous intracellular calcium release and consequently inefficient excitation contraction coupling. High degrees of transverse tubular remodeling at the time of LVAD implantation was associated with absence of functional cardiac recovery during mechanical unloading, whereas preserved transverse tubular systems structure was associated with recovery.

                                                In summary, cardiac recovery during unloading may require an intact transverse tubular system at the time of LVAD implantation. And characterizing this system may help to identify patients with a high probability of functional cardiac recovery in response to mechanical unloading.

                                                There have been a proliferation of algorithms based in high sensitivity assays for cardiac troponins for the diagnosis or exclusion of myocardial infarction. All these algorithms have the potential to overwhelm clinicians with options. Well, there is help in this week's issue with two observational studies directly comparing the diagnostic performances of multiple high-sensitivity troponin testing strategies.

                                                Now, before I describe these two studies in detail, here are some important reminders. Remember that as of early 2017, although high-sensitivity troponin assays are routinely used in many regions of the world, they are not available in the United States. Thus, the specific algorithms discussed here are not applicable with the contemporary sensitive assays that are presently used in the United States. Next, let's remind ourselves that both the United States and European professional guidelines recommend serial measurement of cardiac troponins at presentation or zero hours and three to six hours later with additional testing beyond six hours in patients who have electrocardiographic changes, or intermediate or high clinical risk features.

                                                The 2015 European Society of Cardiology Guidelines also included an alternative strategy reducing the sampling interval to one hour when using a high sensitivity troponin assay with a validated zero and one hour algorithm based on the 99 percentile cutoff of these high sensitivity troponin assays. Now to the two studies in the current issue, which tie together the expanding evidence with direct comparisons of several of the strategies using the same high sensitivity cardiac troponin assay by Abbott.

                                                Dr. Chapman and colleagues from the royal infirmary of Edinburgh, United Kingdom, compared the standard ECS zero and three hour strategy based on the 99th percentile upper reference limit at both time points with the high sensitivity troponin in the evaluation of patients with acute coronary syndrome, or high stakes algorithm, and that would be a zero, three, and six hour algorithm that incorporates a zero hour criteria and at a very low cutoff of five nanogram per liter and a three hour criterion that directs patients with either a rising concentration or with an absolute concentration above the upper reference limit to additional testing.

                                                Among 1,218 patients with suspected myocardial infarction, the high stakes algorithm delivered both a higher proportion ruled out for myocardial infarction at zero hours and a higher negative predictive value of 99.5% versus 97.9%. The ESC pathway missed 18 index and two recurrent myocardial infarction events, whereas the high stakes pathway missed two index and two recurrent myocardial infarction events. These findings demonstrate the value of adding a very low zero hour cutoff to facilitate earlier rule out as well as the value of a delta criterion to exclude increasing values among patients that progress to three hour sampling.

                                                In the next study, first author, Dr. Boeddinghaus, corresponding author Dr. Mueller and colleagues from University Hospital of Basel, Switzerland compared the ESC alternative zero and one hour strategy with three other approaches using either a single cutoff at zero hours, or the one hour strategy. Among 2,828 patients with symptoms suspicious for myocardial infarction and no ST elevation, each of these four approaches delivered a negative predicted value above 99% comparing favorably to the ESC zero and three hour algorithm that had a negative predictive value of 98.4%.

                                                Now, although each of the strategies performed similarly among patients presenting more than two hours after symptom onset, among the early presenters, the negative predictive value and sensitivity were diminished using the single zero hour cutoff of five nanograms per liter. The authors concluded that the single cutoff strategy, the one hour algorithm, and the zero and one hour algorithm, allow the triage towards rule out of myocardial infarction in more than half of consecutive patients presenting with suspected MI to the emergency department. However, the single cutoff strategy should not be used in patients presenting early after chest pain onset.

                                                These papers are discussed in an excellent editorial, which also puts everything in perspective by Dr. David Morrow from Brigham and Women’s Hospital in Boston, Massachusetts. I particularity want to refer all of you to the figure that's found in its editorial which really helps you to understand the different strategies involved.

                                                The final study tells us about potential death averted and serious adverse events occurred from the adoption of the SPRINT intensive blood pressure regimen in the United States. As a reminder, the systolic blood pressure intervention trial, or SPRINT demonstrated a 27% reduction in all caused mortality with a systolic blood pressure goal of less than 120 versus less than 140 mm Hg among American adults at high cardiovascular risk, but without diabetes, stroke, or heart failure.

                                                In the current study, Dr. Bress and colleagues from the University of Utah School of Medicine applied the SPRINT eligibility criteria to the 1999 to 2006 National Health and Nutrition Examination Survey or NHANES and linked this with the national death index through December, 2011. They found that if fully implemented in eligible US adults, intensive blood pressure treatment was projected to prevent about 107,500 deaths and 46,100 of heart failure per year. But, you also give rise to about 56,100 episodes of hypertension. 34,400 episodes of syncope, 43,400 serious electrolyte disorders, and 88,700 of acute kidney injury per year compared to standard blood pressure treatment. Thus, they take home message is careful patients selection and implementation are important because intensive treatment while preventing deaths is associated with increased risks of hypertension, syncope, electrolyte abnormalities and acute kidney injury.

                                                Well, that brings us to a close for the summaries, now for our feature discussion.

                                                We are discussing obesity and heart failure. Now, we've heard of the obesity paradox, but we also know that obesity may be a risk factor for heart failure and the study today really puts perspective on this and is really one of the largest most convincing studies I've read on this topic. I am so pleased to have the person corresponding author, Dr. Johan Sundstrom from Uppsala University Hospital in Sweden. Welcome, Johan.

Dr Johan Sundstrom:      Thank you, lovely to talk to you.

Dr Carolyn Lam:                And especially pleased to have back on the show again, Dr. Torbjorn Omland from University of Oslo, Norway. Hi, welcome back, Torbjorn.

Dr Torbjorn Omland:      Thank you very much. It's a great pleasure being here.

Dr Carolyn Lam:                Johan, you know what? Could you just start by telling us about your study?

Dr Johan Sundstrom:      So, we were fortunate enough to have two great databases here in Sweden. One was the obesity surgery registry called SOREG in which all people have a gastric bypass surgery, for people who are registered. And we also have a company called Itrim who provide intensive lifestyle program, which takes people down on average about 11 kilos, and they have a very structured database as well. So, we were able to pull this data in order to try and understand the effects of intentional weight loss to two different levels of weight loss, what that does to the heart failure incidence.

                                                This is a bit of a comparative effectiveness study, so it's of course necessary to make the examples as similar as possible to apply exclusion criteria. We took away everyone who had a body mass index of less than 30 and above 50 and then we applied propensity scores to those two data sets and we had to trim the data sets a little bit further in order to get so called region of common support, which means that we were left with two samples who could have either had surgery or a lifestyle intervention. And then we applied an inverse probability weighting scheme to that. It's statistically complicated but what that does, is it's a matching, but it's not as complicated as matching. With matching, you just give people a weight of 1 or 0, but this gives people other weights as well.

                                                So, we end up with characteristics that were very similar at baseline. So, we tried to mimic as close as possible what a randomized clinical trial looks like, but of course we did it posthoc and it’s observational. So, we get our table one, sort of, in this paper that shows very similar characteristics of the two groups. So, what we did then is we noted what happened to the people in these two groups in terms of heart failure incidence and we followed them in our national inpatient registry. So, all the Swedish citizens get a personal identification number so we can use that to follow people in our patient registry.  So, we know exactly what drugs people will collect from pharmacies, and we know what they died from, and we know all of their hospitalizations. And we previously validated their heart failure diagnosis in the Swedish Inpatient Registry and we noted that you were in a pretty good position if you were hospitalized with heart failure as the main cause of hospitalization and we noted that people who had agreed to do surgery, had about half the incidence of heart failure than people who were in the intensive lifestyle program.

                                                We also noted, if you looked at the achieved weight loss one year after baseline, we noted that a ten kilo weight loss after one year was related to about a 23% lower risk of heart failure. So we noted a litany of association between the achieved weight loss and heart failure incidence. It should said, though, that heart failure in this age group, they are only 41 on average, 41 years old. Heart failure's still very unusual at this age, even in many of these people. We only had 73 cases of heart failure. So, the exact numbers need to be taken with a pinch of salt and have wide confidence intervals around them.

Dr Carolyn Lam:                Johan, this is exactly why I'm so impressed with your data. First you showed a dose response relationship between the weight loss and risk of heart failure. You also show that it's not an event that occurs very often and so, it would be very difficult to imagine doing a randomized controlled trial for example in this setting and having to wait very long for these events. So, it really goes to show your observational data are extremely important. And I really like the way you took the pains to describe how you tried to overcome the differences that exist between the groups and try to make it as much resembling a randomized trial setting as you could. So, maybe I could turn it over to you, Torbjorn. Could you tell us what you think the implications of this paper are?

Dr Torbjorn Omland:      First, I will say that that this paper has all the characteristics of a very high quality study. It's a very timely topic that interests a lot of people. The paper's very well written. It's a large sample size as you said and it was very clinically meaningful difference between the groups and that translated into very clear and robust answers. So, I think that this has every mark of high quality paper.

                                                But, of course, the very important question is how will this translate into actions?  How can we use this information to prevent problems? We know heart failure is a very prevalent disease, especially in the elderly and although the incidence was lower here, I think my question for Johan at least is what would be the next step? What changes can we implement to reduce heart failure among the obese?

Dr Johan Sundstrom:      That's a great question. I think in this study puts a little piece of the puzzle on the table and that's trying to add a little more evidence towards a causal association between obesity and heart failure. I'm not sure about what we can offer these patients and what will be the translation to lower heart failure incidence in the long run. Of course, we need to follow this sample for longer to have more heart failure cases, because I don't think we've seen the full impact of weight loss in these two samples. We might need to follow them into older age where they would have a higher heart failure incidence.

                                                But, how to tackle obesity, I think we'll need accommodate population strategies and high risk strategies. I think if the general consensus in the scientific community after reading this and other important papers, is that there's causal link between obesity and heart failure, then we might need to understand that people who are obese and who have shortness of breath and perhaps swelling or what not, may not just be having low fitness, they might actually behaving signs of heart failure.

                                                So, I think as a sort of increased diligence on heart failure, these people might be one thing. But, we didn't really study that. So, I wouldn't draw conclusion. But, otherwise I think it's more of a causal inference piece of the puzzle that we've laid rather than a clinical care piece of the puzzle.

Dr Torbjorn Omland:      No, I agree, and here you won't to make any recommendations in regards to what interventions you should recommend particularly based on this particular study.

Dr Johan Sundstrom:      No, because I think there are so many other things that need to be taken into account when it comes to treatment of obesity. Heart failure is actually one of the uncommon outcomes in this age group. We're looking at other outcomes after they present. Myocardial infarction, ventral fibrillation and mortality are actually much more common. So, I think a lot of other data should go into decisions on how to treat patients, not just for heart failure, which is still fairly uncommon at this age.

Dr Carolyn Lam:                Going back to the other question that Torbjorn asked, do you think that this question still needs to be answered in any way? You've got the Mendelian randomization data. Now, you've got your data. Do you think it's still a question of whether obesity is a risk factor for heart failure? And just in case there's any confusion out there, would you put that together with the so called obesity paradox in heart failure?

Dr Johan Sundstrom:      To answer the first one, I think we're not going to have any randomized evidence. Treatment of heart failure with intensive programs and prevention of heart failure ... It needs for huge samples that I don't think we're going to have any much better observational evidence anytime soon either. So, we can probably set that question aside a little bit. But, when it comes to the obesity paradox, first of all that's not what we studied here. We didn't have anyone with heart failure in this sample. We included all those people. We can only speculate. I'm a clinical epidemiologist myself, but I'm envious of people who have animal and other models because I think there's a lot more work to do in terms of ppars and and lipid metabolism in obesity and in heart failure. So, I think there'll be more interesting experimental research to come that can help us answer the obesity paradox.

Dr Carolyn Lam:                Please don't forget to tell your friends about this podcast, and tune in again next week.


Apr 17, 2017

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 feature paper this week discusses the very important patient group with myocardial infarction and non-obstructive coronary artery disease, a paper that we will be digging deep into right after these summaries.

                                                The first paper identifies a novel therapeutic target in pulmonary arterial hypertension, and that is nicotinamide phosphoribosyltransferase, a cytozyme which regulates intracellular NAD levels and cellular redox state, regulates histone deacetylases, promotes cell proliferation, and inhibits apoptosis.

                                                This is a paper from first author Dr. Chen and co-corresponding authors Dr. Machado from University of Illinois Chicago and Dr. Garcia from the University of Arizona. The authors found that plasma and mRNA and protein levels of  nicotinamide phosphoribosyltransferase  were all increased in the lungs and the isolated pulmonary arterial endothelial cells from patients with pulmonary arterial hypertension.

                                                They were also increased in the lungs of rodent models of pulmonary hypertension. Nicotinamide phosphoribosyltransferase deficient mice were protected from hypoxia mediated pulmonary hypertension; whereas, enhanced activity promoted human arterial smooth muscle cell proliferation via paracrine effect and inhibition of activity attenuated pulmonary hypertension in rats.

                                                This paper, therefore, provides evidence that nicotinamide phosphoribosyltransferase plays a role in pulmonary vascular remodeling and its inhibition could be a potential therapeutic target for pulmonary arterial hypertension.

                                                The next study suggests that high sensitivity cardiac troponin T may be an early biochemical signature for clinical and subclinical heart failure. In this study from first author Dr. Seliger, corresponding author Dr. deFilippi, and colleagues from Inova Heart and Vascular Institute, the authors measured high sensitivity cardiac troponin T at baseline among almost five thousand participants in the multi-ethnic study of atherosclerosis MESA cohort, who were initially free of overt cardiovascular disease.

                                                Cardiac magnetic resonance imaging was performed at baseline and repeated 10 years later among 2,831 participants who remain free of interim cardiovascular disease events, among whom 1,723 also received gadolinium enhanced cardiac magnetic resonance for characterization of replacement fibrosis by late gadolinium enhancement. Results showed that a mild elevation of high sensitivity cardiac troponin T identified subjects at highest risk for an increase in left ventricular mass and end diastolic volume over the next 10 years.

                                                Higher levels also associated with an increased incidence of replacement fibrosis, but with no differentiation between ischemic or non-ischemic fibrosis patterns. For the more high levels remained an independent predictor for incident heart failure, coronary heart disease events and cardiovascular events, independent of underlying left ventricular hypertrophy or ejection faction.

                                                The implications are that myocyte injury, measured with a highly sensitive cardiac specific troponin assay may ultimately be an important early signal used to target therapy to prevent or delay left ventricular remodeling and progression to heart failure.

                                                Does maintenance of cardiovascular risk factors at target eliminate the excess risk of mortality in cardiovascular diseases associated with type 1 diabetes? Well, this question was addressed in the next paper by Dr. Rawshani and colleagues of the Swedish National Diabetes Register in Gothenburg Sweden. The authors compared more than 33,300 patients with type 1 diabetes to more than 166,500 match controls without diabetes from the Swedish National Diabetes Register. They found that patients with type 1 diabetes, with five selected cardiovascular risk factors at target, demonstrated a non-significant access risk of death compared to controls.

                                                These five risk factors included glycated hemoglobin, blood pressure, albuminuria, smoking, and LDL cholesterol. Nonetheless, despite having all risk factors at target, persons with type 1 diabetes still had 82% to 97% elevated risk of myocardial infarction and heart failure respectively. For every incremental risk factor not at target, the excess risk of death in cardiovascular outcomes increased in a graded fashion.

                                                In conclusion, there was a steep graded association between decreasing number of cardiovascular risk factors at target and major adverse cardiovascular outcomes with patients with type 1 diabetes. While achievement of current evidence based target levels of five cardiovascular risk factors markedly reduced or even potentially eliminated the excess mortality risk, these patients remained at higher risk of myocardial infarction and heart failure compared with controls.

                                                The final paper suggests that hemodynamic guided heart failure management may be beneficial in general clinical practice and not just in the context of controlled trials. In this study by Dr. Heywood and colleagues from Scripps Clinic Torrey Pines in La Jolla, California, the authors examined the first 2,000 patients implanted with the novel Pulmonary Artery Pressure Sensor, CardioMEMS, in the general cardiology practice setting.

                                                They found that patients uploaded information an average of every 1.2 days, and that pressures were significantly reduced by remote monitoring using the Pulmonary Artery Sensor where patients with the highest mean pulmonary artery pressures had the highest reduction in pressures. Furthermore, they found that these general use patients experienced a greater reduction in pulmonary artery pressure over time compared to those in the pivotal CHAMPION clinical trial.

                                                The results from this large observational study, therefore, demonstrates hemodynamic heart failure management may be effective in U.S. clinical practice with high rates of patient adherence and effective pressure management.

                                                This paper is accompanied by an excellent editorial by Drs. Gorter, Rienstra, and van Veldhuisen from University Medical Center, Groningen, Netherlands, which really places this paper in the clinical context of heart failure and particularly patients with heart failure and preserved ejection faction

                                                Well that wraps it up for your summaries. Now for our feature discussion.

                                                We're discussing a hugely important emerging issue today. And it's MINOCA, a myocardial infarction with non-obstructive coronary arteries, and a very important paper in today's issue, which really provides the first insight into potential long-term medical therapy in the management of MINOCA.

                                                However, now this issue of MINOCA is quite new and I'm sure new to many of those listening on the line. So, I am with the first and corresponding author of the paper, Dr. Bertil Lindahl from Uppsala Clinical Research Center in Sweden. Welcome.

Dr Bertil Lindahl:               Thank You.

Dr Carolyn Lam:                And also the associate editor who managed this paper, Dr. Gabriel Steg from Hospital Bichat in Paris, France. Welcome back.

Dr Gabriel Steg:                Hello.

Dr Carolyn Lam:                Now, we need to start by first understanding what we're talking about. MINOCA ... give us a good definition of what you mean by MINOCA. And does it include the non-coronary causes of AMI, or non-obstructive disease? Does it include myocarditis? Does it include the non-cardiac causes, like pulmonary embolism?

Dr Bertil Lindahl:               Our definition of MINOCA used in this paper is that you received the ICD code for acute myocardial infarction. If you have a clinically clear case of myocarditis or Takotsubo and were not included in this analysis. But we know if we look into patients that have got the diagnosis of myocardial infarction ... if you performed, for instance, MRI afterward, you can see that a portion of the patients experience ... between 10 and 30 percent of the MINOCA patients, have evidence of myocarditis, although it was not clinically expected.

                                                So this is a heterogeneous population ... initial diagnosis was myocardial infarction.

Dr Carolyn Lam:                Thank you for clarifying what you used in your study. Gabriel, could I just, you know, bring you in on this because you invited an excellent editorial that accompanies this paper. And, basically, it helps to get us past all this terminology you know, MINOCA now. Could you maybe just clarify the overall perspective of what it means?

Dr Gabriel Steg:                Yeah. This area is fairly new and we still have a major nomenclature problem. Clearly it's been recognized for many years that patients who have a clinical syndrome of myocardial infarction do not necessarily have obstructive coronary artery disease. At least severe obstructive coronary artery disease. Many patients have mild lesions and some patients apparently have no lesion at all.

                                                Now, over the last few years we've understood that this is really a syndrome. And that under that big umbrella, there are patients who have non-cardiac causes of troponin elevation and chest pain. These should be excluded from MINOCA. If you have pulmonary embolism, this is not MINOCA. This is pulmonary embolism.

                                                The second aspect is there are more subtle distinctions to be made with fairly new entities such as Takotsubo. When this study was started, Takotsubo was an emerging disease concept. And so the authors were not able to properly rule out the Takotsubos and probably a few myocarditis from their data set. We now have learned over the past few years that MRI is an excellent tool to screen MINOCA patients and flush out patients who have myocarditis or Takotsubo, which are not rare. Actually it's a substantial portion of that entity.

                                                And then we're left with what I call the true MINOCA. Now what's fascinating in the study here is really that ... first of all I want to say this is another great study from our Swedish colleagues leveraging their data collection tools, which are remarkable. Really an example to the world.

                                                The second thing is they have collected ten years of data on MINOCA. And they're able to tease out which are the agents that should be using secondary prevention in that population. Elegantly demonstrating with sensitivity analysis and positive and negative controls what are the agents associated with improved outcomes and what are the agents that apparently do not impact outcomes.

                                                So even though at the time they were not able to rule out myocarditis and Takotsubo properly, still the sheer size of their study, long term follow up, and the careful statistical analysis that they've done are remarkable.

Dr Carolyn Lam:                I couldn't agree more. And more so in an area that is really emerging in importance. And for which we don't have any prospective clinical trials. I'm correct in saying that, right ? So Bertil, this would be a great point for you to let us know what are the main findings from your study please.

Dr Bertil Lindahl:               The main findings are that statins are associated with a beneficial effect on the cardiac event. And also, ACE inhibitors or ARBs , while we were not able to show statistically things you can affect with beta blockers and similarly not with dual anti-platelet treatment. So that's basically the main findings of the study.

Dr Carolyn Lam:                May I ask how have these findings personally impacted your clinical practice or do you think the next steps are gaps that need to be addressed first?

Dr Bertil Lindahl:               I think that's an ongoing discussion in Sweden now and in our hospital on how this should be applied to clinical practice. Nothing. It will have an effect that statins and ACE Inhibitors or ARBs will be used. I'm not sure whether we still can say that we should not use beta blockers or dual antiplatelet treatment. But I think also that we are now discussing we should do a randomized clinical trial to really tease out whether we should use beta blockers or not or also verifying the findings regarding ACE Inhibitors and ARBs.

                                                So, I think there's always a discussion whether we can really use observation studies for treatment decision. But I think since we don't have any better trials so far I think that this is the best that we can get. So I think it will be used and applied in clinical practice.

Dr Carolyn Lam:                Indeed. I really agree with what Gabriel said this is the best available evidence we have now. And my personal take home message was to pay more attention to the statins and the ACE Inhibitors. So congratulations on this great study.

                                                Gabriel, what do you think? What are next steps? I mean, MINOCA's not even in the guidelines now. Our guidelines talk about type 1, type 2, AMI does it all fit in?

Dr Gabriel Steg:                Well, we've seen a sea change in the concepts regarding myocardial infarction over the last fifteen years with the advent of troponin and the ability to diagnose new patients that previously we wouldn't even label as an MI.

                                                The second aspect is we've recognized over the years that there are some genuine MI's that don't have severe obstructive coronary artery disease. Now what's interesting is that some of them may have apparently mild obstructive disease. Which presumably is related to coronary dissections, embolism, plaque rupture with thrombosis that disappeared in the interim. And some of them may have actually "clean" coronary arteries and have myocardial infarction related to other mechanisms such as micro vascular mechanisms. What's interesting, and I'd like to ask the opinion of Dr. Lindahl is, these three types of diseases; mildly obstructive disease, coronary dissection, and microvascular angina are all more frequent among women. And I wonder whether you have any insights regarding gender differences in your registry.

Dr Bertil Lindahl:               In this study, in the sub-group analysis we saw no significant interaction between gender and the effects. But unfortunately we don't have the registry information between , let's say completely "normal coronary arteries" versus "mildly obstructed coronary arteries". And that's a clear limitation of this study. It will be very interesting to see whether these effects are similar in these two sub-groups.

                                                It seems from other studies that approximately fifty percent of the MINOCA patients that have normal coronary arteries and fifty percent that have mild aortic disease. So this is a limitation of this study and I think that's just something we have to look for in the future. And I hope that we will have in the registry onwards, data on whether this normal or mild coronary artery disease.

Dr Carolyn Lam:                Really appreciate that and really appreciate the insights you gentlemen have shared. Any final words or concluding remarks, Gabriel?

Dr Gabriel Steg:                Well, again congratulations on the great study. I would refer our readers to the excellent editorial of John Beltrame that accompanies this paper, which reviews the concepts of MINOCA, the nomenclature, and some of the remaining and lingering questions that plague the field. And delineates way forward for studies.

                                                I think it's a fascinating area. I'm sure we're going to hear a lot more, both from the Swedish Heart Registry as well as other data sources. I think we all need to stay tuned to this important area. The prognosis of these patients is not so good, so we need to pay attention to that entity.

Dr Carolyn Lam:                Wonderfully put. Well, thank you listeners for joining us this week. Please share this episode with all of your friends. So thank you and join us next week.


Apr 10, 2017

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.

                                                Today's issue features two exciting papers regarding heart failure in patients with breast cancer. We will be discussing this right after these summaries.

                                                Are we any closer to improving survival in Eisenmenger syndrome? Well, today's first original paper looks at contemporary trends and presents a multivariable mortality risk stratification model based on five simple noninvasive predictors of death in this population. Dr. Kempny and colleagues from Royal Brompton Hospital in London in the United Kingdom preform a large multicenter study in 1098 patients with Eisenmenger syndrome followed up between years 2000 and 2015.

                                                At the end of the study almost two-thirds of patients were on advance therapy for pulmonary arterial hypertension, while only six patients underwent lung or heart and lung transplantation. The study showed that despite advances in management, there was significant mortality amongst contemporary adults with Eisenmenger syndrome and 25.3% of patients died over a median follow up period of 3.1 years. Mortality was higher in older patients, those with a pre-tricuspid shunt, lower oxygen saturation, absence of sinus rhythm, or with a pericardial effusion.

                                                This important study is accompanied by an editorial by Drs. Lange, from Texas Tech University Health Sciences Center El Paso and Dr. Brickner from UT Southwest Medical Center in Dallas, Texas. The editorialists call for a prospective randomized control trials of the effect of current, or future pulmonary vasoactive disease targeting therapies on mortality in Eisenmenger syndrome patients, and say it's time to direct our efforts from improving risk-stratification towards improving survival.

                                                The next study provides experimental evidence of tolerogenic dendritic cell therapy as a novel anti-remodeling therapy in myocardial infarction. Tolerogenic dendritic cells are promising, potent, beneficial regulators of the post-infarct healing process via their control of T-regulatory cells and M1 M2 macrophages. Plus they have the advantage of the ease of administration and feasibility of a heart specific tolero-dendritic cell production.

                                                In the current paper by co-first authors, Drs. Choo and Lee, and co-corresponding authors, Drs. Chang and Lim, from Catholic University Korea and Chai University in Korea, authors generated tolerogenic dendritic cells by treating bone marrow-derived dendritic cells with TNF-alpha and cardiac lysate from mice with myocardial infarction. They then injected myocardial infarction mice twice with tolerogenic dendritic cells within 24 hours and at 7 days after LAD ligation. In treated animals, in vivo cardiac magnetic resonance imaging and ex vivo histology confirm the beneficial effects on post-infarct LV remodeling. Furthermore, subcutaneously administered tolerogenic dendritic cells near the inguinal lymph node migrated to the regional lymph nodes and induced infarct tissue specific T-regulatory T-cell populations in the inguinal and mediastinal lymph nodes, spleen, and infarcted myocardium, all of which elicited an inflammatory to reparative macrophage shift. The altered immune environment in the infarcted heart resulted in better wound remodeling, preserved left ventricular systolic function, and an improved survival following myocardial infarction. Thus, this study shows that tolerogenic dendritic cell therapy in a preclinical model of myocardial infarction may be potentially translatable into an anti-remodeling therapy for ischemic repair.

                                                The final paper reports results of cell therapy on exercise performance and limb perfusion in peripheral artery disease from the PACE trial, which is an NHLBI-sponsored randomized double-blind placebo-controlled phase two clinical trial, designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright cells in peripheral artery disease, and to explore associated claudication physiological mechanisms. In this paper from corresponding author Dr. Moye from UT School of Public Health in Houston, Texas and colleagues of the Cardiovascular Cell Therapy Research Network, a total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at nine sites to receive alcohol dehydrogenase bright cells or placebo. All patients underwent bone marrow aspiration and isolation of aldehyde dehydrogenase bright cells followed by 10 injections into the thigh and calf of the index leg. Results showed that there were no significant differences in the change over six months between study groups for the co-primary endpoint of peak walking time, collateral count, peak hyperemic popliteal flow, and capillary profusion measured by magnetic resonance imaging.

                                                Additionally, there were no significant differences for the secondary endpoints including quality of life measures. There were no adverse safety outcomes. Interestingly, a post-hoc exploratory analysis suggested that aldehyde dehydrogenase bright cell administration might be associated with an increase in the number of collateral arteries in participants with completely occluded femoral arteries.

                                                In summary, cell therapy did not improve peak walk time or magnetic resonance outcomes, and the changes in peak walk time were not associated with the anatomic or physiologic MRI endpoints. However, future peripheral artery disease cell therapy trial design may be informed by new anatomic and perfusion insights. These and other issues are discussed in an accompanying editorial by Drs. Breton-Romero and Hamburg from Boston University School of Medicine. Well, that wraps it up for our summaries, now for our feature discussion.

                                                We are really in the grove here in Washington, D.C. and I am borrowing the words of my very special, star associate editor, guest, Dr. Gregory Hundley, and he's from Wakefield University School of Medicine. We're discussing two very important papers and they deal with the risk of heart failure following breast cancer. Why they're so important? Well, first of all, it's about time we looked at this problem in detail, and secondly, they actually represent papers in a new section of the journal called "Bridging Disciplines," and in this case cardio-oncology. Very, very important topics.

                                                We're here with the corresponding authors of both papers, Bonnie Ky from University of Pennsylvania School of Medicine and Dr. Margaret Redfield from Mayo Clinic.

Dr Gregory Hundley:      Thank you, Carolyn. I really appreciate that wonderful introduction and also the chance to talk with Bonnie about this exciting topic.

                                                So, Bonnie, you've got a paper here, now, where you did a study in patients with breast cancer, and it sounds like you acquired echocardiograms over a period of time. Can you tell us a little bit about that?

Dr Bonnie Ky:                     Correct. So this is longitudinal prospective cohort study, it's an NIH-funded R01, whereby we are enrolling patients from the breast cancer clinic who are receiving doxorubicin or trastuzumab or a combination of the two therapies. And we're performing very careful cardiovascular phenotyping, from the time at which they initiate chemotherapy through their chemotherapy and then annually once a year we have them come back, for a total follow up time of 10 years.

                                                We took a subcohort, 277 patients, and from their echocardiograms, we analyze them very carefully for various measures of left ventricular size, function, not only systolic function but also diastolic function. We also looked at measures of contractility such as strain in multiple dimensions, and then also measures of ventricular arterial coupling, as well as arterial loads, so how the ventricle interacts with the arterial system. And what we found was that over a 3.2 period time period, on population average, these modest declines in left ventricular ejection fraction, and even across all three treatment groups, and even at three years there were persistent LVF declines.

Dr Gregory Hundley:      So, I understand, Bonnie, that you also collected some information as to whether or not these patients were experiencing symptoms associated with heart failure. How did the imaging markers relate to the symptomatology associated with heart failure?

Dr Bonnie Ky:                     What we found was that early changes in arterial stiffness or total arterial load, as well as early changes in EF were associated with worse heart failure symptoms at one year. A lot of our other analysis was focused on defining what echo parameters of remodeling, size, function are driving or associated most strongly with LVF decline, as well as LVF recovery.

Dr Gregory Hundley:      And then at two years, what happened? Did the echo parameters, were they still associated with heart failure or was there a little discrepancy there?

Dr Bonnie Ky:                     Interestingly, at two years ... no, there was no significant association with changes in arterial load and heart failure symptoms at two years.

Dr Gregory Hundley:      So there might be something transient that's occurring that is associated with heart failure early, and then the patients still had heart failure late, so maybe something else is operative. What do you think we need to do next? What's the next step in your research and then other investigators around the world; what do we need to do to design studies to look at these issues further?

Dr Bonnie Ky:                     Yeah. What does the field need, the field of cardio-oncology that's really growing and developing at rapid paces. Some of the major findings from the study was that changes in total arterial load were very strongly associated with both LVF decline and LVF recovery. So total arterial load is the measure of blood pressure or total arterial stiffness, it's derived from blood pressure. And to me, that begs the question, or begs the next step is that changes in blood pressure are associated with decline as well as recovery. I think, oh, as cardiologists we've also always recognized the importance of afterload reduction. And to me, this study suggests that we need a study, a randomized clinical trial, looking at blood pressure lowering in this population to help mitigate LVF declines.

Dr Carolyn Lam:                I'd actually like to turn it back to you. You are world-renowned for your work in cardio-oncology. Where do you think this fits in, and where do you think we need to address most urgently?

Dr Gregory Hundley:      I think where this fits in wonderfully is a lot of individuals around the world are collecting echocardiographic measures, and all different types. And what Bonnie has helped do is clarify what we would expect to see in this particular patient population. How those measures change over time and that feeds into another block of data, when the measurements head south, do we change therapy, do we add protective agents, and things of that nature. So I think Bonnie's work really contributes on that front. What she has also pointed out is that more research needs to be performed, not necessarily because the patients had heart failure symptomatology at two years, but not necessarily associated with the decline in EF; are there other systems in the cardiovascular realm that are being affected? The vascular system-

Dr Carolyn Lam:                Yeah.

Dr Gregory Hundley:      Skeletal muscle, many other areas. So as cardiologists start to work more with oncologists in this space, and we're all working together to make sure that not only patients survive their cancer, but they have an excellent quality of life, I think we'll see, as we have in other heart failure syndromes, a look toward other aspects of the cardiovascular system, body in general, to reduce the overall morbidity associated with the disease.

                                                I think what we need to recognize as cardiovascular medicine specialists is that now for many forms of cancer, cardiovascular events, and certainly morbidity are becoming the primary issue that folks have to deal with with survivors. It's not necessarily the cancer recurrence, it's not necessarily a new cancer, it's cardiovascular. So we've got to integrate cardiology earlier in working with oncologists to improve overall survival and create an excellent quality of life from our different perspectives.

Dr Carolyn Lam:                So, Maggie, let's move on to your paper now. You looked at radiotherapy's effect, whereas Bonnie looked at chemotherapy's effect. Could you tell us what you did and what you found?

Dr Margaret Redfield:    The rationale for doing this study was, of course, seeing a lot of patients with HFpEF who had had radiation therapy for breast cancer, and I always just sort of assumed that that was because 12% of women over the age of 40 get breast cancer and 20% of women over the age of 40 get heart failure, but it seemed to be somehow more common than that. The other rationale was that radiation therapy does not actually affect the cardiomyocytes; they are very radiation resistant. And what radiation does is cause microvascular endothelial cells damage and inflammation, and that is felt to be fundamental in the pathophysiology for HFpEF.

                                                So we thought we should look at this. I collaborated with a radiation oncologist and oncologists, and they were interested in looking at this because there's a lot of techniques now to reduce cardiac radiation exposure during radiation therapy, including proton beam therapy, and they're trying to prioritize who they use this new technology on. So what we did was start with a population-based study, all women who lived in Olmsted county who received radiation therapy for breast cancer in the contemporary era, where they're already using these dose reducing techniques. So we wanted to make it relevant to what's going on today. And so we started with a base cohort of all women. We matched patients' cases, it was a case-control study, so we matched cases and controls according to their age at the time of breast cancer, whether they had heart failure risk factors, like hypertension or diabetes, whether they got adjuvant chemotherapy, and tumor size, because we felt it was important that radiation could affect different parts of the heart, depending on whether it was right- or left-sided tumor.

                                                And what we found is that the risk of heart failure increased with the mean cardiac radiation dose. We measured the mean cardiac radiation dose in every case and every control from their CT scans and their radiation plants. And as the radiation dose went up, the risk of heart failure went up, even matching or controlling for chemotherapy, which wasn't used that often in this group, or heart failure risk factors. And the vast majority of these cases were indeed HFpEF.

                                                So we then looked at factors that happened in-between the radiotherapy and the onset of heart failure, making sure that this all wasn't just coronary artery disease, 'cause we know radiation can increase the risk of coronary artery disease. And indeed there were, only in about 18% of cases was there a new episode of coronary disease in the interim between the radiotherapy and the breast cancer. So, basically found that the mean cardiac radiation dose, even in today's era, does increase the risk of heart failure with preserved ejection fractions.

Dr Carolyn Lam:                The things that stuck out to me ... it's population based. You did such a comprehensive study to really answer very key questions: dose of radiation, is it really just mediated by age and age-related risk factors, is it just about MI or could it be more microvascular disease? Congratulations, I really appreciated this paper. Some of the take-home messages are directly related to the treatment of breast cancer, isn't it? And about the importance of minimizing radiation dose if possible. I suppose one of the take-homes is, as well, for screening and watching out for heart failure. One thing though: how were these woman diagnosed with HEpEF? I mean, this is always the questions I get. How do you get diagnosed with HEpEF?

Dr Margaret Redfield:    Right, well, first we started with looking to see if they had a ICD code for heart failure, and then we looked at each case of heart failure and determined if they either met Framingham criteria at the time of the diagnosis and the majority of them did. If they didn't actually meet the Framingham criteria, we looked to be sure there was a physician diagnosis of heart failure in the record and that they had supportive evidence of heart failure: echocardiographic findings, natriuretic peptide findings, and other clinical characteristics of heart failure.

                                                And importantly, in the large control group from where we, you know, got our controls, people, a very large group of patients who did not get heart failure, we'd use natural language processing to look at all those records to make sure we weren't missing anybody who didn't have an ICD diagnosis or code for heart failure to make sure we weren't missing any cases of heart failure. So, we really tried to use very stringent methods to make sure we had true cases and control groups.

Dr Carolyn Lam:                Indeed, and it actually goes back to Bonnie's paper as well, where we have to remind everyone that the diagnosis of HEpEF really starts with the symptomatology of heart failure in particular, that you so rigorously determined. I think just one last thing, Maggie: what do you think this implies now, for HEpEF? What do we do in general so the non-radiation-associated, do we believe more the Walter Paulus-Carsten Tschope hypothesis, and if so, what do we do?

Dr Margaret Redfield:    Yes, well I think it really does support that hypothesis. We know that radiation therapy, again, we know what it does to the coronary microvascular endothelial cells and that's been elegantly worked out both in patients and in animal models. I think this really supports the Paulus hypothesis because this microvascular damage was able to produce heart failure, so I think that really supports that hypothesis. And there's been some studies showing decreased coronary flow reserve in HEpEF patients; it's very common. So I think indeed it does support that hypothesis and that the coronary microvasculature is key in the pathophysiology of HEpEF.

                                                However it's a little scary to me because that sort of damage, once it's established, may be very hard to treat. You know, proangiogenic strategies in peripheral vascular disease have not yet yielded the benefits that we hoped for, so I think it's a tough therapeutic challenge that'll be very important to try to address in pre-clinical studies to try and figure out once the microvasculature is so damaged how do we treat that? How do we reverse that process?

Dr Carolyn Lam:                Yeah. Words of wisdom. Maggie, thanks so much for inspiring, just all of us in this field. I just had to say that. You know, you are the reason that I am totally in love with HEpEF. (laughter)

Dr Margaret Redfield:    (laughter)

Dr Carolyn Lam:                So thank you so much for joining me today on the show. In fact, thank you to all my three guests.

                                                You've been listening to Circulation on the Run. You must tell everyone about this episode, it is full of gems.

                                                Thank you, and tune in next week.


Apr 3, 2017

Carolyn:                               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editor's. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our Journal this week features important new data telling us that a common genetic variant risk score is associated with risk of drug induced QT prolongation and torsades de pointes.

                                                First, let's give you your summary of this week's journal. The first paper provides both clinical and experimental data to show that the adipokine, retinal binding protein four promotes atherosclerosis. First author, Dr. Liu, corresponding author, Dr. Xia and colleagues from Sun Yat Sen University in Guangzhou, China first evaluated the association between serum retinal binding four levels and the incidents of adverse cardiovascular events in a community based prospective cohort and then examined the effects of retinal protein four gain or loss of function on macrophage foam cell formation and atherogenesis in an apple lipase protein E deficient mouse model. They found, in the clinical cohort study, that base line serum retinal binding protein four level was an independent predictor of incidents of adverse cardiovascular events after adjustment for traditional risk factors.

                                                In the experimental study's, they showed that retinal binding protein four promoted macrophage derived foam cell formation through the activation of scavenger receptor CD36 mediated cholesterol uptake. In turn dependent on June and terminal kinase and signal transducer and activator of transcription one, as well as upstream regulation by the tracing kinase CSRC. These findings, therefore, support the use of retinal binding protein four as a novel biomarker for the prediction of cardiovascular risk. The data also provide insight into the mechanism of action of retinal binding protein four in the path of physiology of atherosclerosis.

                                                The next paper is the first clinical trial, looking at remote ischemic pre conditioning prior to carotid artery stinting in patients with severe carotid artery stenosis. Remote ischemic pre conditioning is a protective, systemic strategy by which cycles of bilateral limb ischemia are applied briefly to confer protection from subsequent severe ischemia and distant organs. First author, Dr. Zhao, corresponding authors, Dr. Ji, and colleagues from Xuanwu Hospital, Capital Medical University in Beijing, China performed a proof of concept, single center, prospective, randomized control trial to assess whether remote ischemic preconditioning was safe and effective in attenuating ischemic injury related to carotid artery stinting in 189 patients with severe carotid artery stenosis. Results show that daily remote ischemic pre conditioning for two weeks, prior to carotid artery stenting, was feasible, safe, well tolerated, and may effectively attenuate secondary brain injury as evidence by a decreased incidence and reduced volumes of new ischemic legions on magnetic residence imaging performed within 48 hours post operation. The clinical implications are that if results are confirmed by future, larger studies, remote ischemic preconditioning may evolve into a nonpharmacological, neuro protective method for inhibiting carotid artery stenosis related cerebral ischemic events.

                                                This potential for clinical translation in discussed in an accompanying editorial by Doctors Bell and Yellen, from University College, London.

                                                The final paper discusses firefighting and the heart. What's the link? Well, cardiovascular events are the leading cause of death amongst firefighters and the risk is known to be substantially increased during fire suppression duties. In the current study, first author Dr. Hunter, corresponding author, Dr. Mills, and colleagues from University of Edinburgh in United Kingdom sought to understand this link better by assessing the effects of simulated fire suppression on measures of cardiovascular health in an open label, randomized cross over study of 19 healthy firefighters. These firefighters performed a standardized training exercise in a fire simulation facility or like duties for 20 minutes. Following each exposure, ex vivo thrombus formation, fibrinolysis, platelet activation and for armed blood flow in response to intra-arterial infusions of endothelium dependent and independent vasodilators were all measured. The authors found that exposure to extreme heat and physical exertion during fire suppression activated platelets, increased thrombus formation, impaired vascular function, and promoted myocardial ischemia and injury in healthy fire fighters. These finding provided pathogenic mechanisms to explain the association between fire suppression activity and acute myocardial infarction in fire fighters.

                                                The implications of these findings for prevention are discussed in an accompanying editorial from Dr. Kales, of Harvard school of Public Health and Dr. Smith from Skidmore College and University of Illinois fire service institute.

                                                Well, those were your summaries. Let's welcome our guests for our feature discussion.

                                                Today's feature paper describes a pilot study that shows that a common genetic variant risk score, is associated with drug induced QT prolongation and torsades de pointes. This paper is so interesting to me because I found that the learning points, at least for me, really extended well beyond the trial itself. I'm so delighted to have with me the co corresponding authors, Dr. David Strauss from the US FDA, as well as Dr. Christopher Newton-Cheh from Massachusetts General Hospital. Welcome, gentlemen.

David:                                   Thanks very much, glad to be here.

Christopher:                       Thank you, Carolyn.

Carolyn:                               So, I've always thought that common genetic variants identified via GWAS, for example, are individually very weak effects on medical traits. For example, systolic blood pressure or in this case, QT interval. But what I'm so impressed with this study is that you show, I think for the first time, that even these small effects can add up to clinically meaningful results that are testable or demonstrable in a trial. David, could you begin by telling us a little bit about this trial and what the primary results were.

David:                                   In the study, we tested the hypothesis that a weighted combination of common genetic variants, contributing to the QT interval at base line, identified through prior GWAS studies, can predict individual response to multiple QT prolonging drugs. We performed a genetic analysis of 22 subjects and a secondary analysis of a randomized, double blind, placebo controlled cross over trial, that included three QT prolonging drugs, with 15 tie matched QT and plasma drug concentration measurements. This allowed us to carefully control for the inter individual differences in pharmacokinetics and just focus on the pharmacodynamics so the direct effect of the drug on the heart.

                                                What we found was, there was a significant correlation between the weighted combination of common genetic variants, which we call the genetic QT score, and drug induced QT prolongation. More specifically, we found that the genetic QT score explained 30 percent of the variability in response to dofetilide, 23 percent in response to quinidine, and 27 in response to ranolazine.

                                                We also investigated how response to one QT prolonging drug predicted the response to other QT prolonging drugs. There were significant correlations between all the drug/drug relationships with response to each drug explaining 24 to 29 percent of the variability in response to each of the other drugs. It's important to note that QT prolongation, by itself, is not harmful. The real concern is torsades de pointes, which can degenerate into ventricular fibrillation and cause sudden death. So, the test, irrelevant to the common genetic variants in predicting drug induced torsades, we then went on to examine a previously published, genome wide association study that included 215 patients with drug induced torsades, compared to 771 ancestry match controls and that prior study that was previously published had found that each individual common genetic variant did not reach genome wide significance, as you suggested, Carolyn. However, when we applied the weighted combination of common genetic variants, we found that the genetic QT risk score was associated with significantly increased risk of drug induced torsade, explaining 12 percent of the variation in risk.

Carolyn:                               So, my simplistic understanding was more or less there. That these genetic risks of these common variants kind of add up. I'm just curious ... Chris, do you think that this has implications for even other diseases? That's one question. And then secondly, I really appreciated your comment about using an intermediate trait, if you may, of QT interval versus looking at the disease itself of torsade de pointes. Could you give me comments on both these things?

Christopher:                       The study of intermediate traits, such as, quantitative traits like QT variability on the EKG are, I think very tractable for the study of genetic bases of underlying physiologic processes because we can study so many people. So the original genome wide association study that detected these individually weak genetic effects could only find them because we studied about 75,000 people who had had genome wide genome typing and QT intervals measured. It requires such large sample sizes to reach p values that are able to distinguish true positive associations from false positive associations, due to the multiple testing burden.

                                                I think a challenge of what to do with these genetic effects once they've been reliably detected is that they do have weak effects and they influence intermediate traits. Nobody really cares whether their QT interval is three milliseconds longer, or three milliseconds shorter. What they care about is hard outcomes, or the likelihood that they'll have a toxic drug response. So, it was a natural follow on to that work to try to test these variants, and we knew that based on their weak effects individually on QT interval in the general population, that it was unlikely that they would individually explain a significant portion of either drug response or torsade. Which is why we aggregated the facts into the weighted score.

                                                I think we tried to examine what we thought were the most proximal, clinically relevant outcomes. Specifically, drug response. QT drug response to drugs that are established to cause QT prolongation and arrhythmias. Whether the QT score will have meaningful or detectable impact on drugs that have much weaker effects on re polarization and risk of torsade, I think, would remain to be seen.

Carolyn:                               That's really remarkable.

                                                David, how about your perspective of the implications of this? It's so unique that you're actually from the FDA so, why is this important to the FDA?

David:                                   As Chris mentioned, the specific application we studied here, a drug induced QT prolongation and torsade have resulted in the withdrawal of several drugs from the market both in the US and worldwide. Many critical drugs remain on the market that are associated with QT prolongation and torsade…over 100 drugs, likely. What some people may not be familiar with is that at FDA we perform research to move new science into the drug review process and close the gap between scientific innovation and drug review. Like practicing clinicians, we seek to understand inter patient variabilities and we conduct research to better evaluate, benefit, and risk of medications. This is in line with the broader initiative ... the precision medicine initiative, which seeks to move away from the traditional “one size fits all” approach for medical therapy and instead, take into account specific characteristics of individual patients.

                                                People are most familiar with this being applied in oncology and advances in pharmacogenomics have been more limited in other areas with the exception of the genetic bases of metabolism and pharmacokinetics  where the traits are often controlled by one or a few genetic mechanisms, rather than the many mechanisms responsible for complex traits and diseases, as Chris discussed. As I mentioned earlier, what was relatively unique about this study is that we were able to control for the difference in pharmacokinetics and investigate the inter individual differences in the direct effect of drugs on the heart, the pharmacodynamics. We think it's very exciting that a combination of common genetic variants and aggregate can explain a significant portion of the inter individual variability and, as Chris mentioned, this is also important because the incidence of torsade is quite low. Only a small number of patients will develop drug induced torsade. It's possible that in the future analysis of a large number of common genetic variants that can be identified through genome wide association studies as in this case, may help to better define the personalized benefit risk profiles for individual patients.

Carolyn:                               You've really articulated that remarkably. That's exactly the excitement I think the entire editorial team shared when we read your paper. Thank you so much for it. Maybe just one last question thrown out to both of you, what's the next step? What's in the future.

Christopher:                       I think one next step, based on this proof of principle study, will be to try to test the impact of these genetic risk scores in real world clinical settings where individual patients with the diversity of different comorbidities and different drug exposures are also receiving QT prolonging drugs. Because that will have the biggest relevance for our patients who faced increased risk of drug toxicity.

David:                                   The issue of cardiac safety of drugs is something that is very important to us at the FDA and we have some parallel initiatives that, in collaboration with other global drugs ... regulatory agencies and industry and academic collaborators ... we are working to develop new cardiac safety evaluation paradigms for new drugs, or existing drugs, that could even be applied in the preclinical setting and really focus on the mechanistic base, pro arrhythmic risk. So, we should have more exciting work coming forward in the near future for better prediction and individualized prediction of benefit and risk of medication.

Carolyn:                               Thank you, listeners, for joining us. You've been listening to Circulation on the Run. Join us next week.


Mar 27, 2017

Caroline:                              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. Up next, we are discussing the featured paper in this week's journal regarding the increased risk of cerebrovascular events in young cancer survivors, the downside perhaps of surviving cancer, so to speak. But first, here's your summary of this week's journal.

                                                The first paper describes the US national trends in atrial fibrillation hospitalization, readmission, and mortality. This paper from Dr. Freeman and colleagues of Yale University School of Medicine in New Haven, Connecticut used data from all Medicare fee-for-service beneficiaries between 1999 and 2013, and found that the adjusted rates of hospitalization for atrial fibrillation increased by almost 1% per year. Median hospital length of stay remained unchanged at three days, but median Medicare inpatient expenditure per beneficiary increased from $2,932 to $4,719 per stay.

                                                During the same period, the rate of inpatient mortality during hospitalization for atrial fibrillation decreased by 4% per year, and the rate of 30-day readmission also decreased by 1% per year, while the rates of 30-day and one-year mortality decreased more modestly by 0.5% and 0.26% per year, respectively. Thus, between 1999 and 2013, among Medicare fee-for-service beneficiaries, rates of hospitalization for atrial fibrillation and the cost of those inpatient stays increased substantially, but this was associated with improved outcomes, including lower rates of readmission and mortality. These findings suggest that increased hospitalization and more costly contemporary treatments, such as atrial fibrillation catheter ablation, may be associated with improved outcomes.

                                                The next study provides insights into the mechanisms underlying augmentation of muscle blood flow by ultrasound cavitation of microbubbles. Now, this is a promising approach for rapidly correcting tissue profusion in acute ischemic syndromes or for treating chronic ischemic symptoms. In this paper by first author Dr. Belsik, corresponding author Dr. Linder, and colleagues from Night Cardiovascular Institute Oregon Health and Science University in Portland, Oregon, the authors hypothesized that pure endergic signaling may be responsible for sheer dependent increases in muscle profusion during therapeutic ultrasound cavitation.

                                                To test this hypothesis, the authors studied unilateral exposure of the proximal hind limb of mice with and without ischemia produced by iliac ligation, to therapeutic ultrasound after intravenous injection of lipid microbubbles. They further performed a proof of concept study with twelve patients with stable sickle cell disease. They found that therapeutic ultrasound cavitation increased muscle profusion by seven-fold in normal mice, reversed tissue ischemia for up to 24 hours in the murine model of peripheral artery disease, and doubled muscle profusion in patients with sickle cell disease.

                                                Augmentation inflow extended well beyond the region of ultrasound exposure. Ultrasound cavitation produced a nearly forty-fold focal and sustained increase in ATP, the source of which included both endothelial cells and erythrocytes. Inhibitory studies indicated that ATP was a critical mediator of flow augmentation. Furthermore, combined indomethacin and inhibition of eNOS abolish the effects of therapeutic ultrasound, indicating downstream signaling through both nitric oxide and prostaglandins. Thus, the authors concluded that therapeutic ultrasounds using microbubble cavitation to increase muscle profusion relies on sheer dependent increases in ATP, which can act through a diverse portfolio of purinergic signaling pathways. Cavitation-related release of ATP may further serve to explain ultrasound's role in other therapeutic applications, such as wound and bone healing, and ultrasound facilitated drug or gene uptake.

                                                The final original paper describes the age-specific trends of heart failure in Denmark over the last two decades. Dr. Christiansen and colleagues of University of Copenhagen in Denmark studied more that 210,000 Danish individuals over the age of 18 years, with a first time in-hospital diagnosis of heart failure from three nation-wide Danish registries.

                                                They found that the incidents of ischemic and non-ischemic heart failure in Denmark declined by approximately 50% among older adults more than 50 years old, but increased by about 50% among younger individuals, or individuals less than 50 years old, between 1995 and 2012. Furthermore, they observed a concomitant increasing trend of various treated co-morbid conditions, including hypertension, diabetes, and ischemic heart disease in the population. These findings from Denmark imply a change in the profile of the heart failure community and portend a higher burden of heart failure in the future. The increasing trend of incident heart failure among young individuals especially warrants further investigation.

                                                Well, those were the original papers this week. Now, for our feature discussion.

                                                Our feature paper today discusses a hugely important modern issue that may seem like good news at first sight. We know that survival in cancers has rapidly improved with advances in early detection and treatment, however the improved survival also extends the window for the occurrence of long-term complications such as psycho-social effects, fertility problems, secondary malignancies, and, as highlighted in today's paper, the risk for cerebrovascular events. I'm so pleased to have with us first, author Chloe Bright from University of Birmingham, United Kingdom, as well as associate editor Dr. Graeme Hankey from University of Western Australia. Welcome, Chloe and Grim!

Chloe Bright:                      Thank you for having me.

Graeme Hankey:              Thank you Caroline.

Caroline:                              Chloe, what an interesting and important focus on cerebrovascular events following survival from cancer. Please, can you share your inspiration for looking at this and what you found?

Chloe Bright:                      As you've just said, the five year survival rate from teenage and young adult cancer has been increasing and increasing, and it's over 80% now, which means there's such a large population of survivors who are at increased risk, or potentially increased risk, of developing adverse health outcomes. So, as you know, cerebrovascular disease can be potentially fatal so it's really important that we estimate how much teenage and young cancer survivors are at risk of this. So to start of with our group in Birmingham actually set up the teenage and young adult cancer survivor cohort study. And this is a cohort of over 200,000 five year survivors of cancer who were diagnosed between 15 and 39 years of age. And this was set up because there's hardly any literature regarding the adverse health outcomes of teenagers and young adults who have had cancer.

                                                So, as I said, cerebrovascular disease is a really important outcome to look at. So we decided we've got this resource in the UK, which is the Hospital Episode Statistics, and this carries information on all the inpatient hospitalizations in England. So from this we were able to determine how many people with teenage and young adult cancer had been hospitalized for cerebrovascular events and compare this to what we would expect to see in the general population to see if they had an increased risk or not. So from limited previous literature that was out there we did know that TYA cancer survivors had an increased risk of developing a cerebrovascular event. However, we were unsure how this risk varied with certain explanatory factors, such as age of cancer diagnosis or the decade of cancer diagnosis, gender, and attained age, so that's the age at which a stroke event might occur. So the main aim of our study was to quantify this.

Caroline:                              Yes and to put some numbers to that increased risk. It was a 40% increased risk, wasn't it? That is striking.

Chloe Bright:                      We observed almost 2,800 cerebrovascular events. That related to a 40% increased risk of being hospitalized compared to what we would expect to see in the general population, which is really quite substantial.

Caroline:                              Now, were there particular risk factors that were associated with more cerebrovascular complications like certain types of tumors or certain types of therapies and so on?

Chloe Bright:                      Survivors of central nervous system tumors, head and neck tumors, and leukemia were all at the greatest risk compared to the general population. And this is probably related to radiotherapy that they had for their initial treatment. So radiotherapy to the neck, which could involve damage to the carotid artery, or radiation to the head which again could cause damage to the cerebral arteries in the brain. And then also we found that the risk increased dramatically as people aged for neck tumor survivors and CNS tumor survivors. So specifically cerebral infarctions, the additional number that we saw was a lot greater in, say, survivors over age 60. And this is probably because this is when strokes in the general population are becoming more incident.

                                                And actually an interesting finding, we observed that males actually had a higher number of excess infarctions than females, and this was especially among head and neck tumor survivors. So we can't confirm this, but this could potentially be due to difference in smoking habits because there could be a said etiology between smoking and the risk of head neck cancer and also smoking and the risk of stroke. Unfortunately, we didn't have the information on smoking status to confirm this.

Caroline:                              This is a huge study. It shows a substantial increased risk of stroke in these young cancer survivors, and also sheds light on the possible underlying mechanisms. What you mention about vasculopathy following radiotherapy really reminds me about what we learn about breast cancer radiotherapy and the risk of myocardial infarction.

                                                Graeme, what are your perspectives on this paper please?

Graeme Hankey:              Well as an editor, as everyone knows, what we're really looking for are four main points. Firstly that the study was ethical, which it was. Secondly that the results are valid, internally and also externally. And we're very confident in the validity of the results. This was a very large study of 180,000 people, and more importantly had 2,800 cerebrovascular events so that's a lot of [inaudible 00:12:25] and the followup was pretty rigorous over 11 years, and the outcome events were [inaudible 00:12:32] by a data linkage through the hospitalization for the cerebrovascular events.

                                                The other two key features of course is are the results novel and are they important? And these are novel results. There's only been one previous similar study of a Danish cohort that was only 43,000 but one quarter the size of this study, and one year survivors of teenage and young adult cancer from 1943 to 2009 and followed up. And the results were actually very similar, showing a 1.3 or 30% increased risk of hospitalization for cerebrovascular events. Again supporting the validity of this recent study to obtain similar results, but in a four times greater population and in a more contemporary population whose patients were recruited between 1971 and 2006 and followed up from 1997 to 2012.

                                                And the other thing is it's not just ethical, valid, and novel, but it's important because it really has big implications for stroke prevention in young adult survivors of cancer. And it has implications for once they get the diagnosis and they're through their treatment to really focus on what were their pre-morbid vascular risk factors? Are they actually causal risk factors and not just cancer but also for future stroke like smoking and alcohol, and hypertension and diabetes? Secondly to try and recognize what is their absolute risk? Are they men who are at higher risk? Have they had previous irradiation that probably puts them at higher risk, as well as their current respective profile?

                                                Thirdly for them to then realize what's the impact of their cancer diagnosis on their future behaviors if they become depressed or change their diet or taking other treatments, or abusing drugs, and could that increase their vascular risk? And fourthly, what should be done? Should they just control their vascular risk factors through lifestyle? Or should we actually have a randomized trial of risk factor control, and/or antiplatelet therapy and/or statins and/or blood pressure lowering in these high risk survivors of cancer who are sill in their forties or fifties. Should they actually be taking antiplatelet therapy or statins? We probably need a randomized trial because they're high risk, we would think, or certainly a sub-population.

Caroline:                              Thanks Graeme for framing that so excellently. You're absolutely right that these are the things we look for in a paper as editors. And for our listeners to hear that is just so important.

                                                Well, I'd like to hand it over to you now Chloe. What are the next steps in your mind? What are the remaining gaps in knowledge you'd like to address?

Chloe Bright:                      I really think it relates to what Graeme just said. We need to get the information on the specific radiotherapy, the doses that have been used, the potential lifestyle factors of these individuals to see how much of an effect that has on the risk of stroke. So potentially conduct a case control study while we're able to get this information and then use that. And then, as Graeme said, once there is more information potentially a randomized control trial might be useful. But again, I think we need some more information before we can get the go ahead to doing that.

Caroline:                              Great. Just one more quick question please. You know, Chloe, you found that those who were more recently treated had a higher risk of cerebral hemorrhage than among survivors diagnosed earlier. Now, did you have any postulations on why this was the case?

Chloe Bright:                      This increase in the hemorrhage with more recent diagnosis was actually restricted to glial tumor survivors. So one explanation that we thought might explain this was that in recent years due to advances in treatments those glial tumor survivors, glial tumors who had more advanced stage at diagnosis, potentially surviving a little bit longer, so reaching five year survival which would enter them into our study. However they potentially might be having another occurrence, which would be causing them to have a hemorrhage, which in the previous decades perhaps they wouldn't have survived that long in the first place. That's just one of many ideas.

Graeme Hankey:              I think the recurrence of not just glioma but perhaps also melanoma that the survival is much greater now with new immunomodulating therapies for melanoma, we'll probably see longer survival in melanoma which typically when it metastasizes is hemorrhagic and perhaps also leukemia with thrombocytopenia, with more hemorrhage and other metathesis. The other thing it could be though is a diagnostic ascertainment bias in that I'm 60 now, and when I started neurology 35 years ago we didn't really have much brain imaging and couldn't diagnose intracerebral hemorrhage very well. And clinical diagnosis wasn't very reliable. Now the imaging which can actually distinguish hemorrhagic from ischemic stroke is much more widely available. And I suspect there's a greater increase in the diagnosis of cerebral hemorrhage now because of better imaging. We've seen that in other epidemiologic studies with that diagnostic trend.

Caroline:                              What excellent points. Thank you so much Chloe and Graeme.

                                                Well you've been listening to Circulation on the Run. Thanks for joining us today and don't forget to tune in next week.



Mar 20, 2017

Dr. 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 this week's issue, we are discussing if public placement of defibrillators in the community can be improved. First, here's your summary of this week's Journal.

                                                Stroke incidents, prevalence, and risk factors have been changing over the past 50 years so do we need a more contemporaneous revised Framingham Stroke Risk profile to reflect these trends? Well the first paper in our issue looks at this and this is from first author Dr. Dufouil, corresponding author Dr. Seshadri and colleagues from the Boston University School of Medicine.

                                                Let's first recall that the Framingham Stroke Risk profile was originally described in 1991 and integrates the effect of age, sex, and baseline measurements of various vascular risk factors such as systolic blood pressure, use of anti-hypertensive medications, left ventricular hypertrophy on ECG, prevalent cardiovascular disease, current smoking status, atrial fibrillation and diabetes all to describe the 10-year probability of incident stroke.

                                                In the current paper, the authors updated the Framingham Stroke Risk profile using the means of risk factors that reflect current prevalence, the estimate of incident stroke to reflect current rates, and the hazards ratio that reflect current associations. They used the same risk factors identified in the original stroke risk profile with the exception of left ventricular hypertrophy. The authors compared the accuracy of the standard old risk profile with the revised new risk profile in predicting the risk of [alt 00:01:58] and ischemic stroke and validated the new risk profile in two external cohorts, the three cities and regards or reasons for geographic and ethnic differences in stroke studies.

                                                They found that the new stroke risk profile was a better predictor of current stroke risks in all three samples than the original old Framingham Stroke Risk profile. The new stroke risk profile was also a better predictor among whites compared to blacks in the regard study. The authors therefore concluded that a more contemporaneous revised Framingham Stroke Risk profile could serve as the basis for examining geographic and racial differences in stroke risk and the incremental diagnostic utility of novel stroke risk factors.

                                                The next study provides preclinical proof of principle that an apelin receptor agonist may be of therapeutic use in pulmonary arterial hypertension. And the agonist in this case is  Elabela/Toddler or ELA, first identified as an essential peptide in the development of the heart in Zebrafish, and subsequently proposed as a second endogenous ligand at the G-protien coupled apelin receptor, which works at this receptor despite a lack of sequence similarity to the established ligand, apelin.

                                                In this study from first author Dr. Yang, corresponding author Dr. Davenport and colleagues  from University of Cambridge in the United Kingdom, ELA competed for binding of apelin in human hearts with overlap of the two peptides indicated by encyclical modeling. ELA activated G-protein and β-arrestin dependent pathways and as expression was detectable in human vascular endothelium and plasma. Comparable to apelin, ELA increased cardiac contractility, ejection fraction, cardiac output, and elicited vasodilatation in rats in vivo. 

                                                ELA expression was reduced in cardiopulmonary tissues from patients with pulmonary arterial hypertension and in rat models. Finally, ELA treatment significantly attenuated the elevation of right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in monocrotaline exposed rats. Thus, these results suggest that a selective agonist that mimics the action of indulgence ligand apelin or Elabela/Toddler, ELA, may be a promising therapeutic strategy in the treatment of pulmonary arterial hypertension.

                                                The final paper looks at sudden cardiac death after coronary artery bypass grafting, its incidents, timing, and clinical predictors. First author Dr. Rao, corresponding author Dr. Velazquez and colleagues from Duke Clinical Research Institute in Durham, North Carolina, looked at the patients enrolled in the STICH, or Surgical Treatment of Ischemic Heart Failure Trial who underwent coronary artery bypass grafting with or without surgical ventricular reconstruction. They excluded patients with a prior ICD and those randomized only to medical therapy. Over a median followup of 46 months, 113 out of 1,411 patients who received coronary artery bypass surgery, had sudden cardiac death while 311 died of other causes.

                                                The five-year cumulative incidence of sudden cardiac death was 8.5%. In the first 30 days after bypass surgery, sudden cardiac death accounted for 7% of all the deaths. The numerically greatest monthly rate of sudden cardiac death was in the 31 to 90 day time period. In multivariable analysis end-systolic volume index and BNP were the most strongly associated with sudden cardiac death. Thus, this study shows that the monthly risk of sudden cardiac death shortly after bypass surgery among patients with a low ejection fraction is highest between the first and third months, suggesting that risk stratification for sudden cardiac death should occur early in the post-operative period, particularly in patients with an increased preoperative end-systolic volume index and/or an increased BNP.

                                                Well, that wraps it up for you summaries, let's turn to our feature paper.

                                                I love our feature paper this week. You know why? It actually tells us what Tim Hortons, Starbucks, Second Cup and ATMs may have in common and may have to do with sudden cardiac death. Indeed, our feature paper actually tells us that coffee shops and ATMs may be the best spots to place AEDs at, well at least in Toronto. And to discuss this really interesting paper, I have the corresponding author, Dr. Timothy Chan from University of Toronto as well as Dr. Sana Al-Khatib, welcome again Sana, Associate Editor from Duke University, welcome to you both.

Dr. Al-Khatib:                     Thank you, my pleasure.

Dr. Chan:                             Thank you, very nice to be here.

Dr. Lam:                               So Tim, was that an interesting enough lead up? I mean you have to tell us about your study, it is so fascinating.

Dr. Chan:                             I'm very pleased that you find it interesting and not just us. So we undertook this study, we started this actually a couple of years ago, and we've been working on this issue of defibrillator location optimization for several years, and we've been talking and we have meetings in coffee shops and we were just wondering one day, what would be the risk or the coverage provided by all these different well-recognized location types around the city, and that was really the motivation that got us started looking at this study.

Dr. Lam:                               Tell us what you did and also how it differs from the study you did that was published in 2016 where you also reported on the spatial temporal analysis of registered AEDs in Toronto. The current study clearly extends it, but could you clarify to us all how it does?

Dr. Chan:                             Maybe just give a little bit of a background and context with regards to other literature that's similar. There have been studies in the past that looked at what we would call spatial coverage of cardiac arrest, so they looked at different broad location types and they tried to calculate, they basically calculated how many cardiac arrests happened, let's say within 100 meters of those location types. And what we've done here is we've extended that in a couple of directions. The first direction is looking at spatial temporal coverage and so this is not just in the nearby vicinity, IE, 100 meters, but also that cardiac arrests happen when that nearby location that had the AED was open. So if a cardiac arrest happens, but for example, let's say there's a coffee shop that actually has an AED and that coffee shop is closed, it's almost as if that AED is not even there. So one of the major things we made sure to include was this idea of temporal coverage as well, on top of the spatial.

                                                The second major difference I would say would be the fact that we're really looking at more granular location types, so you mentioned a few businesses in your opening such as Tim Hortons and Starbucks and so on, which are coffee shops, and so one of the things that we find is when we look at very broad location types, we tend to aggregate together lots of different types of businesses. For example, if you think about a restaurant, there are many different types of restaurants that get lumped in to this category, and they do have different cardiac arrest coverage associated with them. So by breaking it up into smaller location types, we wanted to get a better idea of the risk at different locations and if you also think about one of the long term goals of this work would be to try and help policy makers identify promising partners to partner with for, let's say public access defibrillation programs, by identifying specific businesses or municipal locations, it might actually give them better targets to try and pursue rather than let's say a group of different businesses.

Dr. Lam:                               That makes so much sense and it really just seems like such an important public health message as well. The sensible part being of course, if you have an out of hospital cardiac arrest, you need an AED that's both nearby and available, so that was really clever. Sana, could you give us your take on the public health implications of Tim's findings?

Dr. Al-Khatib:                     I think the public health implications of this work can be vast and if you look at what he's done in terms of ascending to out of hospital cardiac arrests a lot of initiatives have been launched to try to improve the outcomes of patients who have the out of hospital cardiac arrests. Unfortunately despite all the work that has been done and all the wonderful initiatives that have been launched, we still have a lot of work to do to improve the survival of those victims. So certainly a crucial step is how we deploy AEDs in a strategic way based on data and evidence such as these data that are provided to us by Tim and his colleagues.

                                                I think this is very clever, I do agree that we have to be more strategic in how we deploy AEDs and having the data such as these will only help us improve and get better of course. Everybody has limited resources, and so if we can be more selective in terms of how we deploy AEDs I think that would help everybody. I realize this was done within Toronto and some of these findings may not be generalizable to other cities, but I think this is definitely a great way to make us reshape our thinking in terms of how we do this, and so a question I have for Tim if I may, are you aware of any similar studies that have been done looking at this in other cities and then if not, how do we encourage other groups to do similar work?

Dr. Chan:                             There have been similar studies done that have focused really on the spatial side of things, so doing this 100 meter radius and counting cardiac arrests that have been nearby, there's actually been fairly little work that's been done on the spatial temporal side. And a couple of exceptions that I will note that I think are important to point out is there was a very nice study that was done out of a group in Copenhagen, and they were looking at actually spatial temporal coverage, particularly the loss in coverage that you experience when you go from looking at spatial to spatial temporal. For example if you count all of the cardiac arrests that happen nearby a registered AED based only on 100 meters, and then you count the same number, but you have to now layer on top of that when the building that the AED is in is open, then you tend to get a big loss. They found quite striking numbers, I think they found a 50% loss, when you look at evenings and weekends I believe, in Copenhagen. So basically all the cardiac arrests that happened where you thought there was an AED nearby, there's actually only one in two is actually nearby and accessible when you looked into hours of operation.

                                                And this actually comes back to the earlier question from Carolyn about how our study relates to our previous study in 2016, so we actually replicated that Copenhagen study in Toronto where we measured spatial coverage and we measured spatial temporal coverage and we measured that loss, and we found a similar loss overall, about 20%, so 1 in 5 cardiac arrests happened where there was an AED nearby, but that AED was not available because that location was closed. So that was one of the impetuses for leading us to do this study where we start to examine specifically the different location types and the specific businesses that were involved.

Dr. Lam:                               Wow, that's just really inspiring Tim, I mean I'm kind of thinking about the Singapore situation too and I think it's actually applicable and I would love if we had local data similar to yours, so congratulations, I really share what Sana said. Thinking though about the public health and the larger implications of what you're talking about, what do both of you think of the implications for a public commercial partnership in these things if it is coffee stores or banks that seem to be the best locations, perhaps these have implications to how the public and private should collaborate to make these things happen, what do you think?

Dr. Chan:                             I completely agree. These types of public private partnerships, specifically for AED deployment are not necessarily new, they already happen in some parts of the world. One of the examples I always like to bring out is if you go to Japan and they have vending machines everywhere in Japan and then you'll often run into vending machines that have an AED right in them, so one of the benefits is that first the vending machines are everywhere and second, if you're a citizen there, you probably know where the vending machines are where you travel in your day to day life and so I would say that would be a very similar thing here in North America, whether it be coffee shops or ATMs, if someone were to put me in a random part of the city and ask me, "Hey Tim, do you know where the nearest AED is?" I'd probably have a lot of trouble, but if they said could you figure out where the nearest ATM is for your bank or where the nearest Starbucks is you know, there's pretty much one on every corner. It would be much easier to identify and find, so I think there are significant benefits to partnering with these companies or these businesses that have very broad name recognition and brand recognition, are geographically well spread and located in populated areas.

                                                I should also mention, I feel like there's a few other benefits for these types of locations, so for example for ATMs, I think there's a lot of secondary benefits, so for example, there's a built in security component, there's a video camera there, that might be able to help make sure that no one's vandalizing or stealing an AED. There's perhaps built in weather protection because there's electricity there already, so in a cold climate like Toronto where you might worry about putting an AED outside, you could have potentially a heating cabinet that would be fed by the electricity for the ATM and so on. So I think there's actually a lot of benefits if we could actually operationalize a system like this.

Dr. Lam:                               Sana, do you think there are some more unanswered questions?

Dr. Al-Khatib:                     I did want to agree with Tim on what he said, that these public private partnerships have been in place. Unfortunately we haven't been able to make much progress. As I said, I do see the results of this study as being potentially a catalyst to improve the work that we are doing and ensuring stronger partnerships and collaborations to help us achieve what we want to achieve which is basically improve the survival rate of out of hospital cardiac arrests, so I completely agree with that and I loved your idea, Tim, when you talked about now people may not recall where AEDs might be, but if you link them with teller machines or coffee shops, I think that would be much easier to remember.

                                                You know of course there are a lot of questions that remain unanswered unfortunately. Again as was stated by Tim and his colleagues in the paper and on the call, how we can translate these findings to other locations I think is really key and then of course doing the work, meaning let's use these data to deploy more AEDs and then really looking at the impact of that. Ultimately we want to make sure that if we hypothesize that by doing this we can improve outcomes for these victims, we would want to prove that. So I think the next steps would be to see if this can be replicated in other places, but also even within Toronto, if we can accomplish some of this and then examining the impact, I think would be extremely beneficial.

Dr. Lam:                               Fabulous, thank you so much Sana, thank you so much Tim for sharing your thoughts today.

                                                Listeners, you heard it right here on Circulation on the Run. Don't forget to tell all your friends about this podcast and tune in next week.









Mar 13, 2017

Caroline:              Welcome to Circulation On The Run! Your weekly podcast, summary, and backstage pass to The Journal and it's editors. I'm Doctor Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore. What does the gut microbiome have to do with Cardiovascular Disease? Well to find out you'll just have to stay tuned for our featured discussion debate. First, here's our summary of this week's journal.

                                The first paper seeks to answer the question "does first trimester screening modify the natural history of Congenital Heart Disease?" To answer this question Doctor Jasinskyl and colleagues from the University Hospital in Masaryk University in the Czech Republic, analyze the spectrum of congenital heart defects and outcomes of 127 fetuses diagnosed with congenital heart defects in the first trimester compared to 344 fetuses diagnosed in the second trimester screening. All of these analyzed between 2007 and 2013.

                                They found that the spectrum of congenital heart defects diagnosed in the first versus second trimesters differed significantly with a greater number of comorbidities, defects with univentricular outcomes, intrauterine deaths, and terminations of pregnancy in those diagnosed in the first compared to second trimester.

                                They further analyze 532 fetuses diagnosed with congenital heart defects in the second trimester but in an earlier period of 1996 to 2001, which is the period before first trimester screening was introduced. In this group they found significantly more cases of defects with univentricular outcomes, intrauterine deaths, and early terminations of pregnancy. In comparison to fetuses also diagnosed with congenital defects in the second trimester but in the later period of 2007 to 2013.

                                Thus, the authors concluded that first trimester screening had a significant impact on the spectrum of congenital heart defects and on the outcomes of pregnancies with defects diagnosed in the second trimester. Early prenatal cardiac ultrasound screening may therefore, in some countries, reduce the number of children born with severe cardiac abnormalities and associated comorbidities.

                                The next study sheds light on the use of intravenous recombinant tissue plasminogen activator, or "RTPA," in patients with acute ischemic stroke also receiving no wax or the newer oral anticoagulants. Doctor Sienne and colleagues from the Duke Clinical Research Institute in Durham, North Carolina use data from the American Heart Association "Get With The Guidelines" stroke registry in 42,887 ischemic stroke patients treated with RTPA at 1,289 hospitals in the United States between 2012 and 2015. They basically found no statistically significant differences in the risk of symptomatic intracranial hemorrhage between patients who were taking Noac, Warfarin, or not taking any anticoagulant before the stroke.

                                This largest clinical experience of stroke thrombolysis in patients receiving Noac before the strokes thus suggest that RTPA is reasonably well tolerated without prohibitive risks for adverse events amongst selected Noac treated patients. However, the authors are quick to say that their observations must be considered as preliminary due to the absence of coagulation parameters, timing of the last Noac intake, and whether or not non-specific reversal strategies may have been applied.

                                The next paper provides experimental evidence of the unique effects of plasminogen activation and Alpha 2 antiplasmin inactivation on the fibrinolytic system in pulmonary embolism. In this paper from Dr Sing, Hong, and Reed from the University of Tennessee Health Sciences Center in Memphis, Tennessee the authors use mouse models of experimental pulmonary emboli to show that monoclonal antibody inactivation of Alpha 2 antiplasmin, which is an endogenous inhibitor of plasmin, effectively dissolved pulmonary emboli with similar potency to high dose RTPA.

                                Alpha 2 antiplasmin inactivation synergize with low dose RTPA to enhance thrombus dissolution. And like RTPA, Alpha 2 antiplasmin inactivation alone or in combination with low dose RTPA, did not cause fibrinogen degradation or increased bleeding. The authors therefore concluded that Alpha 2 anti plasmin is a dominant regulator that prohibits thrombus dissolution in vivo.

                                Therapeutic modulation of Alpha 2 antiplasmin activity may therefore prove an effective strategy to enhance fibrinolysis without significantly increasing the bleeding risk. These results are discussed in an accompanied editorial by Doctor Yurano from Hamamatsu University School of Medicine in Japan.

                                More exciting experimental data in the next paper showing that novel beta arrestin signaling pathways may be viable targets in dilated cardiomyopathy. First author Doctor Reba, corresponding author Dr Solaro, and colleagues from University of Illinois at Chicago treated a dilated cardiomyopathy mouse model expressing a mutant tropomyosin for three months with either a beta-arrestins two biased ligand of the entertance and receptor or losartan and angiotensin receptor blocker as control. Treated mice showed improved cardiac structure and function associated with myofilamins that had significantly improved myofilament calcium responsiveness. Which was depressed in the untreated mice.

                                These functional changes were mediated through beta arrestin which may have a novel role in increasing MLC2V phosphorylation through a previously unrecognized interaction of beta arrestin localized to the sarcamore. Thus, long term beta arrestin 2 biased agnonism of the angiotensin receptor may be a viable approach to the treatment of dilated cardiomyopathy. Not only by preventing maladaptive signaling but also by improving cardiac function by altering the myofilament calcium response via beta-arrestin signaling pathways. The concept of a two in one angiotensin receptor blocker and calcium sensitizer is discussed in accompanying editorial by Doctors Wu, Ju, and Siao from Peking university in China.

                                The final paper asks the question "are three arterial graphs better than two coronary artery bypass grafting?" Doctor Galdino and colleagues from Weill Cornell Medicine in New York performed a meta analysis of eight propensity score matched observational studies on more than 10,000 matched patients comparing the long term outcomes coronary artery bypass grafting with the use of two verses three arterial graphs.

                                They found that the use of a third arterial condo et in bypass grafting is a associated with superia long term survival irrespective of sex and diabetes status and without a higher operative risk. These results therefore support a strategy of the use of a third arterial graph and really deserve confirmation in prospective randomized trials. Well, that's it for the summaries. Let's welcome our guests.

                                Our topic for discussion today is so exciting. In fact, I am going to read from the paper describing it as an exciting, new, and important field of investigation where we start to understand how nutrition, our gut micro-community composition, and our genetics actually all play a part in Cardiovascular Disease. And to discuss this paper I have the first and corresponding author Doctor Wilson Tang from Cleveland Clinic Foundation as well as Doctor Nikhil Munshi, Associate Editor from UT Southwestern. Welcome Wilson and Nik!

Nik:                        Thank you.

Wilson:                 Thank you.

Caroline:              Wilson, please set the stage for us! What does our gut microbiome have to do with cardiovascular disease? I agree it's a hot area but, you know, could you just describe what it actually means.

Wilson:                 This has been somewhat of an accidental discovery from our group when we start encountering different types of metabolites that we measure to kind of associate them with Cardiovascular Disease. And unbeknownst to us, some of them are produced by the bacteria that live inside us to which we convert and try to eliminate. So one such metabolite that we identify is, which in many of the foods that we tell our patients, advise our patients that have high risk of Cardiovascular Disease. So all these connections come together to form a scientific basis to which how one of the biggest environmental exposures that we have which is what we eat every day is filtered by trillions of bacteria that live inside us and many of these metabolites become hormones that effect our every day function and activity.

                                And, in many ways, can actually lead to diseases that are so remote from the gut but such as Cardiovascular Disease, Atherosclerosis, and we further identify these process and they impact downstream organ function like heart function and kidney function. So these are all very excited areas and this is just one of several metabolites. There are other metabolites that also impact blood pressure and even brain function and so all these areas become kind of a new avenue for us to look at potential therapeutic targets.

Caroline:              Yeah I think it's so completely fascinating that we can actually each experience a given meal differently based on the different types of gut microbial communities in our bodies isn't it? And that that actually can effect things all the way from atheroscleroses, to obesity, insulin resistance, and so on. Could you give us a specific example from your research?

Wilson:                 We actually identified a metabolite, a very small molecule called Trimethylamine N-oxide, we abbreviate it as TMAO. And TMAO is actually formed from the bacteria from a precursor called Trigosamine which is, you know, gas. In other words, the bacteria taken substances of nutrients such as choline and connetine which is actually common in many foods but particularly in red meats, in egg yolks, and many other foods that we know are potential contributors to Cardiovascular Disease.

                                And actually converted into this gaseous compound that our liver converted into a neutral compound, that we think is neutral for a long time and nitrogenous waste, except that when we have both animal studies and human studies patients with high levels of this TMAO metabolite has been associated with a high risk of Cardiovascular Disease. And in fact in animal studies we have direct evidence that show its contributing to the mechanistic compartment.

Caroline:              Now extrapolating from what you just said so vegetarians, for example, or vegans even more so, would have less TMAO levels then?

Wilson:                 Yeah, obviously there are wide variation in these levels actually change almost by the minute because obviously we eat different times of the day and it comes in and out of our bodies. But in general, yes, in other studies that we actually identified a higher level of in carnivores which are meat eaters verses vegans and vegetarians who do not eat meat.

Wilson:                 Yeah and we actually use... I sort of labeled choline and connetine to actually directly show that the synthesis of TMA and TMAO by a labeled connetine is higher in meat eaters, carnivores, verses vegetarian or vegans.

Caroline:              Oh, I really have to ask both you Wilson and Nik the following question then. What do you think is the, you know, take home message? How do you apply this clinically and even more cheeky, perhaps, how are you applying this in your own life? I mean with this knowledge have you become vegetarian? I'm putting you on the spot here.

Wilson:                 I think this is basically a very scientific demonstration of how what we eat does impact our every day bodily function. And I think many cultures have this identification. Obviously many Asian cultures have seen the impact of food. In fact, it actually opens entire insight into how different medicinal food may actively be impacting the gut microbiome that actually creates different effects in the body. But in terms of diet and nutrients, yeah I have totally have eaten less meat in my every day dietary habits.

                                I definitely think it's something that is certainly quite insightful and probably very impactful. That being said, I think different cultures also have different populations of microbiome and I think it's not a one size fits all. In fact I think every individual has his own dynamic ranges and we are still in the very very first early stage of understanding how this impact helps in disease. So there's a lot of excitement and there's a lot of technology that hopefully can help us to unravel this mystery.

Caroline:              Exactly, a new and important field just like you said. Nik, what do you think?

Nik:                        From my standpoint, I'm actually not a big meat-eater so this was very welcomed news when this all came out. But, you know, from another standpoint it really opens up a lot of new questions. You know, it kind of blurs the line between sort of genetics and environmental factors. You know, so the questions of maybe a family who shares certain genetic traits may also share certain environmental traits. In other words, they share certain gut microbial components and maybe this sort of complicates how we're going to disentangle some of these risk factors going forward. I'm interested to get Wilson's take on this.

Wilson:                 Yeah it gives us a lot of insight to the I guess what happens is the microbiome is isolated in the family lineage because the lifestyle exposure are very similar in each household. So, what we thought is inherent is being inherited from both the genomic but also a microbiome perspective.

Caroline:              Nik, you manage this paper. I really love, for example, that figure which I think everyone should get ahold of the journal and have a look at. Could you tell us a little bit more about this category of papers?

Wilson:                 I'm sort of charged with this task of bringing sort of basic Science across the aisle to clinicians so that we can all sort of talk the same language and perhaps interact on a higher level. And so I was really excited reading some of Wilson's work and you know I really wanted to bring that to some of our broad readership just so that we could sort of appreciate what sort of science was going and I really think that this is a really great example of something that's on the verge of being translated.

                                You know you can imagine that by either effecting certain metabolite compositions or maybe by treating certain subsets of bacteria we may be able to influence long term cardiovascular risks not to mention obesity, diabetes, and some of these other diseases that Wilson is actively working on. So I really read this with a lot of excitement and I wanted to bring this to a broader audience and you know we have a number of other articles that are in the pipeline that I think will serve to bridge this gap and put us on the same field so that we can kind of speak the same language.

Caroline:              Wilson, did you have a good time sort of writing something like this its not long.

Wilson:                 It's actually very difficult. In fact, its just like writing poetry. You know it's hard to write in simple and short sentences. So it actually was a big challenge for me and I really thank the opportunity to be able to do that but I also want to emphasize I think it was a very insightful experience for me too. Because as a practicing physician and a commissioned scientist don't always merge these too few, these two areas in a way to actually see the importance we like to learn the science and try to explore I think clinicians really need to take charge and learn exciting science that's occurring. I think this is a wonderful avenue and I applaud [inaudible 00:18:10] for setting this radio [inaudible 00:18:11]

Caroline:              Well listeners you heard it first here on Circulation On The Run it is poetry by Wilson Tang. So please, please pick up a copy of today's journal and don't forget to tune in again next week!

Mar 6, 2017

Dr. Carolyn Lam:               Welcome to Circulation on the Run. Your weekly podcast summary and [inaudible 00:00:06] of the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. In just a moment we will be discussing really fascinating preclinical data to suggest that high fiber diet and acetate supplementation may change the gut microbiota and thereby prevent the development of hypertension and heart failure. But first here's your summary of this week's issue.

                                                The first paper describes the impact of heart transplantation on the functional status of children with end stage heart failure in the United States. First author, Dr. Peng, corresponding author Dr. Almond and colleagues from Stanford University, use the organ procurement and transplantation network to identify 1,633 US children age less than 21 years, and surviving one year or more post-heart transplant, from 2005 to 2014, with a functional status score available at three time points. Namely at listing, at transplant, and one year or more post-heart transplant. They found that at the one year assessment 64% were fully active with no limitations, or a functional status score of 10. 21% had minor limitations with strenuous activity, or a functional status score of 9. And 15% scored a functional status score lower than 9. Compared to the listing functional status, functional status at one year post-transplant increased in 91%, and declined or remain unchanged in 9%. Early rejection, older age, African-American race, chronic steroid use, hemodynamic support at heart transplantation, and being hospitalized at transplantation, were all associated with abnormal functional status post-transplant.

                                                These findings may be helpful to patients, families, and referring providers by providing a contemporary picture of the post-heart transplant life in children as they weigh the risks and benefits of transplantation.

                                                The next paper brings cardiac reprogramming one step closer to clinical translation. In this paper by first author Dr. Mohamed, corresponding author Dr. Srivastava, and colleagues from Gladstone Institute of Cardiovascular Disease in San Francisco, the authors used a high throughput chemical screen in post-natal mouse cardiac fibroblasts, and found that transforming growth factor beta, or TGF beta, and WNT, or wint inhibition, enhanced transcription factor based direct reprogramming of cardiac fibroblasts to induce cardiomyocyte like cells in vitro and in vivo. A combination of TGF beta and wint chemical inhibitors increased the quality, quantity, and speed of direct reprogramming, resulting in improved cardiac function after injury as early as one week after treatment. These chemical inhibitors enhanced human cardiac reprogramming and reduced the number of transcription factors needed for human cardiac reprogramming to just four factors. These findings if validated in large animals could facilitate a combined gene therapy and small molecule approach to heart failure.

                                                The next study is the first report of the risks of cardiac mortality among five year survivors of childhood cancer beyond 50 years of age. First author Dr. Fidler, corresponding author Dr. Hawkins, and colleagues from University of Birmingham in United Kingdom, looked at the British childhood cancer survivors study, a population based cohort of 34,489 five year survivors of childhood cancer that was diagnosed from 1940 to 2006 and followed up until February 28th in 2014. The authors quantify the cardiac mortality access risk. Overall 181 cardiac deaths were observed, which was 3.4 times that expected. Survivors were two and half times more at risk of ischemic heart disease, and almost six times more at risk of cardiomyopathy or heart failure at death than expected. Among those aged over 60 years, subsequent primary neoplasms, cardiac disease, and other circulatory conditions accounted for 31%, 22%, 15% of all deaths. Specifically for cardiomyopathy or heart failure deaths, survivors diagnosed between 1980 and 1989 had 29 times the excess number of deaths observed per survivors diagnosed either before 1970 or from 1990 onwards. Thus the authors concluded that excess cardio mortality among five year survivors of childhood cancer remains increased beyond 50 years of age, and has clear messages in terms of preventative strategies. However, the fact that the risk was greatest in those diagnosed in 1980 to 1989, suggests that initiatives to reduce cardio toxicity among those treated more recently may be have a measurable impact.

                                                The last study describes the 30 day results of the Source 3 Registry, that is the European Post Approval Registry of the latest generation of the Sapien 3 trans-catheter heart valve. Dr. Wendler and colleagues from King's Health Partners in London, describe that these 30 day results of the Source 3 Registry demonstrate that trans-catheter uratic valve implantation, or TAVI, using the Sapien 3 resulted in high procedural success with low procedural complications, and excellent post-implant hemodynamics. Moderate to severe paravalvular leakage appeared to be lower with the Sapien 3 than reported with prior versions of this trans-catheter heart valve. Rates of pacemaker implantation were higher with the Sapien 3 than in earlier generations of the valve. This, in combination with the growing experience of patient selection, procedure planning, execution, and post-operative care has led to one of the best short-term outcomes ever reported after TAVI. These results are discussed in an accompanying editorial by Dr. [Altassi 00:06:58], and Dr. [Urani 00:06:58], from the Emery Midtown Hospital in Atlanta, Georgia, where they say that these early results from Source 3 Registry are a source of encouragement with some caveats.

                                                Well, those were your summaries. Now for our feature discussion.

                                                I am so honored to have two lovely ladies join me today on the show. And they are the first author of a feature paper, Dr. Francine Marques from Baker Heart and Diabetes Institute in Melbourne, Australia, as well as Dr. Peipei Ping, associate editor from the David Geffen UCLA School of Medicine. Welcome ladies.

Dr. Peipei Ping:                 Hi, hello.

Dr. Francine Marques:   Hi, thank you for having us.

Dr. Carolyn Lam:               As a clinician, I have very very often advised my hypertensive patients to go on the dash diet. And you know, I have no had any trouble explaining the low salt bit, right? I understand it. But then I realize that I've always advocated as well the high fiber bit, not actually really understanding how high fiber directly impacts blood pressure. And I'm so excited because your paper, Francine, shed some light on this and it actually has something to do with the gut. So could you please explain what you did and what you found?

Dr. Francine Marques:   So we fed a mouse model called [adoca 00:08:25] model of habitation, that also developed heart failure, we fed them a high fiber diet for three weeks, and then after that we did a surgery to make them become [habitant 00:08:36] safe and we followed them up for six weeks. And what we observed through that trajectory is that mice that were fed a high fiber diet had significantly lower systolic and diastolic blood pressure, and also an improvement in the heart function, and also a decrease in both heart and brainal fibrosis. And the reason why the fiber is so important is because although we usually don't digest the fiber, the bacteria in our gut absolutely love it. And that allows the bacteria, good bacteria to grow. And with that growth we have release of the fermentation of the fiber, releases in short chain fatty acid. So these specific molecules can then be put back into our body and can help us in our health. So we also fed these mice acetate, which is one of the short chain fatty acids, directly and we also observed very good improvements in blood pressure and cardiovascular health.

Dr. Carolyn Lam:               It's just fascinating. So these are studies in mice. What do you think of clinical translational aspects of this?

Dr. Francine Marques:   Large epidemialogical studies have shown that there is an inverse correlation between fiber consumption and blood pressure. And they have seen this through very small clinical trials looking into the intake of fiber lowering blood pressure. But our study opens the possibility of new interventions using maybe short chain fatty acids specifically, but are also looking into a different type of fiber. So most studies would look into either soluble or insoluble fiber directly. Our study, the diet that we used, is mostly resistant starches. So these are their preferred type of fiber for bacteria growth in our gut. And maybe they use a [inaudible 00:10:32] type of fibers as well could be a new [inaudible 00:10:36] opportunity.

Dr. Carolyn Lam:               Peipei, I remember you discussing this paper at our editorial meetings and you so beautifully highlighted the novelty of this paper. Could you share this with our listeners?

Dr. Peipei Ping:                 Often within many complex studies trying to understand cellular pathways and mechanisms of cardio protection, it's a very important topic as we have had our research focus on in the pas t 25 years. What's very unique and provocative of this particular study is that it simply identified critical metabolic pathways that actually is underlying the protective effects. Many of us have wondered about with eating, for example vegetables or high fiber diet, it is examined specific molecules that have both a direct as well as an endocryne path that would circulate things back to the cardiac muscles, and having the muscles becoming more protective because of regulation of certain transcriptomic pathways to support cardiac muscle contraction. So we were very impressed by both the new concept as well as the state of the art technologies employed in this investigation.

Dr. Francine Marques:   Thank you, that's very nice.

Dr. Carolyn Lam:               I couldn't agree more, you put it so beautifully Peipei. I thought that it was really nice also linking pathways as well as linking several organ systems. Is there anything you might want to highlight about the renal effects, not just cardiac?

Dr. Francine Marques:   Yes. Many times investigations been focusing on if something went wrong how do we cure it? More precious is when we find novel results telling us the healthy individuals, what are the things we should be doing so our blood pressure would stay at the normal level, or our cardiac function is being protected if there's an insult or injury. And so in this situation, the examination of the entire renal transcriptomic do give us very valuable information on how the blood pressure regulation system that maybe actually protected by the short chain fatty acid acetate.

Dr. Carolyn Lam:               So true Francine. Anything else to add?

Dr. Francine Marques:   Just to say circulation, for giving the opportunity to submit this paper, and share it with the world. We're very very excited about the data.

Dr. Carolyn Lam:               Yeah we should be the ones to thank you. It's a beautiful paper. We're very privileged to publish it in circulation. May I ask what are next steps for you? What do you think needs to be done from here?

Dr. Francine Marques:   We're validating this in other models now. And we're also looking into the [inaudible 00:13:57] microbiome and how that's related to habitation. So trying to really pinpoint mechanisms and how we can move this forward into the clinic.

Dr. Carolyn Lam:               That's so great. And Peipei, do you think that there's certain gaps that urgently need to be addressed now?

Dr. Peipei Ping:                 Yes, I think one of the most beautiful thing that ... Concept, illustrated this investigation is we really couldn't be just focusing on one organ, our primary interest organ, heart, alone. What's demonstrated here is a beautiful link of both mechanism as well as governed by transforming parbolytes with endocryne effects. How the gut, the kidney, and the heart are all connected together in this process, achieving a better protective condition in the environment for the cardiac muscle.

Dr. Carolyn Lam:               Thank you listeners. You've been listening to Circulation on the Run. Tune in next week for even more news.


Feb 27, 2017

Dr. Carolyn L.:                    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. On our podcast today we are discussing the role of diastolic stress testing and the evaluation of heart failure with preserved dejection fraction, a really hot topic indeed, but first here's your summary of this week's issue.

                                                The first study tackles the obesity paradox in cardiac surgery, where morbidity and mortality are lower in obese patients. This study sought to ask the question, "Is this due to reverse epidemiology, bias, or confounding?" To answer this question, Dr. Maris Kelko and colleagues from University Leicester in United Kingdom used two separate analysis. One, registry data from the National Adult Cardiac Surgery Registry and two, a systematic review in meta-analysis of studies. Of more than 400,000 patients in the cohort study and more than 550,000 patients in the systematic review, the authors found a U shape association between mortality and body mass index classes, where lower mortality was observed in overweight and obese class one and two patients, relative to normal weight patients, and mortality was increased in underweight individuals.

                                                Now, the obesity paradox has been attributed to reverse epidemiology where the survival benefit associated with obesity is thought to actually reflect worse outcomes in the underweight patients who also had frailty, cachexia, or severe chronic disease. However, in the current study, counter to the reverse epidemiology hypothesis, the protective effects of obesity were less in patients with chronic renal, lung, or cardiac disease and greater in older patients as well as in those with complications of obesity, such as metabolic syndrome and atherosclerosis. Furthermore, adjustments for important confounders did not alter the results. The authors therefore concluded that obesity is associated with lower risks after cardiac surgery with consistent effects noted in multiple analysis even after attempting to address residual confounding and reverse causation.

                                                The authors even went as far as to suggest that their findings do not support common practice where weight loss is recommended prior to surgery or where very obese patients are refused surgery in the morbidly obese. These provocative findings are discussed in an accompanying editorial by Doctor's Carnethon and Kahn from Northwestern University. While the editorialists agree that this well-designed study highlights an important knowledge gap, they pointed out that the obese class two patients had nearly five times greater risk for deep sternal wound infection and 25% higher likelihood of needing renal replacement therapy.

                                                In such patients additional intervention in the perioperative period may still be indicated and include weight loss recommendations and postoperative surveillance for complications. Thus, a more cautious final recommendation may be for future studies to prospectively assess weight loss interventions prior to elective surgery in the context of overall surgical risk as assessed by the EuroSCORE or STS models.

                                                The next paper describes mechanistic studies showing for the first time that nucleoside diphosphate kinase suppresses cyclic-AMP formation in human heart failure. In this paper by First Authors, Dr. Abu Taha and Hagemann, corresponding authors Dr.'s Tobref and Weilend from the Heidelberg University in Germany, the authors performed biochemical studies of nucleoside diphosphate kinase and G Protein signaling in human and rat tissue samples, assessed the functional impact of nucleoside diphosphate kinase C on cyclic-AMP levels and contractility and isolated red cardiomyocytes and determined that in vitro effects of these nucleoside diphosphate kinases on contractility in zebra, fish and mice.

                                                They identified nucleoside diphosphate kinase as the critical isoform for the regulation of G Protein function and cyclic-AMP levels in the heart with important consequences for cardiac contractility. The increased nucleoside diphosphate kinase membrane content in human heart failure could potentially counteract a fading beta adrenoceptor response in the early stages of heart failure by increasing the amount of G Alpha stimulatory proteins in the plasma membrane. However, by switching from stimulatory to G Alpha inhibitory to activation, nucleoside diphosphate kinase may play a role in heart failure progression by reducing cyclic-AMP levels, typical for end-stage human heart failure.

                                                The study, therefore contributes to a better understanding of the molecular processes, underlying alter G Protein signaling in heart failure, and may help to develop new heart failure therapies.

                                                The next study tested the hypothesis, that high intensity interval training is superior to moderate continuous training in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure and reduced ejection fraction.

                                                Doctor Ellingson and colleagues from the Norwegian University of Science and Technology, performed a multicenter trial, comparing twelve weeks of supervised interventions of high-intensity interval training at 90 to 95% maximal heart rate, moderate continuous training at 60 to 70% maximal heart rate, or a recommendation of regular exercise in 261 patients with heart failure and ejection fraction less than 35%, in New York Heart Association class II or III status.

                                                The primary end point of change in left ventricular end-diastolic diameter from baseline to twelve weeks was not different between the high-intensity and moderate continuous groups. There was also no difference between the high-intensity and moderate groups in peak oxygen uptake, although both were superior to the recommendation for regular exercise. None of these changes were maintained at follow up after 52 weeks. Serious adverse events were not statistically different. However, training records showed that 51% of patients exercised below the prescribed target, during supervised high-intensity interval training, and 80% above the recommended target in those with moderate continuous training. Given that high-intensity interval training was not superior to moderate continuous training, in reversing remodeling or improving secondary end points, and considering that adherence to the prescribed exercise intensity based on heart rate was difficult to achieve even in the supervised setting.

                                                The authors concluded that moderate continuous training remains the standard exercise modality for patients with chronic heart failure.

                                                The final paper tells us, that brain emboli after left ventricular endocardial ablation may be more common than we knew. First author Doctor Whitman, corresponding author Doctor Marcus and colleagues from University of California studied eighteen consecutive patients, scheduled for ventricular tachycardia or premature ventricular contraction ablation, over a nine month period. Twelve patients undergoing left ventricular ablation were compared to a control group of six patients, undergoing right ventricular ablation only. Heparin was administrated with a goal activated clotting time of 300 to 400 seconds for all left ventricular procedures. Pre impulse procedural brain magnetic resonance imaging was performed on each patient within a week of the ablation procedure. The authors found that seven of the twelve patients, or 58% undergoing left ventricular ablation, experienced a total of sixteen cerebral emboli, compared with none among patients undergoing right ventricular ablation. Seven of the eleven patients undergoing a retrograde approach to the left ventricle, developed at least one new brain lesion. Thus, more than half of patients undergoing routine left ventricular ablation procedures, experienced new brain emboli after the procedure, even in the absence of clinically apparent stroke.

                                                Future research is critical to understanding the long-term consequences of these lesions and to determine optimal strategies to avoid them. This is further discussed in an editorial entitled "The Sound of Silence". How much noise should we make about post ablation silence strokes? By Doctor Z and Vora from Stanford University. Well, those were your summaries, now for our featured discussion.

                                                I am so thrilled to have with me two special guests to discuss the topic of the diagnosis of heart failure preserved ejection fraction or HFpEF. As you all know, that's my favorite topic and I have favorite people with me today. First, the corresponding author of our feature paper, Doctor Barry Borlaug from Mayo Clinic, Rochester, Minnesota. And, for the first time on the podcast, Doctor Mark Drazner, Senior Associate Editor from UT Southwestern. So, welcome Barry and Mark.

Barry Borlaug:                    Thank you Carolyn.

Mark Drazner:                   Thank you, great to be here.

Dr. Carolyn L.:                    So, Barry, you talked about the role of stress diastolic testing, shall I call it, in the  diagnosis of HFpEF in your paper. Could you tell us why you looked at it and what you found?

Barry Borlaug:                    Sure, Carolyn. When you have dyspnea and fatigue and you got a low EF, it's pretty easy to make the diagnosis of heart failure reduced EF, but we've been struggling for years with making the diagnosis of dyspnea, whether it's HFpEF or not in people with normal ejection fraction. And that's because physical and laboratory and clinical signs of high filling pressures and congestion, are either difficult to see or only present during stress, like physical exercise, in patients. So that's really what motivated us to pursue this study.

                                                We took patients, that were referred to our cath lab for invasive hemodynamic exercise testing, so we directly measured filling pressures, PA pressures and cardiac output reserve, to get a gold standard assessment, whether people have heart failure or not. And then we performed simultaneous echocardiography and blood testing to measure NT-proBNP levels, and then we just looked at what we could figure out. Can you accurately discern HFpEF patients from patients without cardiac dyspnea, using these non invasive estimates.

                                                We saw that a lot of people, with, for example, NT-proBNP levels that are low enough to be where most would consider HFpEF excluded, actually had HFpEF. And we saw that there were modest correlations between non-invasive echocardiographic estimates of filling pressures, specifically the E to E Prime ratio, and directly measured left heart filling pressures. But when we applied the criteria that had been initially proposed, we saw poor sensitivity to make the diagnosis with exercise. And this was largely related to the difficulty with getting all of the different echocardiographic indices, that are currently examined as part of the diastolic stress testing non-invasively. Next, we looked at just adding the exercise E to E Prime, which is an estimate of filling pressures, and when we used the cut-point, that's already been proposed, according to contemporary data, we found that this substantially improved the sensitivity to identify HFpEF, but there was a bit of a trade-off in that specificity decrease.

Dr. Carolyn L.:                    That's so cool. So let me summarize some of these take-home messages here. First of all, using just rest echo. I was really impressed to see that rest echo indices alone only identifies a third to maybe up to 60% of the patients you found with invasively proven HFpEF. So, we may be specific, but we're really missing quite a number of patients. And then if you exercise them, what your data is really showing is that it's better to exercise them and use this data for the negative predictive value, isn't that what you're saying?

Barry Borlaug:                    You know, the exercise is really the gold standard, so it gives you both, the negative and positive. With the echocardiography, relying on the exercise E to E Prime ratio, that was really helping us, as you say, Carolyn, with the higher negative predictive value. So most people, that had HFpEF, in this series, where we could get adequate, highly controlled environments, adequate diagnostic echocardiographic data, most people that ended up having HFpEF fit those criteria, we could see an elevation in this E to E Prime on exercise, so it did provide good negative predictive value.

Dr. Carolyn L.:                    These are just such important data, because I think we're all still struggling with how to make this diagnosis of HFpEF. Mark, could you just share some thoughts on whether you think this is going to really change practice, even change guidelines?

Mark Drazner:                   I think, if you read this paper, you would recognize it, that it's certainly a critical question that we're all facing, how to make the diagnosis of HFpEF. And all of their guidelines that have been advocated, there really wasn't much data, and these really are the best data out there. So, certainly, it's [inaudible 00:15:41] me a direction of changing practices. Barry says, certainly, the approach will need to be validated, I think, before it reaches high level guidelines, but certainly I think it's a step in the right direction, and points the way towards the future in terms of improving our ability to diagnose HFpEF. And really, that's why both reviewers and [inaudible 00:15:59] this is such an important paper.

Dr. Carolyn L.:                    Right. Barry, I have a quick question for you though. Doing exercise echo, not easy. E to E Primes are all over the place usually. How easy was it? How feasible was this test?

Barry Borlaug:                    So, first I'd like to say that we have outstanding, very well-trained, very highly skilled research scenographers, here at Mayo doing this. In very controlled environment, we're providing plenty of time for them to obtain images and that's going to be a question moving forward, because not everybody in clinical practice has that capability. But with that said, in this very controlled environments, skilled scenographers, we were able to measure the exercise data during low level exercise about 85 to 90% of the time and at peak exercise about 75 to 80% of the time. So, it's fairly feasible, but even in this best case scenario, we can't get it on everybody.

Mark Drazner:                   Even in the [inaudible 00:19:49] echo lab, the recommended approach by the ASE with the four measures. How many times they were not able to acquire all those images, are necessary for those four techniques and so, here you have a [inaudible 00:20:03] of AS echo lab not being able to do that, and being transparent about that, and [inaudible 00:20:08] to the community, saying that, although these are ideal measures, even the [inaudible 00:20:12] perhaps you can't acquire them. I think that was another important point that came out of this and then lead to the focus on the E to E Prime.

Barry Borlaug:                    I couldn't agree more. You got one of the world renowned labs, very skilled scenographers doing imaging, and we're still not able to get it all in each patient, and that just points to the difficulty of getting really high quality diagnostic images, and a lot of time you need the next level test, when that happens. And invasive exercise testing is really that test, the gold standard.

Mark Drazner:                   When you get echos from the outside and you look at the E to E Primes, are you confident that the data, that's generally acquired, is gonna be acceptable for this [inaudible 00:20:50]?

Barry Borlaug:                    Yes and no, I mean I'm always a little bit concerned, but it's not just being a control freak, you know, wanting to see everything, but I think that if it's a still frame doppler, tissue doppler spectrum, you can see that the sample volume is in the right place, and it's really unequivocally normal or abnormal, I feel pretty good about that. Not as good as when they get a full dedicated study here.

Mark Drazner:                   Of course, the gold standard is also difficult. The invasive measurement.

Barry Borlaug:                    Yes it is, I didn't [inaudible 00:21:18] that, but we've been doing a lot of invasive exercise tests for the last ten years now. And we do like 250 a year here, so we're really quite [inaudible 00:21:28] but we have all hands on deck in the lab. We have a couple technicians running gas samples around, all over the place. Somebody is on the medgraphics card, measuring oxygen consumption. We've got a nurse in there, that's helping out, so it's complicated, and of course we're using the micromanometer catheters for the pressure assessments, because you get so much more artifacts from width and under damping and over damping with the pressure tracing, so that's also not easy to do if you say.

Mark Drazner:                   So maybe for practicing cardiologists it's gonna be hard to duplicate that and perhaps spend the energy in terms of doing the exercise echo techniques off the speed, for example. Perhaps, it's another message.

Barry Borlaug:                    I would agree completely. And I think that again, when you do that, if you do a really high quality exercise echo and it's still not quite definitive, then you can refer on to a center that does have that capability, because obviously it's just reality, not everybody is going to be able to do this. Not every place has the size and resources to be able to do these really advanced tasks.


Dr. Carolyn L.:                    And do you apply exercise echo now in making your diagnosis? How do you use this data, for yourself, clinically?

Barry Borlaug:                    We started to think about this, and I think that the best case scenario where the  people, that really have an intermediate pretest probability, based on their clinical characteristics. Somebody has jugular distension and a very high NT-proBNP level, and edema, you really don't need further testing, you know that that's going to be HFpEF. And if somebody has no risk factors, and everything is stone cold normal, they don't.

                                                But in some of these people that have some signals, but they don't quite meet criteria, we are doing this, again, if they have adequate echocardiographic images at rest. And then we're looking really carefully at the exercise echocardiography data, one concern from this data, I want to make sure people are very circumspect and really critically looking at the quality of their data, because we shouldn't over-interpret equivocal findings. And as you said earlier, E to E Primes can be all over the map, they're very difficult to obtain during exercise. But I think that if everything looks very high quality and is definitely abnormal or definitely normal, that can be helpful. More so, if it's normal. We     did see more false positive, so if it is abnormal, we did suggest that you may want to perform further confirmatory testing, because of the higher false positive rate with exercise echo.

Mark Drazner:                  

                                                I would say for the listeners, they should take a look at his figure six, which really is a nice diagnostic algorithm, where Barry shows, or advocates, for taking patients with intermediate probability and then using this to restratify that, using [inaudible 00:19:40] approach. I know that, that figure resonated with the editors and the reviewers dramatically, so I'd encourage listeners to take a look at that.

Dr. Carolyn L.:                    Listeners, you heard it right. [inaudible 00:22:36] Circulation on the Run. Don't forget to tell all your friends about this podcast and tune in next week.


Feb 20, 2017

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. I am so excited to be discussing the diabetic HFpEF or heart failure with a preserved ejection fraction phenotype, with world experts and new insights from the I-PRESERVE Trial. That will just be in a moment and here are your summaries first.

                                                The first paper in this issue is a systematic review and meta-analysis of risk factors for Co-Arctation of the Aorta on pre-natal ultrasound. In this paper by first author Dr. Familiari and corresponding author Dr. D'Antonio and colleagues from Arctic University of Norway, the authors performed a systematic review of 12 studies on 922 fetuses with echo-cardiography, and found that those with a post-natal diagnosis of co arctation had significant differences in several cardiac morphological parameters compared to cases without co arctation. The presence of a co arctation shelf, or hypoplastic arch, was associated with a significantly increased risk of co arctation. Furthermore, they reported multi-parametric diagnostic models that were associated with an increased detection rate. Thus, this paper tells us that assessment of left inflow and outflow tracts prenatally may help in stratifying the risk of co arctation.

                                                The next paper reports pre-clinical data that truly represents a paradigm shift in our understanding of vascular resident endothelial progenitors in tissue regeneration. In this paper by first author Dr. Patel, corresponding author Dr. [Cossroterrani 00:02:00], and authors from Royal Brisbane and Women's Hospital in Australia, the authors studied protein expression levels of common endothelial markers in mice using flow cytometry. They discovered an endovascular progenitor cell in vivo that is present in normal endothelium in the aorta and lungs and activated in vessel walls during various endogenic situations, such as in the placenta, skin wound healing, and tumors. They further define at a molecular level an entirely novel endothelial hierarchy from an endovascular progenitor cell to a mature different-shaded endothelial cell via complete RNA sequencing. They further clarify the linage of endothelial progenitors in their origin by using bone marrow transplantation and vascular-specific, lineage-tracing mouse models, showing that the endovascular progenitor cells were derived neither from bone marrow nor from hematopoietic progenitors. This discovery of an endovascular progenitor cell will have significant implications for the development of endothelial progenitors as a cell therapy.

                                                The next paper addresses the chicken or egg question regarding the association between obesity and atrial fibrillation, and this is done using Mendelian randomization to define a causal association between body mass index and atrial fibrillation. In this study by Dr. Chatterjee and colleagues from Massachusetts General Hospital, the authors looked at more than 50,000 European individuals without atrial fibrillation at baseline and showed that genetic variance associated with increasing body mass index were significantly associated with an increased risk of atrial fibrillation. The association between genetically determined obesity and atrial fibrillation persisted even after adjustment for traditional atrial fibrillation risk factors, such as hypertension, diabetes, coronary artery disease, and heart failure. Taken together, these data are consistent with a causal association between increasing body mass index and incident atrial fibrillation. These findings therefore support the primordial prevention of obesity as a significant public health target to combat the expanding global burden of atrial fibrillation.

                                                The last paper provides contemporary estimates of the stroke burden in China, a country which bears the biggest stroke burden in the world. In this paper by doctors Wang and Fagen from the Capital Medical University in Beijing, China and Auckland University of Technology in New Zealand, and colleagues, the authors reported results of a nationally represented door-to-door survey conducted in 2013 in 155 urban and rural centers in 31 provinces in China, totaling 480,687 adults. They found that the age standardized prevalence was 1,115 per 100,000 people, incidence rate was 247 per 100,000 person years, and mortality rates were 115 per 100,000 person years. The stroke prevalence estimates in 2013 were greater than those reported in China three decades ago, especially among the rural residents. Finally there was a north to south gradient of stroke in China, with the greatest burden observed in the northern and central regions. Well, that wraps it up for our summaries. Now for our discussion.

                                                For our featured discussion today, we are talking about my favorite topic and of course that is HFpEF, or heart failure with preserved ejection fraction, and I am so thrilled to have with us today Dr. John McMurray from University of Glasgow, who's the corresponding author of our featured paper referring to diabetes in patients with HFpEF and really talking about the novel results from the I-PRESERVE Trial. Welcome, John!

John McMurray:               Thank you Carolyn, it's always a pleasure to speak to you.

Carolyn Lam:                      Oh, I have been waiting for this one, and I'm so excited I don't know where to begin, but how about with this? Diabetes and HFpEF, first of all, haven't we spoken to death about co-morbidities in HFpEF? And secondly, what makes this paper special? Because we've heard about diabetes and HFpEF from CHARM, from DIG, from Relax, so tell us: why the interest in diabetes and HFpEF?

John McMurray:               Sure, Carolyn. I think you and I have been interested in diabetes and heart failure, that terrible combination, for a long time. But I think there's a lot more interest in it today because, of course, we've had several new clinical trials with interventions to lower blood glucose that have showed both beneficial and potentially harmful effects on the development of heart failure. But really what these trials have highlighted is just how common heart failure is as a complication of diabetes. And we strongly suspect, though we don't know for sure of course, but we strongly suspect that most of that heart failure developing amongst patients with diabetes is probably heart failure with preserved ejection fractions. So, I think the context currently is that what's different about our study compared to the ones that you mentioned is that in I-PRESERVE we measured a number of things that were not available in, particularly, the large clinical trials previously. So, in I-PRESERVE we measured natriuretic peptides, we looked at health-related quality of life, and maybe most importantly of all we had a large echo-cardiographic sub study. So I-PRESERVE is quite different than DIG-Preserved and CHARM-Preserved, and of course a lot larger than the RELAX HFpEF study.

Carolyn Lam:                      I was the associate editor managing your paper and I was so excited about this that I invited an editorial as well by Brian Lindman, and he's got this beautiful table that summarizes what your study really adds to the literature, and I think it's so critical. Could you start by summarizing? What are the main findings?

John McMurray:               Well, I-PRESERVE, as you know, was a trial of just over 4,000 individuals with HFpEF defined clinically and with an ejection fraction of 45% or above. There was actually a trial comparing the angiotensin receptor-blocker [inaudible 00:09:17] placebo, though in fact there is no difference in morbidity and mortality between those two treatment groups. So we've looked, as you said, at the patients who had diabetes and compared those to the patients who didn't have diabetes. I think there was some very interesting novel information; if you look at the two subsets of patients, they actually don't differ in terms of age and sex and, importantly, in left ventricular ejection fraction.

                                                But there are other differences that you would expect; for example, many more of the patients with diabetes were obese. But interestingly, and despite that, the patients with diabetes had higher, significantly higher, NT-proBNP levels. So as you know, obesity tends to be associated with lower rather than higher natriuretic peptide levels, so here we were finding higher natriuretic peptide levels in a subset of patients who were actually, by and large, more obese. And there was no difference in other things that might have accounted for that difference; natriuretic peptides, for example, there was no difference in the proportion of patients who had atrial fibrillation.

                                                So that was important, and that's also important when we come to think of outcomes because of course the previous studies reporting worse outcomes in patients with diabetes had not adjusted for natriuretic peptides because they by and large weren't available in the large prior trials. So that, of course, could have accounted for some of the worse outcome.

                                                Some of the other things, features, maybe to pick out in terms of baseline characteristics ... one was that these patients had many more features of congestion, so patients with diabetes had more edema, more often had a raised jugular venous pressure and so on, and that's interesting given some of the recent clinical trial data that we might come back to. And even though the [inaudible 00:11:22] class distribution was not different between patients with diabetes and those without, what was very different was health-related quality of life, which was much worse in patients with diabetes than those without. Now you could if you chose to, Carolyn, look at that as saying that physicians weren't assessing worse functional status or symptomatic status in the patients with diabetes, but the patients were certainly self-reporting a much worse health-related quality of life.

                                                So those were the, sort of, clinical characteristic differences. We did, as I said, have an echo-cardiographic sub study. There were 745 patients in total in the trial who had a detailed echo study, and there were perhaps more modest differences than I might have expected (and I'd be interested in your opinion about this) in patients with diabetes. So they had a somewhat greater, statistically significantly greater left ventricular mass, they had increased early diastolic mitral inflow velocity through E, they certainly had increased E over E prime increased left atrial areas, so there was some left ventricular remodeling and there was some evidence of increased left ventricular filling pressure, maybe diastolic disfunction. But the differences were not very striking; they were there, and as I said previously, ejection fraction (which most of us regard as perhaps not a very good measure of systolic function) was similar between the two groups. We didn't look at more sophisticated and [inaudible 00:13:09] measures of systolic functions so those could have been different, we just don't know.

                                                So that's the baseline clinical features and baseline echo-cardiographic findings. And then, of course, we followed these patients for a median of just over four years and what we found was that the cardiovascular and all cause mortality was about twice as high in patients with diabetes as in those without. And if you adjust for conventional clinical variables, including NT-proBNP, which is individually the most powerful predictor of outcome, you only very slightly attenuate that greater risk associated with diabetes. The risk of heart failure and hospitalization was also about doubled in an unadjusted analysis, but that was more attenuated in the adjusted analysis. But you've also got to remember that, of course, the patients with diabetes were not surviving as long, so the very fact that they had a substantially higher risk of heart failure and hospitalization despite a shortened longevity is important.

                                                Then lastly, again I think a fairly unique aspect of this study was that we then added the echo-cardiographic findings into the multi-variable model [inaudible 00:14:33] because it was only a subset of patients in which we had echo-cardiographic measurements. The statistical reliability of this is not as robust as in the main model, but what we saw was that there was more attenuation of the risk associated with diabetes when you added in the remodeling and diastolic dysfunction findings that we saw in the echo-cardiographic sub study. So that's a summary, I think, of the key points.

Carolyn Lam:                      John, I was really impressed and struck by the consistency of the message, which is what I really appreciated. What you added to the field was this consistent message that the diabetic HFpEF just had more signs of fluid overload in general, be it clinical, be it by NT-proBNP, be it by echo. And I thought that was something you said it was a moderate difference by echo; it was enough to be convincing to me, and I really appreciated that. The fact that adding the echo findings attenuated the significance ... you know we went back and forth about that quite a bit together, didn't we?

John McMurray:               We did.

Carolyn Lam:                      I think at the end it is consistent, it is useful information. It tells me that perhaps some of these outcomes are mediated by this access fluid, to me, at least part of it. And I think that is how we ended up expressing it in the final paper.

John McMurray:               I think you are absolutely spot on, Carolyn, because I don't think I had anticipated that the features of congestion would be so different. And you are correct in that, of course, correlates very well with natriuretic peptides, with the left atrial enlargement and so on.

                                                And then of course (and this is clearly extrapolation) but then of course it makes one wonder about some of the trials with diabetes drugs that we've seen. The TZDs, glycosomes, which calls a little bit of fluid retention, of course precipitating heart failure, and then the opposite recently with the SGLT2 inhibitors which of course are diuretics, and those drugs preventing the development of heart failure.

                                                And it does make me wonder if the diabetic phenotype maybe was a little bit of renal dysfunction, some subtle renal dysfunction, is a sodium and water avid phenotype state and that it doesn't take very much to tip those patients into frank heart failure and perhaps we need to think (and I think you might have been alluding to it) think about insuring that we adequately diurese these patients given that in this study where people were supposed to be optimally treated, clearly there was still a lot of evidence of residual fluid overload.

Carolyn Lam:                      I absolutely agree, and yes you read my mind that I was going to allude to the implications for therapies that have a diuretic effect, you know, like the SGLP2 inhibitors and in fact this was discussed in Brian Lindman's editorial, which is a must read.

                                                Just another question though. What do you think of peripheral mechanisms contributing to all this?

John McMurray:               Yeah, obviously there is the kidney aspect that we saw a relatively small difference in estimated GFR. Of course that only tells you one aspect of renal function and the nephron in diabetes may well be sodium avid maybe more likely to retain water. So certainly the kidney as a peripheral mechanism might be very important.

                                                And then of course the blood vessels, I mean there's no question that patients with diabetes have more abnormal endothelial function probably have got enhanced vascular stiffness. And of course we know from a long time ago at least in HFrEF (I'm not so sure about HFpEF) but in HFrEF there's evidence that some of the vascular stiffness you see in patients with HFrEF is actually due to sodium in the vessel wall and there's some beautiful old-style clinical physiology experiments showing that if you diurese patients with HFrEF you restore vasodilation you restore basal motor responsiveness. It could also be true in HFpEF though of course patients with HFpEF and many other reasons to have vascular stiffness.

                                                So yes, peripheral mechanisms may well be important. Your humoral abnormalities may be more pronounced in patients with HFpEF and diabetes compared to those without diabetes. We don't know because I'm not sure that's been measured very often. Certainly natriuretic peptides are, but what about things like the angiotensin system and arginine/vasopressin and the sympathetic nervous system. You know, there's still so much to study looking at patients with heart failure with and without diabetes because they're really quite distinct. And whatever's going on it makes a big difference the way those patients feel, what they can do, and what happens to them.

Carolyn Lam:                      Yeah, and your study really establishes that. Congratulations once again John, it's just been such a delight chatting with you.

John McMurray:               Likewise, Carolyn.

Carolyn Lam:                      Listeners, you heard it right here on Circulation on the Run. Don't forget to tell all your friends about this podcast and turn in next week!



Feb 13, 2017


Dr. 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 podcast is taking us to Japan today where we will be talking about aspirin for primary prevention in patients with diabetes. First, here's your summary of this week's issue.

                                The first study provides insight into the development of neurologic injury in patients with single ventricles undergoing staged surgical reconstruction. In this paper by Dr. Fogel and colleagues from the Children's Hospital of Philadelphia, the authors recognize that single ventricle patients experience greater survival with staged surgical procedures culminating in the Fontan operation, but experience high rates of brain injury and adverse neurodevelopmental outcome. They therefore studied 168 single ventricle patients with MRI scans immediately prior to bi-directional Glenn, prior to the Fontan, and then three to nine months after the Fontan reconstruction. They found that significant brain abnormalities were frequently present in these patients and that the detection of these lesions increased as children progressed through staged surgical reconstruction. In addition, there was an inverse association of various indices of cerebral blood flow with these brain lesions. This study therefore suggests that measurement of cerebral blood flow and identification of brain abnormalities may enhance recognition of single ventricle patients at risk for poor outcomes, and possibly facilitate early intervention.

                                The next paper uncovers a unique mechanism underlying arrhythmogenesis and suggests that the anti-epileptic drug valproic acid may possibly be repurposed for anti-arrhythmic applications. In this paper by first authors Dr. Chowdhury and Liu and corresponding author Dr. Wang and colleagues from University of Manchester UK. The authors used mouse models and human induced pluripotent stem cells derived cardiomyocytes to discover a new mechanism linking mitogen activated kinase-kinase 7 deficiency with increased arrhythmia vulnerability in pathologically remodeled hearts. Mechanistically, mitogen activated kinase-kinase-7 deficiency in the hypertrophied hearts left histone deacetylase-2 unphosphorylated, and filamin A accumulated in the nucleus, which then formed an association with kruppel-like factor 4 preventing its transcriptional regulation. Diminished potassium channel reserve caused repolarization delays resulting in ventricular arrhythmias, and the histone deacetylase-2 inhibitor, valproic acid restored potassium channel expression abolishing the ventricular arrhythmias. This study therefore provides exciting insights in developing a new class of anti-arrhythmics specifically targeting signal transduction cascades to replenish repolarization reserve, all for the treatment of ventricular arrhythmias.

                                Does the Mediterranean diet improve HDL function in high risk individuals? Well, the next paper by first author Dr. Hernaiz, corresponding author Dr. Fito and colleagues from Hospital Del Mar Medical Research Institute in Barcelona, Spain addresses this questions. The authors looked at a large sample of 296 volunteers from the PREDIMED study and compared the effects of two traditional Mediterranean diets, one enriched with virgin olive oil, and the other with nuts to a low-fat control diet. They looked at the effects of these diets on the role of HDL particles on reverse cholesterol transport, HDL antioxidant properties, and HDL vasodilatory capacity after one year of dietary intervention. They found that both Mediterranean diets increased cholesterol efflux capacity and improved HDL oxidative status relative to the baseline. In particular, the Mediterranean diet enriched with virgin olive oil decreased cholesterol ester transfer protein activity, and increased HDL ability to esterify cholesterol, paraoxonase-1, arylesterase activity, and HDL vasodilatory capacity. They therefore concluded that adherence to a traditional Mediterranean diet, particularly when enriched with virgin olive oil, improves HDL function in humans.

                                The final study tells us that among hospitalized medically ill patients, extended duration Betrixaban reduces the risk of stroke compared to standard dose enoxaparin. In this retrospective sub-study of the APEX trial, Dr. Gibson and colleagues from Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts randomized 7,513 hospitalized acutely ill patients in a double-dummy, double-blind fashion to either extended duration of the oral Factor Xa inhibitor Betrixaban at 80 mg once daily for 35 to 42 days, or standard dose subcutaneous enoxaparin at 40 mg once daily for 10 days all for venous thromboprophylaxis. They found that the extended duration Betrixaban compared with enoxaparin reduced all cause stroke by almost one half with a relative risk of 0.56 equivalent to an absolute risk reduction of 0.43 percent and number needed to treat of 232. The effect of Betrixaban on stroke was explained by a reduction in ischemic stroke with no difference in hemorrhagic stroke. The reduction in ischemic stroke was confined to patients hospitalized with acute heart failure or non-cardioembolic ischemic stroke.

                                This paper is accompanied by an editorial by Drs. Quinlan, Eikelboom, and Hart in which they articulate three reasons that they think these results are important. First, the results demonstrated an unexpectedly high rate of new or recurrent ischemic stroke during the first three months in hospitalized medical patients receiving standard enoxaparin prophylaxis, the rate being even higher in patients presenting with heart failure or ischemic stroke. Secondly, the data demonstrated for the first time that a NOAC reduces the risk of ischemic strokes in patients without known atrial fibrillation. Thirdly, the effects of Betrixaban on stroke were dose dependent, all of the benefits were seen in those who received the 80 mg dose, whereas the 40 mg dose did not provide advantages compared with enoxaparin or placebo. While these results are encouraging, the editorialists also warn that these are based on a post-hoc analysis and should be considered hypothesis generating.

                                Well, that brings it to the end of our summaries. Now for our feature discussion.

                                Today our feature discussion focuses on the exciting 10-year follow up results of the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes, or JPAD trial. I am simply delighted to have with me first and corresponding author Dr. Yoshihiko Saito from Nara Medical University, Japan. As well as a familiar voice on this podcast, Dr. Shinya Goto associate editor of Circulation from Tokai University in Japan. Welcome gentlemen!

Dr. Goto:             I am very pleased to have this opportunity. I am always enjoy listening your podcast, and this is very interesting topic of aspirin in prevention cardiovascular event in patients with diabetes, type II diabetes.

Dr. Lam:               I couldn't agree more, because the burden of cardiovascular disease globally is actually shifting to Asia, and the burden of diabetes especially, is one of the fastest growing in Asia. So a very, highly relevant topic indeed. Could I start, Yoshi, by asking you: these are the 10 year follow up results, what inspired you to take a re-look at the original JPAD results and to report this 10 year result?

Dr. Saito:              The American guidelines said that low-dose aspirin is recommended to the type II diabetes patient for the primary prevention of cardiovascular events who are older than 30 years old, and who are not contraindicated to aspirin. That meant that almost all type II diabetes patients were recommended to low dose aspirin. However, at that time there was no direct [inaudible 00:09:49] evidence for it. So we connected the prospective randomized control trial that examined the effects of the low dose aspirin on primary prevention of cardiovascular events in type II diabetes patients without preexisting cardiovascular disease. The name of this trial, JPAD trial, that stand for the Japanese Primary Prevention of Atherosclerosis with aspirin in Diabetes. We enrolled 2,539 patients who were assigned to the low dose asprin group or the no aspirin group. So we followed them with a median follow up period of 4.4 years.

                                The results of the original JPAD trial were that low dose aspirin reduced CV events by about 20%, but the reduction could not reach statistical significance. So I don't know the exact reason, but one is the reason is low statistical power, because event rate was about one-third of the anticipated. Another reason is that low dose aspirin really could not reduce cardiovascular events. So we decided the extension of the follow up of the JPAD trial to elucidate the efficacy and safety of long term therapy with low dose aspirin in type II diabetes patients. This extension study was named the JPAD 2 study. We followed them up to the median follow up period of more than 10 years.

                                In this time the JPAD trial study, we analyzed the patients in a pod protocol method because the randomized control trial was ended after 2008. Finally, we analyzed the 992 patients in the aspirin group, and 1,168 patients in the no aspirin group who retained the original allocations throughout the study period. The primary endpoint were composite endpoint of cardiovascular events including sudden cardiac death, the fatal and the non-fatal coronary artery disease, fatal and non-fatal stroke, peripheral vascular disease, and aortic dissection. This end point is the same as the original JPAD trial. The main results are the primary endpoints, 15.2% of patients occurred primary endpoints in aspirin group, and 14.2% in the no aspirin group occurred in the primary endpoints. So the primary endpoints rate is singular in both groups, with the hazard ratio is 1.14 with a 95% CI is 0.91 to 1.42 with a p value of 0.2 by log-rank test. So the low dose aspirin therapy could not reduce cardiovascular events in the type II diabetes mellitus.

                                We also analyzed these data by intention to treat analysis, the results is singular. Again, the low dose aspirin therapy could not reduce the cardiovascular event in type II diabetes mellitus. However, I was told the hemorrhagic events, total hemorrhagic events was singular in both groups, but gastrointestinal bleeding of about 2% in the aspirin group but only 0.9% in no aspirin group. That means our gastrointestinal bleeding is doubled in the aspirin group compared with no aspirin group. This is the main outcome of the JPAD and JPAD-2 trials.

Dr. Lam:               Thank you so much Yoshi, and really congratulations on such a tremendous effort. I completely applaud the idea of looking at the 10 year follow up trying to address the issue of whether or not it was a lack of power that limited JPAD-1, but what you found really reinforced what you found in JPAD-1, which is low dose aspirin did not reduce cardiovascular events in the diabetic group. They're still huge numbers, I'm so impressed that 85% of the treatment assignment was retained. Then furthermore you even showed increased gastrointestinal bleeding with aspirin. So really remarkable results. Can I just ask, are you surprised by the results, and how do you reconcile it with what was found in the general population studies like the Physician Health Study, or the US Preventive Services Task Force, where they really seem to say that primary prevention aspirin works in the general population when your risk is a certain amount?

Dr. Saito:              I think that we studied only the type II diabetes patients, so it is not clear that our results are applied to the general population, but our results is very much similar to the current European guidelines and American guidelines.

Dr. Lam:               That's a very interesting point about diabetic versus non-diabetic population and the utility of low dose aspirin. Shinya, you brought this up before. What do you think?

Dr. Goto:             For the primary prevention population cohort study, aspirin demonstrated 25% reduction of cardiovascular event. We are not recommending aspirin for primary prevention due to the balance of bleeding and cardiovascular protection, absolute risk. In Yoshi's paper, in patients with type II diabetes aspirin evened that [inaudible 00:16:13], and that is very important message he had shown in this long term outcome randomized trial.

Dr. Lam:               Do you think that there are some pathophysiologic differences when you study a diabetic versus non-diabetic population?

Dr. Goto:             Yes, that is a very important topic, and we have very nice review paper by Dr. Domenico and Fiorito. In patients with diabetes the platelet time over becomes relatively rapid as compared to general population. New platelets come to blood and COX-1 inhibition by aspirin cannot reach to enough level in diabetes patient. Still, this [inaudible 00:16:57] hypothesis, very interesting hypothesis.

Dr. Saito:              I think so, I think so. That review that proposed the same concept, their higher dose of aspirin as possibly effective for diabetic patient.

Dr. Lam:               That's interesting. Are you planning any future studies Yoshi?

Dr. Saito:              Yeah, maybe two times study.

Dr. Goto:             But anyway, the event rate is currently very low than the old [inaudible 00:17:28]. So the sample size should be huge. Huge sample size is needed for the primary prevention setting to analyze the effect of aspirin, so the number needed to treat in the primary prevention setting is more than 1000. If diabetes patient, aspirin is resistant to aspirin so the number needed to treat is getting larger. So the sample size is getting larger and larger. That is not practical to perform that clinical trial.

Dr. Lam:               That's a very good point that the contemporary trials like yours are really challenged by the low event rates because of improved preventive treatment across the board like high dose statins, like very, very low LDL targets, and so on. That's a good point. Actually, could I ask both of you gentlemen, and maybe Shinya you can start, can you let us know what is it like to perform such a large rigorous clinical trial in Japan? It must be a lot of effort. Could you give us an idea?

Dr. Goto:             In Japan, medical care system is a little bit different from the U.S. Every patient covered by the homogeneous health care system so it means it is rather difficult to conduct a clinical trial. I appreciate the effort by Professor Saito, Yoshi, it is extremely difficult to conduct the study. Japan is relatively small island, patient stick to the clinic so the long term follow up with relatively low follow up can be expected. [inaudible 00:19:15] number of patients is a challenge, and Yoshi did succeed it. We can do that and due to the baseline therapy is quite homogenous, impact of the clinical care like this has very strong impact.

Dr. Lam:               Exactly, and I share your congratulations once again to Yoshi for really tremendous effort, important results. Thank you so much Shinya for helping with this paper, and for really highlighting how really important it is. Did anyone have anything else to add?

Dr. Saito:              Yes, I have one thinking, in respect to the Japanese clinical trials. I think the Japanese evidence, as derived from Japanese clinical studies is getting better and better in quality. Almost all Japanese clinical trials enrolled only Japanese patients, so the way the Japanese not so good at to organize the international clinical trial because of the, one is the language problem, and the other is funding problem. In Japanese funding agency, the AMED, that is similar to the NIH in United States, but AMED is not so strong as NIH so that they cannot give a bigger budget to the Japanese clinicians. That is another problem to organize a big clinical trial. The funding [inaudible 00:20:49] apprenticeship without holding investigators are very, very important to be better clinical situation in Japan, I think so.

Dr. Lam:               Thank you for listening to Circulation on the Run, don't forget to tune in next week.


Feb 2, 2017


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 Centre and Duke-National University of Singapore.

                                                Today is special, special, special because here with me is the editor of special populations and that is Dr. Sharon Reimold from UT Southwestern, who is the editor handling the special issue for Go Red For Women.

                                                Welcome, Sharon.

Dr Sharon Reimold:         Thank you, Carolyn. I'm happy to be here.

Dr Carolyn Lam:                This is so cool. Just us ladies chatting about issues that we need to be talking about.

                                                Now first of all, this is the first time that Circulation is doing a focus issue for Go Red for Women. Could you tell us a little bit more about that?

Dr Sharon Reimold:         Sure. The Go Red for Issue campaign has been around for many years. The editorial staff realized that we really hadn't had an entire issue devoted to cardiovascular issues in women. We decided several months ago to try to make this a reality and asked for submissions of articles and we’re delighted to see the interest that our cardiologists across the country had, as well as across the world, in submitting their research for consideration in this issue.

Dr Carolyn Lam:                I know. There are seven original papers. There are review papers. There are research letters. It's an amazing issue.

Dr Sharon Reimold:         We had hoped to focus on a lot of different areas in which heart care in women is influenced. We're really quite delighted that we had papers on pregnancy, papers related to strategies to get women involved in trials. We were able to look at novel risk factors in women, and also, have an excellent review about arrhythmias in women versus men that I think everyone will want to take in.

Dr Carolyn Lam:                Yeah. Congratulations once again right off, but let's jump straight into this set of twin papers that deal with post MI outcomes and sex differences. There've been quite a number of publications on this. What makes these two papers special?

Dr Sharon Reimold:         I think these papers are special because they're trying to think more deeply into why women tend to get re-hospitalized after a heart attack more often and what are the reasons that they're getting readmitted.

                                                For instance, it seems that women, as we know, may get a variety of different symptoms that are their equivalent or anginal equivalent after they've been in the hospital and also before they were in the hospital. I, personally, suspect that when somebody comes to the hospital with chest discomfort and they've recently had a heart attack, then often times, they get readmitted and re-hospitalized.

                                                These papers are starting to look at mechanisms, why this happens. I think this will be the bridge to the point where we figure out what can we about this, to hopefully, make men and women more equal in this regard.

Dr Carolyn Lam:                That's so true and well put. I also found very, very interesting and important that paper that really highlighted the importance of coronary flow reserve and microvascular ischemia, not just obstructive disease. Can you say a few words about that paper?

Dr Sharon Reimold:         Sure. It's been known for a long time that if you perform catheterizations on men versus women with similar presentation ... Women may not have as much obstructive disease. This particular manuscript explores coronary flow reserve and identifies this as being part of the difference between men and women in that regard. That, obviously, could have important implications for the clinical care of these patients.

Dr Carolyn Lam:                I like that. All these papers really took what we may have known a bit before, but took them to a deeper level and in a very novel way. So important. You mentioned some of the novel aspects that were also explored in the issue, the pregnancy related factors, in fact, novel risk factors that we should be taking note of in women. Do you want to comment on a few highlights?

Dr Sharon Reimold:         The relationship of pregnancy complications to long term, both maternal and offspring health has been around for a while, but really, we don't know very much about it. We, certainly, have known previously that women with preeclampsia, or those who have significant hypertension, or diabetes in pregnancy may have later problems when they are in middle age or older.

                                                What we are learning from some of these new entries into the research domain is that women who have premature labor and delivery are also at risk for having complications, and this sort of fits in the middle. It's not just preeclampsia, or hypertension, or diabetes. It's that you delivered earlier. Then moreover, we have a couple of research focused letters that describe arrhythmias in pregnancy and what happens to those women during pregnancy. I think we all have seen young women come in and have symptoms, but we really don't know what their outcome has been because any single physician probably just sees a few of them. This highlights arrhythmias as a issue in that population.

                                                We also looked at other articles that focused on other risk factors for heart disease, ranging from breast arterial calcification to traditional biomarkers that we may be drawing in hospital, BMP, troponin, and such. There's a nice manuscript that focuses on hormone changes in women and how they're associated with development of cardiovascular disease. So a fairly broad look at a variety of different risk factors that we don't think about when we're simply asking, "How old are you? What's your blood pressure? What's your diet? Do you have diabetes, and do you have lipid disorders?"

                                                What I would hope that we would get out of this is to open all of our minds and our approaches to patients to think about asking about their pregnancies, did they have any complications, figuring out if they have any hormonal issues, and then being free to consider whether or not the woman that you have in front of you actually has obstructive disease or perhaps has issues with abnormal flow reserve.

Dr Carolyn Lam:                Exactly. I would, actually, add to that, also, looking at our commonly used cardio metabolic biomarkers with the lens of realizing that there are important sex differences in all these biomarkers. That was a very nice paper, corresponding author, Dr. James de Lemos. All these papers are just so practical.

                                                I'm actually going to switch tracks now, Sharon, because I really want to talk about this final paper. All I need to do is read the title of the editorial and it’ll be self-evident. "Women are less likely than men to be full professors in cardiology. Why does this happen and how can we fix it?" I love that you invited this editorial. Could you tell us a bit about the paper that sparked this editorial and your thoughts on this?

Dr Sharon Reimold:         Yes. The original article has as its first author, Dr. David Blumenthal. It's an article that's one of a series of manuscripts that looked at academic cardiologists and looked at faculty rank where they were able to gather data on sex differences, clinical productivity, research funding, publications, et cetera. They have looked at other disciplines other than cardiology, but this particular manuscript focuses on cardiologists. What it demonstrates is that we are getting, perhaps, a little bit more women in at the assistant professor level, but there’s still a significant lag at the full professor level.

                                                In fact, in many centers if you query development offices, there's probably at least a seven year lag between women and men in terms of making it through the whole spectrum. While perhaps, this is not new conceptually, I think it does quantitate it for us and it highlights the concept that this is an issue now, similarly to what it was 25 years ago when I was a cardiology fellow.

                                                The interesting compliment to this is the editorial by Dr. Karns and Dr. Bairey Merz which tries to go into why does this happen and how can we fix it. They took a very academic approach to their editorial in terms of looking at data and then talk about implicit bias and how even a very small degree of implicit bias will cause men to be promoted, perhaps more in a faster manner than in women, and also bring up some things we don't even think about. One of the best ones was the concept that you advertise for a new position as a cardiologist. If you advertise for someone and you list the skills you want and what you want to build, then that's a more gender neutral way to approach a job. If you advertise for a dynamic, outgoing, I don’t know, vigorous sort of person, and there are ads out there that read like that, you are, inadvertently, advertising for a man, most of the time.

Dr Carolyn Lam:                Male characteristics.

Dr Sharon Reimold:         Yeah. They talk about that. Then they obviously end up with how can we fix it? I think that's a real challenge.

                                                There are some data within the field of literature for development that suggest that mentoring and coaching are important, but that they don't necessarily push people up the ladder very rapidly. There are some places, for instance, our University of Texas system now that is very interested in the concept of sponsorship. That someone sponsors another individual, could be male or female, to get involved and pushes them ahead, not pulls them, so that they have opportunities for faster career development and success. In any event, I think this compliment of paper and editorial really highlights an issue that, while not necessarily affecting female patients, certainly affects cardiology as a destination career.

Dr Carolyn Lam:                I agree. I think part of the how to fix it is simply by being aware and acknowledge the issue. That is exactly what we’re doing in these papers. I love that they are academically written. Like you said, you read a lot about these gender biases in the popular press, but it's so refreshing to see it addressed in an editorial, in a beautiful paper, in circulation.

                                                Sharon, congratulations on just this excellent, excellent issue. Is there anything else you may want to highlight about the issue?

Dr Sharon Reimold:         I think that's the major thing. I think we moved a long way from the beginning of Go Red For Women as a campaign where we really wanted patients to be aware that hypertension or elevated cholesterol levels were an important issue. I think now is a time where we move forward. We’ll learn more about differences between men and women and we figure out how we can treat or account for these differences as we strive to make health care for all and cardiovascular care for all improve over time.

Dr Carolyn Lam:                Thanks Sharon. Everyone of you listening to this, go pick up this issue. I'm sure we've peaked your interest.

                                                Thank you for listening to Circulation On The Run. Don't forget to tune in next week.


Jan 30, 2017

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 Centre and Duke-National University of Singapore. Our featured discussion today relates to 20 year outcomes after mitral valve repair versus replacement for severe degenerative mitral regurgitation.

                                                But first, here's your summary of this week's issue. The first paper suggests that agonistic angiotensin receptor autoantibodies may be biomarkers of adverse outcomes. In this study from first author Dr. Abadir, corresponding author Dr. Fedarko, and colleagues from Johns Hopkins University School of Medicine in Baltimore, Maryland, authors developed a quantitative immunoassay for measuring agonistic angiotensin AT1 receptor autoantibodies in the serum.

                                                They then assessed its operating characteristics in a discovery group of 255 community dwelling adults from Baltimore and validated these findings in a second group of 60 individuals from Chicago. They found that AT1 receptor autoantibody levels were significantly associated with higher levels of inflammatory cytokines, weaker grip strength, slower walking speed, higher risk for frailty, more falls and increased mortality.

                                                Furthermore, chronic treatment with angiotensin receptor blockers, it attenuated the AT1 receptor autoantibody association with decline in grip strength and increased mortality. These results therefore suggest that followup studies and intervention trials in chronic inflammatory diseases should test whether AT1 receptor autoantibody levels can be used to stratify patient risk and whether they can be used to identify patients who may benefit from angiotensin receptor blocker treatment.

                                                The next paper suggests that baseline target mismatch on CT perfusion imaging may predict the response to tenecteplase in ischemic stroke. Dr. Bivard and colleagues from John Hunter Hospital University of Newcastle in Australia pooled two clinical trials of tenecteplase compared with alteplase for the treatment of acute ischemic stroke.

                                                Baseline CT perfusion was analyzed to assess if patients met the diffused two target mismatch criteria. These criteria are absolute mismatch volume of more than 15 mL, mismatch ratio of more than 1.8, baseline ischemic core less than 70 mL and volume of severely hypoperfused tissue less than 100 mL.

                                                Among 146 pooled patients, 71 received received alteplase and 75 received tenecteplase. Overall tenecteplase treated patients had greater early clinical improvement by NIH Stroke Scale change and less parenchymal hematoma, but did not show a significant difference in three month patient outcome by the Modified Rankin Scale.

                                                74 of the 146 patients met target mismatch criteria. It was only among these patients with target mismatch that treatment with tenecteplase result in greater early clinical improvement and better late independent recovery than those treated with alteplase. In summary, tenecteplase may offer an improved efficacy and safety profile versus alteplase, benefits that are possibly exaggerated in patients with baseline CT perfusion defined target mismatch.

                                                The next study is the first to provide a comprehensive analysis of circulating metabolite levels and relate these to clinical outcomes in patients with pulmonary arterial hypertension. First author Dr. Rhodes, corresponding author Dr. Wilkins and colleagues from Imperial College London conducted a comprehensive study of plasma metabolites using ultra-performance liquid chromatography mass-spectrometry in 365 patients with idiopathic or heritable pulmonary arterial hypertension and 121 healthy controls.

                                                They found that increases in circulating modified nucleosides originating from transfer RNAs, energy metabolism intermediates, tryptophan and polyamine metabolites and decreased steroids, sphingomyelins and phosphatidylcholines independently discriminated pulmonary arterial hypertension from controls and predicted survival. Furthermore, correction of metabolite levels overtime was linked to better clinical outcomes and patients who responded well to calcium channel blocker therapy had metabolic profiles comparable with healthy controls, thus these findings suggest that monitoring plasma metabolites overtime could be useful to assess disease progression and response to therapy in pulmonary arterial hypertension. Therapeutic strategies targeted against metabolic disturbances, particularly translational regulation and energy metabolism, may merit further investigation in pulmonary arterial hypertension.

                                                The final study takes a contemporary look at age associated changes in left ventricular diastolic function. Dr. Shah and colleagues from Brigham and Women's Hospital in Boston, Massachusetts related diastolic measures including tissue Doppler E prime, E to e prime and left atrial size, to the risk of heart failure hospitalization or death in 5801 elderly participants in the ARIC study. They further defined sex-specific 10th percentile limits in 401 participants free of cardiovascular disease or risk factors. They found that each diastolic measure was robustly associated with incident heart failure hospitalization or death. Reference limits for E to e prime and LA size were generally in agreement with existing guidelines, whereas limits for tissue Doppler E prime were substantially lower at 4.6 for septal E prime and 5.2 for lateral E prime in the ARIC study compared to 7 and 10 respectively in international guidelines. Compared to the guideline cut points, the ARIC base limits improved risk discrimination and reclassified over one-third of the study population as having normal diastolic function. These findings were further replicated in the Copenhagen City Heart Study.

                                                In summary, this study suggests that a decline in left ventricular longitudinal relaxation velocity occurs maybe as part of healthy aging and is largely prognostically benign. This supports the use of age-based normative values when considering an elderly population.

                                                Well, that wraps it up for the summaries, now for our featured discussion.

                                                Today we are discussing the very important result of the mitral regurgitation international database and we have with us today no other than the corresponding author Dr. Jean-Louis Vanoverschelde, and he is from University of Louvain in Brussels. Welcome Jean-Louis, I made it.

Dr Jean-Louis Vanoverschelde:  Hey, how are you?

Dr Carolyn Lam:                Thank you so much for joining us. Also joining us today is Dr. Victoria Delgado, associate editor from Leiden University Medical Center in the Netherlands. Welcome Victoria.

Dr Victoria Delgado:        Hello. Thank you very much for having me in this podcast.

Dr Carolyn Lam:                So, severe degenerative mitral regurgitation with flail leaflets, a very important condition and your study, Jean-Louis, really provides important clinically applicable information. Could you please address our clinicians out there with a take home message from your paper.

Dr Jean-Louis Vanoverschelde:  Well, the take home message is very easy, once this condition needs to be operated on, there are really two options, one which is to repair the valve and keep the native tissue and the other is to replace the valve and trash the native tissue if I can say so. The results of the study are really clear. There is a major survival advantage by repairing the valve as opposed to replacing it. So for everyone of those who have degenerative mitral regurgitation with flail leaflets, the best treatment option is mitral repair.

Dr Carolyn Lam:                Now these results came from a multi-center registry of thousands of patients. I was really struck with the duration of the study. I think that's something that's really novel. You had a 20 year follow up but also patients were recruited from 1980 all the way to 2005, am I right? So could you expand a little bit about the possibility of techniques changing during that period?

Dr Jean-Louis Vanoverschelde:  Although there has been subtle changes in the practice, the basic principle have remained the same. So we have not really accounted for these changes in the practice over time, with regard to what happened to mitral valve replacement, clearly the prostheses that were there 30 years ago are not the same as the ones that are currently implanted to the patients, but none the less when we performed an analysis, a sensitivity analysis to look at whether the results were different from 20 years ago compared to those that were more recent, we found exactly the same result.

Dr Carolyn Lam:                Yes, I thought that was a very important sensitivity analysis. Tell us a bit more about the propensity score matching as well because another thing people will be thinking is, you know, this is a registry, huge numbers very important but obviously there would be differences in indication for repair versus surgery.

Dr Jean-Louis Vanoverschelde:  For sure, the fact is that there are statistical means that allow you to mimic not to be the exactly the same as, but to mimic randomization and it is the propensity score matching. That means that you perform a prior analysis that will identify similar patients in the two cohorts and match them so that you are basically having the same kind of patients that are treated with two different ways. So it's not randomization but it’s getting close to randomization when you use cohorts like the one from the MIDA registry.

Dr Carolyn Lam:                Perfect. Victoria, did you take the same take home messages and are you applying this clinically? I noticed that you invited an editorial, a lovely editorial on this paper as well, so please share your thoughts.

Dr Victoria Delgado:        Yeah, I share the same take home message that Dr. Vanoverschelde has outlined. I think that this is very important article, it's a landmark article highlighting one of the most important things that mitral valve repair should be probably the standard of care for patients with severe mitral regurgitation without degenerative cause with a flail and the article basically what it does is also endorsing the recommendations of current guidelines highlighting the value of mitral valve repair. Of course that mitral valve repair should be performed in centers with experience and with good durability of these repairs, so the centers need to have a good heart team where they can analyze their results in such a way like the MIDA registry has done demonstrating a good durability of the repair.

Dr Carolyn Lam:                And do you have anything to add to that Jean-Louis?

Dr Jean-Louis Vanoverschelde:  No, I think basically Victoria very well summarized the basic features not only of the paper itself but also of the condition and what currently is in the guidelines. In fact, the guidelines have already said that we should be preferring mitral valve repair over replacement, but the data on which this was based were probably not as conclusive as the one that are provided by this analysis of our registry, so I think it's really reinforcing the idea that we should go ahead and try to perform repair as much as possible, now with a caveat of course that the surgeons need to be skilled enough to perform that. But with the type of differences that we see in survival between the two cohorts I think that if a surgeon does not feel comfortable with repairing the valve and would rather replace it, he might refer the patient to another surgeon that is capable of repairing the valve. The impact and outcome is such that I think this really supports the idea that the patient should be referred to high volume and skilled centers.

Dr Carolyn Lam:                Could you give us an idea of what kind of impact you're talking about, what kind of numbers that you see?

Dr Jean-Louis Vanoverschelde:  It's the same in all the analysis, whether it's in the overall population or in the matched cohorts by 20 years, we have something like 20 to 25% survival difference, absolute survival difference between the two groups. So it's a reduction of mortality approximately by half if you perform repair compared to replacement, and it is increasing with time, so it's not something that is only present in the first years but is increasing with time, so it's about 20 to 25% absolute difference between the two cohorts.

Dr Carolyn Lam:                That truly is remarkable. Congratulations again on such a landmark paper like Victoria said. Now to either of you, question that's a bit left field maybe, but what do you think the role is now for percutaneous techniques of mitral valve repair or replacement then?

Dr Jean-Louis Vanoverschelde:  That's an interesting question. I think that if you really look far away into the future probably everything at some point in time will be percutaneous. At this stage I’m not sure that the percutaneous technique able to mimic what we can do with surgery in terms of mitral valve repair. So, it's an alternative to surgery in patients who are inoperable. In those who can undergo a surgical mitral repair, my first choice will certainly be to go surgically rather than percutaneously, at least right now.

Dr Carolyn Lam:                Victoria?

Dr Victoria Delgado:        I also agree with those comments. I think that now we have a lot of possibilities to treat these patients but the most important thing is to have the entire clinical picture of the patient, to see the pros and cons of preparing the patient for surgery or for percutaneous valve. There should be also an integration of imaging to know which is the cause of the valve dysfunction and to see whether the anatomy could be easily repaired by surgery or instead if the patient has contraindication for surgery, if it could be repairable as well with transcatheter therapy. But then for that I think that is really important and this is what the editorial also highlights, the role of the heart team, where there are different specialist surgeons, clinical cardiologists, heart failure specialists, imaging specialists that can integrate the entire information of the patient in order to select the most appropriate therapy. But still for patients who do not have contraindications for surgery who have repairable valve and as you can see from this registry, the percentage of repairability is quite high, I would still refer the patient as well for surgical valve repair.

Dr Carolyn Lam:                You heard it right here. Thank you so much for joining us today and please don't forget to tune in next week.


Jan 23, 2017


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 Centre and Duke-National University of Singapore. In just a moment, we're going to be discussing new results of the pioneer trial, and the patient with atrial fibrillation who undergoes intracoronary stenting, a familiar conundrum. What's the role of NOACs? Is there still a role for full-dose triple therapy with warfarin? First, here's your summary of this week's journal.

The first paper tells us about the clinical impact of left atrial appendage closure. Dr. Melduni and colleagues from the Mayo Clinic in Rochester, Minnesota, studied 9,792 patients undergoing bypass or valve surgery between 2000 and 2005. They used propensity score matching to estimate the association of left atrial appendage closure with early post-operative atrial fibrillation- defined as atrial fibrillation within 30 days of surgery- ischemic stroke, and mortality. They found that after adjustment for treatment allocation bias, left atrial appendage closure during routine cardiac surgery was significantly associated with an increased risk of early post-operative atrial fibrillation, and did not influence the risk of stroke or mortality.

They therefore concluded that it remains uncertain whether prophylactic exclusion of the left atrial appendage is warranted for stroke prevention during non-atrial-fibrillation-related cardiac surgery.

The next study provides pre-clinical evidence that genes on sex chromosomes may contribute to the sexual dimorphism of abdominal aortic aneurysms. That is, we well know that abdominal aortic aneurysm is a male-predominant disease. Now, in this paper, by first author Dr. Alsiraj, corresponding author Dr. Cassis and colleagues from the University of Kentucky, female LDL-receptor-deficient mice, with an XX or XY sex chromosome complement, were infused with angiotensin II for 28 days to induce abdominal aortic aneurysms. DNA microarrays were performed on the abdominal aortas, and to mimic the males, the female mice were administered a single dose of testosterone.

They found that an XY sex chromosome complement, in phenotypic females, profoundly influenced aortic gene expression profiles and promoted abdominal aortic aneurysm severity. When XY females were exposed to testosterone, aneurysm rupture rates were striking. The mechanisms for augmented abdominal aortic aneurysm severity in XY females included increased inflammation, augmented matrix metalloproteinases, and oxidative stress. These results, therefore, demonstrate that genes on the sex chromosomes regulate aortic vascular biology and contribute to sexual dimorphism of aortic abdominal aneurysms. Sex chromosome genes may therefore serve as novel targets for sex-specific abdominal aortic aneurysm therapeutics.

The next two studies shed light on the mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism. In the first study, Dr. Watts and colleagues from University of Western Australia carried out a two-by-two factorial trial, of high-dose atorvastatin versus evolocumab on stable isotope tracer kinetics in 81 healthy, normal lipidemic, non-obese men.

They found that both atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL apoB, IDL apoB, and LDL apoB. On the other hand, evolocumab, but not atorvastatin, also decreased the production rate of IDL apoB and LDL apoB. The reduction of LDL apoB and LDL cholesterol was significantly greater with a combination versus either mono-therapy. In summary, they found that in healthy, normal lipidemic men, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism, and by reducing IDL and LDL production. The latter effects are incremental to statins.

The second paper to deal with this topic comes from Dr. Ginsberg and colleagues from Columbia University in New York, who studied 18 participants, this time 10 of whom were women, who completed a placebo-controlled two-period study, receiving two doses of placebo followed by five doses of alirocumab. These authors found that alirocumab decreased LDL cholesterol and LDL apoB by increasing IDL and LDL apoB fractional clearance rates, and by decreasing LDL apoB production rates. These results were consistent with increases in LDL receptors available to clear IDL and LDL from the blood during PCSK9 inhibition. These two papers are discussed in a beautiful accompanying editorial by Dr. Chris Packard from University of Glasgow. In his editorial entitled "Unpacking and Understanding the Impact of PCSK9 Inhibitors on Apolipoprotein B Metabolism." Those were your highlights! Now for our feature discussion.

Today we are going to be discussing one of the most common conundrums in all of cardiovascular medicine, and that is the care of patients with atrial fibrillation who also need percutaneous coronary intervention. Of course, both dual antiplatelet therapy and oral anticoagulation therapy would be indicated to reduce the risk of stent thrombosis and thromboembolism in atrial fibrillation, respectively. However, with the intensification of the anti-thrombotic regimen, there is the inevitable trade-off with more bleeding. Now, to discuss this, we have the first and corresponding author on a very novel study of the pioneer trial, and that is Dr. Michael Gibson, from Harvard Medical School and Beth Israel Deaconess Medical Center. We also have the editorialist for this very exciting paper, Dr. Deepak Bhatt from Brigham and Women's Hospital, and finally, we have Dr. Dharam Kumbhani, associate editor from UT Southwestern. Welcome, gentlemen!

Dr Deepak Bhatt:           Thank you.

Dr Michael Gibson:          Thanks.

Dr Dharam Kumbhani:   Thank you.

Dr Carolyn Lam:                So, Michael, could I start with you? This is a sub-study of the pioneer study. Could you tell us how this is different from the primary results, what were you looking for, and what you found?

Dr Michael Gibson:          As you know, as [inaudible 00:07:40] said, we have a lot of bleeding with conventional triple therapy, and we used two regimens to try and reduce that bleeding. One was a reduced dose of rivaroxaban, 15 milligrams, plus thienopyridine. The other strategy was baby dose rivaroxaban, 2.5 milligrams twice a day, plus DAPT. What we found in the overall study was a significant reduction in bleeding- from, say, 26.7% down to 18% for riva plus DAPT- that's the baby dose plus DAPT- and down to 16.8% for the 15 milligrams of riva plus the thienopyridine.

You'd have to treat about 11 to 12 patients to prevent one significant bleeding event. That's the mainstay. What we found in this very, very important sub-study is that that was associated with reduction in hospitalization. All-cause hospitalization was reduced, and cardiovascular hospitalization went down from 28.4% to about 20% for the two regimens. Bleeding with hospitalization went down, from 10.5% to about 6%. At the end of the day, you'd only have to treat 10 to 15 people to prevent one hospitalization, so from a health economic perspective, and from a patient viewpoint and hassle perspective, this was very important.

Dr Carolyn Lam:                In fact, Michael, I would say from a clinician-cardiologist perspective, these results are really very applicable. In fact, I really like, in the accompanying editorial, what Deepak wrote, that it may be one of those rare occasions where a sub-study provides very clinically meaningful information compared to the primary study. Deepak, would you like to elaborate a little bit more about that?

Dr Deepak Bhatt:             Sure. A really great point that you've raised. It wasn't, in fact, a sub-study we're talking about in Circulation. It was an analysis from the overall trial, looking at a different endpoint than the primary endpoint, the hospitalization, and the composite of hospitalization and mortality. I think that's a very important endpoint. If it were a heart failure trial, for example, that's the endpoint everyone would hone in on- mortality and hospitalization. The fact that that was significantly reduced, I think, is very clinically meaningful. Mike mentioned the economic implications, which for sure are there, by reducing hospitalizations and re-hospitalizations.

The impact on cardiovascular hospitalizations- the reduction there- I find particularly remarkable. The reduction in bleeding, of course, is good, and in its own right has a great deal of value, but the additional reduction in cardiovascular hospitalizations, I think, is quite reassuring for those that are worried about the efficacy of the two experimental regimens that he and his colleagues studied. Sure, the trial's not powered in each individual sub-group for rare events like stroke, but the fact that CV hospitalizations are not increased, and in fact reduced, tells me that this is a winning strategy or strategies.

Dr Carolyn Lam:                Right. Michael, another issue, though- this is open label, and I suppose one of the criticisms could be that there is a bias for clinicians managing patients on the traditional Vitamin K antagonist to maybe hospitalize patients more for some reason. What is your response to that?

Dr Michael Gibson:          That is always the criticism of an open label trial, but again, the events were adjudicated, and for the heart events, that's done in a blinded fashion, so it's reassuring that there was a blinded assessment of the heart events.

Dr Carolyn Lam:                True. How about comments on generalizability? I mean, what do you think? Trial setting, real world ...

Dr Michael Gibson:          Yeah, I think that's one of the advantages. This was very much a real-world kind of study. It was truly done throughout the world. We had a very broad entry criteria. Anyone who was getting a stent put in- you didn't have to have ACS, although about half the patients did. The only real exclusive criteria was you couldn't have any bleeding or be profoundly anemic. You couldn't have a stroke or [TIA 00:11:58] in the past. Other than that, it made real-world practice in a lot of ways.

Dr Dharam Kumbhani:   This is Dharam. If I may ask both the other people on the call, is ... Rivaroxaban is not FDA approved, in these doses, for use. I'm wondering if they might provide some comment, given the benefit that we see in this trial, overall, what their thoughts are and what the next steps might be.

Dr Carolyn Lam:                Sure. Maybe Michael, then Deepak?

Dr Michael Gibson:          Yeah, that's a good point. It is important to point out that you'd need to check the prescribing information in your country. In some countries- I think it's about 54 countries- the 2.5 milligram dose is available. It is approved for ACS, but is not approved for a-fib. Then, you have a dose of 20 milligrams that's approved worldwide for a-fib, but there are some countries- it's important to note, in some countries, 15 milligrams is the full dose that's approved- say, in Japan and Taiwan. There are Japanese studies showing that 15 milligrams was not only safer than warfarin, but more efficacious than warfarin in a trial like J-ROCKET. You're right, the 15 milligram dose is available in the US- it's approved for renal insufficiency, but at this time, it's not labelled for the ACS or stented patient.

But again, physicians are at liberty to look at this data, which is the first real data that we have to guide decision-making in this setting, and they're at liberty to make their own choices.

Dr Deepak Bhatt:             Yeah, I would agree with that assessment, and emphasize ... Like Mike said, it's an international audience for Circulation, so I would say, look in your own country, and in many parts of Europe, the 2.5 milligram rivaroxaban dose is available and approved for ACS, and could therefore be used for this purpose, though not strictly falling within the label indications. In the US, there's the 15.

I think, if I just answer the previous question, the results are very generalizable, and for doctors that critique that point, I'd say, "Why didn't you enroll your patients in the trial?" There's the RE-DUAL as well, that's ongoing, with dabigatran, AUGUSTUS with apixaban, and I'm missing one that's also ongoing as well, I think, but there are four different trials that are out there. The Pioneer was the first to report ...

Dr Carolyn Lam:                I think you're thinking of the Entrust AF-PCI with Edoxaban.

Dr Deepak Bhatt:             The most recent one, yes. I forgot the acronym, there. If people are really thinking that the results don't apply to their patients, well, there are trials that are ongoing. Enroll your patients. But to say, "Oh, my patients, I'm not going to enroll them in the trial," and then say, "The results aren't generalizable," I always find that an odd thing. I think the results are very generalizable. The one word of caution I would say, though, is to make sure to renally dose, as was done in the trial. That is, there was a downward adjustment in dose from the 15 milligrams to the 10. In real life, we've seen in registries with NOAC use, whether it's rivaroxaban or any of the others, a lot of times, the renal function is not carefully monitored in those patients that are on the fringe in terms of their renal function, and that's the one situation NOACs can backfire, where the dose isn't corrected for their degree of renal dysfunction. Other than that one caveat, I think the results are quite generalizable.

Dr Carolyn Lam:                Excellent comments. We should wrap up soon, but not before I want to ask Dharam. Thank you for managing this beautiful paper. What, to you, is the take-home message for clinicians out there?

Dr Dharam Kumbhani:   Yeah, it was an absolute honor and delight to manage this, and I think the paper's great. The editorial's great. It's gotten a great response. I think the take-home message is that this is a very clinically relevant question, and a very clinically relevant trial, and it shows that the needle will be moving towards using non-VKA-based agents, especially in patients such as this, who have both a-fib and PCI. I think this is very exciting space, a very important space. This trial suggests that if you use the strategy rivaroxaban low dose, with or without a DAPT, that it is safer, both in terms of mortality and bleeding, compared with what is traditionally being used with warfarin plus DAPT. I think this was a very, very exciting trial.

Dr Carolyn Lam:                Indeed, and congratulations to all three of you. Thank you so much for joining me on Circulation On The Run. Thank you, listeners, for joining us too, and don't forget to tune in next week.


Jan 16, 2017


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. Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

                                                In today's episode, we are discussing very important new data regarding stroke risk stratification in patients with atrial fibrillation. First though, let me give you the highlights of this week's journal.

                                                The first paper provides mechanistic evidence that endothelial-derived microparticles may play a key role in the development of endothelial dysfunction following acute coronary syndrome. In this paper from first author, Dr. Abbas, co-corresponding authors, Dr. Toti and Morel from the University of Strasbourg in France, authors expose core sign coronary artery endothelial cells to microparticles shed from senescent cells, or circulating microparticles from patients with acute coronary syndrome.

                                                They showed that exposure to these microparticles induced increase senescence-associated beta-galactosidase activity, oxidative stress, and early phosphorylation of MAP kinases and AKT, and upregulation of p53, p21 and p16. Depletion of endothelial-derived microparticles from acute coronary syndrome patients reduced the induction of senescence.

                                                On the other hand, pro-senescent microparticles promoted endothelial cell thrombogenicity. These microparticles exhibited angiotensin-converting enzyme activity and upregulated AT1 receptors and ACE in endothelial cells. Losartan and AT1 receptor antagonist and inhibitors of either MAT kinases or PI3-kinase prevented the microparticle-induced endothelial senescence. 

                                                In summary, these findings indicate that endothelial-derived microparticles from acute coronary syndrome patients induce premature endothelial senescence and thrombogenicity suggesting that targeting endothil-derived microparticles and their bioactivity may be a promising therapeutic strategy to limit the development of endothelial dysfunction post-acute coronary syndrome.

                                                The next study is the first large and prospective study showing that NT-proBNP is associated with cardiovascular events in patients with adult congenital heart disease independent of multiple clinical and echocardiographic variables.

                                                This is a study from first author, Dr. Bekan; and corresponding author, Dr. Roos-Hesselink and colleagues from the Erasmus University Medical Center in Rotterdam, the Netherlands. The author studied 595 clinically stable patients with adult congenital heart disease who attended the outpatient clinic between 2011 and 2013.

                                                All patients underwent clinical assessment, electrocardiography, echocardiography and biomarker measurement, including NT-proBNP, high-sensitivity troponin T and growth differentiation factor 15. Patients were prospectively followed over a median of 42 months for the occurrence of cardiovascular events including death, heart failure, hospitalization, arrhythmia, thromboembolic events and reintervention.

                                                They found that of the three evaluated biomarkers, NT-proBNP was most strongly associated with cardiovascular events. Importantly, patients with a low-risk of death and heart failure could be accurately identified with a high negative predictive value.

                                                In patients with elevated NT-proBNP, elevations of high sensitivity troponin T and growth differentiation factor 15 identified those patients at highest risk of cardiovascular events.

                                                In summary, these biomarkers may play an important role in the monitoring and management of patients with adult congenital heart disease.

                                                The next study describes heart failure stages among older adults in the community. Dr. Shah and colleagues from the Brigham and Women's Hospital in Boston Massachusets classified more than 6,000 participants in the atherosclerosis risk and community study into heart failure stages. These were stage A; asymptomatic individuals with heart failure risk factors, but no cardiac structural or functional abnormalities. Stage B; asymptomatic individuals with structural abnormalities such as left ventricle hypertrophy, dilation, dysfunction, or valve disease. Stage C1; clinical heart failure without prior hospitalization. Stage C2; clinical heart failure with prior hospitalization.

                                                They found that only 5% of examined participants were free of heart failure risk factors or structural heart disease. 52% were categorized as stage A, 30% stage B, 7% stage C1, and 6% stage C2. Worst heart failure stage was associated with a greater risk of incident heart failure hospitalization or death at a median follow up of 608 days.

                                                Left ventricular ejection fraction was preserved in 77% of stage C1 and 65% of stage C2 respectively. In corporation of longitudinal strain measurements and diastolic dysfunction into the stage B definition, reclassified 14% of the sample from stage A to B.

                                                Abnormal LV structure, systolic function, whether based on ejection fraction of longitudinal strain, and diastolic dysfunction, were each independently and additively associated with the risk of incident heart failure hospitalization or death in stage A and B participants.

                                                The authors concluded that the majority of older adults in the community are at risk of heart failure, appreciably more compared to previous reports in younger community-based samples. The study also highlighted the burden of heart failure with preserved ejection fraction in the elderly and provided evidence that left ventricular diastolic function and longitudinal strain provide incremental prognostic value beyond conventional measures of LV structure and ejection fraction in identifying patient at risk of heart failure hospitalization or death.

                                                The next study sheds light on the association of the LPA gene, ethnicity and cardiovascular events. First author, Dr. Lee; corresponding author Dr. Tsimikas and colleagues from University of California San Diego studied 1,792 black, 1,030 white, and 597 Hispanic subjects all enrolled in the Dallas Heart Study. They measured LPA snips, apolipoprotein A isoforms, LP(a) and oxidized phospholipids on apolipoprotein B100.

                                                These individuals were also followed for a median of 9.5 years for major adverse cardiovascular events. The authors found that the prevalence of LPA snips and apolipoprotein A isoforms were very different across ethnic groups. LPA snips that were associated with elevated LP(a) in whites were associated with low LP(a) in Hispanics mainly due to differences in apoliproprotein A isoforms size.

                                                After multi-variable adjustment, LP(a) and oxidized phospholipids on apolipoprotein B were both predictors of major adverse cardiovascular events. Conversely, LPA snips and apolipoprotein A isoforms did not add predictive value to models and did not show clinical utility in this study.

                                                These data suggests that much of LP(s) mediated major adverse coronary events is driven by oxidized phospholipids. Importantly, elevated LP(a) and oxidized phospholipids on apolipoprotein B must be recognized as important predictors of major adverse cardiovascular events across racial groups.

                                                The final study addresses the question of the optimal antithrombotic regimen for longterm management of patients with symptomatic peripheral artery disease, or PAD, with a history of limb revascularization. To answer this question, Dr. Jones and colleagues from Duke Clinical Research Institute looked at the EUCLID trial, or examining use of ticagrelor in PAD trial, which randomized patients with PAD to treatment with ticagrelor 90 milligrams twice daily, or clopidogrel 75 milligrams daily.

                                                As a reminder, patients in EUCLID were enrolled based on a normal ankle-brachial index of less .8, or a prior lower extremity revascularization. The current paper really focus on the subset of 7,875 patients who were enrolled based on a prior lower extremity revascularization criterion.

                                                The authors found that after adjustment for baseline characteristics, patients enrolled based on prior revascularization for PAD had higher higher rates of myocardial infarction and acute limb ischemia with similar composite rates of cardiovascular death, myocardial infarction and stroke when compared with patients enrolled based on the ankle brachial index criterion.

                                                Overall, there were no significant differences between ticagrelor and clopidogrel for the reduction of cardiovascular or acute limb events.

                                                Those were your highlights. Now, for our featured discussion.

                                                On today's podcast, we are discussing the very, very important issue of stroke risk in patients with atrial fibrillation. Most of us use the international guidelines for anticoagulation in atrial fibrillation that mostly suggest that we use the CHADS VASc scoring system to determine the stroke risk in a particular patient and then determine whether or not this patient meets the threshold for anticoagulation.

                                                This assumes that the CHADS VASc score corresponds to a fixed stroke rate. Today, in our journal, we have very, very interesting results from a paper with corresponding author, Dr. Daniel Singer who really suggest that we may need to rethink that. Dr. Daniel Singer joins us today from Massachusets General Hospital.

                                                Welcome Daniel.

Dr. Daniel Singer:             Thank you for having me.

Dr. Carolyn Lam:               Great. Today, we also have Dr. Sana Al-Khatib who's the associate editor from Duke University who managed this paper. Welcome Sana.

Dr. Sana Al-Khatib :         Thank you Dr. Carolyn, I'm happy to be here.

Dr. Carolyn Lam:               Daniel, could we start by you letting us know what you sought to do in your study and what you found?

Dr. Daniel Singer:             We all know that anticoagulants are extraordinarily effective at preventing stroke in patients with atrial fibrillation, but they also raise the risk of bleeding, and sometimes that bleeding could be quite serious and even fatal. As a result, for that past 10, 15 years, we have used a risk-based approach to the decision about whether to start a patient on anticoagulation, and that risk is the stroke risk that a patient faces if they weren't taking anticoagulants. Then we figured that anticoagulants will reduce it by about two-thirds.

                                                There are formal decision analysis and then a more informal sense that a patient has to face an anticoagulated risk of stroke of about 2%, some people might say 1% to 2% before anticoagulation results in an expected net clinical benefit that the effect in reducing ischemic stroke will exceed the risk of increasing bleeding.

                                                While the CHADs VASc score has been widely accepted as the basis for estimating that risk, it became apparent to us as we looked across the studies that were underlying that assumption, that the risk that were associated with various CHADs VASc scores were extremely variable. Many of these risks actually were less than that 1% or 2% threshold for anticoagulation.

                                                What I mean is that the stroke risk associated with CHADs VASc score of one, or two, which is the basis for the guideline threshold for anticoagulation actually corresponded to risk less than 1% in many of these very large studies. We have conducted a systematic review just to be sure that we were capturing the overall evidence base for this, and that's what we report in our paper.

Dr. Carolyn Lam:               Perhaps you could start by letting us know exactly how far off are we in our stroke risk estimation.

Dr. Daniel Singer:             We looked at 34 studies that were quite large and then we zeroed in on the largest one. If you looked at the rate for stroke overall, they varied enormously in terms of the overall stroke rate. Then when we focused down on CHADs VASc score of 1, or 2, we found that the majority of these studies, actually, for CHADs VASc 1, was less than 1% per year. For CHADs VASc 2 score was in the majority these studies less than 2% per year.

                                                Both of those stroke risks have raised us the question where are these patients could gain in that clinical benefit from being anti-coagulated, because those stroke risk, if they were reduced by two-thirds, would really be a very small reduction in risk and yet they'd still face the bleeding risk.

                                                Among the most interesting findings actually is that we found that a Swedish national database and the large Danish national database came up with threefold difference in their estimate of stroke rates. The Swedish database produced lower risk, and the Danish database produced substantially higher risk.

                                                If you think about it, there are probably no two countries in the world that are more similar in terms of gene, social environmental, medical care systems, and that raises the specific question of, "Is it underlying rates that vary across different cohorts and different geographies, or is it a different in methodology?"

                                                We think a lot of the differences are due to methodologic difference, and that we need to standardize these differences together, better handle on what the real stroke rate is among patients with these low CHADs VASc scores.

Dr. Carolyn Lam:               The variability that you pointed on your paper is really striking, but another possibility, do you think, is that maybe stroke risk isn't static.

Dr. Daniel Singer:             Yeah. If that's the case, we face a great difficulty in developing predictions rules of what the stroke risk could be. I think most people feel it's the function of their age, and whether they've had a prior stroke, and whether they have the comorbidity, hypertension, and diabetes, and so on, that are incorporated into the various stroke risk scores, in particular, CHADs VASc.

                                                We tend to think that that's pretty fixed until you get older or until you accumulated another comorbidity. I think the striking difference is that, one, that we actually anticipated in the beginning, was that the stroke rates in people with atrial fibrillation were also coming down. The stroke rates in general have been dramatically decreasing for decades now.

                                                One issue is whether that applies as well to atrial fibrillation associated stroke. There is a suggestion of that, but the variability across the cohorts is so great that you can't pick up a strong signal in terms of calendar time. Although I suspect that there is a strong calendar effect. Exactly why that is, we could speculate. I suspect a lot of it is control of blood pressure, but that's speculation.

Dr. Carolyn Lam:               Daniel, congratulations again for that fascinating and really very sobering findings.

                                                Sana, you managed this paper. It's very important paper. In fact, important enough that you invited an editorial. Could you please share some of your thoughts?

Dr. Sana Al-Khatib :         Oh, yeah. Absolutely. First, I'd like to start by congratulating Daniel and his team on conducting this really important study. I enjoyed reading it and managing it. Definitely, congratulations.

                                                A couple of thoughts that I have. I completely agree with this really important finding, that there is a lot of variability in the rates of stroke that come from different patient populations and databases. As you pointed out Daniel, I think this is indeed largely due to differences in methodology in terms of how the information was selected, how certain things were defined.

                                                I agree with you there. You called for standardization of this, and I wonder if you have any thoughts about how we can go about doing that. I also want to bring up some of the newer studies now that are showing some significance in terms of biomarkers. Is that really adding significantly to the predictive ability of risk prediction models? I wanted to get your thoughts on that as well.

Dr. Daniel Singer:             Let me address your last question, which is simply you state that the CHADs VASc score, the CHAD score and so on, are based on very simple clinical features, and it would be unusual for them to be highly predictive. In fact, they're only mediocrely predictive, and the addition of biomarkers high-sensitivity troponin proBNP, now, people have suggested the imaging biomarkers like magnetic resonance to asses fibrosis in the left atrium. These are all very, very promising in terms of getting better models.

                                                The problem is to do that on a very scale such that we can get precise and well-calibrated predictions. We've found when we're analyzing to pair risk scores, we found that the most important issue is the underlying risk, so that, yes, you can get a great model, but if you have high variability in the underlying rate, you can have a problem specifying an individual with a stroke risk.

                                                We have to standardize and improve the quality of bringing people into these cohorts, and of interrogating the cohorts and databases and making sure that we have the same approach to assessing outcomes.

                                                This could probably be best done in very big scientific prospective registry studies, but it's tough to get all that information. There are some registry studies now ongoing, the ORBIT registries, the GARFIELD registries that may help us a lot with specifying stroke risk, but they don't have the biomarkers embedded in them. I'm hopeful that with better message, and large studies, and incorporating biomarkers, that we'll really get down to very accurate and generalizable stroke risk.

                                                I think the CHADs VASc and similar simple stroke risk scores will be in the rear-view mirror.

Dr. Sana Al-Khatib :         That's great. Can I ask one other question, because I completely agree with you looking at your numbers and the data that you presented, is that when you look, especially at the CHADs VASc score 1 patient, the risk seems to be pretty low.

                                                As you very well know, the guideline documents don't really ... At least, for the American AHA/ACC guideline document, they don't really verbalize very definitively the need to anticoagulate patients with a CHADs VASc score of 1.

                                                If you look at the numbers related to a CHADs VASc score of 2, I'm not sure that I completely agree that the risk is very low. Certainly, there was 33% of the studies reported stroke rates of greater than 2% per year. I think maybe different people have different thresholds. While I completely agree with you on the CHADs VASc score of 1 patients, I find that the findings on patients with a CHADs VASc score of 2 a bit more concerning.

                                                In fact, if anything, I would want based even on your data, not on the guidelines to offer anticoagulation to patients with CHADs VASc score of 2. What would you say to that?

Dr. Daniel Singer:             I'm looking at our table that has this, and a lot of the CHADs VASc 2 scores are under 2%, but they're in mid 1%. In the North American cohorts in particular, the rates tend to be lower. That said, I think the heart of the problem here is that we have focused on the threshold for anticoagulation. I think there's an argument to be made that you lay out the risks and benefits to the patients and engage them in a decision, particularly with regards to these lower CHADs VASc scores.

                                                At least you make a lot of, perhaps, even more emphasis on being sure that the higher CHADs VASc scores, that anticoagulation is the net benefits of anticoagulation are made very clear to the patient, and that we don't have large fractions of patients who can take anticoagulants not taking them.

                                                We know from the pinnacle registry and other registries, that even at high CHADs VASc scores, we have 40% plus of atrial fibrillation patients who are not getting anticoagulants. I think that's where we have a lot more assurance that the net benefit is positive and that we can make a different both in terms of a patient in front of us, and in terms of the overall public health aspects of atrial fibrillation and stroke.

Dr. Sana Al-Khatib :         I do believe that this is really important, but it is also important to keep in mind that with the novel novel oral anticoagulants, I think the whole landscape has changed. Not only do patients have different options to consider, but certainly, the risk of bleeding, which is the other part of this equation, has gone down significantly with the novel agents.

                                                I think as we engage in shared decision making with patients, I think it is really important to highlight these really very remarkable features about the agents that have really changed the care of patients with atrial fibrillation.

                                                One thing to add to this whole topic is, really, all the new advances that we're seeing in this field that has been really life-changing for us and for our patients.

Dr. Carolyn Lam:               Indeed Sana. I was about to bring up the bleeding risk part, the flip side of the coin as well. Also, the point that most of my patients with atrial fibrillation, they really strongly value the avoidance of stroke even more than avoidance of bleeding. Someone, that needs to be taken into consideration as well.

                                                Daniel, I'd love to give you the last words. You mentioned that you like to highlight, maybe, some more of the implications of your findings.

Dr. Daniel Singer:             I guess I would say there's a scientific implication, which is what we've ben discussing, which is the importance of trying to get these rates down correctly and accurately, and maybe we have to get people together to say how they're doing these studies.

                                                The second is, for the individual patient, that we should engage them in this discussion. Maybe patients who are perfectly willing to a novel anticoagulant and CHADs VASc score of zero. That would come out of a discussion with the patient. That our emphasis at this point since we're a little unsure about the threshold level, our emphasis both at the individual patient level, and then from the public heath perspective should be on the higher CHADs VASc scores where we know that we can expect a net clinical benefit from the vast majority of patients with AF.

                                                I agree with Dr. Al-Khatib, that the novel anticoagulants post an important advantage in the sense not so much in their overall bleeding, but particularly in terms of their intercranial bleeding, which is the lethal bleeding we most want to avoid.

Dr. Carolyn Lam:               Thank you both for joining us. Thank you listeners for joining us. Don't forget to tune in next week.


Jan 9, 2017

Dr. 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. This episode marks the six month milestone of our run together, a run that has taken us around the world from the United States to Europe, South Africa, and Asia, and one that is shared by listeners all over the world.

                                                On behalf of the editors, and from the bottom of my heart, I want to thank you for your support and request that you please subscribe to our podcast and share it with your friends and colleagues. We commit to bringing you the best of cardiovascular science in the most accurate and digestible way possible, thus suiting the busy cardiologist on the run.

Dr. Lam:                               All right, here are your highlights of this week's issue.

                                                The first paper looks at tissue plasminogen activator, or TPA treatment in ischemic stroke, addressing two aspects that are still unclear. Number one, the degree of additional benefit accrued with treatment in the first 60 minutes after onset of ischemic stroke; and number two, the shape of the time-benefit curve through 4.5 hours. First author, Dr. Kim, corresponding author Dr. Saver and colleagues from UCLA stroke center analyzed more than sixty-five thousand acute ischemic stroke patients treated with intravenous TPA within 4.5 hours of onset from the "Get With the Guidelines" Stroke U.S. National Program.

                                                They found that 878 of these over sixty-five thousand patients were treated within the first 60 minutes after onset, a ten-fold increase over previously available data. Thrombolytic treatment within the first 60 minutes was associated with the highest rates of favorable discharge outcomes. The shape of the time-benefit curve throughout the first 4.5 hours was non-linear for some outcomes. Discharge to home and discharge free of disability decayed more rapidly in the first hundred to a hundred and seventy minutes after onset than later. While independent ambulation at discharge and in-hospital mortality declined in a steady fashion through the time window.

                                                These findings reinforce the importance of quality improvement programs to accelerate door to needle time for thrombolytic therapy in acute ischemic stroke.

Dr. Lam:                               The next study sheds light on mechanisms underlying red blood cell mediated hypoxic vasodilation. A highly conserved response coupling oxygen delivery to metabolic demands of the tissues, and very clinically relevant in states of systemic hypoxemia and impairment in oxygen delivery, such as in patients suffering from cardiovascular, pulmonary, or hemolytic diseases.

                                                In this paper, Dr. Bailey and colleagues from University of British Columbia Okanagan in Canada studied ten healthy participants who were randomly assigned to a normoxic, or 21% oxygen, and hypoxic, or 10% oxygen trial with measurements performed at rest and following 30 minutes of cycling at 70% of maximal power output. Blood was sampled simultaneously from the brachial artery, internal jugular, and femoral veins with plasma and red blood cell nitric oxide metabolites measured. Cerebral and femoral venous blood flow were determined by transcranial doppler ultrasound and constant infusion thermodilution respectively.

                                                The authors found that hypoxia was associated with a mild increase in both cerebral and femoral blood flow, with further more pronounced increases observed in femoral blood flow during exercise. Plasma nitrite gradients reflecting consumption were accompanied by red blood cell iron nitrosyl hemoglobin formation at rest in normoxia, during hypoxia and especially during exercise, with the most pronounced gradients observed across the femoral circulation. In contrast, there were no gradients consistent with S-nitrosohemoglobin consumption.

                                                Collectively, these findings suggest hypoxia, and to a far greater extent exercise, independently promote arteriovenous delivery gradients of intravascular nitric oxide with deoxyhemoglobin mediated nitrite reduction, identified as the dominant mechanism underlying hypoxic vasodilation. This is as opposed to the competing hypothesis of S-nitrosohemoglobin formation.

                                                In summary, by distinguishing between the two competing mechanisms that underpinned endocrine nitric oxide vasoregulation, that is, the S-nitrosohemoglobin hypothesis versus the nitrite reductase hypothesis, these data help us to understand the dynamic interplay that takes place between nitric oxide metabolites as a function of oxygen demand in vivo, and will help to establish the most specific and sensitive prognostic markers of vascular health and therapeutic interventions that optimize tissue oxygenation.

Dr. Lam:                               The next study addresses the controversial issues of thrombus aspiration during percutaneous coronary intervention, or PCI, for the treatment of ST elevation myocardial infarction, or STEMI.

                                                Dr. Jolly and colleagues from Hamilton General Hospital in Ontario, Canada performed an individual patient meta-analysis of three eligible large randomized trials that is the TAPAS, TASTE and TOTAL trials including more than eighteen thousand patients who underwent PCI for STEMI. They found that as a routine strategy thrombus aspiration did not reduce cardiovascular mortality for STEMI patients undergoing primary PCI, and that exploratory analysis of patients with high thrombus burden suggested that thrombus aspiration may improve cardiovascular mortality but at the price of an increased risk of stroke or transient ischemic attack.

                                                In summary, these data suggest that thrombus aspiration should not be used as a routine strategy in patients with STEMI, however in patients with high thrombus burden, further large randomized trials are needed to determine if improved forms of thrombus aspiration can reduce cardiovascular mortality and to determine its safety with regards to stroke.

Dr. Lam:                               The next paper is the first study to look at coronary artery calcium imaging as a tool to personalize systolic blood pressure treatment goals.

                                                Dr. McEvoy and colleagues from Johns Hopkins University School of Medicine in Baltimore, Maryland studied 3,733 participants from the multi-ethnic study of atherosclerosis with systolic blood pressure between 120 to 179 millimeters of mercury. Within subgroups categorized by both systolic blood pressure and estimated ten year atherosclerotic cardiovascular disease risk, they compared multi-variable adjusted hazards ratios for the composite outcome of incident atherosclerotic cardiovascular disease or heart failure after further stratifying by coronary artery calcium.

                                                The authors found that combining coronary artery calcium imaging and assessment of global atherosclerotic cardiovascular disease risk had potential to guide personalized systolic blood pressure goals, particularly among adults with an estimated risk between five to fifteen percent, and pre-hypertension, or mild hypertension.

                                                For example, among those with an atherosclerotic cardiovascular disease risk of less than fifteen percent and who had systolic blood pressure between 140 and 159, those with a coronary artery calcium score up to 100 were at two times the risk, while those with a coronary artery calcium score more than 100 were at 5.7 times the risk of events, all compared to a coronary artery calcium score of zero. Thus, information on coronary artery calcium burden may be considered when making personalized treatment decisions about blood pressure targets, particularly among patients with an estimated cardiovascular risk between five and fifteen percent, and who have either pre-hypertension or mild hypertension.

                                                In summary, information on coronary calcium burden may be considered when making personalized treatment decisions about blood pressure targets, for example, choosing a traditional goal of 140 or a more intensive goal of 120 millimeters of mercury. The authors ended by calling for a precision medicine clinical trial evaluating risk-based blood pressure treatment goals, preferably incorporating coronary artery calcium.

                                                Well, those were your highlights, now for your feature discussion.

Dr. Lam:                               On today's episode we are going to be discussing the very important issue of type-two myocardial infarction, very important yet usually neglected compared to type-one myocardial infarction. As a reminder to our listeners, type-two MIs are the ones where there is myocardial demand-supply mismatch whereas type one is the usual acute coronary artery plaque rupture and thrombosis. To discuss this I am really honored to have two James' on the podcast. The first is Dr. James Januzzi from Massachusetts General Hospital, the second is Dr. James de Lemos, executive editor of Circulation from UT Southwestern.

                                                Welcome to you both.

Dr. Januzzi:                         Thank you very much Carolyn, really great to be speaking with you.

Dr. de Lemos:                    Thanks Carolyn, it's great to be on.

Dr. Lam:                               Dr. Januzzi, could you please let us know what you found in this paper, it's really extraordinary. Just give us a top line of the results.

Dr. Januzzi:                         Basically we set out to examine the question of how frequent type-two myocardial infarction is in a population of patients followed longitudinally after they have taken a trip to the cath lab for one reason or another. Really with the goal to better understand the type-two MI syndrome. It was our hypothesis that type-two MI was perhaps more common than people may have recognized, and that type-two MI would be higher risk in terms of the likelihood for ischemic complications than what people had previously recognized. As you point out, type-two MI is often neglected from a management perspective.

                                                What we found, basically, was among a cohort of patients, 1,250 patients coming through the cath lab at the Massachusetts General Hospital Heart Center, in follow up over a several year follow up period with a maximum of eight years of follow up, with a mean of about 3.4, a median of 3.4 years follow up. Out of the 1,251 patients that we enrolled and followed, 152 actually had an incident type-two myocardial infarction during follow up. Additionally, type-two MI was actually quite recurrent in many patients, and in each of the cases whether individual or in most patients with recurrent type-two MI, the mortality risk was really quite striking. Patients that had a type-two MI, partially because they were more complicated medically speaking, as one might have expected, they were older and had lower blood pressure, more coronary disease, heart failure and other medical comorbidities. The likelihood for a major adverse cardiovascular event was more than doubled in patients that suffered an incident type-two MI, the risk for mortality was actually remarkably almost ten-fold higher with a cardiovascular death rate that was around nine-fold higher, heart failure was tripled.

                                                Really just illustrates the very morbid nature of the type-two myocardial infarction, and illustrates the fact that studies are urgently needed to better understand how we should manage these patients.

Dr. Lam:                               Dr. Januzzi when I manage patients I find this diagnosis of type two-MI to be a very dirty one to make, if you know what I mean. It's hard to really be sure what's happening, and what to attribute rises in troponin to, and so on. Could you tell us a little bit more about how difficult it was to adjudicate the events, and what's the risk of misclassification in your study?

Dr. Januzzi:                         It's a challenge, and that's something that came up during the peer-review process. We really wanted to make sure that we got this right, so in fact we went back and did a cross-sectional re-review of cases to make sure that our adjudication process was accurate. It's not a very straightforward thing to judge, obviously. A rise and/or fall in troponin may be from a type-one myocardial infarction. There's increasing interest in a syndrome of myocardial injury in the absence of a classical myocardial infarction. Then lastly, we recognized that troponin may rise and fall, for example, in patients with heart failure, possibly due to non-coronary mechanisms. You are correct, it may be a challenge to classify these patients solely on the basis of the presence of a rise or fall of troponin.

                                                What we did was classify them utilizing the Universal Definition of MI Task Force criteria, which includes symptoms and signs, as well as a rise and/or fall of troponin, plus evidence for loss of myocardial function on non-invasive testing. We were pretty strict, actually, in terms of how we judged them, and when we went back and re-reviewed ten percent of the cases, we actually found that all of the fifteen cases that we went back and re-reviewed met the criteria that we had articulated in the front end. We feel pretty confident that we got the diagnosis correct, but obviously it's a challenge in every day practices, as you rightfully point out.

Dr. Lam:                               It does certainly sound very rigorous, indeed. Dr. de Lemos, you managed this. He mentioned reviewers giving him a hard time, what was it like managing this paper?

Dr. de Lemos:                    It was fascinating because the Universal Definition that introduced type-two MI into the classification scheme is only a decade old. It's remarkable how little we know about the problem, and how much we struggle in clinical practice. We thought this paper was one of the first and most comprehensive evaluations to put some construct around the problem. As you pointed out, Carolyn, it is a messy diagnosis. Even when you do it in an organized, researched fashion this reflects what we all deal with in clinical practice where it's not so easy to define myocardial infarction even when given the criteria of the Universal Definition. The challenge really is that only a minority of the troponin elevations that are the classic type-one MIs that we know what to do with. The rest of them are either these troponin elevations NOS, type-two MI, or something on a continuum on this spectrum that's really hard to differentiate.

                                                This paper's important because it really highlights that these non-type-one MIs whatever they are, are common and associated with really high risk, and it's sort of a call to arm that we better start to understand and sub-classify these if we're going to be able to reduce risk in this very high risk population. That's really why we were so interested in the paper, and why we worked so closely with Jim and his team to address some of the issues that you just raised.

Dr. Lam:                               I completely agree, in fact it's beginning to remind me of the world of HFpEF when we first started realizing that people with heart failure, even though ejection fraction's normal are definitely not doing well. James Januzzi, if you don't mind, what do you think are the implications for treatment, what are the things that you think need to be examined going forward?

Dr. Januzzi:                         Carolyn I laughed when you mentioned HFpEF because at one of the recent Universal Definition of MI Task Force meetings, I actually said that type-two MI is the HFpEF of the myocardial infarction world. To answer your question, I have approached this question very much the way we do in the heart failure space relative to heart failure with preserved EF. In order to develop a strategy for treatment for type-two MI, we need considerable advances still in our understanding of just what exactly is a type-two MI, what types of patients have type-two MI, and on an individual level, the treatment strategies may follow.

                                                The problem here is if you look just at all comers who suffered a type-two MI in our study, the majority were actually taking statins, they were taking aspirin, they were more likely to be taking beta-blockers. So the patients themselves were actually on the very treatments that we might think about prescribing in those folks that have a type -wo MI, and yet they still suffered the MI, and they had worse outcomes. One might think about coronary disease and revascularization, and indeed one of the nice things about our study is we enrolled patients at the time of coronary angiography, and then followed them subsequently, so we actually had detailed coronary angiograms on every one. Those suffering an incident type-two MI certainly had more coronary disease, so one might argue revascularization might either be protective if done prior to the onset of type-two MI, or at the time of type-two MI a revascularization-driven strategy might be a logical approach.

                                                I think more fundamentally, bringing it back to heart failure and to the HFpEF analogy, I think that in order to better understand treatment we need to better understand just who these patients really are. So much like has been done in the heart failure space we're now doing cluster phenotype analyses where we're looking at the various phenotypes of patients with type-two MI using network analyses, which is one way to approach a problem when you've got a mix of various diseases that fall under the same title. So in those patients with preserved ejection fraction heart failure, there are patients that are younger obese patients, there are the patients with advanced diabetes, et cetera.

                                                Our hypothesis for our present research is to examine this question within the type-two MI diagnosis to see if we can identify specific clusters of phenotypes that might be treated in specific ways. The coronary patients might deserve revascularization, the heart failure patients might deserve a different approach for their care. That, I think, might be the way forward, exactly taking a page from the playbook that you just mentioned with respect to preserved ejection fraction heart failure.

Dr. Lam:                               Wow, how terribly exciting. Congratulations again for this paper, I really think it's a landmark and will open the door to many more important papers. I would like to switch tracks a little bit at the moment. We are coming to six months into the new Circulation editors that have been under the leadership of Joe Hill and James de Lemos, and I'd actually like to start by asking you, Dr. Januzzi, what was it like working with our new Circulation team? Then handing the mic over to Dr. de Lemos to tell us a little bit more about what the journey has been so far in the last six months.

Dr. Januzzi:                         Thanks for asking, it was an absolute pleasure. I trained with Dr. Hill and with Dr. de Lemos in one degree or another during all of our respective residency and/or fellowship training, so I've known these guys for a long long time. I think that the most important aspect in the peer review process is a collaborative and collegial process where the division between author and editor can allow for communication. In this experience with this manuscript, it was a very easy-going and collaborative process where the paper from beginning to end grew in its quality, and ultimately landed in the journal, and the way that it did was, I think, a substantial likelihood for heavy citation. That says a lot about the editors who really help us to bring it to this final product.

Dr. Lam:                               Dr. de Lemos?

Dr. de Lemos:                    We're now six months in to the new Circulation editor team's tenure, and I think all of us are having a blast. I think we've put together this team of diverse international experts that build off each other and thrive off each other, so from the team perspective, we're just having great fun, working hard, learning a great deal. We hope that those of you out there that are listening and reading, and submitting papers, and using our journal for your own research, are noticing the changes that we've made and think we're headed in the right direction. We'd love to hear from you about the things you like, and those things you don't like. We do think we've, in many ways, modestly changed the focus of the journal. There's so many new content categories that are designed to speak to the global burden of cardiovascular disease, the international aspect of cardiovascular research, and new clinically relevant problems, translating basic science so that clinicians can understand it. We hope that clinically active, as well as basic investigators are finding these changes useful in their own daily lives.

Dr. Lam:                               Thank you both so much for spending time with me on Circulation on the Run. Thank you everyone, don't forget to tune in next week.



Dec 27, 2016

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. Caroline Lam, associate editor from The National Heart Center and Duke National University of Singapore. Today we will be discussing the results of an individual level meta-analysis regarding venous thromboembolism and its risk factors, but first, here's your summary of this week's issue.

The first paper provides insights into paracrine signalling pathways that regulate epicardial adipose tissue formation. That is, referring to the adipose tissue located between the epicardium and underlying myocardium that is known to be strongly associated with coronary artery disease. In the current study from Dr. Lira of Icahn School of Medicine at Mount Sinai, New York, Dr. Pu from Boston Children's Hospital, Dr. [Chien 00:00:56] from Karolinska Institute and colleagues, the authors used a novel modified mRNA screening approach to probe the effect of individual paracrine factors on epicardial progenitors in the heart. Using two independent lineage tracing strategies in murine models, they showed that cells originating from the WT1-positive mesothelial lineage, which includes epicardial cells, differentiate into epicardial adipose tissue following myocardial infarction. This differentiation process required WT1 expression and was stimulated by insulin-like growth factor 1 receptor activation. Insulin-like growth factor 1 receptor inhibition significantly reduced its adipogenic differentiation and reduced WT1 lineage cell differentiation into adipocytes following myocardial infarction.

These results thus establish insulin-like growth factor 1 receptor signalling as a key pathway that governs epicardial adipose tissue formation in the context of myocardial injury. And it does this by redirecting the fate of WT1-positive lineage cells. The study also demonstrates the utility of a modified RNA based paracrine library screening to dissect signalling pathways in homeostasis and disease.

The next study brings us closer to understanding the mechanisms underlying diabetes-associated heart failure. In this study by first author, Dr. Wang, corresponding authors, Dr. Abel and Xiang from University of California, Davis and colleagues. High-fat diet feeding was used to induce obesity and diabetes in wild-type mice or mice lacking the beta-2 adrenergic receptor or beta-arrestin 2. High-fat diet feeding was found to selectively increase the expression of phosphodiesterase 4D in the mouse hearts in concert with the reduced phosphokinase A phosphorylation of phospholamban which contributed to systolic and diastolic dysfunction. The expression of phosphodiesterase 4D was also elevated in human hearts with diabetes. The induction of phosphodiesterase 4D expression was mediated by an insulin receptor and substrate as well as by beta-arrestin-2 dependent activation of a beta adrenergic receptor, ERK signalling cascade.

Genetic deletion of beta-2 adrenergic receptor or beta-arrestin-2 or pharmacological inhibition of beta-2 adrenergic receptor with carvedilol or G-protein receptor kinase 2 with paroxetine all significantly attenuated insulin-induced phosphorylation of ERK and phosphodiesterase 4D induction thus preventing diabetes-related systolic dysfunction. Thus, targeting the insulin beta-2 adrenergic receptor pathway may be a novel way to prevent diabetes-associated heart failure.

The next study addresses the gap in care pertaining to implantable cardioverter-defibrillator or ICD use among Medicare patients with low ejection fraction following myocardial infarction. Dr. Pokorny and colleagues from Duke University Medical Center examined rates of post-discharge ejection fraction assessment and ICD implantation among more than 10,280 Medicare-insured patients age 65 years above with an ejection fraction 35% and below during an index myocardial infarction admission in the ACTION Registry Get With the Guidelines. They found that the cumulative incidence of ejection fraction reassessment within one year of myocardial infarction was 66.8%. Within the first year of post-myocardial infarction, 11% of patients who had an ejection fraction reassessment underwent ICD implantation which was significantly higher than patients without an ejection fraction reassessment. After multivariable adjustment, ejection fraction reassessment remained significantly associated with a higher likelihood of ICD implantation within one year in both revascularized and non-revascularized patients. Based on these findings, the authors recommend that all patients who are potential candidates for ICD therapy be scheduled for follow-up outpatient ejection fraction assessment prior to hospital discharge to bridge these currently observed gaps in care.

The next study is the first multi-institutional study in Asia describing current treatment strategies for total anomalous pulmonary venous connection. This retrospective study of 768 patients with total anomalous pulmonary venous connection operated on between 2005 and 2014 is from first authors Dr. Shi, Zhu, and Chen, corresponding authors, Dr. Chen and Zhuang and colleagues from the Shanghai Children's Medical Center and Guangdong General Hospital in China. While most patients underwent conventional repair, a sutureless patient was technique was employed in 10% of patients. Over a median follow-up of 23 months, there were 38 intraoperative deaths and 13 late deaths. A younger age at the time of repair, next an infracardiac total anomalous venous connections, pre-operative pulmonary venous obstruction, prolonged cardiopulmonary bypass time and longer duration of ventilation were all factors associated with increased mortality. Among these 717 survivors, recurrent pulmonary venous obstruction was found in 15% or 111 patients. Risk factors for recurrent pulmonary venous obstruction included pre-operative pulmonary venous obstruction, infracardiac total anomalous pulmonary connection, mixed venous connections and prolonged cardiopulmonary bypass time, a sutureless technique was associated with a lower restenosis rate compared to conventional repair in patients with pre-operative pulmonary venous obstruction but not in newborn patients. Thus, this study provides an important data on the outcomes following surgical correction and risk factors for poor prognosis in total anomalous pulmonary venous connection in Asia.

The final study is the first systematic review and meta-analysis on the association of genetic polymorphisms and outcome of clopidogrel-treated patients with ischemic stroke or transient ischemic attacks. In this paper from first author, Dr. Pan, corresponding author, Dr. Wang and colleagues from Beijing Tiantan Hospital, Capital Medical University in Beijing, China. Authors looked at 15 studies of 4,762 patients with stroke or transient ischemic attack treated with clopidogrel and this included 3 studies from Europe and 12 studies from East Asia. They found that carriers of the CYP2C19 loss-of-function alleles were at increased risk of stroke compared to noncarriers. Composite vascular events were also more frequent in carriers compared to noncarriers while bleeding rates were similar. There was no evidence of statistical heterogeneity among the included studies for stroke but there was for composite vascular events suggesting that publication bias cannot be ruled out. Genetic variance other than CYP2C19 were not associated with clinical outcomes. The author suggested that their findings may justify genetic testing when clopidogrel is otherwise considered the preferred treatment modality, especially in East Asian patient populations in whom the prevalence of CYP2C19 loss-of-function allele is high.

In an accompanying editorial, Dr. Simon and [inaudible 00:10:11] suggest it maybe time to consider a prospective trial of personalized medicine using CYP2C19 genotyping in acute ischemic stroke and perhaps considering alternative medications in poor or intermediate metabolizers such as in the popular ongoing genetics trial in STEMI patients undergoing PCI. That wraps it up for the summaries this week. Now for our feature discussion.

Today's feature paper talks about the association of traditional cardiovascular risk factors with venous thromboembolism. And it is the first individual level meta-analysis of prospective studies. I am so delighted to have the first and corresponding author here with us, Dr. Bhaktawar Khan Mahmoodie from San Antonio's Hospital in the Netherlands. Hi Khan, thanks for being here.

Dr. Bhaktawar Khan Mahmoodie:            

Thank you for inviting me. Thanks a lot.

Dr. Carolyn Lam:              

And I am particularly delighted to have associate editor, Dr. Josh Beckman from Vanderbilt University joining us today as well. Welcome Josh.

Dr. Josh Beckman:          

Caroline, it is such a pleasure to be here with you. I've been listening to these podcasts and they have been incredible. I've been waiting to be able to jump in and today's paper is an awesome place to start.

Dr. Carolyn Lam:              

It certainly is. Congratulations on managing such an important paper. Khan, maybe I could start with you. Venous thromboembolism versus arterial thromboembolism. We're very familiar with the latter. We know it comprises coronary heart disease, stroke, peripheral artery disease. We're very familiar with the risk factors such as hypertension, hyperlipidemia, diabetes, smoking. But here you're asking, are these same risk factors applicable in venous thromboembolism. That would include deep venous thrombosis, pulmonary embolism, where we traditionally classify it into provoked events that is triggered by things we know well like immobilization, surgery and so on. And then there are the unprovoked events that don't have any risk factors. So could you, first of all, point out ... you were looking at venous thromboembolism. What was your hypothesis with regards to the traditional cardiovascular risk factors?

Dr. Bhaktawar Khan Mahmoodie:            

Many researchers in the last 10, 15 years, they go questions whether there is connection between venous and arterial thromboembolism. Since then, several studies published on that with controversial results. So our hypothesis for this paper was to see whether there is real associations or are we looking at some kind of associations due to confounding factors such as age and overweight which are risk factors for both.

Dr. Carolyn Lam:              

Yeah. And yours is actually the first individual level meta-analyses of prospective studies dealing with this. Tell us what you found in ... Were you surprised by your findings?

Dr. Bhaktawar Khan Mahmoodie:            

What we found that actually traditional, modifiable, cardiovascular risk factors like hypertension, diabetes and hyperlipidemia were not risk factors for venous thromboembolism. The exception was smoking, current smoking, which was particularly associated with provoked venous thromboembolism which is probably pro its association with cancer. And cancer itself is a strong risk factor for venous thromboembolism. About whether I was surprised, I was not surprised at all. We saw in several cohort studies and well-defined cohort studies that the association disappeared after adjustment for age and body mass index which are important confounders in these [inaudible 00:14:06]. That's what I expected and we found it and it is confirmed with this large individual level meta-analysis.

Dr. Carolyn Lam:              

Great. But what did you think of the association of higher systolic blood pressure not with higher but with lower risk of venous thromboembolism?

Dr. Bhaktawar Khan Mahmoodie:            

That was a bit surprising for us too but I think the best explanation we can give at the moment is probably that we have some kind of competing risk. And one suggestion that we gave in the paper as well is that maybe what we already know is that higher blood pressure is a strong risk factor for atrial fibrillation. Most of these people they receive oral anticoagulants. That is subsequently probably a protective factor for venous thromboembolism. We probably deal with some kind of competing risk from another condition like the atrial fibrillation and use of anticoagulants which we could not unfortunately adjust for in this analysis.

Dr. Carolyn Lam:              

Sure. That makes sense. Josh, can I bring you into this? I mean I remember well our multiple and long discussions at the editors meetings. This is one of those papers that is extremely important for its negative, neutral associations isn't it?

Dr. Josh Beckman:          

I think this is one of the more important papers in this field in a long time. I am one of those people who has followed this literature and believed, based on the best previous publications, that there was a link between many of the arterial thrombosis or atherothrombotic risk factors and venous thromboembolism. In fact, Circulation published one of these meta-analyses, and I'm going to say only because this little paper is so large with only 21,000 patients demonstrating a clear association. So the first question I would have, we published that back at 2008, the first question I would have is can you describe for the general readership what such a large series of patients allows you to do that was not permitted by the other meta-analyses of say twenty to thirty thousand patients that have been previously in the literature.

Dr. Bhaktawar Khan Mahmoodie:            

Thank you Dr. Beckman and thank you also for managing this paper. This is an important question and I think what we were able to do compared to the previous analysis in 2008, we were able to adjust for confounding risk factors. In the course, we included were all with validated venous thromboembolism events and also the events are temporal character, like all the risk factors were measured and then followed-up for event. While in that paper, there were many case-controlled studies added and the results were not adjusted for age and also not adjusted for body mass index. And if we do the same with what's done there, then we have the same results like in our [inaudible 00:17:14] associations, all of these risk factors were indeed positively associated with risk for venous thromboembolism.

Dr. Carolyn Lam:              

Let me just state, I mean, there were almost 245,000 participants in your study. With 4,910 thromboembolism events, so this is really huge and gives you a lot of power to look at this thing very carefully.

Dr. Josh Beckman:          

It was a 10-fold increase from any of the major publications in this area. It was almost geometrically larger in size which is why, I think its conclusion will be accepted differently than all the previous analyses. Now, let me ask one question about what you already identified in your discussion as a possible limitation. Is this study applicable to all populations around the globe or do you think it is a bit more focused?

Dr. Bhaktawar Khan Mahmoodie:            

I think it is focused at least. We don't have Asian population in these analyses and also the proportion of African-Americans were limited which was only limited to some U.S. cohorts so I think that there is a limitation which is results are probably only applicable for Caucasian population.

Dr. Josh Beckman:          

I guess my other question is, one of the reasons that people, I think, advance the argument that there may be overlap between the two kinds thrombosis is that there was evidence that the medication, statin, may ... to a much smaller degree, reduce venous thrombosis as well as reducing arterial thrombosis. Do you think that this is evidence of some common pathophysiology? Or is it like smoking, it's truly working separately from arterial disease?

Dr. Bhaktawar Khan Mahmoodie:            

Personally, I think that this association or the finding of statins reduce the risk of thromboembolism could be due to some pleiotropic effects of statins. Like even for stroke, we know that the association of cholesterol with stroke is not so clear-cut as it is with myocardial infarction but still it reduces risk of stroke. And also for venous thromboembolism, the risk reduction of venous thrombosis in the JUPITER trial was like 50%, which is very high, even better than aspirin. But I think that may not be directly related cholesterol levels but more to another pleiotropic effects of statins. It could influence levels of various coagulation [inaudible 00:19:56] in the endothelial stabilization which may be also important risk factors for venous thrombosis.

Dr. Josh Beckman:          

One of the reasons that this paper is very important is that we begin to look for therapies and risk factors based on what the disease is caused by. And so the fact that you guys were able to establish, in my opinion, quite clearly what does and what does not contribute to venous thrombosis allows us to begin to think about the disease differently and approach it differently. I would like to provide congratulations. My one little ask of you is that one of the things that I think this podcast is great for is to explain to the readership what goes into this kind of work. Everybody thinks that someone else's research is easier to do than their own, which of course is a ridiculous thing. But can you describe for us what it's like and how long it took from the study initiation to when you completed it? How much work went into trying to get all these studies together to create this individual patient level data?

Dr. Bhaktawar Khan Mahmoodie:            

Yeah. That was a great amount of work. Actually, I did a systematic review of the only PubMed publications back in 2014 and it took almost 2 years at least. I was not always active the whole 2 years but still I had to visit several PIs of the studies to get them so far to share their data. Eventually, I had to develop a code that will make it possible without sharing the individual level data by using the same definitions and the same categorization of variables so we call it a two-stage meta-analysis similar to one-stage if the definitions are similar. And eventually, I think that the real part of the analysis and inclusion of studies took like half a year or so. There was a lot of work.

Dr. Josh Beckman:          

I think this is a tremendous amount of work and for those members of our readership who do basic research, or translational work, or practice in the clinics, it really needs to be made clear that this is a heroic effort of hundreds and hundreds of hours. And that getting together all of these studies is just an enormous undertaking. And that even though, we can read the paper in 10 minutes and gleam the most important part. It is an incredible amount of work for which you guys are to be congratulated.

Dr. Bhaktawar Khan Mahmoodie:            

Thank you for acknowledging this. Thanks a lot.

Dr. Carolyn Lam:              

Josh, I couldn't agree with you more and I truly couldn't have said it any better. Thank you both of you for making this just one of the best discussions we've had on this podcast. I'm sure the listeners all agree what a wonderful time we've had.

You've been listening to Circulation on the Run. Please remember to tune in next week.


Dec 19, 2016

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. We have such a special issue today. You see, it's entirely focused on resuscitation and I am delighted to have with me today, Associate Editor, Dr. Mark Lane from Puffs Medical Center, who really put this issue together. Welcome, Mark.

Dr. Mark Lane:                  Thank you Carolyn.

Dr. Carolyn Lam:               Mark, maybe you could start by telling us why the focus on resuscitation? I do believe this is the first time we've done this at Circulation.

Dr. Mark Lane:                  Yes, this is the first time we've done this at Circulation. It really was a confluence of a couple things coming together. Once is that over the spring and summer, we had a very high volume of high quality resuscitation papers come to Circ. This was not something that we actually asked for but we noted that there were a number of these. Also, it's an important time in resuscitation because a number of the resuscitation counsels across the world have called for improvements in the survival rate, noting that we already have the tools that we need to increase survival and we have to better apply these tools. The HA has provided a goal of doubling resuscitation and resuscitation counsels in Europe, New Zealand and Australia have also echoed that call.

Dr. Carolyn Lam:               That's great, so this is a really important issue. I just echo your words about their being a remarkable number of original papers. We have seven and they're just such high quality. Let's chat through them, shall we? I'm going to go by pre-hospital setting to the out of hospital setting and finally end up in the in-hospital setting. Shall we do that?

Dr. Mark Lane:                  That sounds great.

Dr. Carolyn Lam:               The first paper is really about identifying patients at risk for pre-hospital sudden cardiac death at the early phase of myocardial infarction. You want to tell us a bit about that one?

Dr. Mark Lane:                  This is a study coming from the emergency medical services in the greater Paris area, where they looked at their cardiac arrest and STEMIs over the last seven or eight years. What they were specifically looking at is, can you identify STEMI patients who are at risk for having a cardiac arrest, because if you could identify those patients, you'd want to get there very quickly because if you know they're going to arrest or they're going to have a cardiac arrest, then having a defibrillator there would be very important.

                                                What they found, is that you can actually identify STEMI patients who are higher likelihood of arrest and those STEMI patients are those with younger age, they're not obese, they don't have diabetes. They have shortness of breath in addition to their chest pain and they have a very short delay from the time of chest pain to their call EMS. That is they're very concerned about their chest pain. You could use these characteristics to predict which STEMI patients, which chest pain patients were at highly likelihood of having a cardiac arrest. There was as much as a 19-fold difference between individuals without any of these factors and individuals with several of these factors.

Dr. Carolyn Lam:               What I like about this, is that simplicity of that score. Age, symptoms and kind of the absence of diabetes, absence of obesity and that short time frame. It's something that could be asked on a routine questionnaire by EMS dispatchers, for example.

Dr. Mark Lane:                  Right. It highlights the importance of the dispatch system. That simple questions, you can really stratify risk and it's not just getting an ambulance out there. Truly stratifying risk in order to get there quicker.

Dr. Carolyn Lam:               There are two papers that deal with out of hospital cardiac arrest. One of them interestingly focusing on the neuro-protective effects of Glucagon-Like Peptide-1 analog Exenatide. Thoughts about that one?

Dr. Mark Lane:                  This is a randomized study from Denmark. Notable that there are very low number of randomized trials in resuscitation so the fact that they did this is remarkable. What they did, is this glucagon-like peptide analog is a type II diabetic medicine and there is some reason to believe that that may protect the brain after resuscitation and ROSP. They had two goals in this trial. One was to see if it was feasible to administer a drug within six hours of a cardiac arrest and the other was to get any sort of outcome measure of whether this could provide some benefit. They randomly assigned 120 comatose patients and half of them got the peptide analog and the other half did not. What they showed, it is feasible to give IV administration of a drug within six hours of a cardiac arrest. Unfortunately, the drug they used did not appear to have any clinical benefit and this was both a composite end-point of death in neurologic function but also an evaluation of a brain neuron specific amylase, which was actually brain damage so they didn't see any biological or clinical neuro-protective effects of this drug.

Dr. Carolyn Lam:               I didn't realize it until you said it, it is very difficult to do a randomized control trial. This is very significant just for that. The next study about the out of hospital arrest, really talks about bystander CPR and I think seeks to answer to what degree bystander CPR remains positively associated with survival with increasing time to potential defibrillation. Important question, what do you think of that?

Dr. Mark Lane:                  It's an important question that surprisingly has not been evaluated that closely. Most either studies either look at bystander CPR or EMS arrival times but don't look at the interaction between the two. This study looks at the interaction between bystander CPR and EMS response time and that's the critical thing in this paper that's very interesting.

                                                What they did is, they split bystander CPR with or without and then EMS response times five minutes, 10 minutes and longer. If EMS responds within five minutes and you had bystander CPR, the survival rates with good neurological outcome were 14.5%, which is really a remarkable number. If there was no bystander CPR and the EMS arrived within five minutes, it dropped to 6.3%. There was 2.3-fold higher likelihood of good neurologic survival with bystander CPR with EMS within five minutes.

                                                They also looked at the 10 minute response time of EMS and if you had bystander CPR and EMS arrived within 10 minutes, the survival rate was 6.7% and without bystander CPR, it was 2.2%. With bystander CPR and EMS arrival within 10 minutes, there was a three-fold higher likelihood of survival with bystander CPR. It's interesting that by 13 minutes, there really was essentially no difference in those individuals who had bystander CPR or not, suggesting that at that point it's taken so long for EMS to arrive, it really doesn't make really much difference between whether you have bystander CPR.

                                                A really important paper showing that bystander CPR is critical, but so is EMS arrival within five minutes especially, but even 10 minutes.

Dr. Carolyn Lam:               I like that paper and I really like the way you crystallized the findings so clearly like that. What I'm also liking is the way, even though these papers weren't invited or anything, there is this nice flow because from bystander CPR we now talk about duration of resuscitation. There's one regarding adults and followed by one in pediatric population so very nice set of papers. Could we start by maybe talking about the adult one? The one looking at the association between duration of resuscitation and favorable outcomes after out of hospital cardiac arrest from North America.

Dr. Mark Lane:                  The reason that these two papers are important is really the futility issue. When is it futile to continue a CPR and that's a very important question. This adult paper is from the ROC Consortium. The ROC is a North American Seer NIH Sponsored consortium that's been going on over the last 10 or so years. What they looked at was outpatients and they had a very large number of greater than 11,000 subjects and of those 8% survived with a good outcome. That's 8% of those 11,000. If you looked at those 8% that survived, 90% of those had return of spontaneous circulation with 20 minutes. You really wanted to get their blood pressure back within 20 minutes.

                                                If you went beyond 20 minutes to the return of spontaneous circulation, you still could get good outcome. It was less likely but it was more likely if you had initial shockable rhythm, you had a witnessed cardiac arrest or you had bystander CPR. If you had some of those features, then you would argue to continue CPR for a longer time period. Actually a very nice important paper that if you had those other three features, you could still get good neurologic functioning, even with resuscitation attempts up to 40 minutes.

Dr. Carolyn Lam:               Exactly. I thought I saw 47 minutes somewhere, but it gives us a bit of a guidance when we're making these really tough decisions and talking about tough decisions and futility, I think it's even more amplified in the pediatric population, isn't it? This next paper from Japan talks about the duration of pre-hospital CPR in the pediatric population. What are your thoughts on that one?

Dr. Mark Lane:                  This was a study from Japan, using their nation-wide Japanese data base. Actually, in many ways mirrored the adult experience. The number of patients analyzed with roughly the same. This was nearly 13,000. They looked at 30 day survival both overall and 30 day survival with good neurologic function and 30 day survival overall were 9% so similar to the 8% in adults and good neurologic function were 2.5%, which wasn't quite as good as in the adults and that the duration of CPR also was very important. Once CPR went out to 42 minutes there was less than 1% chance that that individual was going to survive with any significant neurologic outcome. If you had bystander CPR you could increase that time by four to five minutes but again showing very similar numbers to the adult population that once you start hitting that 40 to 45 minute time frame, if there's no return of spontaneous circulation then the odds of survival are really quite low.

                                                The time frame may be extended a bit by CPR, maybe be extended by a bit if you had a shockable rhythm. Again, very similar features to what were found in the adult study.

Dr. Carolyn Lam:               What a nice pair of papers. You know, the pediatric paper was paired by yet another, wasn't it? This one now addresses very importantly conventional versus compression only CPR in the pediatric population. Again, from Japan. I know both the pediatric papers were of great interest because you invited an editorial on this as well. You want to comment on those?

Dr. Mark Lane:                  This issue of compression only CPR versus standard CPR, which includes compression and ventilation is a very hot one because we know that if you can do compression only CPR, the individuals willing to do that type of CPR are much greater than the individuals willing to do mouth to mouth. In the adult population, there's been a number of very good retrospective registries and also randomized trials that showed that compression only CPR may be very similar ... In fact some studies better, some studies a little worse than compression-ventilation CPR.

                                                Whether this applies to the pediatric population is not clear. There is more asphyxial arrest in the pediatric population whereas in the adult it's more cardiac so there is concern that compression only CPR will not be as good in children. This group of investigators used the same registry. A little shorter time-frame. They looked at it for two years and thus only had 2,000 patients in this registry. Of these 2,000 patients 400 received conventional CPR, 700 received compression only CPR and 1,000 did not receive any CPR. The important findings in this study was that any CPR increases survival so if you did not get any CPR, your survival was 3.7%. If you got conventional CPR your survival was 25.9% and if you got compression only CPR your survival was 9.3%.

                                                When you compared unadjusted survival with compression only versus the standard CPR, the odds ratio were 3.42 that standard CPR was better than compression only CPR. However when you did multi-variable adjustment, that big difference decreased and was no longer statistically significant between conventional CPR and compression only CPR. The same was true when you did propensity score matching which is an attempt to randomize to match groups. There was really no difference between conventional CPR and and compression only CPR.

                                                From this study, it's clear that any CPR is better than no CPR. There was a hint here that standard CPR was better than compression only CPR but because that improvement disappeared with multi-variable adjustment and propensity score matching both the authors and the editorialists have called that it's time for a randomized trial of compression CPR in kids.

Dr. Carolyn Lam:               Very nice. That brings us already, to the last original paper. Into the in-hospital setting and it talks about time to epinephrine. That's nice. We've got time to balloon and time to door and and now we've got time to epinephrine. Tell us about this one.

Dr. Mark Lane:                  This was a very nice study from the guidelines database. This is a data base that the HA is using to evaluate resuscitation in hospitals. In this database, the investigators looked at times to the epinephrine administration and then overall patient survival for the hospitals. What they found is that there was wide variability in the time to first epinephrine dose. The HA and other counsels have recommended that it be given as soon as possible or early-on in resuscitation and in this database 12.7% of patients had delays greater than five minutes to epinephrine.

                                                What importantly they showed, when you looked at the hospital's overall time to epinephrine administration and the hospital's overall resuscitation survival rates, they were inversely proportional. That is, the longer that hospitals took to give the first dose of epinephrine, the lower their survival rate. This really leads to a very important question, is it the delay in epinephrine administration that makes the difference between these good functioning hospitals and poor functioning hospitals, or is it that the delay to epinephrine administration is really a surrogate for poor CPR performance. I suspect that both of them could be true, although I suspect the second one is probably a higher likelihood.

Dr. Carolyn Lam:               Congratulations again on this amazing issue with extremely important take-home messages just from the original papers. Were there other papers you wanted to highlight in this issue?

Dr. Mark Lane:                  Yeah, there were three research letters and this is a newer type thing for SERP. These are original manuscripts but in a very succinct fashion in that they're making a single point. I actually thought these three research papers were very interesting also. One was on the mechanical CPR in the cares database and in this paper they actually showed that mechanical CPR was associated with poor outcomes in resuscitation so a paper well worth reading. In another paper from France looked at pulmonary embolism related to sudden cardiac death and what they found is that PEs were present in a significant percentage of people who had sudden cardiac arrest and again if you had a non-shockable rhythm, female, prior thromboembolism or absence of heart disease you were more likely to have a pulmonary embolism.

                                                The final research letter looked at ticagrelor versus clopidogrel in comatose patients undergoing PCI, a randomized study. Succinct paper well worth reading. In addition to those three research letters, there were four frames of reference. These are more a personal perspective on resuscitation and resuscitation signs over time and interesting reading, all four of them.

Dr. Carolyn Lam:               Mark, that was a beautiful summary and I am sure you've whet the appetites of all the listeners to just grab hold of this issue. Thank you so much for joining me today. Thank you listeners for tuning in and don't forget to tune in next week.

Dec 12, 2016

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. Today we will be discussing the pooled analysis results of the 10 ODYSSEY Trials with important implications for the reduction of lipids in major cardiovascular events. But first, here's your summary of this week's journal.

The first paper provides experimental data on vascular disease that brings into focus the critical roles of transcription factors such as GATA2 in the maintenance of endothelial cell function, as well as the role of selected microRNAs as a novel player of vascular regulation. In this study by first author Dr. Hartman, corresponding author Dr. Thum from Hanover Medical School, and colleagues, authors used GATA2 gain and loss of function experiments in human umbilical vein endothelial cells to identify a key role of GATA2 as a master regulator of multiple endothelial functions, and this via microRNA-dependent mechanisms.

Global microRNA screening identified several GATA2-regulated microRNAs, including miR-126 and miR-221. GATA2 deficiency led to vascular abnormalities, whereas supplementation with miR-126 normalized vascular function. In a mouse model of carotid injury, GATA2 was reduced and systemic supplementation of miR-126-coupled nanoparticles enhanced miR-126 availability in the carotid artery and improved reendothelialization of injured carotid arteries in vivo.

In summary, GATA2-mediated regulation of miR-126 and miR-221 has an important impact on endothelial biology. Thus, modulation of GATA2 and its targets miR-126 and miR-221 represents a promising therapeutic strategy for the treatment of vascular diseases.

The next study is the first to show that current smokers from the general population have lower levels of circulating cardiac troponin I, a seemingly paradoxical observation given the known detrimental cardiovascular impact of cigarette smoking.

First author Dr. Lyngbakken, corresponding author Dr. Omland, and colleagues from the University of Oslo used data from the large population-based HUNT study, in which cardiac troponin I was measured in 3,824 never smokers, 2,341 former smokers, and 2,550 current smokers. Current smokers had significantly lower levels of cardiac troponin I than never smokers and former smokers, an association that remains significant even after adjustment for potential confounders.

The authors also found an association between increasing concentrations of troponin I and clinical endpoints, namely acute myocardial infarction, heart failure, and cardiovascular death in the total cohort. However, this association was attenuated in current smokers and was significantly weaker than in never or former smokers with a p for interaction of 0.003. The prognostic accuracy of troponin I as assessed by C-statistics was lower in current smokers than in never smokers. Troponin I provided no incremental prognostic information to the Framingham Cardiovascular Disease risk score in the current smokers.

Together, these results suggest that mechanistic pathways other than those involving subclinical myocardial injury may be responsible for the cardiovascular risk associated with current smoking. Future studies are needed to determine whether a lower cardiac troponin I threshold should be considered for exclusion of myocardial infarction in smokers or whether prognostic tools other than measurement of cardiac troponins should be utilized when evaluating risk of future events in current smokers.

The next study contributes to our understanding of cardiomyocyte signaling in response to ischemic injury. In the study by first author Dr. [Wool 00:05:04], corresponding author Dr. [Ju 00:05:04] from Tongji University School of Medicine in Shanghai, and colleagues, authors sought to understand the role of low-density lipoprotein receptor-related proteins 5 and 6 as well as beta-catenin signaling in the heart. They did this using conditional cardiomyocyte-specific knockout mice who had surgically induced myocardial infarction. They found that deletion of lipoprotein receptor-related proteins 5 and 6 promoted cardiac ischemic insults. Conversely, deficiency of beta-catenin, a downstream target, was beneficial in ischemic injury. Interestingly, although both insulin-like growth factor-binding protein 4 and Dickkopf-related protein 1 are secreted beta-catenin pathway inhibitors, the former protected the ischemic heart by inhibiting beta-catenin, whereas the latter enhanced the injury response mainly through inducing lipoprotein-related protein 5 and 6 endocytosis and degradation.

These findings really add to our understanding of the beta-catenin signaling pathway in ischemic injury and suggests that new therapeutic strategies in ischemic heart disease may involve fine-tuning these signaling pathways.

The next paper from the International Consortium of Vascular Registries is the first study allowing an assessment of variations in repair of abdominal aortic aneurysms in 11 countries over 3 continents represented by the Society of Vascular Surgery and European Society for Vascular Surgery. Dr. Beck from University of Alabama-Birmingham School of Medicine, and colleagues, looked at registry data for open and endovascular abdominal aortic aneurysm repair during 2010 to 2013, collected from 11 countries. These were Australia, Denmark, Hungary, Iceland, New Zealand, Norway, Sweden, Finland, Switzerland, Germany, and the United States.

Among more than 51,000 patients, utilization of endovascular aortic repair for intact aneurysms varied from 28% in Hungary to 79% in the United States, and for ruptured aneurysms from 5% in Denmark to 52% in the United States. In addition to the between-country variations, significant variations were present between centers within each country in terms of endovascular aortic repair use and rate of small aneurysm repair. Countries that more frequently treated small aneurysms tended to use the endovascular approach more frequently. Octogenarians made up 23% of all patients, with a range of 12% in Hungary to 29% in Australia. In countries with a fee for service reimbursement systems, such as Australia, Germany, Switzerland, and the United States, the proportion of small aneurysms and octogenarians undergoing intact aneurysm repair was higher compared to countries with a population-based reimbursement model.

In general, center-level variation within countries in the management of aneurysms was as important as variation between counties. Hence, this study shows that despite homogeneous guidelines from professional societies, there is significant variation in the management of abdominal aortic aneurysms, most notably for intact aneurysm diameter at repair, utilization of endovascular approaches, and the treatment of elderly patients. These findings suggest that there is an opportunity for further international harmonization of treatment algorithms for abdominal aortic aneurysms. This is discussed in an accompanying editorial entitled, Vascular Surgeons Leading the Way in Global Quality Improvement, by Dr. Fairman.

The final paper from Dr. Gibson at Beth Israel Deaconess Medical Center and Harvard Medical School and colleagues, presents the results of the apoAI event reducing in ischemic syndromes I, or AEGIS-I, trial, which was a multicenter, randomized, doubleblind, placebo-controlled dose-ranging phase 2b trial of CSL112, which is an infusible, plasma-derived apoAI that has been studied in normal subjects and those with stable coronary artery disease, but now studied in the current study in patients with acute myocardial infarction.

The trial showed that among patients with acute myocardial infarction, four weekly infusions of a reconstituted, infusible, human apoAI, CSL112, was associated with a dose-dependent elevation of circulating apoAI and cholesterol efflux capacity without adverse hepatic or renal outcomes. The potential benefit of CSL112 to reduce major adverse cardiovascular events will need to be assessed in an adequately powered phase 3 trial.

Now for our future discussion. Today I am delighted to have with us Dr. Kausik Ray from Imperial College London, who's the first and corresponding author of a new paper regarding the pooled analysis of the 10 ODYSSEY Trials. To discuss it with us is Dr. Carol Watson, associate editor from UCLA. Kausik, just let me start by congratulating you on this paper. I believe this is the first data that allows us to look under the 50 mg/dL mark of LDL and really ask if the LDL MACE relationship extends below this level.

Dr. Kausik Ray: Yes, the reason for looking at this is that the IMPROVE-IT trial really looked at people down to an average LDL cholesterol of about 54, and with the new PCSK9 inhibitors, which instead of giving you a 20% further reduction LDL, they give you the opportunity for a further 50 to 60% reduction. We actually get the chance to get people down to levels like 25 mg/dL, and the question is, does the benefit continue at that level?

We did a pooled analysis of 10 of the ODYSSEY Trials, really in some ways to try and help predict what you might see in ODYSSEY outcomes, what you might see in the [Fuliay 00:12:00] trial, and to also manage expectations as well, because there's probably been a lot of hype around the two New England Journal papers about 50, 60% reductions of all potential reductions based on small numbers of events. So the question is, if you reduce LDL by 39 mg/dL, how might that reduce your risk, and is the relationship continuous? So those were the aims.

Dr. Carolyn Lam: That's great, and maybe could you give us an idea of the number of patients you are looking at and the number of events?

Dr. Kausik Ray: Yeah. In the 10 pool studies, we had just under 5,000 individuals, and we had just about 6,700 person years' worth of followup. In total, we had 104 first MACE events. To put this into context, it's about one third of the number of events that the first [framing 00:12:53] of analysis had. It's an observation analysis rather than randomized trial data, so you got to bear that in mind with the usual caveats that go with observational data. But the same endpoints that were adjudicated, this is [inaudible 00:13:10] heart disease death, non-fatal MI, ischemic stroke, and unstable angina requiring hospitalization. This is the same endpoint that is in the ODYSSEY Outcomes Trial, so it's interesting in that regard.

Dr. Carolyn Lam: Yeah, it sure is. So what's the bottom line? What did you find?

Dr. Kausik Ray: What we found was that there was a continuous relationship all the way down to LDL cholesterol levels of about 25 mg/dL, that every 39 mg/dL lower on treatment LDL, your risk went down by about 24%. If you looked at [apo-like 00:13:48] approaching be on non-HDL cholesterol, again, you found the same continuous relationship with a similar point estimate for a similar standardized difference in LDL cholesterol. We also looked at many of the guidelines, talk about percentage reduction. We actually looked at percentage reductions. If you start with a baseline LDL of X and you achieve a 50% further reduction in LDL, how much further benefit does that give you? A 50% further reduction gave you a 29% further lower risk of MACE. So we didn't find any threshold or limit all the way down to LDLs of about 25.

Dr. Carolyn Lam: That's really a key, novel finding that you contributed, so congratulations once again. I suppose the question will always be, you're talking about relative risk reductions here. At such low levels, can you give us an idea of the absolute risk reductions?

Dr. Kausik Ray: Yes. You've got to remember that the relative risk reductions are what you can apply to population differences. If you pick a high-risk patient population, you would expect to see a much bigger absolute risk reduction than maybe this study or another study. Similarly, if you pick a low-risk group, you are going to see a much smaller absolute benefit. I always try to advise a little bit of caution that if you basically look at the range ... If you start with let's say an LDL of 150 and you go down to let's say an LDL of 25, you are talking about a 1.25% absolute risk reduction. Remember, these patients are possibly going to be a slightly lower risk than the ones that are recruited into the ODYSSEY Outcomes and into the [Fuliay 00:15:46] trial, for example.

Dr. Carolyn Lam: I think you mentioned what I was going to just ask you about. This is observational. You had 104 events, and I suppose another limitation might be that your followup was two years at max, if I'm not wrong? What do you say about that, and are there plans for future analyses?

Dr. Kausik Ray: Within the context of these studies, I think that the whole of this data will eventually become dwarfed by what we see with the big CDOTs, because you've got 18, 27,000 people, 3 years' worth of exposure and followups, so you are going to have many, many more events. That is a limitation, but I think what is interesting is that we know that the baseline LDL cholesterol level is around about 90 mg/dL. We don't actually know what the actual baseline ... because the baseline [characters 00:16:43] haven't been published for ODYSSEY Outcomes, but the [Fuliays 00:16:46] around about 89. What it tells you is what the point estimate is likely to be. It's likely to be in the 24 to 32% ballpark because that's what your baseline LDL is and that's what we'd predict in the regression lines that we observed here.

I think that we're not going to get many more events in these studies because largely the randomized period of followup is now over. Many of these people are now into open labels, extensions for safety, so we won't get many more events from this. In terms of, I think, the way people should maybe look at this is possibly as a taster for what's to come in the next 18 months or so. I think for the time being it answers two questions. Is lower likely to be better? And it is. I think the other question it tells is how might you get people down to LDLs below 50?

One of the important things was that if you were just on statins, in this population, if you were recruited on the basis of a high baseline LDL, you got no additional people down to LDLs below 50. You got under 10% with add-on [inaudible 00:18:05], but you got around about 50% when you used the PCSK9 inhibitor as an add-on to existing therapy. It tells you about how to get to such low levels as well. I think that's the other key thing that it actually gives you.

We did an analysis of safety [inaudible 00:18:23], and I think that's really important. Once you see the efficacy, or if you see the MACE events continue to go down ... If you looked at treatment-emergent adverse events ... and I completely take the fact that it's every side effect reported altogether, which may or may not be linked to LDL levels specifically, but when we did that, the relationship actually was just a horizontal line, so there was no relationship with percentage reduction or on treatment LDL, so it gave us a nice idea of both safety and efficacy that we might experience in the big outcome studies.

Dr. Carolyn Lam: All right. Obviously the big outcome studies are going to be game changers, and I'd really love to invite [Carol Scotts 00:19:09] here, because there's a whole lot of other things that need to be considered if this becomes the case, isn't it? Carol, I really appreciated that you invited an editorial, and the editorial is by Neil Stone who entitles it, Looking Beyond Statins: Will the Dollars Make Cents? Please tell us about the discussions about this paper that occurred.

Dr. Carol Lam: I would again like to congratulate Dr. Ray on a fantastic paper, and I would like to reiterate exactly what he said. I think it really does give us some comfort about this class of medication and its relative safety. I think that's very important, because I can't tell you how many patients I get and how many referring physicians I get who worry when their patients come back with LDLs of 20 or below. I think that gave us some comfort, and I do also think it was very important to show that this would fall along the same regression line that statins perhaps would fall.

As with all the caveats that Dr. Ray said, I agree with all of them, but I do say this is a tasty little taster, and I appreciate and congratulate you for publishing this. The editorial by Dr. Neil Stone was quite interesting. As you said, he subtitled it, Will the Dollars Make Cents? C E N T S or S E N S E, sort of a play on words there. Will the relative benefits that we can achieve with this class of medications make sense for the cost of these drugs?

That's obviously a very separate issue from what was discussed in the manuscript, but it's something to think about. We understand that there are additional patients that will be helped if they can get their LDL down, and we hope that that will translate into the outcomes. Again, just as Dr. Ray mentioned, we will have to wait for the cardiovascular outcomes trials to be completed. When they are, if they do show the benefits that we hope, will their price point make them accessible to enough patients for this to be a widely applied, utilized therapy? Or will they not? That's part of what was discussed in Dr. Stone's editorial.

Dr. Kausik Ray: When we were writing the manuscript and stuff like that, and we were doing this and everybody's like, "Oh, wow, look at the graphs." I said, "Look, we need to balance all of these bits and reassure ... We've got an opportunity." So I suggested them giving those additional analyses, and you saw how big the online supplement was. There was a ton of work that we put into this, and to format it into a concise ... I really want to just thank the editorial board for giving us the chance and actually being able to help us and work with us on this, because it's really important. I hope people look at all of those things because it will help people also that question the LDL. They all talk about the hypothesis and the safety of really low LDLs, and people come off statins as a result. I think this will help.

Dr. Carolyn Lam: You're listening to Circulation on the Run. Thank you so much for being with us, and don't forget to tune in next week.

Dec 5, 2016

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 feature discussion is regarding the exciting results of the masked hypertension study showing that clinical blood pressure underestimates ambulatory blood pressure, but first here's your summary of this week's issue.

The first study reviews the largest clinical experience so far with pulmonary vein stenosis following ablation for atrial fibrillation. First author Dr. Fender, corresponding author Dr. Packer and colleagues from Mayo Clinic Rochester, Minnesota evaluated the presentation of 124 patients with severe pulmonary stenosis between 2000 and 2014 and examined the risk for re-stenosis after intervention utilizing either balloon angioplasty alone or balloon angioplasty with stenting. All 124 patients were identified as having severe pulmonary vein stenosis by CT in 219 veins. 82% were symptomatic at diagnosis with the most common symptoms being dyspnea, cough, fatigue and decreased exercise tolerance. 92 veins were treated with balloon angioplasty, 86 with stenting and 41 veins were not intervened on. The acute procedural success rate was 94% and did not differ by initial management. Overall, 42% of veins developed re-stenosis, including 27% of veins treated with stenting and 57% of veins treated with balloon angioplasty.

The three-year overall rate of re-stenosis was 37% with 49% of balloon angioplasty treated veins compared to 25% of stented veins developing re-stenosis. This was a difference that remained significant even after adjusting for age, CHADS2 VASC score, hypertension and time period of the study with an adjusted [inaudible 00:02:30] ratio of 2.46 for risk of re-stenosis with balloon angioplasty versus stenting. In summary, this study shows that the risk for pulmonary vein re-stenosis is significant following atrial fibrillation ablation. The diagnosis is challenging due to non-specific symptoms and while there is no difference in acute success by type of initial intervention, stenting significantly reduces the risk of subsequent pulmonary vein re-stenosis compared to balloon angioplasty.

The next paper shows that the index of microvascular resistance, which is a novel invasive mreasure of coronary microvascular function, has emerging clinical utility as a test for the efficacy of myocardial re-perfusion in invasively managed patients with acute ST elevation myocardial infarction. In this study by first author Dr. [Carrick 00:03:30], corresponding author Dr. Barry and colleagues from the University of Glasgow in Scotland, index of microvascular resistance and coronary flow reserve were measured in the culprit artery at the end of percutaneous coronary intervention in 283 patients with ST elevation myocardial infarction. Authors found that compared with standard clinical measures of the efficacy of myocardial re-perfusion, such as ischemic time, ST segment elevation and angiographic blush grade, the index of microvascular resistance was more consistently and strongly associated with myocardial hemorrhage, microvascular obstruction, changes in left ventricular ejection fraction and left ventricular end diastolic volume at six months as well as all caused death of heart failure during the median follow up of 845 days.

In fact, compared with an index of microvascular resistance greater than 40, the combination of this index and coronary flow reserve less than two did not have incremental prognostic value. The take-home message is therefore that an index of microvascular resistance above 40 represents a prognostically validated reference test for failed myocardial re-perfusion at the end of primary percutaneous coronary intervention. This study supports further research into microvascular resistance based therapeutic strategies in these patients.

The next study provides experimental data regarding molecular mechanisms underlying calcific aortic valve disease. First author, Dr. Haji, and corresponding authors Dr. Matthew and [Bose 00:05:24] from the Quebec Heart and Lung Institute in Canada performed genomic profiling and in-depth functional assays in human aortic valves. They demonstrated for the first time that the promotor region of the long non-coding RNA H19 is hypomethylated in patients with calcific aortic valve disease. This hypomethylation in turn increases H19 expression in the valve interstitial cells where it prevents Notch 1 transcription by blocking or out-competing P53’s recruitment to the Notch 1 promotor. Thus, H19 appears to be the missing link connecting Notch 1 to idiopathic calcific aortic valve disease. It may therefore represent a novel target in calcific aortic valve disease to decrease osteogenic activity in the aortic valve.

The next paper describes the largest cohort of mycotic abdominal aortic aneurysms to date and is from Dr. [Sorelias 00:06:37] and colleagues of Uppsala University in Sweden.  These authors identified all patients treated for mycotic abdominal aortic aneurysms in Sweden between 1994 and 2014. Among the 132 patients, they noted that the preferred operative technique shifted from open repair to endovascular repair after 2001 with the proportion treated with endovascular repair increasing from 0% in 1994 to 2000 to 60% in the 2008 to 2014 period. Survival at three months was lower for open repair compared to endovascular repair at 74% versus 96% respectively with a similar trend present at one year. A propensity score adjusted analysis confirmed the early better survival associated with endovascular repair. During a median follow up of 36 months for open repair and 41 months for endovascular repair. There was no difference in long-term survival, infection-related complications or re-operation. The take-home message is that endovascular repair appears to be a durable surgical option for treatment of mycotic abdominal aortic aneurysms.

The final study provides insights into the molecular mechanisms by which aldosterone triggers inflammation and highlights the particular role of NLRP3 inflammasome, which is a pivotal immune sensor that recognizes endogenous danger signals and triggers sterile inflammation. Authors Dr. Bruden [Esimento 00:08:32], Dr. [Tostes 00:08:33] and colleagues from the University of Sao Paulo in Brazil analyzed vascular function and inflammatory profiles of wild-type NLRP3 knockout, caspase-1 knockout and interleukin-1 receptor knockout mice, all treated with vehicle or aldosterone while receiving 1% saline. They found that mice lacking the interleukin-1 beta receptor or lacking inflammasome components such as NLRP3 and caspase-1 were protected from aldosterone-induced vascular damage. In-vitro, aldosterone stimulated NLRP3-dependent interleukin-1 beta secretion by bone marrow derived macrophages. Chimeric mice reconstituted with NLRP3 deficient hematopoietic cells showed that NLRP3 in immune cells mediated the aldosterone-induced vascular damage.

In addition, aldosterone increased the expressions of NLRP3, caspase-1 and mature interleukin-1 beta in human peripheral blood mononuclear cells. Finally, hypertensive patients exhibited increased activity of NLRP3 inflammasome. Together these data demonstrate that NLRP3 inflammasome via activation of interleukin-1 receptor is critically involved in the deleterious vascular effects of aldosterone, thus NLRP3 is a potential target for therapeutic interventions in conditions with high aldosterone levels.

That wraps it up for our summaries. Now for our feature discussion.

On today’s podcast we are going to be discussing the very important issue of masked hypertension. This is an issue that gets a lot less attention than I think compared to white coat hypertension. I’m so pleased to have the first and corresponding author of the masked hypertension study, Dr. Joseph Schwartz, from Stony Brook University and Columbia University in New York. Welcome to the show, Joe.

Dr. J. Schwartz:
My pleasure. I’m delighted to join you.

Dr. Carolyn Lam:
We have a regular on the show today as well, Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome back Wanpen.

Dr. Wanpen V.:
Thank you so much. Happy to be here.

Dr. Carolyn Lam:
Joe, I want to start by addressing the common misperception that ambulatory blood pressure is usually lower than clinical blood pressure. That seems to make a lot of sense to us clinically because, for example, I always use ambulatory blood pressure to diagnose white coat hypertension and so the assumption there is that my clinically measured blood pressure is higher than what I’m going to be finding if this patient measures the blood pressure on an ambulatory 24-hour basis. It’s also from the cutoffs that we use. For example, ambulatory blood pressure we use a 24-hour cutoff of 130/80 to make the diagnosis whereas with clinical blood pressure we use a cutoff of 140/90 so all of this kind of reinforces that ambulatory blood pressure is usually lower. Your study, though, tells us otherwise so please fill us in here.

 Dr. J. Schwartz:
You're right that in the doctor's office there are a certain set of people who probably get anxious when they're around a doctor and with that anxiety may cause a temporary increase in their blood pressure, a temporary elevation, and that's the basis of where we think white coat hypertension comes from. That's a very widespread belief among doctors and it's even been in previous guidelines, there have been statements to that effect. When I talk to people out in the general public and tell them I'm doing a study comparing blood pressure out in the real world compared to blood pressure in the doctor's office, all of them tell me, "Well, usually when I'm in a doctor's office that's a relatively calm period for me unless there's really something wrong with me and out in the everyday world I have to face a variety of stressors. I have deadlines. I have places I need to get to. Sometimes I have people yelling at me. Sometimes I'm just in a hurry."

All these things elevate your blood pressure out in the real world and so when we were trying to recruit people for the study, and we were very agnostic in recruiting them, telling them that we were interested in the differences in blood pressures between the doctor's office and the ambulatory blood pressure and they might go in either direction. When I told them about the fact that their ambulatory blood pressure or real world blood pressure might be higher than in the doctor's office, the vast majority of people nodded affirmatively and said, "It wouldn't surprise me at all."

Dr. Carolyn Lam:
Could you define masked hypertension compared to white coat hypertension and tell us a little bit about the population you studied.

Dr. J. Schwartz:
Sure. First with the definition. I'm going to say something a little bit different from something you said before. You mentioned cutoffs that we typically used for ambulatory blood pressure of 130/80 and those are the cutoffs that are used if you compute an average blood pressure over the entire 24 hours. What many people do, and what we did for this study, was compare the average blood pressure when people were awake to their blood pressure in the doctor's office because obviously in the doctor's office everybody is awake. The typical cutoffs there are 135/85, recommended by numerous guidelines in this country and with our international collaborators. The definition of masked hypertension is having a blood pressure in the clinic setting that's below 140/90 but having an ambulatory blood pressure where either the systolic blood pressure is above 135 or the diastolic is above 85 millimeters of mercury.

In terms of the sample, for years I've had a particular strategy for trying to recruit participants. I do worksite-based studies and so I identify large organizations that will allow me to recruit their employees and then what we did for this study is go to individual departments, both here at Stony Brook University, at Columbia University, at a residential veterans' home that's affiliated with Stony Brook University and then also at a local private hedge fund management company. We would go to these sites, I talk to the head of a department and tell them a little bit about masked hypertension and what the study was about and ask them if they would be willing to have their employees participate in the study. Once I had the okay from the department head then we would conduct public health screenings, blood pressure screenings. My staff and I would go into the department for multiple days and invite anybody who was interested to have their blood pressure taken on site and while we were taking those blood pressures carefully.

The proper way to take those is to take three readings and leave a minute or two interval between them and rather than just have silence then between the readings we would tell them a little bit about our study. At the end of the study if they didn't have extremely high blood pressure and were not taking blood pressure medication we would ask them if they might be interested in participating in the study that we just described. That's how we identified potential participants and about 2/3 of the people that we talked to who looked eligible indeed chose to participate.

Dr. J. Schwartz:
The one other thing I might mention that I think we mentioned, I hope we mentioned as a limitation of the study, is that everybody in the study had health insurance and at least until recently there were very large portions of the population that didn't have health insurance, everybody by virtue of their employment by the organizations that participated in the study, did have employer-based health insurance.

Dr. Carolyn Lam:
Thanks for clarifying the population so well. Could you just give us the top line of your findings. How big a difference did you find, which direction and that intriguing effect of age?

Dr. J. Schwartz:
Sure. The first thing we found is that on average the systolic blood pressure is seven millimeters mercury higher out in everyday life than it is in the clinic setting where we take our clinic readings. I should mention that unlike most studies, and all studies at the time that we began our study, we brought people in three separate times to take the clinic blood pressure. Up until that, almost all of the studies of ambulatory blood pressure monitoring only had clinic blood pressures from a single visit. I think we have a very reliable measure of the clinic blood pressure as well as reliable measure of ambulatory blood pressure. We see a seven millimeter difference in the systolic blood pressure and a 2 millimeter difference, again the ambulatory being higher for diastolic blood pressure.

What's more remarkable is if you think about what's a sizable difference. If you think if we perhaps somewhat arbitrarily say 10 millimeters of systolic blood pressure is a large difference. More than 35% of the population has an ambulatory blood pressure that is more than 10 millimeters higher than their clinic blood pressure whereas only 3% of our sample had that large a difference in the opposite direction, what many people would call a white coat effect. It's more than a 10 to 1 difference in numbers of people who have elevated ambulatory versus elevated clinic.

You asked me to mention something about the age difference. When you look at how that difference in systolic blood pressure varies by age, it's quite a bit larger for people who are younger. If you're under 30 the difference is, on average, 10 millimeters rather than seven millimeters and if you go up as you approach 60 years of age or so the difference becomes relatively small, perhaps in the neighborhood of two millimeters. We don't have enough people because it's a working population over 65 to say very much about what would happen. In fairness to prior research, which often is on older populations and particularly hypertensive populations, the studies that have historically shown that ambulatory blood pressure tends to be lower than clinic blood pressure are in these older populations and populations that have elevated blood pressure to start with.

My speculation there, and you haven't asked me to mention it but I will, is that older people and those with hypertension have a reason to be more nervous or more anxious when they go to the doctor than people who are not taking medication and probably don't even know that they have hypertension. People who are just being screened perhaps during a routine physical for the possibility of hypertension, because the doctors take a blood pressure reading every time you go in, they're doing that in order to see whether you might have hypertension, but most people who are going in for what we call a well patient visit are not nervous about their blood pressure being high.

Dr. Carolyn Lam:
I have to say, the take-home message for me when I read this was, I am not paying enough attention to masked hypertension and then another thing was, maybe I need to think about more white coat hypertension in the older and masked hypertension in the younger. Wanpen, do you think it's as simple as that? What were your take-home messages?

Dr. Wanpen V.:
I think this is a very important study that examines this in a systematic way. I'm not surprised that Joe found as much masked hypertension here. I think that he's absolutely right. We looked at this in Dallas Heart Study as well recently and we found that in the population-based sample in Dallas almost 20% of people have masked hypertension and white coat we found only like 3% and the average in the Dallas Heart Study was very close to those samples, about mid-40s. I think that's a very important finding in that the people with masked hypertension would not be suspected otherwise to have problems. Also, in the Dallas Heart Study they used home readings but Dr. Schwartz used ambulatory blood pressure monitoring. Unless extra out of office monitoring is being done we will totally miss these people who are more likely to have target organ damage from high blood pressure. I think that's absolutely important.

Dr. Carolyn Lam:
Actually, Wanpen you brought up something I was going to bring up as well. Where does home blood pressure fit in with this? Do you think it's home blood pressure versus ambulatory blood pressure?

Dr. Wanpen V.:
The US Preventive Services Task Force has issued a little bit of recommendations recently that we need to either use ambulatory blood pressure monitoring or home blood pressure monitoring to confirm diagnosis of hypertension in the office. If someone shows up with elevated blood pressure in the office either home blood pressure or ambulatory blood pressure needs to be done. If we just followed that guidelines we're still going to miss people with masked hypertension because by definition they don't have elevated blood pressure in the office. I think that from these findings and Dr. Schwartz' study I think to catch these people we really need to pay attention to people with pre-hypertension type of blood pressure because it seems like those are the group that has the most probability to have elevated ambulatory blood pressure so anyone with borderline blood pressure in the clinic, those are the ones who the doctor needs to tell the patient to monitor blood pressure at home or order ambulatory blood pressure themselves if that's available in their facility.

Dr. Carolyn Lam:
Wanpen, I fully agree. What an important message. Joe, I'd like to give you the final word but I'd love to hear how you have maybe taken this into your own practice.

Dr. J. Schwartz:
I think we mostly focused on and indeed the paper mostly focuses on the difference between clinic blood pressure and ambulatory blood pressure. When we talk about the young people, the young people have a bigger difference but those differences are for the most part all in the normal range. You might see a 10- or a 12-point difference but it might be that the ambulatory is 124 and the clinic is 112 and no doctor is going to worry about that very much. There are really always two things that we're trying to look at simultaneously: The first is what is that difference between the ambulatory and the clinic, but the second is for whom does the clinic stay under the threshold for diagnosis of hypertension but the ambulatory is over? That's the diagnosis of masked hypertension.

We haven't said it today so I'll say it: Of those people who had normal clinic blood pressures averaged across three repeated visits, 15.7% of them had elevated ambulatory blood pressure and would have been diagnosed as having hypertension based on their average daytime ambulatory blood pressure reading. That's one message.

The last message is unfortunately there is almost no research yet telling us what we should do in terms of treating people with masked hypertension. We are now at the point where we can identify these people and we're also at the point where we now know that there are a lot of such people and we don't even have any research to base guidelines on for deciding what we should do with them. The most obvious thing is to recommend lifestyle changes. If they're overweight we could suggest that they lose weight. We could suggest that they exercise more. We might think about treating some of those people, especially if their ambulatory blood pressure is well above 140/90. There are no statements out in the literature by any of the organizations, and in fact there's no research examining whether there's a benefit or not a benefit to perhaps putting some of those people on medications. I think that's a big question that future research needs to address.

Dr. Carolyn Lam:
Joe, thank you so much. I think your last statements just really emphasize how important this paper is. It increases awareness and it's going to open the door to much more needed research in this area. Thank you so much. Thank you Joe and Wanpen for being on the show today.

Thank you listeners for joining us. Don't forget to join us next week for even more news and exciting discussions.


Nov 28, 2016


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 feature discussion today is about the validation of a novel biomarker-based stroke risk score for atrial fibrillation, the ABC stroke score. But first, here's your summary of this week's journal.

The first paper provides experimental insights into endothelial nitric oxide synthase uncoupling in endothelial dysfunction. In this paper by first author Dr. Lee, corresponding author Dr. Wong and colleagues from Qilu Hospital of Shandong University in China, authors assessed endothelial function in animal models of hyperglycemia, hyperhomocysteinemia, and a dyslipidemia. They demonstrated that GTP cyclohydrolase 1 is the target of the microRNA-133a and that it's a topic expression and endothelial cells mediates endothelial dysfunction.

Furthermore, Lovastatin up-regulated GTP cyclohydrolase 1 and tetrahydrobiopterin and re-coupled endothelial nitric oxide synthase in stress endothelial cells. These actions of Lovastatin were abolished by enforced micro RNA 133A expression and mirrored by a mir-133a-antagomir. Finally, the beneficial effect of Lovastatin in mice were abrogated by in vivo mir-133A over-expression or by GTP cyclohydrolase 1 knockdown. In summary, this paper offers a mechanistic basis for targeting micro RNA 133A as a therapeutic approach to correct endothelial nitric oxide synthase dysfunction. It also provides further support to the role of statins in combating endothelial dysfunction.

The next study shows us that in hypertrophic cardiomyopathy, calcium mishandling may be the potential link between the primary genetic cause and downstream signaling cascade that leads to hypertrophy and arrythmias. In this study, Dr. Helms and colleagues from University of Michigan analyzed gene expression, protein levels and functional essays for calcium regulatory pathways in 35 human hypertrophic cardiomyopathy surgical samples with and without sarcomere mutations and compared that with 8 control hearts. They found a marked reduction in circa2 abundance, which correlated with reduced circa2 function in hypertrophic cardiomyopathy compared to controlled hearts regardless of the underlying genetic etiology.

However, calcium calmodulin depend protein kinase type 2 or cam2, which is a calcium sensing kinase, was deferentially activated only in the sarcomere gene mutation positive samples. Activation of chem kinase 2 was associated with an increase in phospholamb and phosphorylation in hypertrophic cardiomyopathy. However, neither calcineurin MRNA nor MEF2 activity was increased, suggesting that calcineurin pathway activation was not an upstream cause of increased chem kinase 2 protein abundance or activation.

In summary, this paper demonstrated that calcium mishandling occurs through both genotype specific and common pathways in human hypertrophic cardiomyopathy. Post-translational activation of chem kinase 2 pathway is specific to sarcomere mutation positive hypertrophic cardiomyopathy. While Sarco 2 abundance and sarcoplasmic reticulum calcium uptake are depressed in both sarcomere positive and negative hypertrophic cardiomyopathy. Thus, chem kinase pathway inhibition may improve aberrant calcium cycling in hypertrophic cardiomyopathy. This is discussed further in an accompanying editorial by Dr. Jill Tardiff.

The third study suggests that in patients with a dilated aortic route and trileaflet aortic valve, a ratio of aortic route area to height provides independent and improved stratification for prediction of death. First author Dr. Masry, corresponding author Dr. Desai and colleagues from the Center for Aortic Disease, Heart and Vascular Institute of Cleveland Clinic, studied consecutive patients with a dilated aortic route of greater or equal to 4 centimeters who underwent echocardiography and gated contrast enhanced thoracic aortic computer tomography or magnetic resonance and geography between 2003 and 2007.

A ratio of aortic route area over height was calculated on tomography and a cutoff of 10 squared centimeters per meter of height was chosen as abnormal. In 771 patients with trileaflet aortic valve and concomitant aortopathy, there was incremental prognostic value for indexing aortic route or ascending aortic area to patient height rather than using an unindexed aortic diameter. Incorporation of the ratio significantly and independently reclassified the risk for death and at normal ratio was independently associated with higher long-term mortality while cardiovascular surgery was associated with improved survival. Importantly, a sizable minority of patients with aortic route diameters between 4.5 and 5.5 centimeters had an abnormal aortic route when indexed to height ratio. 78 percent of deaths in this subgroup occurred in those with an abnormal aortic route area to height ratio. Findings were similar when ascending aortic measurements were considered. The take home message is that an aortic route area to height ratio above 10 squared centimeters per meter of height has significant and independent prognostic utility and may be used to re-stratify patients with trileaflet aortic valve and a dilated aorta.

The final study provides pre-clinical data to show that Ticagrelor reduces cardio damage post myocardial infarction to a greater extent than Clopidogrel by an adenosine induced organ protective response. First author Dr. Villaher, corresponding author Dr. Bademan and colleagues from the Cardiovascular Research Center in Barcelona, Spain studied a close-chest swine model of ischemia reperfusion in which myocardial infarction was induced by 1 hour balloon occlusion of the mid-left anterior descending coronary artery followed by 24 hours of re-flow. Prior to occlusion, the animals were randomly assigned to receive either placebo, a loading does of Clopidogrel, a loading does of Ticagrelor or a loading does of Ticagrelor followed by an A1 A2 receptor antagonist. Edema infarc size left ventricular size and left ventricular function were assessed by three T cardiomagnetic resonance imaging. Inhibition of platelet aggregation was the same between the groups receiving a P2Y-12 inhibitor.

Yet, Ticagrelor reduced infarc size to a significantly greater extent than Clopidogrel, reducing it by a further 23.5 percent, an effect supported by troponin eye assessment and histopathological analysis. Furthermore, compared to Clopidogrel, Ticagrelor significantly diminished myocardial edema by 24.5 percent, which correlated with infarced mass. Administration of an adenosine A1 A2 antagonist abolished the cardio protective effects of Ticagrelor over Clopidogrel. At a molecular level, aquaporin 4 expression decreased and the expression and activation of AMP kinase cyclin and COX-2 increased in the ischemic myocardium of Ticagrelor versus Clopidogrel treated animals. In summary, this study shows that Ticagrelor exerts cardio protective effects beyond its anti-platelet efficacy by adenosine dependent mechanisms, which reduce necrotic injury and edema formation. This is discussed in an accompanying editorial by Drs. Gerbel, Jung and Tantry. That wraps it up for the summaries. Now for our feature discussion.

Today, we are going to be discussing the performance of the ABC score for stroke in atrial fibrillation. And as a reminder for all our listeners there, ABC stands for A for age, B for biomarkers, that's NT-proBNP and high-sensitivity troponin, and C for clinical history of prior stroke. And again as a reminder, this risk score was originally derived in the Aristotle trial. However, we have new results about its performance and validation today from first and corresponding author Dr. Jonas Oldgren from Uppsala Clinical Research Center in Sweden. Welcome, Jonas.

Speaker 2:
Thank you very much.

Carolyn Lam:
We also have today the associate editor who managed this paper, Dr. Sandeep Das from UT Southwestern. Hi Sandeep.

Speaker 3:
Hi Carolyn, thanks for having me.

Carolyn Lam:
So Jonas, could you start off by telling us why you did this study and what you found?

Speaker 2:
We did this study to validate the recently derived ABC stroke risk score. We have had risk scores for predicting stroke in patients with atrial fibrillation derived since the late 1990's and refined later on. But those risk scores have only used clinical markers for risk. We have for several years developed new risk prediction models with biomarkers and now we are combine them in a very simple biomarker based risk score, taking into account age as a clinical variable and the clinical history of prior stroke and only two common used biomarkers. And by that we can predict the risk of stroke with better precision than previous clinical risk scores.

Carolyn Lam:
Yeah, I like what you said. I mean it is literally as simple as ABC. So tell us how you validated it and what you found.

Speaker 2:
It was derived in a large cohort of patients participating in a clinical trial with new or relapsed coagulant compared to Warfarin and we now validated in almost a full size group participating it another clinical trial. So we have large data sets of very well described patients where we have good outcome data. Very solid data to rely on. Now we can see that the ABC risk score is now validated but the good precision and good collaboration of the discriminatory abilities is high and better than the previously used clinical risk scores.

Carolyn Lam:
Could you give us some numbers behind that that are clinically meaningful? Everyone's going to be wondering compared to the chads-vasc score for example, how does this ABC score perform in that validation test set?

Speaker 2:
We can adjust that by several different aspects. One is of course to calculate the C index which is a statistical method to see how good we can predict risk and the C indices for the ABC stroke score both in the duration and now in the validation cohort is higher than for the chads-vasc and atrial risk scores. But we can also look at what we have in this paper in circulation ... we can look at predicted outcome rates and observed outcome rates and can see that they clearly overlap both in the duration and validation court. So if you predict a risk that is less than 1 percent per year, it is observed also a risk that is less than 1 percent a year. Does this always ... the thing is when you derive risk or but when you validate it in another cohort, you need to show that it's a similar result.

Carolyn Lam:
Yeah, that's true. Sandeep, you are managing this paper. It's very important. How do you think that clinicians should be taking the results?

Speaker 3:
I think that clearly using anticoagulation and selected patients at high risk for stroke with atrial fibrillation is one of the best things we do in cardiology. You know in terms of reducing the risk of an important harm to patients. I think there's a fair bit of dissatisfaction out there with currently sort of standard, which is chads-vasc. Especially in people with a chads-vasc ... men with a chads-vasc of 1 or women with a chads-vasc of 1 to 2 where there's a bit of struggling over how to decide. So I think that one real advantage of this score in addition to the fact that it predicts better by the higher C statistic, which is fantastic and pretty uncommon, right? Lars sort of buried the lead a little bit by not emphasizing that it's relatively rare that we're able to move a c statistic by a point of 5 in the modern era.

But the other thing is that it helps give us an ability to come up with good estimates in people at low risk, which I think has been a challenge and something that people are a little concerned clinically. So I think that this is easily available, biomarkers that we routinely check all the time and it doesn't have the sort of gender challenge with chads-vasc where you're trying to figure out whether your low risk woman really needs to be on Warfarin or anticoagulation. So I think that it has a lot of clinical utility right out of the box, which is nice.

Carolyn Lam:
Actually, Jonas could you let us know is there any sex differences in the performance of the score?


Speaker 2:

There are no differences in the performance of the score. So we looked ... the advantage of this score is when we derived it in the original model, we looked at all important clinical and biomarker risk factors and we can see that these were the foremost interesting markers. So we only used those. So we can predict much better and as pointed out so nicely by Sandeep, for patients at the lower end of the risk spectrum, we can find patients or have higher or lower risk even within patients with chads-vasc 1 or chads-vasc 2. And I think it's also important to see what about patients at higher risk despite proper anticoagulation. We did not know how to treat them but in the future we might perhaps tailor treatment also for those patients with residual high risk of stroke despite proper anticoagulation treatment. For instance, if the left atrial appendage occluded devices are shown in the future to be a good option for those patients, we can find them also by this risk score. So both in the higher and lower end of the risk spectrum.

Carolyn Lam:
That's a really good point. On that note, I'm just curious. What do you think is in the future? What more knowledge do we need to address before we put this into practice or are you already using this? Or do you think it should enter guidelines for example? Maybe Sandeep, I could ask for your opinion first.

Speaker 3:
We see a lot of biomarkers associated with increased risk kind of studies come out in the literature. You know probably every week you see several of these things come out. So what's really interesting about this is that it's obviously methodologically extremely well done but its been derived and validated in two large cohorts, which is pretty much best practice right? You want to see people validate these risk scores in large and distinct cohorts of patients to build up sort of clinical validity to the reader or consumer. So I think, from my standpoint, this is ready for prime time. I'm really intrigued by the fact that biomarkers, especially troponin, are predicting stroke in this population and there have been some observational reports out there that have showed an association between troponin and increased risk of stroke or worse outcomes after stroke. So I'd be really curious as to what Jonas thinks about why troponin would be predictive of stroke in this population.

Speaker 2:
We were extremely intrigued by the finding when we first did those single observations of only troponin as a risk marker because we know that troponin is a very specific protein found in the myocardium. But the clinic predicts risk for stroke also and there are several explanations but they are mainly hypotheses about aging and myocardial function really to identify patients of risk. But the clear cut explanation is still not there.

Carolyn Lam:
It's likely that these biomarkers are incorporating aspects that we don't fully understand, which is why they are better predictors isn't it? I mean to your point Sandeep.

Speaker 3:
Yeah, no absolutely. And I think that's great.

Carolyn Lam:
Exactly. It really opens a lot of other questions that need to be answered in the meantime. Jonas, any other last words about how you may be applying this clinically in your own patients?

Speaker 2:
We have no solid data supporting the use of this clinical risk score and as already pointed out, which I think is very good, all clinic risk scores should of course be in the best world validated as useful decision support truth and really in clinics trial seeing that they improve outcomes. This is to my knowledge never been down with a clinical risk scores. We have never used them prospectively to guide treatment and to improve outcomes. Actually, we are aiming to do that. We hope to start a clinical trial next year with ABC score guided treatment compared to standard of care. But it's a very huge undertake of course to that we can improve treatment by risk or guided management.

Carolyn Lam:
That's excellent. So remember everyone, you heard it right here. A new trial that they're engaging. I really congratulate you first for this study, as well as this future efforts which are clearly going to be very important.

Thank you very much both of you for joining us today and thank you listeners for listening. Don't forget to tune in next week.


Nov 21, 2016

Welcome to circulation on the run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. [Carolyn Nam 00:00:08], associate editor from the national heart center and Duke National University of Singapore ...

In just a moment we will be discussing the exciting new results of the [Prague 00:00:21] 18 study of prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary or cutaneous coronary intervention. But first, here's your summary of this week's issue ...

The first study represents the largest published study on the association between PR interval and cardiac resynchronization therapy with defibrillator versus implantable cardioverter defibrillator and real world outcomes. Dr. Friedman and colleagues from Duke Clinical Research Institute studied 26,451 CRT eligible patients from the National Cardiovascular Data Registry ICD Registry. They found that a PR interval at or above 230 milliseconds was associated with increased rates of heart failure, hospitalizations, or death among CRTD but not ICD patients. The real world comparative effectiveness of CRTD versus ICD was significantly less among patients with a PR interval above 230 milliseconds compared to patients with a shorter PR interval.

The authors discuss that these findings may be due to the association between a prolonged PR interval and factors associated with lower rates of CRT response such as non-left bundle branch block morphology, ischemic heart disease, or atrial arrhythmias. It could also be due to the association between delayed AV conduction, disordered diastolic filling, and contemporary CRT reprogramming strategies. The take home message is: in CRT patients with a prolonged PR interval, recognize that they are at high risk for poor outcomes and merit close follow up and consideration of AV optimization ...

The next study is the first adolescent study of serum lipidomics that identifies a new panel of serum glycerophosphocholines that are associated with cardiovascular risk. First author Dr. [Sine 00:02:29], corresponding author Dr. [Palsova 00:02:31], and colleagues from Hospital for Sick Children in University of Toronto recognize that atherogenic dislipidemia is traditionally assessed with high abundance lipids, such as cholesterol and triacylglycerols, which accumulate at millimolar levels in blood. Current advancements in mass spectrometry now allow the discovery and study of new low abundance lipids, which circulate at micro- or nanomolar blood levels. And one such example are the glycerophosphocholine metabolites.

They studied a population based sample of 990 adolescents with age range 12-18 years using liquid chromatography electrospray ionization mass spectrometry. They identify several novel glycerophosphocholines that were associated with multiple cardiovascular disease risk factors. Mediation analysis revealed that these novel glycerophosphocholines mediated their respective relationships between visceral fat and cardiovascular disease risk factors. Furthermore, a particular glycerophosphocholine shown recently to predict incident coronary heart disease in older adults was already associated with several cardiovascular disease risk factors in these adolescents.

The clinical implication is that the development of a lipidomics signature that could facilitate early intervention or treatment of those at high risk of cardiovascular disease or monitor response interventions could help triage limited healthcare resources. Furthermore, future research on glycerophosphocholines might improve biological understanding of disease and identify potential drug targets to impede cardiovascular disease development ...

The next study also describes plasma lipidomic profiles but this time in patients with type 2 diabetes. This study is from first author Dr. [Elchuri 00:04:35], corresponding author Dr. [Meekly 00:04:37], and colleagues from the Baker IDI Heart and Diabetes Institute in Melbourne, Australia. These authors performed a targeted lipidomic analysis using liquid chromatography electrospray ionization tandem mass spectrometry in a case cohort of 3,779 patients with type 2 diabetes and one or more additional cardiovascular risk factors from the advance trial.

They found that sphingolipids, phospholipids, cholesterol esters, and glycerol lipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model of 14 traditional risk factors and medications improved the prediction of cardiovascular events. The prediction of cardiovascular death was also improved with the incorporation of 4 lipid species to the base model. These results were further validated in a subcohort of type 2 diabetes from the lipid trial. In summary, this important study demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes ...

The last study sheds new light on the optimal ablation method for atypical atrioventricular nodal reentrant tachycardia or atypical ARNVT. Dr. [Catrisis 00:06:10] and colleagues from Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, Massachusetts study 2,079 patients with AVNRT subjected to slow pathway ablation. In 113 patients, atypical AVNRT or coexistent atypical and typical AVNRT without other concomitant arrhythmias was diagnosed. Ablation data and outcomes were compared to a group of age and sex matched control patients with typical AVNRT. The authors found that in the atypical group slow pathway ablation was accomplished from the right septum in 110 patients and from the left septum in 3 patients. There was no need for additional ablation lesions at other anatomical sites and no cases of AV block were encountered.

In summary AVNRT, regardless of the type, appears to be successfully ablated by targeting the anatomic area of the slow pathway. When a right septal approach is not successful, the anatopic area of the slow pathway can be ablated from the left septum and so it seems the slow pathway participates in both typical and atypical AVNRT. The take home messages are that catheter ablation at the anatomical area of the slow pathway from the right or left septum may be the treatment of choice for atypical AVNRT. The approach is not associated with an increased risk of inadvertent AV block. The recurrence rate following ablation of atypical AVNRT may not be significantly higher than that seen following the ablation of typical AVNRT.

Those were the highlights from this week's issues. And now for our feature paper ...

We're so pleased to have with us today for our podcast interview first and corresponding author of the Prague 18 study, Dr. [Zuzana Motovska 00:08:12] from Charles University in Prague. Welcome Zuzana.

Thank you for having me.

We're also so lucky to have Dr. [Gabriel Stig 00:08:21], associate editor from Paris, and I understand you're even traveling at the moment. Thank you, Gabriel for making the time.

Yes, hello Carolyn, hello Zuzana.

So let me start by congratulating you Zuzana on this first head-to-head comparison study of prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary or cutaneous coronary intervention. And what a lovely study acronym of course, Prague 18. Could you maybe start by describing, in the Czech Republic before your study, how were clinical decisions being made between prasugrel and ticagrelor in these patients?

The current guidelines prefer newer P2Y12 inhibitors over clopidogrel for patients with acute coronary syndromes. Prasugrel and ticagrelor are being increasingly used in patients [with just 00:09:15] primary PCI in Czech Republic. Analysis of our registry documented that doctors did not view these two drugs as interchangeable and prasugrel is a drug associated with a high risk of bleeding. Our data show that safety in terms of bleeding risk was the most important aspect under consideration when choosing one of new agents for an individual patient. The same observation has been reported from other contemporaries from other countries and according to the published subgroup analysis of [stratum 00:09:54] and other studies we have also perceived prasugrel to be a more effective agent for primary PCI. We prefer this drug in patients with a high thrombotic risk.

Could you, maybe now, clearly describe what you did in this study and what were your findings?

The Prague 18 study truly [inaudible 00:10:19] was designed to test the hypothesis on whether one of the newer drugs, prasugrel or ticagrelor, is more effective and safer than the other one in acute myocardial infarctions, which is the primary [treatment 00:10:36] strategy. We randomized the total 1,230 in 14 participating sites. I highlighted hemodynamic instabilities, was not an [excluding 00:10:52] criterion for study participation. The patients were randomized for prasugrel or ticagrelor immediately on hospital arrival and the recommended dosing regiments were used for both drugs. The prasugrel dose was reduced during the maintenance phase in patients over 75 and [reduced vein 00:11:12] was the [sixth 00:11:14] feature around presence of both these parameters was an exclusion criterion.

So, what we find. Fewer [unsourced 00:11:23] primary endpoint composed of all cause of death or reinfarction show serious bleeding or urgent vessel revascularization within 7 days after randomization or discharge if prior to the seventh day. They did not differ between groups, either for in 4 person prasugrel group and in 4.1 person in ticagrelor group. The appearance of key secondary end point composed of cardiovascular death, nonfatal MI, or nonfatal stroke. Within 30 days did not show any significant difference between prasugrel and ticagrelor, furthermore no significant difference was found in any of the components of the primary and secondary endpoints and also no significant difference was observed in the appearance of definite vein thrombosis [inaudible 00:12:17] days after randomization.

So the study did not show any difference between ticagrelor and prasugrel in the early phase of a mild [treatable 00:12:26] primary PCI. Because of small sample size the confidence for the estimation of the [interval 00:12:35] of either were quite high, however we identify differences, which are very low in absolute numbers and [inaudible 00:12:45]

That was very nicely explained Zuzana, thank you. Now could you share a little bit more about, were you powered for this analysis and the decision to stop early.

Oh yes, the power analysis was computed for primary endpoint difference of 2.5 person and the needed sample size was estimated at 2,500 patients. The interim analysis led to a decision to terminate the study prematurely because of futility. No significant difference in primary endpoint was found between the two study drugs in the course of the entire randomization process, moreover the difference in appearance of the primary endpoint between the compare groups was declining with a growing number of randomized patients and analyzed on the different 0.1% and this was the decision why we stopped the trial prematurely.

Right. Gabriel could you comment a little bit as the associate editor managing this paper, how do you think it's going to impact practice?

First of all, let me start by congratulating Zuzana and the team of the Prague 18 trial for this academic trial. I think it's really important that we have a clinically led effort to investigate optimal treatments in modern cardiology in general and specifically in acute coronary syndromes. We've known for several years now, through large randomized trials, that the novel P2Y12 agents, ticagrelor and prasugrel, are clearly superior to clopidogrel but we don't know which of the two agents to choose and we know that comparison across trials are fraught with major methodological problems. So with evidence that prasugrel is superior to clopidogrel for PCI treated ACS patients, there was evidence that ticagrelor was superior to clopidogrel for ACS patients in general but we didn't have any rational data on which to base a rational selection process between the two agents.

Really, I think it's an important issue and often people state that these are delicate differences between agents, and we shouldn't expect that this is going to impact clinical outcomes. Actually it does impact clinical outcomes because we know that those novel agents have had a roughly 20% reduction in major heart outcomes compared to clopidogrel so this is not a moot point. It's not a minute difference, it's a huge difference and it's an important clinical issue. That's my first point, I think it's an important question and I really want to commend the investigators for launching this trial despite not having the support of industry.

The second point I want to make is I think that the results from the trial are not yet complete because we don't have the one year follow-up and I know that this is planned and the investigators are continuing follow-up of their patient cohort, which I think is going to be important because it's conceivable that differences may emerge over time as was, in fact, the case in some of the previous trials. In [plato 00:15:49] there was a modest difference early on but the curves diverged over time between clopidogrel and ticagrelor so it's conceivable that differences that are absent at 30 days might emerge over time.

In fact, I have a question for Zuzana. One of the interesting features and important issues that needs to be addressed is ... I know that in some sites in the Czech Republic, because of the out of pocket expenses related to the cost of the novel agents, it was allowed for patients to be switched back to clopidogrel after hospital discharge. Do you have any sense of what is the proportion of patients who are scaled back to clopidogrel instead of prasugrel or ticagrelor after initial index submission?

Thank you Gabriel, it's true the study ... a lot of patients who are unable to bear the cost associated with long term treatment with the study medications and switch to clopidogrel. Therefore, a second goal of the study was to assess the rate, the reason, and also the consequences of switching from a study drug to clopidogrel after the acute phase in the course of 12 months follow-up. We are not focusing on the study completion and analysis that are related to the second study. There are, of course, patients who switch from prasugrel or ticagrelor to clopidogrel also in first 30 days and this proportion was about one third of patients.

The other point I want to make really relates to the power issues and Zuzana already pointed out herself this important issue. The paper is actually accompanied by an excellent and very cogent editorial by Steve [Webiok 00:17:31], who discusses explicitly and in great detail the issue of sample size. We know that the relative difference between the novel agents and clopidogrel is in the range of 20% so we might expect that the difference between the two novel agents themselves, when we compare prasugrel and ticagrelor, might be less. Yet the study was powered for actually a greater relative risk reduction than what was seen in the pivotal trials of prasugrel and ticagrelor compared to clopidogrel. So the study is really on the low end of the power spectrum and I think, as you pointed out Zuzana, it's important to keep in mind that the confidence interval for the relative risk between ticagrelor and clopidogrel both act together on prasugrel, both for the primary endpoint, which is a combination of efficacy and safety, as well as for the key secondary endpoint of efficacy.

It's really very wide and we can't rule out a major benefit or a major detrimental effect of one agent versus the other. I think this is important to keep in mind because many people equate a neutral result of a trial, a non-significant result, particularly in the [secondary 00:18:36] trial, with lack of difference or clinical equivalence or non-inferiority and I think it's important to remember the readers that this is not a non-inferiority trial, it's not a clinical equivalence trial, it's superiority trial that is actually with a neutral result. It's really and important issue.

Yet, because it's the first head-to-head comparison, because it's an academic effort independent, and because it's going to report one year outcomes, I think this is a critical effort and the investigators need to be lauded for that. Even if this study isn't powered, it will be able to be pulled in further meta-analysis with other upcoming studies that are similar that also may be underpowered and provide us with a hint of evidence of what might be the best agent to use, which is an every day clinical question. This is a very, very common condition and any unbiased evidence we can get from randomized trials is very valuable ...

Thank you, everyone, for listening to this episode of circulation on the run. Tune in next week ...


Nov 14, 2016

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. In today's podcast interview we will be discussing the ruling in and ruling out of myocardial infarction with the European Society of Cardiology 1-hour algorithm. Stay tuned for a discussion of new data and controversies on this hot topic. Now, here's a summary of this weeks issue.

The first paper brings us one step closer to the ultimate goal of cardiac tissue engineering. That is to replicate functional human myocardium in vitro. In this study, by first author Dr. Ruan, corresponding authors Dr. Murry and Regnier from the Institute for Stem Cell and Regenerative Medicine and University of Washington, authors recognize that human-induced pluripotant stem cells, or iPSC-derived cardiomyocytes, really provide a cell source for cardiac tissue engineering. However, their immaturity limits their potential applications. Hence, they sought to study the effect of mechanical conditioning and electrical pacing on the maturation of iPSC-derived cardiac tissues.

They found that after two weeks of static stress conditioning, the engineered myocardium demonstrated increases in contractility, tensile strength, construct alignment, cell size, and SERCA2 expression. When electrical pacing was combined with static stress conditioning the tissue showed an additional increase in force production and further increases in expression of RyR2 and SERCA2. These studies really demonstrate that electrical pacing and mechanical stimulation promote the maturation of the structural, mechanical, and force generation properties of iPSC-derived cardiac tissues and constitute a really important contribution to cardiac tissue engineering.

The next study is the first large-scale, nationwide, population-based investigation of the association between congenital heart defects and any placental measure. This study by Dr. [Matheson 00:02:27] and colleagues from Aarhus University Hospital in Denmark, included all 924,422 live-born Danish singletons from 1997 to 2011. Congenital heart defects was present in 7,569 newborns. The authors compared the mean differences in placental weight between newborns with and without congenital heart defects and found that only three specific subgroups of congenital heart defects were associated with measures of impaired placental growth. These included Tetralogy of Fallot, double outlet right ventricle, and major ventricular septal defects. In these subgroups, the mean deviations from the population mean head circumference and birth weights were reduced by up to 66%, with adjustment for placental weight. In other words, up to two thirds of the deviations in fetal growth, including fetal cerebral growth, may be related to the impaired placental growth. The present work provides an important contribution to the existing knowledge on the association between congenital heart defects and placental anomalies as well as the possible importance for fetal growth in this population.

The next study provides an up-to-date evaluation of the cost effectiveness of antibiotic prophylaxis in the prevention of infective endocarditis. In this study by first author Dr. Franklin, corresponding author Dr. Thornhill, and colleagues from the University of Sheffield, the cost effectiveness of antibiotic prophylaxis, namely single dose amoxicillin or clindamycin, in patients at risk of infective endocarditis. They did this using, firstly, recent estimates of the effect of antibiotic prophylaxis on infective endocarditis in the English population; secondly, rates of antibiotic adverse drug reactions; and thirdly, estimates of the probability of developing infective endocarditis following dental procedures derived from French data. All this as foundation for analysis of cost and health benefits.

A decision analytic cost effectiveness model was used based on the decision model by the National Institute for Health and Care Excellence, or NICE, that was used to inform the 2008 guidelines. The authors found that antibiotic prophylaxis was less costly and more effective than no antibiotic prophylaxis for all patients at risk for infective endocarditis. In fact, if antibiotic prophylaxis was reinstated in England for those at moderate or high risk of infective endocarditis, it could save 5.5 to 8.2 million pounds and result in health gains of more than 2,600 quality-adjusted life years. Antibiotic prophylaxis was even more cost effective for those at high risk of infective endocarditis, being cost effective even if only on 1.44 cases of infective endocarditis was prevented per year. In summary, these updated findings really support the cost effectiveness of guidelines recommending antibiotic prophylaxis use, particularly in high risk individuals.

The last study provides data on long term cardiac mortality among survivors of cancer diagnosed in teenagers and young adults in the largest population-based cohort to date. Furthermore, the study provided, for the first time, risk estimates of cardiac death after each cancer diagnosed between the ages of 15 to 39 years. For example, survivors of Hodgkin lymphoma, lung cancer, acute myeloid leukemia, non-Hodgkin lymphoma, and CNS tumors experience 1.3 to 3.8 times the population-based mortality rates. This study provides important insight into the cardiotoxicity of the treatments given in the past to teenagers and young adults with each individual type of cancer and importantly, provides an initial basis for developing evidence-based follow up guidelines.

Those were you summaries. Now for our feature interview.

Our feature paper today discusses the hot and controversial topic of ruling in and ruling out myocardial infarction with the European Society of Cardiology 1-hour algorithm. I'm so excited to have with us the corresponding author of the paper that really represents the first multi-center external validation of these ESC guidelines for MI and the first multi-centered direct comparison of the performance of the algorithm with high-sensitivity troponin I and high-sensitivity troponin T assays. This would be Dr. Martin Than from Christ Church Hospital in New Zealand. Welcome Martin.

Thank you very much. It's a great pleasure for me to be able to join everybody and talk here.

It's great to have you. We also have with us the editorialist on this paper, Dr. Allan Jaffe from Mayo Clinic, Rochester, Minnesota. Allen, it's so good to hear your voice again.

Good to talk to you again too, Carolyn.

Finally, we have Dr. Deborah Diercks, Associate Editor from UT Southwestern. Welcome Deb.

Oh, it's good to be here and I'm looking forward to the conversation and what we're going to learn from these two gentlemen.

Absolutely. You know what? I'm going to start with Martin. I love the way to set up your paper. You very correctly pointed out that there's a tension in that ED physicians require really high sensitivity to confidently rule out MI and send patients home, whereas cardiologists do not want high proportion of false positives because we don't want false high risk to lead to invasive testing. I just love, if you could start by telling us how the ESC 1-hour algorithm fits into all this and what you were trying to do in your study.

I heard Deb Diercks on the phone as well, who's a very respected emergency physician in this area, and I think we would both say that we have a certain bias in our perspective on this, which is of course we are the people at the end of the day that have to send people home when they present with chest pain and possible myocardial infarction. We are also, of course, the people that take the fall if there are any mistakes made. Historically, people have not been very kind to emergency physicians who miss such a diagnosis. It's an extremely high source of medical legal action in the United States and, in fact, worldwide. So we're somewhat paranoid as a speciality about missing cases of myocardial infarction because at the end of the day, the worst thing that can possibly happen is for you to send someone home who comes to harm from the very clinical complaint for which they came to you for help. We want to avoid that at all costs and that was the basis behind us trying to put together this paper.

Soon after the ESC guidelines come back and I returned from London, where they were announced at the conference, to New Zealand, I received quite a lot of phone calls and correspondence saying, "Okay, we see these new ESC guidelines are out. When are we going to start introducing them?". I immediately wanted to say, "Well, the key thing is to understand how they would work, how they would be implemented, and whether they'd work in my own setting" because if we want to implement them in New Zealand or Australasia, we would want to double-check on that first. That's the basis and the philosophy behind the manuscript.

Tell us what you found.

As Allan will be the first to point out, I think there are a number of flaws in the data we had available to us that allowed us to do this analysis, but based on the concept that when we've surveyed emergency medicine physicians, the sensitivity that was wanted was at least 99% if not higher. We found that neither of the algorithms produced that level of sensitivity, although the algorithm based on hsTnI was very close. I think it's 98.8%, so that was very good. Reasonably wide confidence intervals on that. The hsTnT algorithm performed slightly less well with a sensitivity around 97%. I guess, if I was to start with an a priori question, which is did we reach a standard of 99%, then our answer to this was, in one case, not quite, and the other case, no, we probably didn't. We said that if you wanted to use a metric of negative predictive value, which I know a lot of people do, then there was actually very good negative predictive value in the high 99 percentage range for both pathways.

Do you mind if I stretch you a little bit and ask you to describe exactly what you did in the cohorts? You were saying that there were some imperfections. Maybe you'd like to tell us a little bit about that.

Absolutely. As always, when you're writing a paper, you look back and you always feel there are far too many imperfections, but I guess the principle one I would say that's been noted is that we had samples done on arrival and the algorithm itself specifies a [inaudible 00:11:43] one-hour second sample. We didn't have those specimens, so we had to base our data analysis on samples done either at 90 minutes afterwards or two hours afterward. It's clearly not being tested exactly as it was written, although one could argue that that slightly delayed sampling is potentially reflective of real life, where it's very hard to hit a one hour mark in a busy emergency department, and two, where the slight delay in getting the samples would actually allow more time for a troponin to rise and therefore give a chance of providing a better sensitivity.

I think the other I guess key flaw is that of course, the people present to emergency departments at different time frames following the onset of their symptoms. There's been some valid concern raised that algorithms may not necessarily perform as well in very early presenters. In fact, that is something that's being emphasized now in the ESC guidelines.

Right. Allan, I loved your editorial. You did mention a couple of these points. Would you like to maybe clarify your view of this?

I think that there are two or three terribly important issues. We all would like to have very facile algorithms. Particularly given removing the high sensitivity, the idea would be gee, wouldn't it be nice to have something really simple that works perfectly? If you look at the validation and the way the algorithm has been put together, immediately there are some concerns that people ought to have and that at least we tried to point out, that were important. One of them Martin has already discussed a little bit, which is one looks at most of the validation studies. There are very few patients who are evaluated very early after the onset of their symptoms. That's a potential problem because the overlap, since they use very low values or very small change, that there could be, with people who have real disease, is in those very early presenters. The initial algorithm from the ESC used both a very low level troponin and a set of change criteria. Actually when they published those criteria, they changed that and eliminated, at least for the first three hours, the very low values. If one looks at Martin's study, it was again, the very early patients who potentially may have been missed. I think we need more data before we go ahead and acknowledge that this will be working for those early presenters.

There are two other problems with the population that we need to be careful about. It's been well known that when you have a negative troponin at six hours all the way back to [Chrisann's 00:14:26] original article in the '90s, that you're pretty safe. The population that you'd like to look at really are the patients who, after two hours in Martin's study, since he took a little bit longer given the logistics that were there in New Zealand and Australia, is the patient who came in at four hours because by six, they're actually meeting that six-hour criteria. When you have a large number of other such patients, you simply add noise and it makes you sensitivity look better, but it's not necessarily the case that that give you that same degree of reassurance that ED physicians would like.

The third population-related issue is that you'd like to do this in all-comers. The protocol was developed for chest pain patients, but there are a variety of patients in whom we evaluate myocardial infarction in, who may not qualify for that. The patients who are critically ill, for example, who may have Type 2 infarctions. The individuals who may come in who are very elderly, who often don't have chest pain so we don't identify them necessarily as a rule out. Interestingly, if you start thinking about those groups, they tend to have much higher troponin, so they may well skew the cut-offs that are used and change the algorithm.

In truth, we don't want more than one way of defining myocardial infarction. We only want one algorithm for ruling in and ruling out. Having an all-comers study, in my way of thinking, would be important. In that same regard, let me point out that you can rule out myocardial infarction because you don't have an acutely changing pattern of troponin elevations, but what we really rule in myocardial infarction? You rule in acute cardiac injury. Could be myocarditis, could a apical ballooning. There are a whole variety of other types of disease entities that could be involved and the arbitrary value of 52 that was put in the algorithm really, I think, is much too low for two reasons. One reason, because it didn't include all-comers. A second reason is because of the way in which the comparison between troponin T and I were done. I'll talk about that in just a moment. I would point out that using a different assay, the troponin I assay, in another set of studies, another group from Hamburg has suggested that very different metrics would be much better.

The final thing to say about extrapolation between the assays, and then I have some suggestions about what would make this better if you want to go there now or we can wait, is the comparison and the way in which the metrics for troponin I were developed really weren't by using troponin I as a gold standard. It was by taking and using troponin T as the gold standard for the diagnosis, then thawing samples many years later, running troponin I, and then extrapolating from the gold standard of troponin T to troponin I. Well, there's several problems with that. Number one is that appropriate comparisons should be fresh samples. Fresh samples. In addition, we believe, from the way in which we think about high sensitivity, which may not be correct, that the troponin I assay should be more sensitive and in [inaudible 00:18:05] fact, in the papers that were done validating this approach or attempting to describe the approach, troponin T was wildly more sensitive than was troponin T. We're extrapolating some data that doesn't sort of fit the way in which the information we have, it would mean all of the troponin I validation studies are incorrect.

That's where those numbers came from and even more problematic are the change numbers, which are very low. For the troponin T assay, they're three in five between ruling in and ruling out, which if you look at the assay imprecision, is something the assay can't do. Now you're extrapolating them in a very, very loose manor to troponin I and making them even lower. Those are not doable sorts of things. There's a real problem with the way in which the metrics for troponin I, even though it performed well in this circumstance, ended up being developed. I think all of those things need to be taken into account when we look at the results of the study. The results that Martin and his group got are very similar to the other validation studies that have been done because they've all done it pretty much that same way. There's not a surprise that their validation is similar, but I think unfortunately, we didn't have an opportunity to unmask, in a data-driven way, the problems that I just described.

Thank you Allan. Deborah, if you could share your thoughts on this.

Martin raises some valid issues. That if something goes out as an algorithm, people want to use it. That use needs to be predicated on does it work in their patient population and is it feasible in the time frame and can it be adopted safely and what the indications are. In the emergency department, the value really is the negative predictive value because we want to be able to safely send people home. That's where rapidity of an evaluation is very important.

The other issue raised was exactly what Dr. Jaffe talked about. Does the algorithm itself reflect what we really need? Can you validate something that was created by the scientific way, but really a combination of a lot of information? Are the thresholds really valid themselves? That's the challenge with it. I think what you heard here are kind of two issues we struggle with it. We have a very respectable organization putting out an algorithm that is scientifically based and we want to adopt early, but there are questions on both sides of the issue on whether it can be adapted into real-world clinical practice on a global nature where prevalence of disease is different and the patients it'll be applied to vary, whether it's been on time of presentation or overall demographics.

Also on the scientific side, on the assays itself, are we using the right cutoff? Especially when we're looking at deltas and looking at such a rapid change. It's very nice to hear both of those points so eloquently described today during the discussion.

Thanks Deb. I fully agree. Hence, again, the importance of this paper. Martin, I'd love to hear your responses to Allan's comments and then also share with us, what's the take-home message for you as a clinician? How are you applying what you just found?

The guidelines are good on the right line, it's just as I said, they may not necessarily translate to all other environments. I guess that's my take-home message to myself, which was if I were to look at my own data from my own center, in Christ Church, and the way it's applied here, if I had applied the ESC guidelines and it had met the metrics which I was satisfied with, which I guess would be a very high sensitivity for me in terms of rule out, then I would actually seriously consider implementing it in my own center. It didn't reach that threshold so now I want to try and refine or explore further how I could allow the guidelines to do that. For example, one way that, and this is in the guidelines, but not necessarily in the flow chart, is the importance of applying clinical judgment and clinical findings with the results of the algorithm. I think that's a very important step in it. For example, if I was going to apply this in my own center, I'd want to be setting out clearly for the doctors concerned, how one would incorporate clinical judgment rather than it being a very subjective thing, which might vary significantly between a junior doctor or a far more experienced one.

I guess the take home message for me is this. The ESC guidelines are a very important piece of work. They've been robustly developed. For people who want to implement them, I'm no saying don't use them at all. I'm just saying that, you know, just think about carefully how you would use them and check whether you think they're appropriate for your setting.

That's great. Allan, what about you? What are your thoughts on how this may be applied in clinical practice and what more needs to be done?

I think we need to have a real trial where patients are managed based on the results of these approaches rather than more observational studies. I would argue that those management trials that involve an all-comers sort of population, so we are comprehensive, and should also interrogate whether or not the protocol itself is adequate or whether or not it requires follow-up to meet the metrics that have been proposed. I would point out that in the past, in the studies from the group from New Zealand and Martin Than particularly, have had very, very good follow-up. One at least needs to ask the question whether or not the algorithms that are proposed work perfectly without any follow-up or whether or not follow-up is an important component. We don't know that yet.

Thanks Allan. I'd love to give the final words to Deb. Take home messages?

You know, I think that we need to look at this as a positive in that we're looking at time frames that provide a rapid evaluation and the discussion is around safety. As long as we keep focused on appropriate evaluations for the patients and applying the right algorithm to the right patient, we're going to benefit the care of those we're really concerned about. I appreciate the work that both Martin and Allan both have done on really pointing out how we can do that in a great manor.

Thank you, all of you, for joining us today. I mean, it's been such an enlightening conversation. I'm sure the listeners have enjoyed it and thank you listeners for tuning in. Don't forget to tune in again next week.


Nov 7, 2016


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 for the National heart center and Duke National University of Singapore. Our podcast is really going around the world, and today's feature interview comes to you live from China. Where we will be discussing the prediction of ten year risks of cardiovascular disease in the Chinese population. So now to all our Chinese colleagues out there: Chinese dialect

First here's your summary of this week's journal. The first study challenges the assumption that all patients with vascular disease are at high risk of recurrent vascular events. First author Dr. Kasenbrud corresponding author Dr. Viceren and colleagues form the University Medical center Utric in the Netherlands, provide new data on the estimation of ten year risk of recurrent vascular events and a secondary prevention population. In other words, in patients with established cardiovascular disease they applied the second manifestations of arterial disease or 'smart' score for the ten year risk prediction of myocardial infarction, stoke or vascular death in more than six thousand-nine hundred Dutch patients with vascular diseases ranging for coronary artery disease, cerebral-vascular disease, peripheral artery disease, abdominal aortic aneurysm and poly-vascular disease. Predictors included in the SMART risk score included age, sex, current smoking, diabetes, systolic blood pressure, total cholesterol, HGL cholesterol, presence of coronary artery disease, cerebral-vascular disease, peripheral artery disease, abdominal aortic aneurysm, estimated glomariaol fruition rate, high sensitivity CRP and years since the first manifestation of vascular disease. They further externally validated the risk score in more than eighteen thousand four hundred patients with various types of vascular disease fro the TNT ideals Sparkle and Capri trials.

The overall findings was that the external performance of the SMART risk score was reasonable apart from over-estimation of risk in patients which a ten year risk of more than forty percent. What was striking was the substantial variation in the estimated ten year risk. The median ten year risk of a reoccurring major vascular event was 17 percent but this varied for less than 10 percent in 18 percent to more than 30 percent in 22 percent of patients.

The authors further estimated residual risk at guideline recommend targets by applying the relative risk reductions form meta-analysis to estimated risks for targets for systolic pressure, LDL, smoking, physical activity and use of anti-thrombotic agents. They found that if all modifiable risk factors were at guideline recommend targets only half of the patients would have ten year risk of less than 10 percent. Even with optimal treatment many patients with vascular disease appear to remain at more than a 20 percent or even more than 30 percent of a ten year risk.

The take home message is that a single secondary prevention strategy for all patients with vascular disease may not be appropriate. Instead novel risk stratification approaches may be helpful to individualize secondary prevention by identifying high risk patient which may derive the greatest benefit from novel interventions.










The next study provides experimental evidence that an indigenous-gastro transmitter hydrogen sulfide may potentially be a therapeutic target in diabetic patients with cardiovascular diseases. In this paper by first author Dr. Chen, corresponding author Dr.Kisher and Colleagues from the Louis Cat's school of medicine Temple University in Philadelphia. Authors aim to evaluate the role of hydrogen sulfide deficiency in diabetes induced bone marrow cell dysfunction and to examine the therapeutic effects of restoring hydrogen sulfide production in diabetic bone marrow cells on ischemic high limb injury in diabetic DBDB mice. They further specifically investigated the effects of hydrogen sulfide deficiency on the nitric oxide pathways under conditions of high glucose. They found that bone marrow cells for diabetic DBDB mice had decreased hydrogen sulfide production and lower levels cystathonine gamma lyaze which is the primary enzyme that produces hydrogen sulfide in the cardiovascular system. Administration of a stable hydrogen sulfide donor and over expression of cystathonine gamma lyaze in diabetic bone marrow cells restore their functional and restorative properties. Further more they demonstrated that the therapeutic actions of hydrogen sulfide were mediated by nitric oxide pathway involving endothelial nitric oxide synthase PT495.

In summary these results support the hypothesis that hydrogen sulfide deficiency plays critical role in diabetes induced bone marrow cell dysfunction and suggests that modulating hydrogen sulfide production in diabetic bone marrow cells may have transformational value in treating critical limbs ischemia.

The next study reinforces the importance of hypertension as a critical risk factor for inter-cerebral hemorrhage, and suggests that Blacks and Hispanics may be a particularly high risk. In this study by DR. Walsh and colleagues for the University of Cincinnati, authors conducted the largest case controlled study to date on treated and untreated hypertension as a risk factor for inter-cerebral hemorrhage. They also investigated whether there was variation by ethnicity. The ethnic racial variations of inter-cerebral hemorrhage or eriche study is a prospective multi-center case controlled study of inter-cerebral hemorrhage among Whites, Blacks and Hispanics. Cases were enrolled from 42 recruitment cites, controls were matched cases one to one by age, sex, ethnicity and metropolitan area. A total of 958 white, 880 black and 766 Hispanic cases of inter-cerebral hemorrhage were enrolled. Untreated hypertension was more highly prevalent in Blacks at almost 44 percent and Hispanics at almost 47 percent compared to whites at 33 percent. Treated hypertension was a significant independent risk factor and untreated hypertension was substantially greater risk factor for all three ethnic groups and across all locations. There was a striking interaction between ethnicity and risk of inter-cerebral hemorrhage, such that untreated hypertension conferred a greater risk of inter-cerebral hemorrhage in Blacks and Hispanics relative to Whites.











The nest study provides the first prospective multi-centered data on mortality and morbidity in rheumatic heart disease from low and middle income countries. First author Dr. Zulky, corresponding author Dr. Mayoci and authors from Gertrude hospital and University of Cape Town in South Africa present the results of two year follow up of the global rheumatic heart disease registry or remedy study in 3343 children and adults with rheumatic heart disease from 14 low and middle income countries. They found that although patients were young with a median age of only 28 years the 2 year case fatality rate was high at almost 17 percent. The median age at death was 28.7 years. Mortality was higher in low income and low middle income regions compared to upper middle income countries. Independent predictors of death was severe valve disease, more advanced functional class, atrial fibrillation and older age. Where as post primary education and female sex were associated with a lower risk of death. The authors carefully noted that apart from age and gender the independent risk factors for mortality such as severity of valve disease heart failure, atrial fibrillation and low education were all modifiable and thus they called for programs focused on the early detection and treatment on clinical rheumatic heart disease.

Well that's it for the summaries, now lets go over to China

For our feature interview today we are going all the way to Beijing at the great Wall meeting where we will be meeting authors as well as editors. So here we have first and corresponding author Professor {Dong Fen Gu} and co-author Professor {Sherliang} both from {Fu Y} hospital Chinese academy of medical sciences in Beijing. Welcome

Welcome we are so delighted to be interviewed by you

Dr. Carolyn Lam:

Thank you so much we are so excited to be talking about your paper predicting the ten year risks of cardiovascular disease in the Chinese population. And here we have as well editor in chief Dr. Joe Hill as well as Dr. Amid Kira digital strategies editor and associate editor. Gentlemen how is it in Beijing? And I hear that you have a Chinese greeting for everyone as well.

Joe Hill:
{Ni how} and {nuchme and senchmen}

Amid Kira:
I can't top that but I agree with what Joe said

Dr. Carolyn Lam:
Dr. Gu, could you please tell us what is it that is so different about cardiovascular disease in China compared to what we heard about in the western world.

Okay cardiovascular disease is both leading cause of death in China and in United States as well in European countries. However the patterns for components of cardiovascular disease including coronary arteries and stroke are still quite different in the Chinese populations compared united states. For example there are coronary arteries mortality rate in the united states is along the 100 thousand per year and this is the first leading cause of death in the united states. And for stroke the annual mortality rate is along 36 per 100 thousand in the united states populations. However in china the stroke mortality rate among Chinese populations is around the 160 per 100 thousand, so that almost 3.5 to 4 as high as in untied states. Obviously for our lifestyle in including battery behavior quite different you can easily identify one kind of difference in the united states and the Europe restaurants from Chinese restaurants and some western style restaurants you can figure it out.





And another example, smoking rate is major component for risk of cardiovascular disease it is very high in Chinese adult men. It over 50 percent right now but in the united states in the past 50 years it declined immensely. And around maybe less than around 20 percent and from the previous experiment from studies by Dr. Liu Chin from and my colleague Dr.WU they used the questions for predictions of coronary arteries compared to equations and also use the similar prediction model compares that its chemical cardiovascular disease from the united states population and the Chinese population. That to over estimation if we use the united states produced this kind of equation. So based on this kind of scenario we based on Chinese long term larger scales cohort to precede and study our own prediction model.

Dr. Carolyn Lam:
Wow that is really fascinating Dr. Gu and I really could not agree with you more because I sort of trained in the united states for quite some time and then I moved back to Singapore and saw for myself in Asia the tremendously high rates of stroke. I was also very struck by the relative youth of the patients suffering cardiovascular disease and the differences in risk factors, the smoking but not just that, obesity is almost defined on a different scale in our relatively sized smaller Chinese population compared to that in the western. Congratulations to you and your team for a successful amazing effort. Could you or Dr. Yang now just let us know what are your main findings.

Dr. Yang:





Well I think there are 2 major finding for our work. First we developed a new prediction risk model you know after analysis is for high risk score or equations released by AJ and ACC and is some other risk scores. We included 6 conditional risk factors in combination with our previous knowledge that included age, treated or untreated ISBP, total classical, HDLC current smoking and diabetes. So this traditional risk factors were set up as a base model and then we use the predefined statistical to include new additional variables they were Chinese special elements. Finally in our model there were rates as constraints and geographic region which means northern part versus the southern part in China and also organization is rural or urban area. And finally the forth one is family history as a CVD so this for additional variables in our model suggest that we maybe as a Chinese prediction and equations has something special. For example we feel more attention for central obesity in primary prevention in Chinese populations and also you know the norther part and the southern part there are large differences in the risk profiles. And so maybe according to our risk prediction model we pay more attentions for the residence living in northern part in China.

And then for the second points I think we found that PCE equation which shows for equations was not appropriate to predict ten year risk of in Chinese populations. For example in our revelation cohort we found that our model just slightly over predicts severity risk by 17 percent in Chinese man but when we use the PCE models released form AHA the over-estimation come to 50 percent so maybe equations from western populations are not appropriate to Chinese populations.

Dr. Carolyn Lam:
Thank you so much Dr. Yang I mean those are just such important findings applicable to a huge population in china, like you said. And just as important as the second point that the pooled equations derived from western populations may not be the most appropriate for certain other ethnic populations. I think that a very important message and that why we are so proud to be publishing this in Circulation. Could I ask then are you applying these new equations in your personal clinical practice?


Risk assessment is a fundamental components for prevention of ASSVD. In Chinese we question {turn the PA on} provide a valuable to identify high risk individuals in Chinese populations. And not with just complicated [inaudible 00:18:02] for further analysis. And propose three levels of groups of risk stratification could be identified by cut off 5 percent and 10 percent. So lower risk individuals with predicted activity risk of less than 5 percent should be offered lifestyle wise to maintain the lower risk status. While the moderate risk individual is predicted risk of 5 to 10 percentage for intensive therapeutic lifestyle change wit drug therapy if necessary. For the high individual risk high or large 10 percent teheraph of clinical aliment taken account for physicians recommendation should be required with therapy for the lifestyle modification. Then annually clinic up, including an echocardiographic information for carotid artery back and even for outer [inaudible 00:19:09] CT examinations for coronary artery are recommended. Also blood pressure, lipids, glucose measurement if necessary are suggest according to Chinese guideline. While cardiovascular disease prevention as well as for the epidemic of this kind a lines. For ACVD patients those are different kinds of risk assessment we could know whether their risk profile had been improved or be progressed so that appropriate clinical elements should be taken in clinical practice.

Dr. Carolyn Lam:
Thank you very much Dr. Gu so that just show that these findings are immediately clinically applicable and I trust that means you're suing it in your clinics too, and once again were so happy to be publishing this in Circulation so in the rest of the time in going to now direct questions at Joe and Amid.

How's China been? How are your chopstick skills and any word on how Circulation is being received there?

Joe Hill:
Well Carolyn its a delight to be here this is a bustling media that get better and better every year. In about 2 hours we have our first ever Circulation session, we brought several editors here to discuss the types of content that we are looking to publish, the type of work across prevention and population and electrophysiology of heart failure. This is an extraordinary media that is now internationally acclaimed and as we've heard here, the face of cardiovascular disease in Asia is changing. And as you pointed out 60percent of the human race lives in Asia and we want to do everything we can to be here on the ground, in Asia trying to address this curve that is already present and is worsening by the day.

Dr. Carolyn Lam:
Amid, you know you've seen the latest statistic on our podcasts and you highlighted that we have quite a number of listeners over there as well. Would you like to tell me how this is all blending it to the digital strategies and anything else you might want to highlight?

Amid Kira:
Sure its been an incredible meeting and we get to meet great colleagues like our colleagues today on this podcast and learning so much from this meeting. Our podcast as you pointed out quite a sizable and growing cadre of people in Asia and Japan and China who are listening and we truly want to enhance that as Joe mentioned with the large splurge of cardiovascular disease and the great science that is going on here. Want to make sure that we are able to be apart of that conversation and interact with researcher and clinitions here. In addition to podcast, we are exploring some other options involving social media, specifically in China so stayed tuned in how those develop but we certainly appreciate the importance of being her and interacting where so much of cardiovascular disease and cardiovascular science is occurring.

Dr. Carolyn Lam:
That's so great. Joe or Amid now there's a specific we would like to highlight to our listeners the doodle, either of you want to pick that up a bit about blipping the doodle?

Amid Kira:
So there is as you know Circulation now has this doodle where we change it periodically and its sort of a fun themed thing. Right now I think it Halloween and we've had several other ones that people have designed to sort of keep thing fresh and light and interesting. There's a new app called blippar which you can download from iTunes or android stores and you can essentially scroll that over with your phone with the doodle and that will take you to new content either table of contents of videos, different kinds of content that it can navigate you to. So I hope people will not only enjoy the doodle kind of anticipate what's next in terms of seasons but will take the time t blip the doodle when they get a chance.

Dr. Carolyn Lam:
That great and that blippar- B l I P P A R. You really c should check it out, anyone who is listening to this really check it out you'll be floored. Joe could I just turn the mic to you for any last words about the global outreach of Circulation, I mean its just so amazing that you're there in China

Joe Hill:
Well heart disease Carolyn knows no boundaries nor does Circulation. There was a day when cardiovascular disease was largely an issue in the developed world that is long since gone and that's why the study that we are talking about today with these authors is so important because the face of cardiovascular disease is different than in the west, the ways in which it is  evolving id different here than in the west and I like many others foresee an increase a significant increase in the types and prevalence of heart disease here in Asia. for all the reasons that we have been talking about, hypertension, obesity, type two diabetes, smoking the environment all of these challenges I fear are going to lead to a substantial increase in the prevalence of heart disease in Asia and that why we're here on the ground with Circulation in Asia that's why we have one of our major leaders Chong Shong Ma who is here in Beijing. Circulation is in China everyday, it’s in Beijing everyday to try and address this problem.

Dr. Carolyn Lam:
And you heard it from our editor and chief, so thank you everyone for listening to this episode of Circulation on run. Tune in next week.



Oct 31, 2016


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 interview today comes to you live from Rome at the European Society of Cardiology, where I talk to authors of The STICH Trial, about their ten year outcomes that help to answer the question, "Is there such a thing as being too old for coronary artery bypass surgery in heart failure?" But first, here's your summary of this week's journal:

The first paper provides experimental evidence that hypertension may be a bone marrow disease. In this paper, first author Dr. Wang, corresponding authors Dr. Li and [Sia 00:00:50] from The First Affiliated Hospital of Dalian Medical University in China, recognize that recruitment of leukocytes from the bone marrow to the vascular wall is a key step in the development of hypertension. Numerous factors stimulate this leukocyte migration during inflammation, including chemokines, which are low molecular weight proteins of the cytokine family which activate g-protein coupled receptors and induce migration of neutrophils, monocytes, and macrophages to the damaged vascular wall.

In this study the authors focus on chemokine receptor CXCR2. Using mouse models with hypertension they found that aortic MRNA levels of CXCR2 and its ligand CXCL1 are elevated in these mice with hypertension. They elegantly demonstrated that mice lacking CXCR2 are protected from blood pressure elevation, vascular inflammation of inflammatory cells, fibrosis, reactive oxygen species formation, NADPH activation and vascular dysfunction in response to either angiotensin 2 or [dolcasalt 00:02:01].

These results were recapitulated using a novel, allosteric inhibitor of CXCR2. Importantly, they also showed in 30 hypertensive patients compared to 20 normatensive controls that hypertensive patients have increased numbers of circulating CXCR2-positive cells and that there is a correlation between blood pressure and the number of CXCR2-positive cells in the circulation.

In summary, these findings that CXCR2 inhibition prevents and reverses hypertension and vascular dysfunction in response to multiple hypertensive stimuli really help us to understand the mechanisms involved in CXCR2 action, but also point to a potential clinical use of CXCR2 inhibition for the treatment of hypertension. This is discussed in a beautiful accompanying editorial by Drs. [Montenel 00:02:56] and Harrison.

The next study suggests that the eyes provide a window to long-term cardiovascular risk. In this paper from first author Dr. [Seidelman 00:03:12], corresponding author Dr. [Solomon 00:03:13] and colleagues from the Brigham and Women's Hospital, authors investigated whether retinal vessel calibers are associated with cardiovascular outcomes in long-term follow-up, and whether they provide incremental value over the 2013 ACCAHA pooled cohort equations in predicting atherosclerotic cardiovascular disease events. They studied 10, 470 men and women from the [Eric 00:03:41] or Atherosclerosis Risk in Community Study who underwent retinal photography at their third visit, which occurred in 1993-1995.

During a mean follow-up of sixteen years, narrower retinal arterials, but wider retinal venules were associated with long-term risk of mortality and ischemic stroke in both men and women. Coronary heart disease in women was also related to narrower retinal arterials and wider retinal venules independent of the the pooled cohort equation variables. In fact, retinal vessel caliber reclassified 21% of low-risk women as intermediate-risk for atherosclerotic cardiovascular disease events.

In discussing the clinical implications of these findings, the authors noticed that identification of coronary heart disease is frequently delayed in women and this under-recognition may party be due to the fact that non-obstructive coronary artery disease is more prevalent in women and micro-vascular dysfunction may largely contribute to myocardial ischemia in women. Since the retinal vessels offer an insight into micro-vasculature, adding retinal imaging may be of incremental value to current practice guidelines in risk prediction in low-risk women. This, of course, deserves further study.

The next study challenges the traditional focus on macro-vascular disease in Type 2 diabetes, namely myocardial infarction, strokes, and peripheral artery disease, and causes us to focus on micro-vascular disease instead. In this paper from first author Dr. [Sorrenson 00:05:33], corresponding author Dr. [Stiehauer 00:05:36], and colleagues from the Maastricht University Medical Center in the Netherlands, authors hypothesized that micro-vascular dysfunction occurs in pre-diabetics, which may explain the increased risk of complications of micro-vascular origin in pre-diabetes and early Type 2 diabetes.

They studied 2,213 individuals in the Maastricht study, which is population-based cohort study enriched with Type 2 diabetes, and they determined micro-vascular function, measured as flicker-light-induced retinal arterial[inaudible 00:06:12] percentage dilatation, as well as heat-induced skin percentage hyperemia. They found impaired retinal and skin micro-vascular function in pre-diabetics with further deterioration in patients with Type 2 diabetes. Inverse linear associations were found between micro-vascular function and measures of glycemia such as HBA1C, fasting and two-hour post-op glucose levels. All associations were independent of cardiovascular risk factors.

The clinical implications are that micro-vascular dysfunction in pre-diabetes may at least partially explain the increased risk of complications that are known to be of micro-vascular origin such as retinopathy and albuminuria but also diseases such as heart failure and cognitive decline. The take-home message is that both early hyperglycemia and micro-vascular dysfunction may be considered potential targets for early preventive intervention.

Well, those were your summaries! Now, let's on to Rome.

Hello, I'm Dr. Carolyn Lam, associate editor of Circulation, and I am so delighted to be reporting from Rome this time at the European Society of Cardiology. We are discussing the 10-year followup paper on STICH that includes an age analysis that is being featured as a hotline session of clinical trials update. I'm here with the distinguished guest, the first author, Dr. Mark Petchey, from University of Glasgow, the corresponding author Dr. Eric [Moleskus 00:07:51] from Duke University, and the associate editor who managed this paper, Dr. Nancy [Scheitzer 00:07:56] from University of Arizona. Welcome! [crosstalk 00:07:59]

Right, let's get straight into this. Eric, remind us what it first showed and why there's a need to look at the effective age.

Dr. Eric M. :
Thank you Carolyn. Thanks to Circulation and to both of you for really helping us work through this paper. We are very excited that we're being able to feature this work in Circulation. So, a STICH trial is a reminder. Surgical treatment of ischemic heart failure trial has been a 15-year effort actually that started with the first patient enrolled in 2002, enrollment ending in 2007 and at the ACC with the simultaneous fabrication in the journal, we published the 10-year results of the STICH trial, combining medical therapy vs. cabbage plus medical therapy in patients with ischemic cardiomyopathy defined as an EF less than 35%. Coronary disease [inaudible 00:08:51] to cabbage was over 90% having class 2 or greater heart failure systems.

What we showed in our 10-year results was that cabbage, when added to guideline-directed medical therapy, led to a substantial reduction in all-cause mortality, cardiovascular mortality as well as all-cause plus cardiovascular hospitalization in those patients who were randomized to the cabbage arm. This translated to about an 18 months extension in survival for the cabbage patients over that time period, a 16% relative risk reduction in mortality and nearly a 10% after the risk reduction is all-cause mortality, with the number needed to be treated of approximately 14.

With those findings, the next question that we want to address rapidly was whether there was an impact by age. This is what we're here to talk about, mostly because everyone recognizes that age is, although something we can't control ... As we age, our risk for everything increases, and clearly heart failure, which is the field that we work in clinically, patients who are older in heart failure have more risks, and worse clinical outcomes in patients who are younger. Whether there would be a benefit that would persist in terms of the treatment in younger as well as older patients was really the subject of this analysis.

Dr. Carolyn Lam:
That's great. So maybe, Mark, you could tell us the highlights of the results. Give us an idea, first of all, of the age range that we're talking about, what you looked at. And then- this is definitely going to be an issue if we're talking about age- the relative risks vs. the absolute risk of the different types of outcomes.

Dr. Mark P:
Sure. So, the patients in the STICH trial were similar age to a normal heart failure trial. The median age was around 61. What we did to look at the patients we had in the trial, we looked at quartiles, first of all. So the lowest quartile was aged less than 54, and the highest quartile aged more than 67. So we had a fair spread of age. We didn't have many patients, we were very elderly or very old. So 65% were above age 75 and 1% above the age of 80. When we looked at the patients we saw a similar [inaudible 00:11:18] to a usual heart failure trial. The older patients had more co-morbidities, not surprisingly, and they had more... they basically died more often as they got older as we see in every other trial.

When we started looking at the results, the treatment effects of cabbage, obviously we were very eager to know if the benefits, which Eric's talked about already were seen across all age groups. I think clinicians, when they look at patients for bypass surgery have anxieties around sending older people for bypass surgery. We were thrilled is probably the word to say that we say benefits across all age ranges. So the point has been for us in terms of all-cause mortality were all [less than one 00:11:58]. We saw consistent benefit, or certain across-the-board benefit in terms of all-cause mortality.

What we did see that we were very interested about were the younger patients got more benefit in terms of all-cause mortality, [inaudible 00:12:12] quite strikingly more. The risk reduction was over 40% for the ... We saw upper age groups having benefits with [hazard issues 00:12:24], risk reductions of, roundabout, the [teens 00:12:28], as in the major overall trial results, the younger patients got particular benefit.

We then looked at cardiovascular mortality and we saw a slightly different pattern. We saw the benefit was actually quite similar across all age groups. The older patients were getting the similar reduction in cardiovascular mortality as the younger patients. So there's the main take-home findings.

Dr. Carolyn Lam:
OK, so by extrapolation then, the younger patients, a greater proportion of their deaths were probably cardiovascular, or there's a bit more of a competing risk, so to speak from non-cardiovascular deaths in the elderly, is that kind of the idea?

Dr. Mark P:
Carolyn, that's exactly right. Because the cardiovascular mortality was similar across all age groups, because all people, as we know, die more commonly of non-cardiovascular events, we saw that clearly in the trial the benefits in terms of all-cause mortality weren't quite as much. Just to emphasize, the cardiovascular reduction was consistent across all age groups.

Dr. Carolyn Lam:
With bypass compared to medical, yes.

Dr. Mark P:

Dr. Eric M. :
I think an important aspect to remember and I think STICH reminds us is that even in the oldest population- and although we did these analyses continuously, we described this in quartiles for the purpose of the paper- we have to remember in heart failure patients like these who have coronary disease, cardiovascular death is the most common cause of death, regardless if you're young or old. What happens is that as we get older, there is an increasing rate of non-cardiovascular deaths. It's not surprising to us, that of the findings we found, which is that as the risk of non-cardiovascular deaths increase in the ages, the impact on all-cause mortality is mitigated slightly, while the effect on cardiovascular mortality remains consistent because it's still by far the most common cause, I think more than double the cause even in the oldest group.

Dr. Carolyn Lam:
That's a great point. Now I've got to ask something though. What did you do about crossovers? Because this is a 10-year thing. The original results of STICH came out 5 years. You'd expect that there's quite a bit of crossover or no?

Dr. Eric M. :
I'll just comment on the effect of crossovers in STICH in general, and then we can focus on the age analyses. What's really interesting is that in STICH approximately over time, over the time period, there was approximately an 18% rate of crossovers. That actually led to, by the intention to treat analysis, a decrease in the effect [inaudible 00:15:15] intention to treat. But when you look at crossovers, the medical therapy patients who were randomized to medical therapy but received cabbage at some point, and the patients who were randomized to cabbage but never did receive cabbage. But actually when you look at as-treated analyses, by the treatment they received, not [inaudible 00:15:36] they were randomized, the effect of cabbage actually increases. The relative risk reduction is about 25% in that group. Thankfully, the effect of crossover into different age quartiles were [inaudible 00:15:51] different. We had the same, relatively the same effect, so there were no, we were [eventually knowing 00:15:57] to make sure that there was no increase in crossover rates in the older vs. the younger and we did not find that. I started the discussion, maybe you can complete it.

Dr. Mark P:
Thank you for hitting the nail on the head, Eric, that there weren't many crossovers, but if there were crossovers, if the crossover towards the cabbage, the benefits seemed the be greater and that was seen across all age groups. There was no differential between the older patients and the younger patients.

Dr. Carolyn Lam:
You know then, I just want to know what's your take-home message and then I'd really like to hear from Nancy the take-home message we wanted to convey in our journal.

Dr. Mark P:
I think for me the take-home message goes back to the fundamental approach to assessing a heart failure patient in a clinic. Over the years there's been a tendency for patients not to investigate and look for coronary heart disease. People tend to focus on medical therapy and device therapy but the coronary arteries have been the poorer cousin. I think we would urge people to think about revascularization by surgery, coronary artery bypass drafting's a treatment for  for heart failure, so certainly, my practice, we look for coronary artery disease more than we think about the patient and weigh out the pros and cons and certainly this analysis was done to give us [granularity 00:17:14] from the perspective of the older person and the young person and the relative benefits. Basically, it's steered me towards looking for coronary artery disease. Also you can inform the patient in the clinic and have discussions with the surgeons about the benefit in terms of the all-cause mortality across the age group, and the cardiovascular mortality as well.

Dr. Carolyn Lam:
Yeah, it's consistent. That's brilliant. Nancy, speak on behalf of our journal.

Dr. Nancy S.:
So at Circulation, we were very excited to get this paper because as heart failure clinicians, we all struggle with this issue in older patients in particular. When we look and find coronary disease, these tend to be patients with higher surgical risks. Our surgical colleagues are often hesitant to operate. The benefits are perhaps less apparent, and this data's very helpful to show us that in a patient in whom the heart disease is the primary morbidity, surgical revascularization has a clear benefit for these patients.

I do think that it's important to remember though, that STICH population is a selected population, and probably a little healthier than the average patient we see in clinic. As Mark rightly pointed out, the discussions with surgical colleagues I think can now occur with a greater level of data substantiation and understanding of the true benefits, and then competing risks and morbidities in this patients need to be considered with the reality that surgical revascularization benefits the patients. We're really excited to have worked with you, this fantastic group of authors to get this paper to a point where I think it's really going to have a clinical impact, and that's what we're trying to do. As you know, Carolyn, editorial board at Circ now has published really high-quality science that's going to impact the practice of clinicians seeing patients on a daily basis.

Dr. Carolyn Lam:
Thanks so much for that Nancy, and actually I was going to congratulate you gentlemen. In your paper you so humbly said that these are exploratory, I think, and I was actually thinking that we're never going to have a better trial than this and it's something I am personally taking to be clinically applicable in my heart failure patients so congratulations. I'm going to switch tracks a little bit... we're actually going to a simultaneous publication in Circulation from the European Society of Cardiology and I think that's really neat for our journal, Circulation. I want to ask each of you as author perspective and as associate editor who made this happen, what do you think of these simultaneous publications? Were there challenges, what was it like, and what was your experience like?

Dr. Mark P:
So I have to confess that usually when we submit papers for review, there is a mixture of trepidation, fear, generally quite negative thoughts. We submitted it, and I've got to say that it was the most interactive, positive experience I've had so far. It was quite clear that was interested in the data, and wanted to publish it in a way that informed the clinical community. They certainly worked with us to make sure the message was honed and as accurate as possible to reflect the results. We were really thrilled. It was a "breakneck pace" is also probably the best way to describe it. We worked day and night actually, but there was phone calls and emails happening in very rapid sequence and lots of responsiveness. I could almost describe it as "fun".

Dr. Carolyn Lam:
Kudos to you, Nancy! And from your point of view, was it fun?

Dr. Nancy S.:
It actually was fun.

Dr. Carolyn Lam:

Dr. Nancy S.:
You know, we've all had the experience of- on both sides- being an editor and being an author. Getting a paper, getting reviews, sending it back, getting the revision, it's not quite what you want, reviewing it again, sending it back, getting it back, it's not quite what you want, and then you feel obligated to publish a paper that's not really what you want. What we've decided to do is a much more interactive process to say "We're going to work with you to make this the paper we want to publish. We hope that as authors that's the paper you want to have written." We're doing this on a regular basis at Circulation but this was at hyperspeed, I would say.

Dr. Carolyn Lam:
[inaudible 00:21:34] how long?

Dr. Nancy S.:
We knew the paper was going to come in. We had been in contact with Eric. I identified reviewers before we even received the manuscript. I identified reviewers who would commit to a 72-hour turnaround. In fact, our reviewers did it in less than 24 hours. Then I looked at it, added to it, called Eric, and we talked it over. And then we sent it back with the formal replies. I think Mark then worked 24/7 to get it back to us very quickly. I worked with one of the senior associate editors; at that point we didn't involve the reviewers. We basically track-changed the paper to make the changes we really thought were necessary at the point. It wasn't a lot but I think they were critically changes. At that point, Mark and Eric were kind enough to accept those changes and the paper was on track for simultaneous publication. I do want to mention that we have simultaneous publication of five different presentations here at ESC in Circulation online which is certainly a record for Circulation and we're really proud of that.

Dr. Eric M. :
First of all, I want to think the journal. Really a remarkable, wonderful experience. I've been very fortunate in my career to be in a position to submit simultaneous publications previously, and this was a wonderful- I think it was a 14-day turnaround, it was remarkable. And the responses from the reviewers were outstanding even if they were reviewed in a very short time, and I think the paper definitely improved.

A general comment about simultaneous publications as you bring it up, I think it's an area of controversy. I think my perspective as a person who does clinical trials, as well as sees a lot of patients, there's an ethical mandate that exists to... Once you have information that you're putting out there, to be in a position, if we think it's clinically impactful, and we feel that the data is mature, to get that into people's hands, all of it, as soon as possible. There's a certainly a difference between what I can speak to in 8-10 minutes on stage with slides that will get distributed anyway across the world, and what, with Nancy's help, we are able to put into journal-wide circulation and really explain the story and give it a full [vetting 00:24:05]. I feel like, from the ethical perspective, being able to push forward with this simultaneous publication is in the best interest of our patients, and it's so exciting to see Circulation now doing this with the European Society, which is a remarkable achievement for this new editorial board, so thank you again.

Dr. Carolyn Lam:
You've been listening to Circulation on the Run. Tune in next week for more.


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