Dr. Carolyn Lam: Welcome to Circulation on the Run your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Is it time to end our debates on short versus long duration of dual anti-platelet therapy? Well I will be discussing this with two very special guests in just a moment. But first here is your summary of this week's journal.
The first paper tells us that HDL particle number may serve as a biomarker of residual risk when assessed on statin therapy. First author Dr. Khera, corresponding author Dr. Mora from Brigham and Women's Hospital and colleagues of the JUPITER trial assessed HDL cholesterol levels, apolipoprotein A-1, cholesterol efflux capacity and HDL particle number at baseline and 12 month in a nested case control study of the JUPITER trial. That was a randomized primary prevention trial that compared rosuvastatin to placebo in individuals with normal LDL but increased CRP levels.
In the current study the authors found that cholesterol efflux capacity was moderately correlated with HDL cholesterol, apoA-I, and HDL particle number. Baseline HDL particle number was inversely associated with incident cardiovascular disease, while there was no significant association for baseline cholesterol efflux capacity, HDL or apoA-I levels. On-statin cholesterol efflux capacity was inversely associated with incident cardiovascular disease but HDL particle number again emerged as the strongest predictor.
Thus for both baseline and on-statin analyses, HDL particle number was the strongest of four HDL-related biomarkers as an inverse predictor of incident events and biomarker of residual risk. Whether therapies designed to enhance cholesterol efflux capacity or an increased HDL particle number can also reduce cardiovascular risk however remains uncertain.
The next study sheds light on mechanisms underlying the de-differentiation and lineage conversion of adult human fibroblast into functional endothelial cells. First author Dr. Zhang, corresponding authors Dr. Rehman and Malik from University of Illinois College of Medicine first generated CD34+ progenitors by de-differentiating adult human skin fibroblasts and showed that these intermediate progenitors could give rise to endothelial cells as well as erythrocytes. They then showed that lineage conversion of fibroblasts via partial de-differentiation recapitulated in part the embryonic development of the vasculature as evidenced by up regulation of anti-aging enzyme telomerase and the bi-lineage potential of the generated progenitors.
Importantly they showed that transcription factor SOX17 functioned as a switch which regulated the cell fate of CD34+ progenitors towards an endothelial versus erythroid lineage. Finally implanted fibroblast derived CD34+ progenitors stably engrafted to form functional human blood cells in mice that improved cardiac function after myocardial infarction. Thus the molecular switch SOX17 provides a means to optimize the generation of endothelial cells for vascular tissue regeneration or disease modeling.
What do drones have to do with out of hospital cardiac arrest? Well in this next study by first author Dr. Boutilier corresponding author Dr. Chan and colleagues from University of Toronto, the authors hypothesized that a drone network designed with the aid of a mathematical model combining both optimization and queuing could reduce the time to AED arrival.
Using data from over 50,000 historical out of hospital cardiac arrests covering over 26,000 square kilometers in Ontario, Canada, they found that a drone network designed to reduce the median AED arrival time by three minutes relative to the historical 911 response could also reduce the 90th percentile of the AED arrival time by between 6 minutes and 43 seconds in most urban regions and 10 minutes and 34 seconds in most rural regions.
Thus this study tells us that drone delivered AEDs have the potential to be a transformative innovation in the provision of emergency care to cardiac arrest patients especially those who arrest in a private or rural setting.
The next study provides thresholds for ambulatory blood pressure among African Americans. Dr. Ravenall and colleagues from New York University School of Medicine analyzed data from the Jackson Heart Study, a population-based cohort comprised exclusively of African-American adults and of whom more than 1000 participants completed ambulatory blood pressure monitoring at baseline.
Based on the outcome derived approach for systolic blood pressure and a regression derived approach for diastolic blood pressure, the following definitions corresponded to clinic blood pressure of 140/90 and were proposed as ambulatory blood pressure definitions for African Americans. Daytime blood pressure above 140/85, 24 hour blood pressure above 135/80 and nighttime blood pressure above 130/75 mmHg. Note that these ambulatory blood pressure thresholds identified for African Americans were higher than those from published recommendations mainly derived in European, Asian and South American populations. The use of these ambulatory blood pressure thresholds for African Americans will lead to a lower prevalence of daytime, 24 hour and nighttime hypertension compared with the current published recommendations.
The next paper provides pre-clinical evidence of a novel target in plaque information in atherosclerosis. Dr. Stachon and colleagues from Heart Center Friburg University in Germany hypothesized a functional role of the signal axis ATP binding to purinogenic receptor P2X7 in inflammasone activation and chronic inflammation driving atherosclerosis.
In an elegant series of experiments they showed that P2X7 receptor activation was crucial for inflammasone assembly and interleukin-1-beta secretion. The lack of P2X7 in mice abolished inflammasone activation in atherosclerotic lesions. P2X7 was expressed in murine and human atherosclerotic lesions. LDL receptor deficient mice lacking P2X7 receptor had reduced plaque inflammation and were less prone to develop atherosclerosis.
Thus this study shows that P2X7 inhibition could be a treatment strategy against plaque inflammation in atherosclerosis.
The next paper describes the first prospective clinical study of adenosine use in pediatric and young adult patients after heart transplantation. Now prior to this study adenosine was relatively contraindicated post-transplant due to a presumed risk of prolonged atrioventricular block in denervated hearts.
In the current study first author Dr. Flyer corresponding author Dr. Silver and colleagues from Columbia University performed a single center prospective clinical study testing whether adenosine caused prolonged asystole after transplant and if it was effective in blocking AV nodal conduction in healthy heart transplant recipients aged 6 months to 25 years presenting for routine cardiac catheterization. Following catheterization, a transvenous pacing catheter was placed and adenosine was given following a dose escalation protocol until AV block was achieved.
Eighty patients completed adenosine testing. And no patient required rescue ventricular pacing. AV block was observed in 77 patients with the median longest AV block of 1.9 seconds and the mean duration of adenosine effect of 4.3 seconds.
Thus, this study suggests that adenosine may be safe and effective in patients post transplantation and establishes both a safe and effective starting dose of 25mcg/kg or 1.5mg for patients weighing 60kg and more. It also establishes a stepwise therapy escalation plan to avoid prolonged bradycardia. Although patients after heart transplantation may require less adenosine to achieve AV block it appears to be safe and effective as therapy for evaluation and or treatment of tachycardia in this population.
Well those were your summaries, now for our feature discussion.
Today for our feature discussion we are talking about a very familiar situation, dual anti-platelet therapy following coronary intervention and the decision of long versus short duration of therapy. A debate we've heard many times but according to the perspective piece in today's journal, maybe a debate we should end. And I am so pleased to have the author, Dr. Glenn Levine from Baylor College of Medicine as well Dr. Laura Mauri associate editor from Brigham and Women's Hospital.
Dr. Laura Mauri: Thank you Carolyn.
Dr. Glenn Levine: Thank you.
Dr. Carolyn Lam: Glenn would you like to start by presenting your case. It's time to end a dualistic short versus long duration of DAPT debate. I really like that title, tell us more.
Dr. Glenn Levine: Thank you Carolyn.
The point we make in our editorial is that over the last five or six years there have been studies comparing what I term standard, which is usually about 12 months DAPT versus shorter duration DAPT and there are other studies comparing standard DAPT versus longer duration DAPT. Those generated important information in different people interpret them in different ways. What though has happened over the last several years is certainly for both educational and entertainment value at meetings as well in editorials, the idea of how long people should be treated with DAPT has been oversimplified to whether all patients should be treated with short duration or long duration. And Laura herself knows that as she has been in many of these debates.
While I think that initially that was educational and entertaining, I think these days people understand those points and a greater issue is in that we should treat some people with short duration, some with what I call standard and some with long duration. And rather than debating whether everyone should treated with short or everyone should be treated with long, I think what we need to focus on now is which patients should be treated with short duration, which are probably best treated with a standard duration and which are best treated with prolonged or extended duration DAPT.
And that in a nutshell is the main point that we make in this perspective editorial.
Dr. Carolyn Lam: Laura, so do you agree?
Dr. Laura Mauri: I couldn't agree more. I think clinicians really are looking for guidance and what happens at these debates is you see these polarizing opinions that debaters are asked to defend when in actuality there's such a wide spectrum of what individual patients need. And the real question I think going forward is how to end these debates and how to provide really more tailored information so clinicians and patients can make better decisions together. And I think that's really where the piece that Glenn has written really helps direct us.
Dr. Carolyn Lam: Yeah, Glenn, I mean are we talking about the usual risk versus benefits and precision metsan or individualized risk assessment here?
Dr. Glenn Levine: Yeah, what we're talking about is looking at the ischemic risks which are primarily leg stent thrombosis or spontaneous MI versus the bleeding risks which is obviously bleeding and balancing them. And there clearly are decision tools available to clinicians. Laura has pioneered the DAPT score which is an incredibly user friendly and easy tool to use to assess which patients should be continued with prolonged DAPT or not. And there are also some other tools out there including the Paris registry score perhaps a little more complex and then there's also now the precise DAPT score which one can at least assess bleeding risk and indirectly assess the ischemic and bleeding risk.
But really I think that is the focus now on balancing bleeding and ischemic risks and having pools to allow clinicians to easily do that.
Dr. Carolyn Lam: That's true. Now do you think guidelines have to catch up or have they caught up?
Dr. Glenn Levine: Our DAPT duration guideline was coming out just as Laura's DAPT score was about to be published, several months after it had been presented. And we did mention the DAPT score in our paper, it was too early to formally incorporate it into the guidelines. Nevertheless, the way our guidelines are written, they clearly give practitioners the option for individualizing therapy based on ischemic and bleeding risk and Laura's DAPT score fits perfectly into what we aim to do, namely to encourage practitioners to assess patients on an individual level and assess what duration of DAPT is best.
Dr. Carolyn Lam: I do have a question for Laura here though. I see Asian patients, I'm talking to you here from Singapore. And sometimes you wonder the trial situations and what you derive there. How does it differ from real world and how is it impacting your practice for example Laura?
Dr. Laura Mauri: That's a great question. I think you have a number of points there. One is the generalized ability or results from one trial across the world where you might have many different patient populations. And while the DAPT score was an international trial it would be interesting to see more data coming out from other different countries. And as you know there are trials in Asia that have looked at randomized DAPT duration as well.
I think now that we have better access to information especially in cardiology globally, we can get that information and better tailor therapy. When we look at any one randomized trial the results might seem kind of black and white and to certain extent so do guideline recommendations but we are getting better at using the results from randomized trials to really identify risk factors. I think that with time we'll be able to either validate the DAPT score in other patient populations or develop tailored scores from unique data sets. I think the challenge really is making sure that we still get good randomized evidence for our treatment decisions but then when we have treatments that have both benefit and risk that we identify which sub-populations of patients really do achieve most of the benefit. And then the other populations that might be harmed. And that's really what we try to do with this score.
And I think what you'll see, you asked about precision medicine which usually we think about using genetics but I think there's so much just really basic information that we have about patient lesion characteristics and other specific factors that we record routinely in their medical records that we can use and you'll see this, I think more and more frequently across different areas of investigation and in cardiovascular medicine.
One really interesting example recently was this French trial. Data was used to be able to predict, very similar to what we did, but to predict which patients would benefit from lower blood pressure without the risk of more aggressive treatment.
Dr. Carolyn Lam: Yeah, I love the way you put that. Those are really words of wisdom, I do think that that is the way cardiovascular medicine is gonna move. Glenn, how do you put all this into practice for yourself?
Dr. Glenn Levine: I think whether or not I formally calculate a DAPT score or Paris registry score, I think clearly we integrate the factors in those scores into our everyday practice. And clearly there are patients who are at high bleeding and low ischemic risk and vice versa. I would also encourage listeners to in addition to all the scores, one has to think about the consequences of a recurrent MI or stent thrombosis. Obviously someone who has stent thrombosis of a proximal LED lesion, if they already have a depressed EF or occluded RCA, those consequences are likely much more dire then someone who occludes say at a distal OM3 stent who has the normal ejection fraction. It also encourages them to think about the consequences of stent thrombosis as well as the consequences of a recurring MI.
Dr. Laura Mauri: Just to make it clear, we know that clinicians have always tried to balance these different risks of ischemia and bleeding when faced with this decisions. I think the challenge really has been the limited amount of information that we've had to be able to do that. And so we've really just used kind of our gut until recently when we've had several large randomized data sets to be able to look to. And what that's done is it's given us the ability to construct these new tools to be able to make practice more data driven. Now still individualized but based on data that's tailored to our patients.
And so I think we can use that to be able to improve outcomes. That being said, we don't want to rely on a statistic or a score alone and things like the DAPT score are based on patients like the ones that were enrolled into the randomized trial. Those were patients who could take longer anti-platelet therapy. It helps to identify who can take it for longer. But there are patients who get anti-coagulation or have other serious bleeding risks who really are going to benefit from new technologies to be able to shorten anti-platelet therapy.
Dr. Carolyn Lam: Well thank you Glenn once again for a wonderful perspective piece that has really got us thinking about situations even beyond dual anti-platelet therapy. Thank you Laura for your insights and thank you listeners for joining us today. Join us again next week.
Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore.
In our feature discussion today, we will be talking about insights from the PROMISE Trial regarding the prognostic value of non-invasive cardiovascular testing in patients with stable chest pain. First, here's your summary of this week's journal.
The first paper reports novel findings on gene smoking interactions in coronary heart disease. Co-corresponding authors Dr. Salahin from the University of Pennsylvania and Dr. Riley from Columbia University and colleagues used data on almost 61,000 coronary heart disease cases and more than 80,000 controls to investigate effect modification by smoking behavior at established coronary heart disease and smoking-related genetic loci.
They found that the cardio-protective effects associated with allelic variation at the A-D-A-M-T-S seven, or ADAMTS7 locus, were attenuated by 60% in patients who smoked tobacco, compared to those who did not smoke. Allelic variation in ADAMTS7 associated with reduced coronary heart disease risk, was associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines.
Furthermore, exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. These human genomic data therefore provide new insights into potential mechanisms of coronary heart disease in cigarette smokers and suggests that inhibition of ADAMTS7 may be a novel potential therapeutic strategy for coronary heart disease that may have particular benefits in individuals who smoke cigarettes. This is discussed in an editorial entitled Holy Smokes, an Interaction, by Dr. Braxton Mitchell.
The next paper provides first evidence that genetic over-expression of CD39 may offer ischemic cerebral protection. CD39 is an ectoenzyme with a PYRase activity, which cleaves ATP and ADP. CD39 is expressed on the surface of myeloid and vascular endothelial cells where it dissipates the high local concentrations of ATP and ADP, which would otherwise serve as potent pro-inflammatory and pro-thrombotic signals.
In the current study from first author Dr. Bick, corresponding author Dr. Pinsky from University of Michigan Medical Center and colleagues, authors used a model of permanent middle cerebral artery occlusion to show that CD39 expression reduced edema, infarct volume, and inflammation with corresponding improvements in neurological outcomes, compared to control mice. Over-expression of CD39 in only the myeloid cells also reduced cerebral infarct volume. Thus, amplification of endogenous CD39 expression, or even administration of exogenous circulating CD39, may be of future interest as a therapeutic target to minimize ischemic injury caused by cerebral ischemia.
The next paper provides pre-clinical data to show that MicroRNA93 may have a therapeutic role in peripheral artery disease. First author Dr. Ganta, corresponding author Dr. Annicks and colleagues from University of Virginia, used MicroRNA-106b-93-25 cluster knockout mice and showed that MicroRNA93 over-expression alone was sufficient to enhance angiogenesis, arteriogenesis, and perfusion in ischemic muscle via increased M2-like macrophages.
MicroRNA93 targeted interferon regulatory factor 9 to inhibit immune response gene 1, and itaconic acid generation in macrophages to induce M2-like macrophage polarization. Furthermore, MicroRNA93 over-expression produced a paracrine effect on macrophages that induced angiogenesis and skeletal muscle recovery under hypoxic conditions in vitro.
Thus, these data demonstrate that MicroRNA93 induces beneficial effects in multiple cells that can enhance perfusion in ischemic limb and thus identifies MicroRNA93 as a putative therapeutic target in clinical peripheral artery disease.
The next study is a large scale genetic analysis that represents the most comprehensive causal assessment of adiposity with cardiometabolic diseases to date. Co-corresponding authors Dr. Cassis and Dale from University College London used 97 snips for BMI, and 49 snips for waist-hip ratio adjusted for BMI, to conduct mendelian randomization analysis in 14 prospective studies supplemented with coronary heart disease data from CADRIoGRAM+C4D, stroke data from METASTROKE, Type II Diabetes data from DIAGRAM and lipids data from GLGC Consortium.
They found that both waist-hip ratio adjusted for BMI, and BMI had causal effects on coronary heart disease and Type II Diabetes, and were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6 and circulating lipids. However, only waist-hip ratio adjusted for BMI increased the risk of ischemic stroke. Thus, both the amount of adiposity and its distribution play important roles in influencing multiple cardiometabolic traits and the development of cardiometabolic disease.
Furthermore, the findings indicate that body fat distribution has multiple roles in disease that are independent of general adiposity. This suggests that physicians should pay attention to measures of adiposity beyond BMI.
The next study addresses the conundrum that clinical trials show benefit of lowering systolic blood pressure in people aged 80 years and above, but yet, non-randomized epidemiologic studies suggest lower systolic blood pressure is associated with higher mortality. In the current study by Dr. Ravindrarajah and colleagues of King's College London, a population based cohort study was conducted using electronic health records of 144,403 participants aged 80 years and older, registered with family practices in the United Kingdom, and followed for five years.
Mortality rates increased with frailty level, and were highest at a systolic blood pressure of less than 110 millimeters mercury. Furthermore, systolic blood pressure trajectories showed an accelerated decline in the last two years of life, without evidence of intensification of anti-hypertensive therapy.
Thus, a terminal decline of systolic blood pressure in the final two years of life suggests that non-randomized epidemiological associations of systolic blood pressure with higher mortality may be accounted for by reverse causation. That is, participants with lower blood pressure values were closer on average to the end of life. This is discussed in an accompanying editorial by Dr. Naveed Sattar.
Well, that wraps it up for our summaries. Now for our feature discussion.
The evaluation of stable patients presenting with suspected coronary artery disease is by far one of the most common diagnostic evaluation strategies that we need to undertake in cardiovascular medicine. There's a whole host of evidence supporting prognostication based on various non-invasive tests, such as anatomic imaging with coronary computed tomography angiography, but also with stress testing, or functional testing, such as stress nuclear or echocardiography, or exercise electrocardiography.
However, our paper today really sheds light on the comparison of these two strategies. And I'm just delighted to have starts with me. First, the primary author of the paper, from the PROMISE Trial, Dr. Udo Hoffmann, from Massachusetts General Hospital, Harvard Medical School, and the editorialist of a beautiful accompanying editorial, Dr. Leslee Shaw from Emory University School of Medicine, Atlanta, Georgia.
Dr. Udo Hoffmann: Hi, Carolyn. Hi, Leslee.
Dr. Leslee Shaw: Hi, Udo, how are you?
Dr. Carolyn Lam: So, Udo, could you start by just sharing what you did in this PROMISE Trial?
Dr. Udo Hoffmann: The Promise Trial is a large comparative effectiveness trial that was done between 2009 and 2012, with follow-up ending 2013, at [inaudible 00:10:13] sites across the U.S. and Canada. And what it did was compare two strategies for testing patients with suspicion of coronary disease, symptomatic patients. These patients were randomized to either receive a functional test first, or an atomic test first, and the idea was to see whether providing the functional information or the anatomic information leads to differences in outcomes of these patients.
As you know, the primary paper showed that the health outcomes of these two strategies were similar and not different. Now in this paper here, we took the slightly different approach and we really wanted to see how the results of the tests as they were seen by the [inside 00:11:02] so it was all based on the sight interpretations of these tests. How the results of these tests actually were associated, or were associated with the health outcomes. And so we directly compared categories of CT results, and categories of functional testing results, and how they are related to outcomes. The good news I think is that sight interpretations in real life do actually have prognostic value for both the anatomic or the CT, and also the functional testing, and so findings as significant disease [inaudible 00:11:36] ischemia have in fact similar prognostic value. And we also saw that on the lower end of the findings, so mildly abnormal findings for example, that the ability to see nonobstructive CAD, perhaps if you're a difference maker and identify from additional patients or group of patients that is at risk for [inaudible 00:12:01].
Dr. Leslee Shaw: I think that often times we struggle with negative trial results, if I can put PROMISE in that negative trial results. And here we have a paper that I think really applies clinically. I think it's going to have far-reaching clinical implications. I think if you look at the CTA findings, this is a real world practice. I think there's a simplicity to CTA interpretations that really is amplified in the nice ability to risk stratify. Whereas the functional interpretation, as you both know, is complex. It integrates a lot of factors, wall motion, perfusion imaging, ST segment changes, exertional symptoms, all of that, and I think we see a lot of sight variability in that image interpretation on the ischemia-side of the functional testing arm.
But there's and important finding from this paper, which I think we have seen in bits and pieces prior to this report, and that is that on the CTA side, you had about a third of the patients having pure normal coronaries. So you see that very low risk in that population. But what you see on the functional testing arm is that the event rate in patients with normal studies and in patients with a mildly abnormal study, the event rates were identical, which is fascinating.
And importantly, two thirds of the population on the functional testing arm were in those normal and mildly abnormal subgroups, something like that. And that has important implications for what is in that one third on a CTA side with normal findings versus three quarters? Well I think from this randomized trial, I think we can infer that you're going to have some non-obstructive disease in that population, but you're also going to have non-ischemic obstructive disease.
We know from FFR and all of the angiographic literature that not every obstructive lesion is ischemic. And so on the stress testing side, we have a lot of obstructive disease that potentially is missed. And I think this study really clearly illustrates that limitation of stress testing and it reflects sight variability in imaging and the interpretation. It reflects the patient populations and the struggles with doing stress testing, but also just flat out reflects the ischemic cascade, and what we can expect from an obstructive lesion, or a non-obstructive lesion, that may not elicit ischemia.
So to that extent, I think Udo's paper is just, just far-reaching and really clearly one of the most advanced papers that we have seen in such a long time. From really providing an important message for those imagers and for folks doing stress testing in this country.
Dr. Carolyn Lam: should we then always do anatomic testing first before selective stress testing?
Dr. Udo Hoffmann: The choice of testing is very much I think tied to the population of the patient you're talking about. I think when you follow the literature, 30 years ago when all the classic studies out of [experienced centers 00:18:53] such as Cedar Sinai, were published, the ischemia burden was much higher in the tested population. Back then you had probably a third or 40% of patients who in fact had some abnormality or ischemia on stress testing. One of the findings here in this study, and that is true for both tests, is that the prevalence of severe findings, severe abnormalities, whether ischemia or obstructive disease, is what I found testing is pretty similar, so it's both around 12%, but it is relatively infrequent. And I think that has changed.
And you cannot expect, as Leslee pointed out nicely, it is not expected from a stress test to detect non-obstructive disease that has prognostic value, but doesn't necessarily explain these symptoms that the patient is presenting. So we should not forget that these patients do not come for primarily for prognostic assessment, they come because they're symptomatic. And the primary question is do we find an equivalent that could explain the symptoms of the patient? And only once we are convinced that there's no such equivalent that would for example lead us to further assess the patient for potential reverse [inaudible 00:20:19] therapy, then the second question that can be answered is for the prognostic implication of the test. And I think in this relatively low risk population, this prognostic aspect gains more importance irrelative to the diagnostic aspect.
Dr. Carolyn Lam: I think Leslee made it very clear in her editorial as well, not to forget in essence at the extremes of disease, that both tests, both strategies conveyed similar prognostic information, and it was more for the fine grain teasing apart that perhaps we need to consider very, very carefully what your paper is saying. But at the end of the day, it's about treating the patients for their cardiovascular risk management, isn't it? Recognizing that even if you don't have ischemia, if you've got the risk factors, like you nicely showed, that we should be treating them for the risk factors.
Leslee, want to share some of your thoughts there? You covered that so nicely in your editorial.
Dr. Leslee Shaw: Well I think that's one thing we've seen from PROMISE, SCOT-HEART, and many, many other recent trials as of late, over the last three or four years, is that the stress test is an opportunity not only to assess ischemic burden, or that CTA's not only a test to assess the extent and severity of coronary disease as well as plaque, but it's an opportunity to identify clear, preventive strategies for the patients.
And this is really something that I don't think at least historically within the stress testing community, that we have taken upon ourselves in order to say, "Okay, here we have a symptomatic patient. We not only are going to assess ischemia, but we're going to look at what else they need to do in order for us to guide prevention." I think this is a clear reminder that this is a great opportunity for us to have a bit of a paradigm shift on the diagnostic testing, to take that whole picture if you will of the patient, and really to focus in on prevention because that is a great opportunity, as Udo talked about just a few minutes ago, it's a great opportunity for us to set the patient on the correct course.
The guidelines, as both of you know, focus in on having that diagnostic evaluation and to implement guideline directed medical therapy as a front line examination. This is a great opportunity for us to just use that diagnostic evaluation ad the initiation of appropriate care for the patient, and then to look at symptom burden, recurrent symptoms, the need for additional interventions. But that first step is guideline directed medical therapy for the patient.
Dr. Udo Hoffmann: Continuing on Leslee's excellent point, I think the paper I think is hopefully a starting point to think about randomized trial, because we assume some maybe come to the conclusion, okay, if you have non-obstructive disease, you should be treated with [inaudible 00:23:13] and aspirin. But we don't know that. I think this is really a call for randomized trial. PROMISE was the one, and it was a good trial. It looked at the association of strategy with an outcome. I think one trial that is needed is to look what specific therapeutic decisions based on imaging or based on test diagnostic test findings, would be justified and would potentially lead to improved outcomes. And that is true for both the stress testing and the CT side. So I think this paper shows the opportunities, but I don't think we have the randomized data to exactly define what are the management options for each of these details of the information that these test results deliver us.
Dr. Carolyn Lam:
Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore. Our featured paper today provides important trial evidence that will guide interventional management of symptomatic femoral artery disease, but first, here's your summary of this week's journal.
The first paper sheds light on the interaction between left ventricular dysfunction and mesenchymal stromal cell activation. First author, Dr. Naftali-Shani. Corresponding author, Dr. Leor and colleagues from Neufeld Cardiac Research Institute in Israel isolated mesenchymal stromal cells from cardiac and subcutaneous fat tissues of mice with left ventricular dysfunction, 28 days after myocardial infarction or sham operation. They further injected mesenchymal stromal cells or saline into the infracted myocardium of mice and evaluated left ventricular remodeling 28 days after myocardial infarction. They found that left ventricular dysfunction switched cardiac mesenchymal stromal cells towards an inflammatory phenotype and that these pro-inflammatory mesenchymal stromal cells contributed to adverse left ventricular remodeling and dysfunction. The inflammatory polarization of cardiac mesenchymal stromal cells by left ventricular dysfunction was mediated by toll-like receptor four. Finally, toll-like receptor four deficiency in mesenchymal stromal cells attenuated their pro-inflammatory activation, improved their reparative properties, graft survival, infarct repair and left ventricular remodeling.
In summary, the environment of the failing and infarcted myocardium drove resident and transplanted mesenchymal stromal cells towards a pro-inflammatory phenotype that restricted their survival and reparative effects in a mechanism mediated by toll-like receptor four. Targeting toll-like receptor four in mesenchymal stromal cells could improve the safety and efficacy of cell therapy in heart failure.
The next study provides evidence that fractional flow reserve or FFR is a useful index for decision-making in real life daily cath lab practice. First author, Dr. Ahn, corresponding author, Dr. Park and colleagues from Heart Institute Asan Medical Center in South Korea, evaluated the prognosis of deferred and revascularized coronary stenosis after FFR measurement in the IRIS-FFR registry of 5,848 prospectively enrolled patients. This large prospective registry showed that the FFR was linearly associated with the risk of cardiac events in deferred lesions. In addition, revascularization for coronary artery stenosis with a low FFR of less than 0.75 was associated with better outcomes than deferral, while for a stenosis with a high FFR of greater than 0.76, medical treatment would be a reasonable and safe strategy. Thus, the authors concluded that FFR may be considered a clinical prognostic index in addition to a physiological quantification for flow-limiting stenosis. These and other issues are discussed in an accompanying editorial by Doctors De Bruyne, Fournier and Barbato.
The next study sheds important insights into a potential disease modifier in pulmonary arterial hypertenstion, and that is vascular endothelial growth factor receptor three, or VEGF receptor three. First author, Dr. Hwangbo, Co-corresponding authors Dr. Chun and Dr. Jin from Yale Cardiovascular Research Center in Connecticut, used a combination of experimental animal models, human patient cells and detailed signaling studies to demonstrate the importance of a novel interaction between bone morphogenetic protein type two receptors, or BMPR2 and VEGF receptor three in regulating the robustness of endothelial bone morphogenic protein signaling response. They demonstrated that the interaction was critical for promoting BMPR2 internalization in response to bone morphogenic protein stimulation. They further showed that genetic deletion of endothelial VEGF receptor three in mice resulted in exacerbation of chronic hypoxia-induced pulmonary hypertension and impaired bone morphogenic protein signaling. Thus, these findings identify VEGF receptor three as a key regulator of endothelial BMPR2 signaling and a potential determinant of pulmonary arterial hypertension penetrance in humans.
The next study tells us that a low-dose drug-coated balloon may be a promising treatment option in symptomatic superficial femoral or popliteal artery disease. Dr. Schroeder and colleagues of the Jewish Hospital in Berlin, Germany, reported results of the ILLUMENATE European Randomized Clinical Trial, which was a prospective randomized multi-center, single-blinded trial, where patients were randomized 3:1 to treatment with a low-dose drug-coated balloon or an uncoated percutaneous transluminal angioplasty balloon. The primary safety endpoint was a composite of freedom from device and procedure-related death through 30 days, and freedom from target limb major amputation and clinically-driven target lesion revascularization through 12 months. The primary effectiveness endpoint was primary patency at 12 months. The main results were that in symptomatic patients, with superficial femoral and/or proximal popliteal artery disease, low-dose, drug-coated balloon was safer and more effective than uncoated percutaneous transluminal angioplasty balloons through follow-up of 12 months. This is discussed as a novel strategy to reduce femoral popliteal restenosis in an accompanying editorial by Doctors Goldsweig and Aronow.
The final study provides important genotype-phenotype correlations of SCN5A mutations in probands with Brugada syndrome. First author, Dr. Yamagata, corresponding author, Dr. Shimizu and colleagues of Nippon Medical School in Tokyo, Japan, studied 415 Japanese Brugada syndrome probands to assess the association between SCN5A mutations and clinical outcomes. During a mean follow-up period of 72 months, the overall cardiac event rate was 2.5% per year. Compared to probands without mutations, probands with SCN5A mutations experienced their first cardiac event at a younger age, had a higher positive rate of late potentials and exhibited longer P-wave, PQ and QRS durations, and had a higher rate of cardiac events, especially when the mutations were located in the pore region of the encoded protein. The conclusion was therefore, that genetic screening for SCN5A mutations among Brugada syndrome probands may be useful for stratifying such patients according to their risk of subsequent cardiac events. Well, that wraps it up for your summaries. Now for our feature discussion.
Our feature paper today is the stuff that really could change guidelines. Now, we're talking about superficial femoral artery disease and its treatment. Unlike most other vascular beds, where stenting is the preferred modality of endovascular revascularization, the optimal therapy for superficial femoral artery disease remain controversial. However, today's paper really adds to our insight and I am so pleased to have the first and corresponding author Dr. Ilka Ott, from German Heart Center in Munich, as well as Dr. Manos Brilakis, Associate Editor, from UT Southwestern. Welcome both.
Dr. Ilka Ott: Welcome.
Dr. Manos Brilakis: Morning.
Dr. Carolyn Lam: Wonderful. So Ilka could you please share what you found?
Dr. Ilka Ott: We already know from previous studies there has been a lot of studies showing the drug-eluting balloon is superior to plain angioplasty in superficial artery disease. So then, in our study, we found that the treatment with the drug-eluting balloon plus stenting was very superior to the balloon angioplasty plus stenting and the directional atherectomy. The primary endpoint we used in the study was an angiographic endpoint. It was diameter of stenosis and this was significantly lower in the patients treated by drug-eluting balloon angioplasty, as compared to the balloon angioplasty and atherectomy group. Moreover, we had a clinical follow-up of 24 months and we found that also the target lesion revascularization was 70% in the group of drug-eluting balloon plus stent as compared to 37% in the balloon angioplasty and stent group, and 53% in the atherectomy group. We found a significant reduction also in the clinical endpoint of TLR at three years.
Dr. Carolyn Lam: Wow Ilka, congratulations, but may I just ask, was there any reason to think that a drug-eluting balloon would not be similarly beneficial as in other vascular beds?
Dr. Ilka Ott: Well, I think is not a novelty of the study. We already know from previous studies that drug-eluting balloon is superior to plain balloon angioplasty so that's not a surprising result. However, in disease of the femoral superficial artery we often have the problems, in particular when we treat complex lesions like along occlusions or along calcified stenosis, that drug-eluting balloon is not sufficient, so you need to also stabilize the lesion to stabilize dissections. You also need to do a stent implantation. Our study now shows that the combination of drug-eluting balloon plus stent is superior than plain balloon angioplasty plus stent. The nice approach is most of the time if you need a stent, if you use drug-eluting balloon and the lesion is stable and you don't need a stent you are glad. This has shown previous studies, however, if you need further treatment and you need to place a stent, we now show that the pretreatment with a drug-eluting balloon is a superior option than just the plain balloon angioplasty.
Dr. Carolyn Lam: Manos, what is your take on these results? Do you think it will impact guidelines?
Dr. Manos Brilakis: First of all, I would like to congratulate Dr. Ott for an excellent study. I think what is particularly important here, is the comparative effectiveness component. We have several studies circulating already about drug-coated balloons, have studies on stents, but we don't have studies addressing the other modalities like atherectomy. Why I was particularly impressed, is I think the study will have a finally an assessment of atherectomy as a primary strategy for calcified lesions and it's interesting that that was not as good efficacy. It was actually tents for worse TLR as compared to plain old balloon angioplasty and stent. Would like to ask Dr. Ott what is your kind thoughts about the alone atherectomy give the results of the study? Are they still doing it or is it falling out of favor?
Dr. Ilka Ott: Yes, I think this is a very important point. I think atherectomy alone is not an appropriate treatment but there are some data that atherectomy in combination with drug-eluting balloon gives much better results, or you may even think about a combination of atherectomy and drug-eluting stent, so it often is the case. This study also raises a lot of questions and gives some thought into further studies. I think in the combination atherectomy might still have its place.
Dr. Carolyn Lam: Could you tell us some of those plans for future studies?
Dr. Ilka Ott: Well, we are just in the initiation phase but I think one also very interesting concept is to compare drug-eluting balloon plus stent to the drug-eluting stents that have been on the market. However, as I said before, there's again the concept if you combine the drug-eluting balloon plus a stent it might be also, from the commercial aspect, better because sometimes you don't need the stent. And then moreover, the drug-eluting stents are much more expensive. It would be interested to see a study like that.
Dr. Carolyn Lam: What about the concern that the superficial femoral artery is subject to a lot of stretching and external compression and it's long and ... Maybe I'm out of date here about the concern of stent fractures and so on. It looks like your study has disproven this, or do you think the follow-up's long enough?
Dr. Ilka Ott: I think the follow-up of two years is quite good, but you're right, it seems like in the superficial femoral artery the restenosis process is much longer and more prolonged. Of course, you would like not to place a stent in the SSA but from the interventional aspect, it's often not possible because if you have a dissection with a limiting the flow, you have to fix that by putting in a stent. Nitinol stents are pretty good these days. Moreover, we have another generation of the woven stents the Supera stents that might also be an interesting point to investigate in comparison to the strategy we now have shown to be superior.
Dr. Manos Brilakis: I think what we need is more studies like this, that they take the other modalities like atherectomy, laser and combine them with what is currently the standard of care, which is drug-coated balloons or drug-coated balloons plus stent, as shared in the study. I just want to congratulate Dr. Ott on her study and encourage future studies from the group. I know the ISAR group is been a phenomenally productive group in coronary intervention and I'm delighted to see they're expanding on the peripheral world.
Dr. Carolyn Lam: I couldn't agree more. Congratulations, once again, for a study that really will impact practice and that we're so proud to be publishing in Circulation.
Listeners, I'm sure you learned as much as me, so please don't forget to tune in next week as well. Thanks.
Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. Our featured paper this week confirms the clinical utility of a polygenic risk score of common variants of cardiovascular disease. More soon after this week’s summary of articles.
The first original article describes distinct cell-specific roles for NADPH oxidase, or Nox2, in blood pressure regulation. This paper from first author, Dr. Sag, corresponding author, Dr. Shah, colleagues from King's College London British Heart Foundation Center of Excellence in the United Kingdom. The authors used novel gene modified mouse models to show that Nox2 in myeloid cells modulates basal blood pressure whereas endothelial cell Nox2 is involved in angiotensin II-dependent hypertension. The finding that Nox2 in different cell types has distinct effects on blood pressure, suggest that different diseases conditions may alter blood pressure through effects on Nox2 in different cell types. For example, it is conceivable that the effects on myeloid cells on basal blood pressure may be enhanced in inflammatory settings, whereas endothelial cell Nox2 activation may be more relevant to renin-angiotensin system-dependent hypertension. The current results are therefore relevant to the design of novel therapeutic approaches for hypertension by targeting NADPH oxidases.
The next paper provides a new, more accurate atherosclerotic cardiovascular disease risk prediction tool in familial hypercholesterolemia that may increase the efficiency of care and use of newer lipid lowering therapies. Co-corresponding authors, Dr. Mata and Pérez de Isla, from Hospital Clinicals San Carlos in Madrid, Spain, use data from SAFEHEART, a multicenter, nationwide, long-term prospective cohort study of 2,404 adult patients with molecularly-defined familial hypercholesterolemia and who have followed up for a mean of 5.5 years. They developed a robust risk prediction equation for incident atherosclerotic cardiovascular disease based on the following independent predictors; age, male gender, history of previous atherosclerotic cardiovascular disease, high blood pressure, increased body mass index, active smoking, LDL cholesterol and LPA levels. The new SAFEHEART risk equation performed better with a Harrell C index of 0.81 compared to 0.78 for the modified Framingham's risk equation and 0.8 for the ACC/AHA Pooled Cohort risk Equations. The authors therefore concluded that the risk of incident atherosclerotic cardiovascular disease may be estimated in familiar hypercholesterolemia patients, using simple clinical predictors, and that these findings may improve re-stratification and could be utilized to guide therapy in patients with familiar hypercholesterolemia.
The next study tells us that late gadolinium enhancement cardiovascular magnetic residents identifies patients with dilated cardiomyopathy but without severe left ventricular systolic dysfunction, who are still at high risk of sudden cardiac death. In this study, by first author Dr. Halliday, corresponding author Dr. Pennell, from Royal Brompton Hospital in London, United Kingdom, the authors prospectively investigated the association between mid-wall late gadolinium enhancement and the primary composite outcome of sudden cardiac death or aborted sudden cardiac death, among 399 consecutive referrals with dilated cardiomyopathy and a left ventricular ejection fraction above 40% seen at their center between 2000 and 2011. These patients were followed for a median of 4.6 years. 17.8% of patients with late gadolinium enhancement reached the pre-specified end point, compared to only 2.3% without late gadolinium enhancement.
Furthermore, following adjustment, late gadolinium enhancement predicted the composite end point, with a hazards ratio of 9.3. Thus, patients with dilated cardiomyopathy and mid-wall late gadolinium enhancement, and mild or moderate reductions of left ventricular ejection fraction should still be recognized as having a high risk of sudden cardiac death. This is important because these patients are not currently offered ICDs for the primary prevention of sudden cardiac death, based on current guidelines. Due to the low competing risk of death from non-sudden causes, it is possible that these patients will benefit from ICD implantation, but randomized trials are now required. These issues are discussed in an accompanying editorial from Dr. Markman of Johns Hopkins University, and Dr. Nazarian, Hospital of University of Pennsylvania.
The next study enhances our understanding of the role of immunity in hypertension. Now, the innate antigen-presenting cells and adaptive immune T-cells have long been implicated in the development of hypertension, however, the T-lymphocytes subsets involved in the pathophysiology of hypertension remain unclear. A small subset of innate-like T-cells expressing the gamma-delta T-cell receptor, rather than the more commonly expressed alpha-beta T-cell receptor, could play a role, and these were the focus in today's paper by first author Dr. Caillon, corresponding author Dr. Schiffrin, and colleagues from Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Canada. In experimental models, the authors showed than angiotensin-2 infusion increased gamma-delta T-cell numbers and activation in the spleen of wall tite mice, as well as in increased the systolic blood pressure, and decreased mesentric artery endothelial function in wild type mice, but not in mice devoid of gamma-delta T-cells, or in mice depleted of gamma-delta T-cells by depleting antibody injections.
Furthermore, angiotensin-2 induced T-cell activation in the spleen and peri-vascular adipose tissue was blunted in null mice. In humans, there was an association between systolic blood pressure and gamma-delta T-cells. In summary, this is the first in-vivo demonstration that gamma-delta T-cells, a subpopulation of T-cells, play a fundamental role in the development of hypertension and vascular damage. These results will help design novel treatments to limit the progression of hypertension and vascular damage.
The final paper describes a novel multi-modality strategy for cardiovascular risk assessment. Dr. de Lemos and colleagues from UT Southwestern Medical Center in Dallas, Texas, hypothesized that a strategy combining promising biomarkers across multiple different testing modalities would improve global and atherosclerotic cardiovascular disease risk assessments among individuals without known cardiovascular disease. These modalities included: left ventricular hypertrophy by electrocardiogram, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high sensitivity cardiac troponin-T, and high sensitivity C-reactive protein.
Using data from 6,621 individuals of the multi-ethnic study of atherosclerosis, or MESA, as well as 2,202 individuals from the Dallas heart study, the authors evaluated the association of test results with the global composite cardiovascular disease outcome, and that would include cardiovascular death, myocardial infarction, stroke, coronary or periphery revascularization, incident heart failure or atrial fibrillation, as well as atherosclerotic cardiovascular disease outcomes, which included fatal or non-fatal myocardial infarction or stroke. Over more than 10 years of follow-up, the authors found that each test result was independently associated with the global composite cardiovascular disease events in MESA. When the 5 tests were added to a base model, the C statistic improved, that was significant integrated discrimination improvement, and net reclassification improvement, and the model was well-calibrated. Using a simple integer score counting the number of abnormal tests, they showed that global cardiovascular disease risk increased with increasing score in a graded fashion. These findings were replicated in the Dallas heart study, and were similar for the atherosclerotic cardiovascular disease outcome.
This study therefore supports the potential value of a multi-modality testing strategy in selected individuals, in whom additional risk stratification is desired, beyond measurement of traditional atherosclerosis risk factors. The authors do highlight that additional studies are needed to validate the present findings, determine the optimal approach to implementation, and address direct and indirect cost implications of the additional testing.
Well, that wraps it up for your summaries. Now for our feature discussion.
Our feature paper today tells us that a polygenic risk score identifies a group of individuals with a higher burden of atherosclerosis, and greater relative benefit from statin therapy in the primary prevention setting. But perhaps even more significant, is that it addresses the fact that even relatively small effect sizes of common snips gathered together in a genetic risk score may have clinical utility in the prediction of cardiovascular disease, and to discuss this I'm so pleased to have the first author, Dr. Pradeep Natarajan from Massachusetts General Hospital, and Dr. Anand Rohatgi, associate editor from UT Southwestern. Welcome, gentlemen.
Dr. Pradeep Natarajan: Thank you very much, Carolyn.
Dr. Anand Rohatgi: Thank you, Carolyn.
Dr. Carolyn Lam: Pradeep, could you start by telling us what you did? This was a tour de force, please.
Dr. Pradeep Natarajan: Yeah, thanks so much for the invitation and the enthusiasm. So, briefly, large-scale, genome-wide association studies have discovered genetic risk variants in the population that individually associate with coronary disease risk. Many others have shown that an aggregate of these genetic risk variants predisposes to an increased risk for coronary disease by about 60%. But we sought to, with this study, understand how primary preventive statins could influence that risk, and whether these insights could be helpful in refining statin eligibility. So, among the individual variants that had been associated with coronary disease, we developed a risk score. This encapsulated 57 individual genetic variants. This risk score is independent of traditional cardiovascular risk factors, and identified individuals with a greater burden of sub-clinical atherosclerosis, defined as coronary artery calcium and carotid plaque, and two observational cohorts in individuals with a greater absolute and relative benefit from statin therapy from a subgroup analysis within the WOSCOPS clinical trial.
What we were surprised by is that the conventional wisdom, that all previously described subgroups within statin trials had the same relative benefit, and statins per unit of alveol cholesterol lowering. So, about 20 to 25% lowering of risk per 40mg per deciliter of alveol cholesterol. So we clinically identify individuals who just start out at high absolute risk, assume that the relative benefit will be the same across everyone, and optimize the number needed to treat simply by just finding individuals at high risk. But, here we didn't see the expected 20 to 25% lowering in the high genetic risk group, we saw actually a 44% relative risk reduction for the same lowering of alveol cholesterol. And we have now observed that across three different clinical trials, and these individuals are at high baseline risk, so this translates into an even more optimized number needed to treat, and really the opportunity to identify individuals earlier with an age independent biomarker.
Dr. Carolyn Lam: That's really cool, in fact, the number needed to treat in the high-risk score group was impressively low at 13.
Dr. Pradeep Natarajan: That's correct. Now, overall in the WOSCOPS trial, if you look at all individuals, it's about 38, so it is a high risk primary preventive group of men with, you know, substantial hyperlipidemia, but if you look at at least a relative difference between the two, going from 38 to 13, that's about a three-fold improvement of the number needed to treat.
Dr. Carolyn Lam: You know, what you said about it not correlating with exactly what you expected with the drop in LDL and so on, does that mean that this genetic risk score, that a lot of the snips are probably associated with LDL levels, but that a lot of them may be giving more information beyond LDL? Is that what it means?
Dr. Pradeep Natarajan: Yeah, you know, it's interesting. Most of the genetic variants that are associated with coronary disease actually do not seem to clearly influence traditional cardiovascular risk factors. The latest best estimate of that is about 39% of them associate with traditional cardiovascular risk factors, and then a subset with LDL cholesterol. So the aggregate score actually does not associate with traditional risk factors, and including with LDL cholesterol.
Dr. Carolyn Lam: Wow, and Anand, I'm sure we had so many discussions with the editors about the paper. Could you share some thoughts?
Dr. Anand Rohatgi: Yes, Carolyn. Circulation as a journal represents the best in cardiovascular science, and we're always interested in the highest-level articles related to atherosclerotic cardiovascular disease. So, when we received this manuscript from Pradeep and Sekar’s group, really leaders in the field, we were really excited, and as we went through the review process we got even more excited because it, as you said, Carolyn, it really was a tour de force, it was a high-quality article and it combined multiple things, and that's what we're really interested in seeing at Circulation, is combining several aspects, in this case genetics, sub-clinical atherosclerotic imaging, and also treatment effect.
And, you know, it's interesting because several recent manuscripts looking at genetic risk scores, they were associated with coronary disease but it wasn't clear that they were improving what we call risk prediction performance indices, at least enough to meet the bar of incorporating them into guideline-type recommendations. So I think the field wasn't sure how to move forwards with this type of information, but now I think this study really demonstrates that this type of risk score, this genetic risk score, really can inform treatment decisions in a big way. And so we were really excited to talk about that and then see it move forward.
Dr. Carolyn Lam: So a question for both of you now. Can these data be extrapolated to other cohorts of patients? I mean, WOSCOPS was predominantly white, and all were males, right? So, Pradeep, would you like to take that first?
Dr. Pradeep Natarajan: That's an excellent observation, and I think ... A clear limitation in the field, but an outstanding question that I think can be addressed going forwards. So, the main challenge is that the epidemiological cohorts that were used for genetic analysis largely have been of European ancestry, and we know that genetic background and a variety of non-genetic factors influence cardiovascular disease risk, so in genetic analysis of European individuals the influencers of coronary disease risk may not influence cardiovascular disease the same in non-European ethnicities. And, you know, we've done some work of this specifically in African-Americans, and there are some differences. You know, African-Americans are largely mixed of both African and European ancestry, some of that seems to also influence how you interpret the cardiovascular genetic risk score.
Ideally you would have a risk score that is not influenced by the genetic background, and so the next step going forward are one to look to see how well this risk score predicts in non-European ancestry, because, obviously, not as much statin clinical trial information in non-European cohorts, but I think looking at the treatment effect in non-Europeans will be important. And then, you know, the third step is we and others are participating in several now large ongoing efforts to really define what the genetic influences are in non-European ancestries, and I think that will be a very important next step that's really critical before the clinical implementation.
Dr. Carolyn Lam: Yeah, talking to you from Asia, that's music to my ears, obviously. Anand, did you have any questions for Pradeep or anything else to add about the paper?
Dr. Anand Rohatgi: Yeah, I wanted to add one or two comments. One thing that this study demonstrates is that the genetic risk scores, whether they relate to traditional risk factors or lipids, that doesn't necessarily translate to what it might mean in terms of treatment benefit, and so I think that concept is generalizable and now it needs to be tested in other ethnicities, other types of subgroups, but I think you can disentangle a relationship with risk factors and lipids to its treatment effect and this study really nicely shows that.
And I think just to take a step back, we know statins work in intermediate-risk patients, maybe even low-risk patients with the most recent studies, but at a public policy level, and just as a cognition, we really want to narrow the focus, it's something called precision medicine that the American Heart Association is promoting as a concept, and I think that this study really demonstrates that here we have now another tool that can reduce this number needed to treat, make this choice for statins more precise, maximizing the benefits and limiting cost. So, I think that concept is very generalizable, it needs to be tested now in multiple populations, like Pradeep said, and I guess one of the questions I had had for the authors is: how do we incorporate this finding that they saw with sub-clinical atherosclerosis, which we thought was very fascinating among the editors at Circulation, that now they're also linking with sub-clinical atherosclerosis, is that something that the investigators think needs to be pursued further? Would that be something that would be used clinically as well?
Dr. Pradeep Natarajan: I think there are lots of opportunities for this going forward, you know, in prior work we've done the genetic architecture for clinical coronary disease is actually very similar to sub-clinical coronary disease, and there are many influences for sub-clinical coronary disease, and clinical coronary-disease, that are both genetic and environmental, and the aggregate effect from the polygenic risk on sub-clinical atherosclerosis suggests that it's obviously not absolute and there are other factors that influence sub-clinical atherosclerosis.
Dr. Carolyn Lam: Well, listeners, you heard it right here. Thank you for joining us this week, tell all your friends about it, and don't forget to tune in again next week.
Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. In just a moment we'll take a deep dive into hemo-compatibility-related outcomes in the MOMENTUM 3 trial of a fully magnetically levitated pump in advanced heart failure. But first, here's your summary of this week's journal.
The first paper sheds light on the biological mechanisms underlying cardioprotective effects of the Mediterranean diet. First author, Dr. Wang, corresponding author Dr. Hu and colleagues of Harvard, TH Chan, School of Public Health in Boston, Massachusetts studied 980 participants from the PREDIMED Trial including 230 incident cases of cardiovascular disease and 787 randomly selected participants at baseline followed up for 7.4 years.
Participants were randomized to a Mediterranean diet supplemented with extra virgin olive oil, a Mediterranean diet supplemented with nuts, or a controlled diet. Plasma ceramide concentrations were measured and the primary outcome was a composition of non-fatal acute myocardial infarction, non-fatal stroke or cardiovascular death.
The authors found a novel positive association between baseline plasma ceramide levels and incident cardiovascular disease. In addition, the association between baseline ceramides and incident cardiovascular disease varied significantly by treatment groups where a Mediterranean dietary intervention appeared to mitigate the potential deleterious effects of elevated plasma ceramide concentrations on cardiovascular disease.
These findings, therefore, strengthen the evidence base for recommending the Mediterranean diet for cardiovascular disease prevention and suggest that plasma ceramides have the potential to serve as markers of future cardiovascular disease risk.
The next paper describes a novel therapeutic approach against hypertensive cardiac remodeling and provides the first evidence of the cardio protective effect of cardiofibroblast-specific activating transcription factor 3 or ATF3. In this study from first author Dr. Li, co-corresponding authors, Dr. Du from Beijing Anzhen Hospital in China, and Dr. Ma from Thomas Jefferson University in Philadelphia and colleagues, the authors used a discovery-driven unbiased approach to identify increased ATF3 expression in mirroring hypertensive hearts and the human hypertrophic heart, expressed primarily by cardiac fibroblast cells. ATF3 knockout markedly exaggerated the hypertensive ventricular remodeling, a state rescued by lentivirus mediated microRNA aided cardiac fibroblast selective ATF3 over-expression.
Conversely, cardiac fibroblast specific ATF3 over-expression significantly ameliorated ventricular remodeling and heart failure. The authors further identified MAP2K3 as a novel ATF3 target, and that p38 was the downstream molecule of MAP2K3, mediating the profibrotic hypertrophic effects in ATF3 knockout animals.
In summary, this study provides the first evidence that ATF3 up-regulation in cardiac fibroblasts in response to hypertensive stimuli, protects the heart by suppressing MAP2K3 expression, and subsequently p38 TGF-beta signaling. Thus, identifying molecules mimicking endogenous ligands or inhibiting microRNA that down-regulate ATF3 expression, may represent novel therapeutic approaches against hypertensive cardiac remodeling. These, and other issues, are discussed in an accompanying editorial by Dr. Jennifer Davis of University of Washington.
The next paper tells us that clinical frailty score may need to be part of the pre-operative assessment of patients undergoing transcatheter aortic valve replacement, or TAVR. First author, Dr. Shimura, corresponding author, Dr. Yamamoto and colleagues of Toyohashi Heart Center in Japan, utilized the optimized catheter valvular intervention or OCEAN Japanese Multicenter Registry of 1215 patients undergoing TAVR and found that clinical frailty score correlated with other markers of frailty, such as body mass index, albumin, gait speed and grip strength. Furthermore, the clinical frailty score was an independent predictive factor of increased late-cumulative mortality risk. Thus, in addition to reflecting the degree of frailty, the clinical implications of these findings are discussed in an accompanying editorial by Dr. Jonathan Afilalo from McGill University in Montreal.
In the final study, we learned that long-term anabolic androgenic steroid use may be associated with myocardial dysfunction and accelerated coronary atherosclerosis. Dr. Baggish and colleagues from Massachusetts General Hospital in Boston, used a cross-sectional cohort design of 140 experienced male weight lifters, age 34-54 years, comprising 86 men reporting at least two years of cumulative lifetime anabolic androgenic steroid use, and 54 non-using men. Compared to non-users, steroid users demonstrated relatively reduced left ventricular systolic function and diastolic function on transthoracic echocardiography. Furthermore, steroid users demonstrated higher coronary artery plaque volume on coronary CT angiography compared to non-users. In summary, this is the first large controlled study of its type to demonstrate that long-term anabolic androgenic steroid use is associated with both systolic and diastolic myocardial dysfunction, as well as coronary atherosclerosis. Thus, when clinicians encounter young or middle-aged men who exhibit evidence of unexplained left ventricular dysfunction or premature coronary artery disease, the possibility of cardiotoxicity due to long-term anabolic androgenic steroid use should be considered in the differential diagnosis.
Well, those were your summaries. Now, let's move on to our featured discussion.
For our featured discussion today, we are actually reviewing a secondary analysis of the MOMENTUM 3 Trial, which is a multicenter study of the mag lev technology in patients undergoing mechanical circulatory support, with the HeartMate 3. And to discuss today's findings I'm so pleased to have the corresponding author, Dr. Mandeep Mehra from Brigham and Women's Hospital in Boston, Massachusetts, as well as Dr. Biykem Bozkurt, Associate Editor from Houston, Texas.
Welcome Mandeep and Biykem.
Dr. Mandeep Mehra: Thank you. It's a pleasure to be with you all.
Dr. Biykem Bozkurt: Thank you.
Dr. Carolyn Lam: Let's start by getting a few definitions right, shall we, just for our audience. This specific article, and congratulations Mandeep, it's just so great, it speaks of hemo-compatibility-related outcomes. Could you start by telling us what that is, and maybe reminding us what the original MOMENTUM 3 short-term results showed.
Dr. Mandeep Mehra: Sure. As our listeners are aware, left ventricular assist devices have really transformed the management of refractory advanced heart failure, by the introduction of a form of flow, called continuous flow, in the devices, which tend to render patients, relatively low pulsatiles to non-pulsatile. Now what we've seen is that the interface between this very unnatural physiology from continuous flow in concert with the patient's biology tends to create a constellation of problems that we sort of refer to as hemo-compatibility-related adverse events.
For example, we have seen a very curious development of recurrent gastrointestinal bleeds that tend to occur in a manner similar to what was observed with critical aortic stenosis, the so-called Heyde's Syndrome. Similarly we see stroke-related problems and we also see evidence of thrombosis that can sometimes develop within the pump. So we refer to the conglomeration of these unique complications that arise from the abnormal interface between the device and the patient as hemo-compatibility-related adverse events.
Dr. Carolyn Lam: And this is a secondary analysis, a six-month secondary analysis, right? So could you give a little bit of background of why you would hypothesize that these events might be different with the HeartMate 3 versus 2? I mean, it's quite unique that we're going back to creating a pulse.
Dr. Mandeep Mehra: Yes. Let me fist define for our audience what the MOMENTUM 3 Trial was designed to initially do, and is still doing. MOMENTUM 3 is a randomized controlled trial of two devices: one, a conventionally available continuous flow device called the HeartMate 2, and the second device, the novel pump called the HeartMate 3. The HeartMate 3 is a pump that took two decades to engineer. And it took that long because it is very unique, based on the following principles.
First, it's a small profile, so the entire pump can be placed intrathoracically. Second is that the way in which it moves blood, its rotor, is fully magnetically levitated, which means that it has no friction when it rotates. The third is that despite its small profile, this device has wide blood flow gaps, meaning that as blood is moving in this centrifugal flow pump, it does not expose the blood elements to as much of sheer stress as one sees with other conventionally available devices. And then finally, what this device has uniquely is a intrinsic pulse, and what that means is that we program this device in a fixed program to actually ramp its speed up and ramp it down so that it creates an intrinsic pulse of about 30 beats per minute, which is engineering-wise designed to improve pump wash out; that's the intention.
So the MOMENTUM 3 Trial was constructed to really compare these two devices and we recently reported, on the primary end point of the six-month outcomes of this trial. And the trial primary end point was set at survival free of a disabling stroke, or the need for re-operation because of pump malfunction. And what we found was that this pump, the HeartMate 3, clearly met its non-inferiority end point, versus the HeartMate 2, but also demonstrated superiority on the primary end point at six months. We were certainly not expecting to see superiority at this early time point, but we were very fortunate to see that.
Now what is unique about this is that for the first time ever, we saw no cases of suspected or manifest established pump thrombosis, as a result of de novo pump thrombosis requiring re-operations with the HeartMate 3 device. And this is a frequency of about 10% that we normally observe with pumps. That is one in 10 pumps will clot off within about six months, and require re-operation. So we were very gratified to see this observation in the short-term data of the primary MOMENTUM 3 database.
Now as a result of that observation, Carolyn, we thought that the hard end points, as are typically adjudicated for the primary basis of these clinical trials, missed the entire constellation of hemo-compatibility-related outcomes because these are patients who develop both bleeding and clotting complications. And the net burden of hemo-compatibility is not entirely available for review, which is the basis of this important secondary analysis that was published in Circulation.
Dr. Carolyn Lam: What striking findings. So tell us the bottom line.
Dr. Mandeep Mehra: What we found in the secondary analysis was evidence that the burden of hemo-compatibility-related adverse events is lower in patients with the HeartMate 3, compared to the HeartMate 2 device. And that was the basis of the bottom line that we found.
In particular, we knew that there were no episodes of de novo pump thrombosis with the HeartMate 3, but we also found that there was evidence of a reduction in non-disabling strokes with the HeartMate 3 device. So we now have evidence that thrombotic complications, minor strokes, as well as pump thrombosis, seem to be abrogated by this new pump.
What we should keep in mind, however, is that this is still early data from the ongoing MOMENTUM 3 Trial, and the trial is actually designed to enroll and observe over a thousand patients, over two years. And we are basically showing in this a very early look at six months of about 300 of these patients. And so that needs to be kept in mind. But we are extremely encouraged by these early trends suggesting that we may have started to break the issues related to the barriers of implementation of such therapy in the hemo-compatibility domain.
Dr. Carolyn Lam: Yeah, and as a heart failure doc, I can tell you that I share that excitement and I know that Biykem does too, as did the editors.
Biykem, tell us a little bit about what we talked about as editors about this paper.
Dr. Biykem Bozkurt: Indeed. Mandeep, the hemo-compatibility concept which is being addressed in this new publication is quite novel and is exciting, and addresses the continual spectrum of the pathology, ranging from the GI bleed, to the stroke spectrum. The question I have, in this study, the overall scores were not different in the absolute number that we saw as a score from the hemo-compatibility ranking.
Do you think we would continue to use this approach as a quantitative score, given the fact that there may be bidirectional impact from different devices on the different spectrum, especially with the recognition that HeartMate 3 seemed to be protective against the thrombotic, perhaps events, or should we use it more of a qualitative score card looking at which perhaps spectrum the device tends to be a little bit more risky or beneficial. So shall we color code this score and try to perhaps focus on the spectrum of thrombosis versus bleeding and then try to strategize?
Dr. Mandeep Mehra: Thank you for that very erudite question, Biykem. You hit right at the heart of the matter. So let me make a few comments about that. The first issue is that so far, the field has not had a clear definition of hemo-compatibility. Hemo-compatibility has been more of a engineering term. When someone said hemo-compatibility, they thought of biomaterials, rather than a clinical definition of hemo-compatibility. So for the first time, we have actually introduced the term hemo-compatibility into the lexicon of definition, managing patients with LVAD, so that's one important point.
The second important point is that we, until this day, until this analysis, have not had the ability to really provide people with a full picture of the entire burden of experience of hemo-compatibility-related complications that an individual patient experiences as they are on this device, because you know that patient's going to have a GI bleed, and then they may have a stroke, because we may change, dynamically we may change anticoagulation for instance if someone has one event then the other, and the traditional way in which studies are done, hey do not give you a clear picture into the burden of hemo-compatibility. So the most innovative thing about this clinical hemo-compatibility definition, is that we've not introduced a score that reflects the burden of disease, and we have also created tiers of severity of the burden of disease experience into three quantitative tiers that include various subsets which are hierarchal.
So for example, is one gastrointestinal bleeding the same as non-disabling stroke? Well, no. One gastrointestinal bleeding may be a milder form a hemo-compatibility-related problem. So our early look at this clearly shows that survival free of a hemo-compatibility-related event is clearly lower in the patients with a HeartMate 3. However, as you astutely pointed out, when you examine purely the burden of hemo-compatibility-related complications experienced by the survivors, one actually sees a trend in favor of the HeartMate 3, but not a statistically significant difference, largely because we have not yet abrogated problems related to bleeding complications on the side of the hemo-compatibility.
Why is that? Well, it's because we still treat all patients in both groups with the HeartMate 2 or the HeartMate 3 with the same intensity of anticoagulation. What this sort of data points out to us in the future, first of all, is that it allows us to compare apples to apples, as we are looking at different device platforms, that's number one. Second is it gives a much more robust look into the total patient experience. And third, it actually gives us insight into whether altering one component of the equation, so let's say there's a bleeder, if you actually react to that clinically, will you start to see problems on the clotting side.
Dr. Biykem Bozkurt: This is a very, very important study that addresses the whole spectrum of hemo-compatibility in a more comprehensive fashion, and also points out perhaps the differences that we see in overall others, centrifugal flow, left ventricular assists, support systems such as the Heartware HVAD study that showed increase in hemorrhagic stroke, especially hemorrhagic stroke in the first six months in the ENDURANCE Trial, whereas the HeartMate 3 has shown in the MOMENTUM 3 publication, as well as the Circulation secondary end point study demonstrates a reduction in disabling strokes and absence of any pump thrombosis.
So there are differences, despite both of the pumps are centrifugal, there are differences in the profile, and the spectrum of the risk and hemo-compatibility. And one other interesting finding from this study is that the predictors for hemo-compatibility outcomes are complementary to what has been known in the sense that lower antiplatelet and anticoagulation management strategies are associated with increased risk of hemo-compatibility adverse events.
And surprisingly, the control of blood pressure did not appear to correlate with the hemo-compatibility outcomes. So from that perspective, it differs from the ENDURANCE Trial where the uncontrolled blood pressure or hypertension was associated with hemorrhagic strokes, in the ENDURANCE Trial, whereas in the MOMENTUM 3, the blood pressure did not appear to correlate with the hemo-compatibility outcomes or pump thrombosis.
So these are very interesting findings and I think are complementary to the evolving field of the risk benefit ratios in patients with LVAD support. And from that perspective, we in Circulation felt that this will be a very valuable publication for our readership as well as for the whole heart failure and transplant community.
Dr. Carolyn Lam: Thank you, so much for joining us today, don't forget to tune in next week.
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. Carlolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. What's the link between DPP4 and aortic valve calcification? Well, to find out, keep listening because we'll be discussing this and an important new paper right after these summaries.
The first original paper in this issue tells us that high sensitivity Troponin I, may have a role in personalizing preventive strategies in patients with Type II Diabetes. Dr. Cavender and colleagues from University of North Carolina, Chapel Hill, sought to describe the relationship between changes in high sensitivity Troponin I and cardiovascular outcomes in the EXAMINE phase 3B trial, which was designed to evaluate the cardiovascular safety of alogliptin. The current analysis was restricted to patients, randomized 30 days or more after the qualifying acute coronary syndrome event, and high sensitivity Troponin I was measured using the Abbot Architect Assay at baseline and six months.
The authors found that high sensitivity Troponin I was detectable in the vast majority - 93% of patients with Type II Diabetes, stabilized within 30 days after acute coronary syndrome. One in six of these patients had high sensitivity Troponin I levels above the 99th percentile upper reference limit. High sensitivity Troponin I had a strong graded relationship with the incidence of subsequent major cardiovascular events.
Changes in high sensitivity Troponin I as small as two to six nanograms per liter over six months, were associated with a heightened risk of adverse outcomes. Particularly cardiovascular death and heart failure. Alogliptin neither increased nor decreased the risk of cardiovascular events in a high risk cohort of patients with elevated high sensitivity Troponin I levels. These findings therefore imply that serial measurements of high sensitivity Troponin may have a role in preventive strategies, either by intensifying or prolonging therapies in patients at high risk or reducing or shortening therapies in patients at low risk of cardiovascular events.
The next paper describes the effects of Pioglitazone on cardiac outcomes after ischemic stroke or transient ischemic attack in patients with insulin resistance without diabetes in the IRIS trial, which stands for Insulin Resistance Intervention after Stroke. As a reminder, the IRIS trial compared the effects of Pioglitazone with placebo on major cardiovascular events after stroke or transient ischemic attack, in patients without diabetes but who had evidence of insulin resistance. And it showed that Pioglitazone improved insulin resistance, prevented diabetes, improved CRP and reduced fatal and non-fatal stroke or myocardial infarction.
In the current paper, by Dr. Young and colleagues from Yale Cardiovascular Research Center in New Haven, Connecticut, the authors performed a secondary analysis of IRIS and examined the effect of Pioglitazone on acute coronary syndromes, mainly myocardial infarction or unstable angina. They found that Pioglitazone reduced the risk of these events by 29%, with benefit emerging after two years of treatment. Furthermore, Pioglitazone reduced the incidence of Type I myocardial infarction with a neutral effect on Type II myocardial infarction. In summary, among patients with insulin resistance without diabetes, Pioglitazone reduced the risk of acute coronary syndromes after a recent cerebrovascular event, and may serve as a useful secondary prevention therapy in addition to statins, aspirin, and other established treatments.
The next study tells us that immune complexes may be an important biomarker in the risk stratification of Antiphospholipid Syndrome. Now recall that Antiphospholipid Syndrome is characterized by recurrent thrombosis in patients with Antiphospholipid predictive antibodies. However, the predictive value of the presence of Antiphospholipid auto antibodies is low. And new markers are needed to identify carriers at higher risk.
In the current study by Dr. Serrano and colleagues from Madrid, Spain, the authors performed a historical cohort follow up study based on the Magnum 12 plus 12 cohort, that included all patients who had received a kidney transplant in their hospital in a 12 year period from 2000 to 2011. Sera used for the analysis were collected in the 24 hours before the kidney transplant surgery, and used to measure circulating immune complexes of immunoglobulin A bound to beta II glycoprotein I.
The authors then investigated the possible association of these immune complexes with thrombosis, graft thrombosis and graft loss in the six months following kidney transplant. They found that in patients with the immunoglobulin A isotope antiphospholipid antibodies, the presence of circulating immune complexes of immunoglobulin A bound to beta II glycoprotein I, pre transplant, was associated with acute thrombotic events. Patients positive for the immune complexes had a much higher risk of developing post transplant thrombotic events, and higher risk of graft thrombosis mediated graft loss. On the other hand, complex negative patients had the same thrombosis risk as the control population. These findings imply that treatment to prevent thrombosis should focus mainly on the immune complex positive patients in this setting.
The final paper addresses the issue that public reporting of PCI Outcomes may create disincentives for physicians to provide care for critically ill patients, particularly at institutions with worse clinical outcomes. In this study from first author, Dr. Waldo from the VA Eastern Colorado Health Care System in Denver, Colorado, corresponding author, Dr. Yeh from Beth Israel Deaconess Medical Center in Boston, Massachusetts, and colleagues. The authors used state reports to identify 31 out of 86 hospitals that were recognized as negative PCI outliers in two states: Massachusetts and New York, from 2002 to 2012.
They sought to evaluate the procedural management and in hospital outcomes of patients treated for acute myocardial infarction before and after a hospital had been publicly identified as the negative outlier. They found that outlier facilities were larger, treating more acute myocardial infarction patients, and performed more PCI's than non outlier hospital. The rates of percutaneous revascularization increased similarly at outlier and non outlier institutions after report of the outlier status. After outlier designation, the in hospital mortality declined at the outlier institutions to a greater extent than was observed at the non outlier facilities. Thus, public reporting of outlier status may prompt outlier facilities to improve case selection, and employ systems improvements that optimize patient care, and improve in hospital mortality among patients with myocardial infarctions.
We are going to have such a fun discussion in today's feature paper. Have you ever wondered what does dipeptidyl peptidase-4, or DPP4 have to do with aortic valve calcification? Well, you're about to learn, because in today's paper we actually learn that DPP4 inhibitors, which you might recognize from diabetes, you know drugs such as sitagliptin, could serve a potential therapeutic target in aortic valve disease. To tell us about it and discuss it, we have corresponding author, Dr. Jae-Kwan Song] from Asan Medical Center in Seoul, South Korea, as well as Dr. Thomas Eschenhagen, Associate Editor from University Hospital Hamburg Eppendorf in Germany. Welcome, gentlemen.
Dr. Jae-Kwan Song: Hi.
Dr. Thomas Eschenhagen: Hi.
Dr. Carolyn Lam: Fascinating paper. I have to congratulate you first and foremost, but please tell us, what inspired you to look at DPP4 in aortic valve disease.
Dr. Jae-Kwan Song: Yeah, actually as a clinician, I think there is two issues. One is the prevalence of calcific aortic valve disease is increasing rapidly in the developed and also developing countries. The second important issue is that we do not have effective medical treatment option. So I will say that the medical treatment of calcific aortic valve disease is a typical example of unmet clinical needs to serve this kind of troubled scientific issues, our team have focused on the reciprocal interaction between endothelial cells and interstitial cells. Because this potential mechanism was well reported by other investigators that the interaction between two cells are very critical for maintaining aortic valve tissues. So first we started with Enos knockout mouse, to go over what's going on in the aortic valve in the models. In the human tissues in patient with calcific aortic valve disease, we have found that DPP4 is specifically activated. That's the beginning of our study.
Dr. Carolyn Lam: Could you please explain to those of us who don't do basic science research everyday, I mean, your study involves tissues both from humans and mirroring models. Could you explain it very simply what you did and what you found?
Dr. Jae-Kwan Song: Yes, in the Enos Knockout mouse, we have found that those mouse showed very strong calcification process compared to the live animals. What is the mechanism of this enhanced calcification in this mouse? And we found that the loss of endothelial function is critical, and then we found that DPP4 is actively involved in the calcification process. The first test we have done is the isolation of developed interstitial cells. And then we focused on osteogenic transformation over this valvular interstitial cell both in the Enos Knockout mouse, and the human developing interstitial cells. So we have found that the endothelial dysfunction activates the DPP4 activity in these tissues, which resulted in the increase osteogenic transformation of developed interstitial cell. So that's the beginning of our observation.
Dr. Carolyn Lam: And could you describe what you did subsequently to prove the whole mechanism?
Dr. Jae-Kwan Song: As you know the DPP4 has many substrates including many peptides involved in glucose metabolism, so the hardest part of our study is what is the molecule target, or associated with DPP4 in the pathologic process of calcification in developing interstitial cells. We tested many different substrates known to the potential targets of DPP4, and we have found specifically insulin-like growth factor-1 (IGF-1) is the key proponent of all this process. With further study, we found that the DPP4 cleaves or inactivates or decrease IGF1 activity in the valvular interstitial cell, and in the normal status IGF1 is a very critical to protect osteoblastic transformation of valvular interstitial cell. We have found that the DP4 and IGF1 exercises key therapeutic target, and the key molecules involved in valvular calcification. As you know we do have a DP4 inhibitors, which were successfully clinically to reduce the diabetes control. So it's very easy to test the DP4 inhibitors in animal models. Both in the Enos Knockout mouse, and we also developed in the calcific aortic valve disease using some treatment, including Vitamin D and hypercholesterol and diet the in vivo experiment showed that [inaudible 00:13:58] inhibitors effectively prevented the development of calcification and prevented the development of calcification and prevented the developement of calcific aortic disease. This the main finding of our study.
Dr. Carolyn Lam: That is so fascinating, and really especially what you just said, that sitagliptin in this rabbit model prevented calcific aortic valve disease with the concurrent increase in plasma IGF1 levels in line with the DPP4 inhibition. That is just such a beautiful piece of work, congratulations. And congratulations Thomas on managing such a nice paper. Take us under the hood about the discussions that happened with the editors. Surely you recognized the translational impact. What do you think? Is it time to reposition DPP4 inhibitors?
Dr. Thomas Eschenhagen: We and the reviewers like the paper because first of all it describes a new, interesting biological mechanism. If we are done, and we like that it uses human samples, but also this treatment in two different animal models. This together, really makes it a strong paper, we've found perfectly suitable for Circulation. As you said Carolyn, the translation perspective is fascinating. Obviously it's very early days. There is no specific evidence yet from patients. But that could, in patients, take actually very very long. Even the big studies already been done with sitagliptin and other DPP4 inhibitors, that don't show a signal in this direction yet, but I would say that could still happen, and maybe in the long term, all of the cardiologists putting all this stuff in German it's call TAVS, in America it's called TAVR does not work anymore, obviously. That's just the speculation.
But it gives a very interesting signal, and this study certainly should stimulate research in humans and do some prospective studies in patients.
Dr. Carolyn Lam: Yes indeed. If I may ask, Jae-Kwan, do you have plans for further steps?
Dr. Jae-Kwan Song: Yeah, we are expecting some [inaudible 00:16:06]. The first process with proof of concept study as you know is DP4 inhibitors have been actually been used for the diabetic controls, so we may have a patient cohort who also underwent [inaudible 00:16:22] echocardiogram [inaudible 00:16:23] while without medication. The analysis of those later can be used for proof of concept study. But we are challenging issues that although many drugs are classified as a DP4 inhibitors, we should really focus on the tissue distribution on these drugs, specifically on the cardiac issues. It may be possible that the different drugs have a different tissue distribution even after all our medication. The second critical issue is what is the actual dose of these drugs to prevent calcific aortic valve disease. Usually these drugs are used for diabetes control. We may need different lab results of these drugs for different critical indications. So that's the two important issues to be solved.
Dr. Carolyn Lam: That's wonderfully put, and I couldn't agree more. Thomas, could we switch tracks a little bit. Because now that I have you online, and you're the first time joining us on the show too, tell us a little bit more about what it's like as an associate editor really looking at these pre clinical data, being able to parse out what you think has translational value, and especially for circulation. We have a very strong emphasis now on clinical translation. Share some of your thoughts there on how it's been for us.
Dr. Thomas Eschenhagen: It's been a great experience. I do have some experience with other journals as an associate editor, or being on an editorial board. But I have to say circulation is really quite unique. I think it's a very strong group of people. I'm amazed by the level of knowledge and also the level of engagement of the other editors and associate editors, in every single paper. What's also really rewarding is the overall quality of papers being submitted to circulation, it's really great. A lot of papers are not only presenting some beautiful, basic science, but also this translational perspective, that's actually what we are looking for. So very solid, exciting scientific work in cells, animals, but always some link, either some materials from humans or a good link to a translation perspective. That's the perfect paper for circulation and I have to say we get quite a bit of them, and it's sometimes even difficult to pick the ones we really like. But it's great, it's really been a lot of fun.
Dr. Carolyn Lam: This is actually one of the purposes of this podcast. It's hoping to share with our readers, with our listeners, what happens at these editor discussions because it's so interesting, I just wish everyone could listen to all the science and the clinical translation that we discuss. Thank you very much for sharing your thoughts today, both Thomas, and Jake Won, beautiful work. We're very proud to be publishing this work in circulation.
Thank you listeners for joining us this week. Don't forget, tell all your friends about this podcast, and tune in again next week.
Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore. In just a moment, we will be discussing the sources of sodium in the US diet, results that may surprise you, and that carry profound public health importance. But first, here's your summary of this week's issue.
The first original paper advances the field of cardiac tissue engineering by establishing a defined serum-free protocol to generate functional human myocardium from pluripotent stem cells. In this paper by first author, Dr. Tiburcy, corresponding author Dr. Zimmermann and colleagues from the University Medical Center Goettingen in Germany, the authors systematically investigated cell composition, matrix and media conditions to generate engineered human myocardium from embryonic and induced pluripotent stem cells and fiberglass, under serum-free conditions. The engineered human myocardium demonstrated important structural and functional properties of post-natal myocardium, including rod-shaped cardiomyocytes with M-bands, systolic twitch forces, a positive force-frequency response, inotropic responses to beta adrenergic stimulation, evidence of advanced molecular maturation by transcriptome profiling and the engineered human myocardium even responded to chronic cholinomimetic toxicity with contractile dysfunction, cardiomyocyte hypertrophy, cardiomyocyte death, and anti-pro BNP release, which are all classical hallmarks of heart failure.
Finally, the authors demonstrated scalability of engineered human myocardium according to anticipated clinical demands for cardiac repair. In summary, this paper provides proof of concept for a universally applicable technology for maturation and scalable production of engineered human myocardium, something that is termed a stride forward in an accompanying editorial by Doctors Yang and Murray, from University of Washington in Seattle.
The next paper describes a new frontier for interventional cardiology, the percutaneous therapy for tricuspid regurgitation. Here, Dr. Nickenig and colleagues, from University Hospital Bonn in Germany, recruited 64 consecutive patients deemed unsuitable for surgery who underwent mitroclip treatment for chronic, severe tricuspid regurgitation for compassionate use. Twenty-two patients were also concurrently treated with a mitroclip system for mitral regurgitation as a combined procedure. The degree of tricuspid regurgitation was severe or massive in 88% of patients before the procedure. The mitroclip device was successfully implanted in the tricuspid valve in 97% of cases.
After the procedure, tricuspid regurgitation was reduced by at least one grade in 91% of patients. 13% of patients with tricuspid regurgitation remained severe after the procedure. There were significant reductions in effective regurgitant orifice area, vena contracta width, and regurgitant volume. There were no intra-procedural deaths, cardiac tamponade, emergency surgeries, stroke, myocardial infarction or major vascular complications.
There were three in-hospital deaths. New York Heart Association class was significantly improved and six minute walk distance increased significantly. In summary, this study demonstrates that trans-catheter treatment of tricuspid regurgitation with the mitroclip system seems to be safe and feasible in this cohort of pre-selected patients.
The next paper describes the pooled safety analysis of evolocumab, a fully human monoclonal antibody to PSK-9. Dr. Toth of Johns Hopkins University School of Medicine and the PROFICIO investigators perform this pooled analysis from the PROFICIO program, which included over 6,000 patients from 12 Phase 2 and 3 trials, and the corresponding open-label extension trials, and they showed that treatment with evolocumab, up to one year, was not associated with discernible differences in adverse events, serious adverse events, or key laboratory assessments, compared to control or standard of care.
In addition, adverse events rates did not increase among patients attaining very low levels of LDL cholesterol, of less than 25 milligrams per deciliter, compared to patients attaining LDL cholesterol levels above 40 milligrams per deciliter. In summary, the present analysis confirms a favorable benefit risk profile for evolocumab treatment for up to one year.
Does aggressive blood pressure lowering prevent recurrent atrial fibrillation after catheter ablation? Well, this question is addressed in a randomized, open-label clinical trial known as the Substrate Modification With Aggressive Blood Pressure Control or SMAC-AF Trial. In this trial, Dr. Parkash of Halifax, Canada and colleagues, randomly assigned 184 patients with atrial fibrillation and a blood pressure of greater than 130 over 80 to aggressive blood pressure lowering, with a target of less than 120 over 80, or to standard blood pressure treatment, to a target of less 140 over 90, prior to their scheduled atrial fibrillation catheter ablation.
The primary outcome was symptomatic recurrence of atrial fibrillation, atrial tachycardia, or atrial flutter lasting greater than 30 seconds, determined 3 months beyond catheter ablation. The authors found no additional benefit to the addition of aggressive blood pressure lowering over a median of 3.5 months, over standard blood pressure therapy, in patients undergoing catheter ablation for atrial fibrillation to prevent recurring atrial arrhythmia.
In subgroup analysis, a signal of benefit was observed in groups whose blood pressure were lower at the point of entry into the study, and in those patients who were older. The duration of blood pressure lowering in the study did not result in reduction of recurrent atrial fibrillation after catheter ablation, however there was a higher rate of hypotension requiring medication adjustment in the aggressive blood pressure group.
Thus, this trial showed that neither aggressive blood pressure lowering compared to standard blood pressure lowering, nor the duration of aggressive blood pressure treatment reduced atrial arrhythmia occurrence after catheter ablation for atrial fibrillation, but resulted in more hypotension.
Well, that wraps it up for our summaries! Now, for our feature discussion ...
Our topic today is so universal and so important. It's about sodium intake and the sources of sodium, at least in the US, and I have with me two lovely ladies, the corresponding author of our paper, Dr. Lisa Harnack, from School of Public Health, University of Minnesota, and a regular on the show, shall I say, Dr. Wendy Post, Associate Editor from Johns Hopkins. Welcome, ladies!
Dr. Wendy Post: Thanks you, Carolyn! It's a pleasure to be here.
Dr. Lisa Harnack: Thanks, thanks.
Dr. Carolyn Lam: Lisa, let's dig right into your paper. Let's start by discussing that there was a prior paper that looked at sources of sodium in the US population. So please tell us, what inspired you to do your paper, and were you surprised by your findings?
Dr. Lisa Harnack: Right, well the previous study was over 25 years old, and it involved just 69 people from one geographic area, and, you know, it was informative, but it didn't tell us about America today, and how much sodium we're getting from different sources, and it didn't tell us much about a variety of ethnic groups ... we're a diverse country. So the CDC actually funded this study, and really they saw the need for it and laid out that this study needed to be done, as it was done, in three geographic areas, representing different ethnic groups.
Dr. Carolyn Lam: Tell us what you did.
Dr. Lisa Harnack: So, we recruited 450 people from 3 different areas, from Minneapolis/St. Paul metropolitan area ... Stanford was a partner in this study and they recruited people from that area of California, and then, finally, Birmingham, Alabama was a partner was a partner, and we got participants from there.
So the racial groups we had represented were white Americans, African Americans, Asian Americans and Hispanics.
Dr. Carolyn Lam: Yeah, I was really struck ... you had almost equal representation of women as well, didn't you?
Dr. Lisa Harnack: Right, so we made sure we had half of the participants were women, so we could really see how things stood with a variety of groups.
Dr. Carolyn Lam: That's excellent. What I was really impressed, as I'm sure, Wendy, you were, too, was the detail of the methodology. Could you tell us a little bit about that?
Dr. Wendy Post: Right, so we wanted to know all the sources of sodium. Part studies have tended to not ask about salt added to food at the table, and in home food preparation, because it's really hard to actually know ... you know, if you ask somebody, "Oh, did you add salt at the table? How much did you add?" They don't know. They just say, "Oh, well, I shook some salt on." So, we had people collect duplicate samples of the salt they added to food at the table and home food preparation. We gave them little baggies ... collection bags ... you know, after they added salt at the table, shake some into the baggy. So, we knew exactly how much because people do add salt in the home, so they have some control over how much sodium is in their diet. But the question is in how much under people's control in their home versus what's coming from the food supply.
Dr. Carolyn Lam: Right. And what I loved about the results is ... I think that it would challenge a lot of what people expect. Because when we talk about sodium restriction, everyone thinks, "Oh, it's the additional salt we add." And your study actually had surprising results. So, could you tell us?
Dr. Wendy Post: Yes, so it really was clear that the salt that people add at the table is just 5% of their total sodium intake, on average, across people in our study, and the salt added in home food preparation, like maybe the salt you add to your pasta when you're boiling it or to your eggs ... that was just 6%. So, 11% of the sodium in our study participants' diets was sort of that under-your-control in-the-home, and the rest was from other sources. So, the other things we looked at was, "Will water contribute some sodium?" So, we wanted to see how much comes from your home tap water. There's sodium that's just naturally occurring in food, like milk just naturally contains some sodium. So we wanted to look and see how much came from just naturally occurring in the food, and then the other question was how much is added by food manufacturers as part of making the food product, and that included the salt that might be added in making potato chips, as well as in restaurants ... the salt that might be added in making French fries or a pasta dish at a restaurant.
Dr. Carolyn Lam: And the biggest culprit?
Dr. Lisa Harnack: Yes, the biggest culprit was that latter source ... food added in processing.
Dr. Carolyn Lam: I thought that was amazing. Wendy, what do you think the public health message is? I mean, 70% almost of the salt's coming from processed foods from outside. What do we do? Stop eating it? What do we do?
Dr. Wendy Post: Right, so, on the editorial board for Circulation, we really liked this paper because of its very high impact for a public health message. So, as was stated, the sodium that we're getting in our diet is largely coming from processed foods and from foods we eat in a restaurant. So there are a number of ways that that can be modified and one is for our patients to read food labels and to make smart choices when they are shopping for processed foods in the supermarket.
But the other is for food manufacturers to decrease the amount of sodium in the products that they are making and there are voluntary suggestions by the FDA that food manufacturers reduce the sodium content of the food, and especially bread is incredibly high in sodium, and I suspect that most of our patients don't know that. So, if we were able to reduce the amount of sodium in the food supply by just a small fraction, it could have a large public health impact because we all eat.
So, it would affect everybody, and then I think the other really important public health message is about eating in restaurants and, of course, some people eat out more than others, and some people eat out in fast food restaurants, which, of course, are very high in sodium, but even in some of the nice restaurants that we go to, even expensive restaurants, the food is very heavily salted and I, for one, when I go out to eat, and sometimes don't like the taste of the food because it has so much salt in it, when I'm used to eating a low sodium diet.
So, there are a number of changes that occur on that level. One is for our patients to understand what foods tend to have a lot of sodium at a restaurant, but also for restaurants to notify their clientele of what foods are potentially lower in sodium and calories and generally provide the nutrient value so that we can make smart choices when we eat out.
Dr. Carolyn Lam: Yeah, indeed, congratulations, Lisa - what an important paper. Quick question, so that was the overall main message, but did you find any differences by different racial groups, by sex, by different socioeconomic status?
Dr. Lisa Harnack: We did find some differences. We found one difference was it looked like African Americans tend to add more salt at the table than some of the other groups, and, actually, Asians add less in our study. But still for all groups, that sodium added to food in processing was still the main source by a long shot, so, although there were some small differences by groups, it was clear that for all groups, the issue was the sodium added in processing.
Dr. Carolyn Lam: And for both Lisa and for Wendy, do you think these results are generalizable even beyond the US?
Dr. Wendy Post: I'd imagine that there would be quite a lot of variability, based on the habits of the various populations. So, here we're talking about eating outside the home, or food that's processed outside of the home, so there may be countries where most people are producing their own food and not necessarily buying processed foods or eating in restaurants, and then this would definitely be less applicable. And, of course, there are differences in foods that we eat based on our different ethnic groups.
Dr. Lisa Harnack: No, I would agree with what's just said. It really could be variable, but it does seem that a lot of countries are concerned about processed foods. Some countries implemented mandatory limits on the sodium in the foods in their food supply, so that would indicate to me that they know there's ... for some countries, there's serious concern about this source of sodium.
Dr. Carolyn Lam: Yeah, and I think this is really a wake-up message for us to examine where these sources of sodium ... I mean, even that simple message that it could be coming from bread, from drinking water, I think that would be surprising to a lot of us, even those of us practicing in medicine. Wendy, finally, you thought this was important enough to invite an editorial. I'd really like your thoughts there.
Dr. Wendy Post: You'll be able to read the editorial when it comes out in print, but the editorial also congratulates the authors on a really important paper, and the important public health messages, and, especially, compliments the authors on having a diverse group of participants, including ethnic minorities and men and women, and different geographic locations, so overall, it's a very important paper that I'm sure will have an important impact on the public health of our country and others.
Dr. Carolyn Lam: Listeners, you heard it right here. Remember, you're listening to Circulation on the Run. Please share this episode, and tune again next week!
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Doctor Carolyn Lam, associate editor for the National Heart Center and Duke National University of Singapore. Our feature paper today presents the first information on the impact of cardiovascular health in middle age and the burden of mobility in older age. This exciting data is from the Chicago Heart Association study. First, let me give you your summary of this week's journal.
The first study tells us that patients with long QT syndrome type II are at increased risk of hypoglycemia. First author, Doctor Hilton Cavallius, co-corresponding authors Doctor Tarakov and Hanson from University of Copenhagen, Denmark, noticed that loss of function mutations in HERG, which encodes the voltage gate at potassium channel 11.1, causes long QT syndrome II, but that the specific voltage gate at potassium channels are also present in pancreatic alpha and beta cells and intestinal L and K cells, which secrete glucagon, insulin, and the incretins, glucagon-like peptide one or GLP1, and glucose-dependent insulinotropic polypeptide, or GIP.
All these hormones are crucial for glucose regulation. The authors therefore hypothesize that patients with long QT syndrome II may have increased incretin and beta cell, but decreased alpha cell function and thus, lower glucose levels. To test this hypothesis, they measured secretion of these hormones and cardiac repolarization in response to a six-hour, 75 gram oral glucose tolerance test in 11 patients with long QT syndrome II with functional mutations in HERG with 22 matched healthy participants.
They found that following glucose ingestion, patients with long QT syndrome II displayed exaggerated incretin and endocrine pancreatic function with more than 50% increased levelsq of circulating insulin, GLP1 , and GIP and defective glucagon secretion, causing low plasma glucose levels and thus, increased risk of symptomatic reactive hypoglycemia following the glucose load.
Furthermore, in rats, pharmacological blockade of these voltage gate at potassium channel 11.1 with [inaudible 00:02:43] had similar effects and inhibition of HERG in beta and L cells increased insulin and GLP1 secretion up to 50%. Finally, glucose ingestion aggravated cardiac repolarization disturbances in patients with long QT syndrome II with a 122% greater increase in QT interval in these patients compared to controls. The take home message is that clinicians should be more aware of the risk of hypoglycemia with glucose ingestion in patients with long QT II syndrome and also recognize that this reactive hypoglycemia can further increase the risk of malignant arrhythmia in these patients.
The next paper is the first study to describe the risk of myocardial infarction after discontinuation of thienopyridine therapy in the DAPT study, or dual antiplatelet therapy study. As a reminder, in this trial, after PCI and 12 months of clopidogrel or prasugrel plus aspirin, eligible patients remained on aspirin and were randomized to continue thienopyridine versus placebo for 18 months. At 30 months, patients stopped the study drug and were observed for three months. In the current study by first author Doctor Schmidt, corresponding author Doctor Mauri, and colleagues from Brigham and Women's Hospital in Boston, Massachusetts. The authors looked at cumulative incidents of myocardial infarction assessed over three months after randomization and three months after study drug discontinuation. They found that discontinuing thienopyridine after either 12 or 30 months was associated with an early increase in myocardial infarction risk, mainly unrelated though to stent thrombosis. The magnitude of risk was highest in the early time frame and lower in patients not treated with the [inaudible 00:04:47] eluting stents.
The authors further compared pateints with DAPT scores above or below 2, and showed that both groups had lower rates of myocardial infarction with continued thienopyridine . Thus, while higher DAPT scores identify patients with a greater absolute ischemic benefit relative to bleeding with continued thienopyridine therapy, discontinuation at 12 months increases the myocardial infarction hazard regardless of DAPT score group.
The next paper describes the impact of depression treatment on one year mortality following acute myocardial infarction. Doctor [inaudible 00:05:28] and colleagues from the University of Missouri School of Medicine in Kansas City looked at the TRIUMPH study, which is an observational multicenter cohort study that enrolled more than 4000 patients with acute myocardial infarction between 2005 and 2008 from 24 US hospitals.
Patients were administered the patient health questionnaire 9 during the index myocardial infarction admission and depression was defined by a score of 10 or above. This was categorized as treated if there was a documentation of a discharged diagnosis, medication prescribed for depression, or referral for counseling, and is untreated if none of these three criteria were documented. Overall, 18.7% of patients met criteria for depression and 30.4% were treated. Compared without depression, patients with treated depression had one year mortality rates that were not different. However, patients with untreated depression had a higher one year mortality when compared to patients without depression. In summary, this study really shows that the association between depression following myocardial infarction and increased mortality differs by depression treatment status at the time of the index myocardial infarction. Patients with untreated depression have a 70 to 90% higher risk of dying at one year after the myocardial infarction than patients without depression or patients with treated depression. These findings should therefore encourage further research to examine the impact of depression recognition and treatment at the time of an acute myocardial infarction.
The final study provides insight into the paradox that folate deficiency is an independent risk factor for congenital heart disease, yet the maternal plasma folate level is paradoxically not a good diagnostic marker of this risk. In the current study by first author Doctor Wang, co corresponding authors Doctors Chow and Wang, from Fudan University, Shanghai, China. The authors examined six folate related polymorphisms in three independent case control groups comprising 1489 patients with congenital heart disease and 1745 healthy individuals from the Han Chinese population. They found that a specific fidgetin intronic 4 variant was associated with decreased circulating folate levels and increased protection against congenital heart disease. They further showed that increased fidgetin expression inhibited proteasomal degradation of reduced folate carrier 1 and dihydrofolate reductase, thus facilitating [inaudible 00:08:29] uptake and metabolism of folate. Their results therefore demonstrated that folate utilization, rather than the circulating folate levels, determined the preventive effects of folate against congenital heart disease. These findings provide new insights into the relationship of circulating folate levels with congenital heart disease and potentially other folate associated diseases.
Well, that wraps it up for your summaries. Now, for our feature discussion.
Today's feature paper really represents the first data we have that tells us what our cardiovascular health in middle age is doing to us in older age, in terms of both morbidity and longevity. To discuss this paper today, I'm so happy to have the first and corresponding author, Doctor Norrina Allen from Northwestern University in Chicago and Doctor Jarett Berry, associate editor from UT Southwestern. Welcome, both.
Dr Norrina Allen: Thank you very much.
Dr Jarett Berry: Thanks, Carolyn.
Dr Carolyn Lam: Norrina, could I start with you? This represents the 40 year follow up of the Chicago Heart Association detection project and industry. Could you maybe start by telling us a little bit about the Chicago Heart Association study?
Dr Norrina Allen: The Chicago Heart Association study was a large study that recruited almost 40,000 individuals who were employed in Chicago. They did a baseline exam between 1967 and 1973. After that baseline exam, we followed those individuals for over 40 years using their Medicare records, so we've been able to monitor their healthcare utilization and the incidence of disease across their lifetime up through 2010.
Dr Carolyn Lam: Then you measured their cardiovascular health by specific measurements, right? Could you tell us how that was defined and then also how was morbidity burden defined?
Dr Norrina Allen: Of course. We really think the overall burden of cardiovascular health tells us something more than looking at individual risk factors, so we classified each of the CHA participants into one of four groups, and each of those groups was defined by the level of main cardiovascular risk factors, including blood pressure, BMI, diabetes, smoking, and cholesterol level. We identified people who had favorable levels of all of those risk factors, individuals who had one elevated but not clinically of those high risk factors, individuals who had one high level, or individuals who had two or more high levels. That was based on their baseline exam. Overall we found that about 6% of the CHA participants had favorable levels of all of the risk factors at baseline, 19% had one or more that was elevated, 40% had one high, and 35% had two or more high risk factors, and again this was at the baseline exam when they were young to middle aged.
We then followed them, as I mentioned, using Medicare data and we identified the burden of whole morbidity based on the ICD9 codes in their Medicare record, and we identified the level of morbidity for each year of age, from entry into Medicare, [inaudible 00:11:54] all the way to their death.
Dr Carolyn Lam: And now, drum roll, your findings, they were pretty stunning.
Dr Norrina Allen: Yeah. As you mentioned when you introduced the study, this study is really the first to look at the whole of an individual's later life, meaning not just looking at the incidence of disease or longevity but taking those both into account. What we were particularly interested in was looking at the cumulative burden of morbidity in older age and the relative proportion of life that people live with cardiovascular or all cause morbidity. What we found was that individuals, who at baseline in young and middle age and favorable levels of all major cardiovascular risk factors, lived longer by almost four years but they also delayed the onset of all cause and cardiovascular morbidity by 4 and a half and almost 7 years respectively. What that means is that the proportion of their life that they live with morbidity was much shorter, they lived longer and healthier as compared to individuals who had one or two more high risk factors.
Dr Carolyn Lam: What an important public health message. Jarett, this concept of morbidity compression, tell us your thoughts.
Dr Jarett Berry: This is a really important paper. We've known for a long time, of course, that low risk individuals live longer, but the question of whether or not low risk individuals lived better throughout their life has been incompletely understood. The problem is that because low risk individuals live longer, the question that many have asked is that when we live longer is there a so-called expansion of misery, which some have talked about? That we live longer, but we have the same burden of disease or is that extended time horizon with the extended life span ... is the burden of morbidity compressed into a shorter period of time? In order to do that you need a couple things. You need a very large study that's followed for a very long time. Importantly, not just follow them for a long period of time, but follow enough individuals all the way until death so you know not just the first part of the story but we know the end of the story.
It really wasn't until [inaudible 00:15:18] paper, with not only the very large sample side but the very long term follow up until death, that we've been able to understand that actually low risk status in middle age does actually compress morbidity. This question of morbidity compression is not just an academic question but it actually has potential implications for cost savings and how we think about health care costs in our health care system. It'd be nice to hear [inaudible 00:15:18] thoughts about that as well, what else she found in regard to the Medicare costs.
Dr Norrina Allen: Right. As Jarett mentioned, not only from an individual perspective but at a societal level, what we're interested in is whether being in favorable cardiovascular health actually lowers healthcare costs at the same time as increasing an individual's health and longevity. What we found was that not only do the individuals in favorable health live longer and healthier, but they also have lower cumulative and annual healthcare costs, meaning that from a societal standpoint the compression of morbidity results in healthcare savings. We really think this is a strong method that provides support for earlier prevention efforts not only to improve an individual's quality of life but to reduce the healthcare costs associated with later life morbidity.
Dr Carolyn Lam: Indeed, what an important message to live longer and better and to save societal cost we need to get healthier cardiovascularly in middle age. Now, what really scares me though, is the statistic you told us a bit earlier. Only 6% of the individuals that you studied had a favorable level of all factors. What do you think this implies? What do you think needs to be done?
Dr Norrina Allen: Unfortunately, at this point, it's relatively rare in our population to reach middle age, 40 to 50 years of age, with favorable levels of all major cardiovascular risk factors. I think ... my research is really focused on trying to identify ways and times to intervene, to really help promote cardiovascular health early in life. I really think that we need to work hard to prevent the occurrence of these risk factors and the elevation of these risk factors much earlier in life. That means, even before the age of 40 and much earlier than that, we really need to be focusing on preserving cardiovascular health so that by the time individuals reach later life they can have a good quality of life and a longer, healthier life.
Dr Jarett Berry: I think the issue of the fact that low risk status is rare is that's a challenge that we continue to wrestle with as a society and as investagators interested in this are and how to improve that. When you look at your data, Norrina, I guess one silver lining here is we do see that ... when you look across the strata of risk groups ... it wasn't just the low risk individuals that seemed to benefit. It seemed that there was a little bit of a dose response. The goal obviously is to promote low risk status, but if we could limit the prevalence of those at the highest risk and shift them down a little bit, that could also have potential implications. I'd be interested to hear your thoughts about that.
Dr Norrina Allen: I think that's very accurate. There really is kind of a dose response level, so that every risk factor that's favorable adds a benefit and the more we can do to reduce the high risk factors over time, the better the long term outcomes are likely to be. I do really think prevention doesn't only have to exist before the development of the risk factors, but also there's a benefit to reducing risk factors that may have already developed or are elevated, and to try and reduce their level. I would say that I think that's an interesting next step that we really want to look at and try and think about how best to intervene even at middle age and help improve outcomes much later in life.
Dr Carolyn Lam: Thank you, listeners, for joining us today. I'm sure you agree, it's such an important message. Share it with your friends and tune in next week.
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.
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 ...how 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.
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.
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.
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.
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.
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!
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.
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.
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.
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!
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.
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.
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.
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.
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.
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.
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.
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.
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.