Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
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Feb 24, 2020

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

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

Dr Carolyn Lam: So Greg, guess what? We are going to be discussing predicting the benefit of evolocumab therapy in patients with atherosclerotic disease using a genetic risk score. That's our featured paper this week coming from the results of the FOURIER trial. I bet you can't wait to discuss it, but I'm not going to let us until we talk about some of the papers in today's issue. Do you have one?

Dr Greg Hundley: Yes, Carolyn, but first I'm going to get a cup of coffee because there's a lot of data in this one. This study is from the ODYSSEY trial and it involves alirocumab and it's from Dr Charles Paulding. Remember Carolyn, the ODYSSEY trial was a randomized double-blind placebo-controlled trial comparing alirocumab, a PCSK9 inhibitor or placebo in 18,924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. And the primary endpoint of this trial comprise death from coronary artery disease, non-fatal MI, ischemic stroke, or unstable angina requiring hospitalization. Now Carolyn, this is a sub-study and it was performed an A genome wide polygenic risk score for coronary artery disease comprising 6,579,025 genetic variants. And they were evaluated in 11,953 patients with available DNA samples. Analysis of the MACE risks, all those outcomes together, was performed in placebo treated patients while treatment benefit analysis was performed across all the patients.

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

Dr Greg Hundley: Well, Carolyn, both the absolute and relative reduction of MACE by alirocumab compared to placebo was greater in high versus low PRS patients. Those genetic, polygenetic risk scores combined in the patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6% and 1.5% respectively, and relative risk reduction in the alirocumab of 37% in the high PRS group versus 13% in the low PRS group. And so Carolyn, these results suggest the possibility of an independent tool for risk stratification using sort of precision medicine by selecting those using these genetic constructs, who may be more likely to benefit from this form of therapy.

Dr Carolyn Lam: Wow Greg, that is really interesting. I genuinely think that our world is moving towards precision medicine and this really, really speaks to remember that feature paper also talking about genetic risk scores, but from the FOURIER trial. But before we get to that, I've got a basic science paper. Now this one provides insights into the mechanisms underlying age related hypertension. And it's from Dr Ying Yu and colleagues from Tianjin Medical University who hypothesize that since proinflammatory cytokines increase in T lymphocytes with aging and prostaglandin D2 suppresses T helper 1 cytokines through the D-prostanoid receptor 1, that this axis in T cells may play a role in age related hypertension.

Dr Greg Hundley: Ah, Carolyn. What did they find in this study?

Dr Carolyn Lam: Prostaglandin D2 biosynthesis and D-prostanoid receptor 1 expression, were both markedly decline in CD4 positive T cells from older humans and aged mice. D-prostanoid receptor 1 depletion in these CD4 positive T cells, exaggerated age dependent blood pressure elevation in mice by increasing tumor necrosis factor alpha and interferon gamma secretion. Whereas its over expression showed the opposite effect and its activation suppressed TH1 cytokines. These results really indicate that D-prostanoid receptor 1 and its downstream pathway may serve as an attractive immuno-therapeutic target for age dependent hypertension.

Dr Greg Hundley: Oh wow. Very insightful Carolyn. Well, I've got a basic science paper to go over and it's from professor Kinya Otsu from Kings College London. This study addresses the mechanism of ongoing inflammation within the hearts of patients with cardiomyopathy. The study involves the assessment of Regnase-1 and RNAs involved in the degradation of a set of pro inflammatory cytokine messenger RNAs in immune cells. And the study involves the role of Regnase-1 in non-immune cells such as cardiomyocytes.

Dr Carolyn Lam: Wow.

Dr Greg Hundley: The degradation of cytokine messenger RNA by Regnase-1 and cardiomyocytes plays an important role in restraining sterile information in failing heart. Once the inflammatory cascade gets going, this is that constant inflammation that's ongoing. In addition, the Regnase-1 mediated pathway might be a therapeutic target to treat patients with heart failure as adeno-associated virus 9 mediated cardiomyocyte targeted gene delivery of Regnase-1 or administration of anti-IL-6 receptor antibody, attenuated the development cardiomyopathy induced by severe pressure overload in wild type mice.

Dr Carolyn Lam: Wow, that's really interesting. I find this whole field of inflammation in heart failure of course, of key interest, but I'm going to next tell you about the results of the FUEL trial, which is the Fontan Udenafil Exercise Longitudinal trial.

Dr Greg Hundley: Tell us about the Fontan operation.

Dr Carolyn Lam: Aha, I thought you may ask, Greg. Well, the Fontan operation to remind us all, really creates a total cavopulmonary connection and a circulation in which the importance of pulmonary vascular resistance is therefore magnified. Over time, the circulation needs to deterioration of cardiovascular efficiency associated with a decline in exercise performance. This FUEL trial and reported this time by David Goldberg and colleagues from the Children's Hospital of Philadelphia was a phase 3 clinical trial, which randomized 400 patients with Fontan physiology from 30 sites in North America and the Republic of Korea. The participants were randomly assigned to Udenafil at 87.5 milligrams twice daily or placebo. And the primary outcome was the between group difference in change in oxygen consumption with peak exercise.

Dr Greg Hundley: Hmmm, very large important trial it seems like Carolyn. What did they find?

Dr Carolyn Lam: Treatment with Udenafil did not result in a significant increase in peak oxygen consumption, which was the primary outcome, but did result in improvements in measures of exercise performance at the anaerobic threshold, which was a secondary outcome. Udenafil was well tolerated with side effects limited to those previously known to be associated with phosphodiesterase type 5 inhibitors.

These results and future perspectives are discussed an editorial called FUELing the Search for Medical Therapies in Late Fontan Failure, by Doctors Gewillig and De Bruaene.

Dr Greg Hundley: Very nice, Carolyn. Now how about the rest of the journal?

Dr Carolyn Lam: Oh well I want to tell you about this in-depth review by Dr Rosenkranz and it's entitled, Systemic Consequences of Pulmonary Hypertension and Right-Sided Heart Failure. Very intriguingly, talking about non-cardiac features, as well as cardiac, of right heart failure, a real, real must read with beautiful figures.

In the cardiovascular case series we discuss a case of left ventricular non-compaction and cardiogenic shock by Dr Shenoy. There are also two research letters I want to tell you about one by Dr Gillinov on the accuracy of the Apple watch for detection of atrial fibrillation. And this time looking at the Apple watch series 4, which interestingly employs electrodes to generate a single lead ECG and provides two mechanisms for rhythm assessment. Won't tell you more. You got to pick up this beautiful letter.

The next is by Dr Mazer on the effect of empagliflozin on erythropoietin levels IN stores and red blood cell morphology in patients with type II diabetes and coronary artery disease. And this really provides evidence to suggest that SGLT 2 inhibition with empagliflozin may stimulate erythropoiesis via an early increase in erythropoietin production in people with diabetes.

Dr Greg Hundley: You know Carolyn, we just keep hearing more about EMPA and DAPA and they are just going to really pave the way I think for a whole new class of agents that we're going to be using frequently.

I've got a couple letters in the mailbox and one is by Sugimoto and Taniguchi regarding the article, Internal Versus External Electrical Cardioversion of Atrial Arrhythmia in Patients with Implantable Cardio Defibrillators, a randomized clinical trial. And then also there's another research letter by Dr Hiroshi Sugimoto from Kobe Red Cross Hospital with a response by Jakob Lüker from University of Cologne.

What a great issue. How about we proceed to that feature article?

Dr Carolyn Lam: You bet.

Can a genetic risk score identify individuals who will derive greater benefit from PC SK9 inhibition? Well guess what? We're going to find out now in our feature discussion. So pleased to have with us the first and the corresponding authors of our feature paper, Dr Nicholas Marston and Dr Christian Ruff, both from the TIMI study group in Brigham and Women's Hospital and Harvard Medical School and also to have our lovely associate editor, Dr Svati Shah from Duke University in Durham, North Carolina. Welcome everyone.

Nick, could I get you started with telling us about this exciting analysis that you did from the FOURIER trial?

Dr Nicholas Marston: The FOURIER trial was a 27,000 patient cardiovascular outcomes trial that studied the PC SK9 inhibitor, evolocumab and it demonstrated a significant reduction in major adverse cardiovascular events in patients who had established atherosclerotic disease. And in the study, there was a 15% relative risk reduction and a 2% absolute risk reduction, which earned it a class 2 recommendation for very high-risk patients with atherosclerosis in the recent cholesterol management guidelines. And what we've done in previous lipid trials is we studied the interactions between genetic risk and treatment benefit. For example, in 2015 we showed that patients with high genetic risk, those in the top 20% of genetic risk, had the greatest benefit from statin therapy in terms of both absolute and relative risk reductions. And so now we have the opportunity with evolocumab and data from the FOURIER trial to ask the same question of PC SK9 inhibitor. That is, could a genetic risk score identify patients who will drive a greater treatment benefit and we hypothesize that like statins, there would in fact be a significant interaction between genetic risk and therapeutic benefit.

Dr Carolyn Lam: That's so cool Nick. But could I ask, the question always comes, is it nature versus nurture? And so I really love the way that you dealt with the clinical risk factors as well. Could you maybe walk us through that and then tell us the results?

Dr Nicholas Marston: Yes, absolutely. We for this study, kind of had two objectives. One was to look at risk prediction and then the other look at treatment benefit and using a genetic risk score for both. However, we wanted to go further than just use the genetic risk score. We wanted to incorporate clinical risk factors since that's how we would do it as physicians in the clinic. We would have not just genetic risk data in front of us but also clinical data. And so when we were grading a patient's risk using genetic risk, we also factored in if they had multiple clinical risk factors. And what we found by combining both genetic and clinical risk was that there was a significant gradient of risk across these risk categories.

That is patients who were without high genetic risk and without multiple clinical risk factors actually had no benefit from evolocumab over the 2.2-year follow-up period. However, those without high genetic risk, but who did have multiple clinical risk factors, derived an intermediate benefit. About a 13% relative risk reduction and 1.4% absolute risk reduction. And then it was the high genetic risk group, independent of whether or not they had multiple clinical risk factors that had the largest benefit from evolocumab with a relative risk reduction of 31%, absolute risk reduction of 4% and the number needed to treat of 25. And that's actually a twofold greater benefit than was seen in the overall FOURIER trial population.

Dr Carolyn Lam: That's really stunning results. Now I know Svati's going to have questions for us, so maybe I should invite you Svati, just put these results into context and let the audience know what we were thinking as editors when we saw this brilliant paper.

Dr Svati Shah: Yeah, thanks Carolyn. And I think Nick has done a fantastic job of describing the exciting results from this paper and just kind of taking a step back to help the audience understand what we're talking about when we're talking about genetics. For decades, we've been trying to figure out the genetics of heart disease and we're not talking about the genetics of things that are really rare like long QT syndrome, but the genetics of just common complex heart diseases. And amongst the scientific community, we've tried all different ways of sort of analyzing these data and so I want to make sure that everybody who's listening understands the novelty of really looking at these polygenic risk scores. Where we have now come to understand that it's not a single gene, it's not even two genes, that it's multiple variants and multiple genes and when they're combined, that's when you really have the power to understand how it might be useful in terms of how we take care of patients.

Really important with how Nick and Christian have laid out this really nice paper as well as their prior work in statins, is that not only did they show that these polygenic risk scores are associated with cardiovascular outcomes or even different amongst whether you get treated with the drug or whether you don't, but really importantly they're getting it clinical utility, not only with regards to showing that they compare it to a clinical risk score, but really showing that if you use these polygenic risk scores, you can identify patients who may derive the greatest benefit from PC SK9 inhibitors. And importantly in their paper, they show that if you have low polygenic risk score and low clinical risk score, you may not derive benefit from PC SK9 inhibitors. With all the caveats that this is a secondary prevention population, so I really applaud Christian and Nick and his team for the nice work that was done.

Dr Carolyn Lam: Oh, couldn't agree more, Svati. You know what I was very struck with too, because some people go, I may have a genetic risk. Maybe I could undo it or somehow overcome it with my clinical risk factors. And that's why I really appreciated that they showed that it was additive, and genetics still matter even if you have risk factors and vice versa. That was really cool. Christian, could I ask you to maybe describe a bit, what kind of genetic risk score this was and maybe perhaps point out some of the limitations therefore of what you studied.

Dr Christian Ruff: As Svati mentioned, this is really a quickly evolving field. We now have the ability to either genotype or sequence all of the variation that makes us different from one another. Our susceptibility to disease as well as our potential benefit for treatment. We had for this study, looked at several different risk scores. The one we focused on was a coronary artery disease genetic risk score that had 27 different variants that had been shown to predict having a cardiac event, both in primary and secondary populations. And we have previously identified patients who may have been at a higher risk who received greater benefit from statin therapy. And in this study, we actually compared this 27 variant genetic risk score with actually a much larger score of over six million variants. And interestingly, the two scores performed fairly similar with respect for risk prediction. One of the big questions going forward is, we have lots of ways to develop genetic risk scores, how many different variants do we need? What more information do we have with more complicated scores?

And I think Svati really hit on a really critical point is that really this study is really layering in genetic risk on top of clinical risk factors, which we can easily assess at the bedside. And I think what's reassuring to patients is that not only is genetic risk able to give us much more information for prognosis, but that this risk is modifiable. People think that their genetic risk, they're sort of born with it and there's nothing that they can do about it. But in this study, as Nick pointed out, even over a very short period of time with powerful lipid lowering therapy with a PC SK9 inhibitor, we essentially reduced these patients at high genetic risk to the risk of the very low risk patients on placebo. I think this is a reassuring message that genetics plays an important role for risk prediction and it identifies patients who we might target for more intensive therapy and that we can potentially reduce that risk even though that risk is based on the DNA that they're born with.

Dr Carolyn Lam: Indeed. That's a great point. And Svati, I'm sure you were thinking along those lines when you invited that beautiful editorial by Doctors Daniel Raider and Michael Levin. But Svati, would you like to comment on your thoughts on, is this ready for prime time?

Dr Svati Shah: I think that's the key question. What Christian and Nick and his team have done is take us a big step forward in how we use these polygenic risk scores. I think there still are many skeptics amongst the genetic scientific community about, well great, you can look at 27 variants and some of these polygenic risk scores, you're looking at a million things. How do we actually use that to take care of patients?

I actually want to turn this back, that question back around Carolyn, and I'd like to ask Christian next, what are the next steps? There are a lot of cardiologists who if you're listening to this podcast, should we all run out and get our patient's genotype to order this genetic chip so that we can figure out what their polygenic risk score is?

Dr Christian Ruff: Yeah, that's a great question and I could start off and then hand off to Nick, but I think one of the key questions is obviously there are a lot of genetic risk scores and I don't think as a field that we've come up with which one we really should implement in clinical practice. There's still a lot of fine tuning and figuring out which score gives us the most amount of useful information.

And then I think as something that you had mentioned that these scores are generated in both a healthy cohort population and now, we're looking at it in clinical trials and there's no sort of reference. Like when we have a blood test and we say, "If your hemoglobin A1C is above or below this number that means that you have diabetes." And we haven't figured out, what are the actual thresholds that you use for these genetic risk scores that you can implement broadly across different patient populations. There's still a lot of work that needs to be done to make these scores ready for prime time. This is really setting the stage. Is this something that we should be doing? And I think these studies and others say that the data looks great that we should be doing this, but we haven't yet figured out the logistics of which score and how do we actually reference to population.

Dr Nicholas Marston: Yeah, I agree with Christian definitely that we need to figure out what's the optimal genetic risk tool and for which population and what the cut points are. And then I think another piece that's going to be very important moving forward is doing a lot of this work and studying in non-European ancestry and cohorts and populations. Because most of the work done so far in discovery has been in databases such as the UK Biobank. And that limits us in our analyses to European ancestry patients. And so, I think for this to go to prime time, we want to be able to offer it to all of our patients. And so that means making sure we have scores that fit all populations, not just primary and secondary, but also all different types of ancestry.

Dr Carolyn Lam: Oh, I'm so glad you mentioned that, Nick. That was exactly on my mind coming from Asia. And the other thing of course, would be cost effectiveness of these approaches. Oh my goodness. I wish we had all the time in the world to talk about this more. The implications are enormous, but just let me thank you on behalf of all of us for publishing this remarkable paper in Circulation.

Audience, you've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr Greg Hundley: This program is copyright, the American Heart Association 2020.


Feb 17, 2020

Dr Biykem Bozkurt: I am Biykem Bozkurt, Professor of Medicine from Baylor College of Medicine, Senior Associate Editor for Circulation and today, I'm joined with Sana Al-Khatib, Professor of Medicine from Duke University, Senior Associate Editor of Circulation, for the podcast for the fourth annual Go Red for Women issue for Circulation. As all our listeners are aware, cardiovascular disease is a leading cause of death among women, but we have significant gaps in our awareness and treatments, and with a recognition of these disparities for cardiovascular care in women, AHA has launched a Go Red for Women campaign back in 2004. We have made great strides, and despite the improvement in awareness, significant gaps persist and adverse trends are emerging for cardiovascular disease in women.

With such recognition, in 2017, Circulation launched the annual Go Red for Women issue, dedicated to cover transformative science, exciting new treatment strategies, recent epidemiological trends, and with an intent to close the gaps and eliminate the disparities for cardiovascular care in women. This is the fourth Go Red for Women issue and we have an exciting portfolio that we'd like to share with our readers and listeners. In this issue, we have quite a few important papers. The first two that we would like to start with are going over the epidemiologic trends. Sana, do you want to walk us through the two papers that we have on myocardial infarction and sudden cardiac death?

Dr Sana Al-Khatib: I would love to start with the paper on sudden cardiac death, which is very fitting. That's what I focus most of my work on. This particular paper actually looked at sudden cardiac death as the first manifestation of heart disease in women, and it was focused on the Oregon sudden unexpected death study, the timeframe for which was between 2004 and 2016 and what they really wanted to do is to assess sex specific trends in sudden cardiac death incidence. And so they focused on out of hospital, sudden cardiac death cases among adults during that time period.

And they divided that 12-year period from February 2004 to January 2016 into three four-year intervals, 2004 to 2007, 2008 to 2011 and 2012 to 2015. And they really looked at these trends among women and men and they found that there were 2,938 sudden cardiac deaths, 37% of who were women. And they found an interesting U-shaped pattern of risk of sudden cardiac death with Anader in 2011. An increase in the years that followed 2011 so regarding that rebound, the rates really increased in 2013 and 2015. And when they specifically looked at women, they found that the rates of sudden cardiac death declined by 30% between the first and second four year time period and increased by 27% between the second and third period.

Interestingly, the subsets with sudden cardiac death as the first manifestation of heart disease, accounted for 58% of the total rebound in sudden cardiac death incidence from period two to three but there was no change in the incidence over time for sudden cardiac death occurring among people with preexisting heart disease. For men actually sudden cardiac death also declined from the first to the second period, but not as much as in women and also increased between the second and third periods. Again, not as much as we saw in women. Subsets of sudden cardiac death occurring in the setting of identifiable heart disease was responsible for 55% of the rebound in overall sudden cardiac deaths incidence. Certainly some significant differences between men and women. Very exciting findings.

Then if we actually turn our attention to the second study looking at sex specific trends in acute myocardial infarction, this particular analysis, Biykem, was done within an integrated healthcare network between 2000 and 2014 and they picked the Kaiser Permanente Southern California network. They were able to identify 45,000 plus acute MI hospitalizations between 2000 and 2014 and they found that age and sex standardized incident rates of AMI declined from 2000 to 2014. And they found that a decline for women was actually more so than in men. And in fact for men it was pretty much stable. And they found that the incidence of hospitalized MI had declined, however, declines are slowing among women compared with men in recent years.

That's actually identified some unmet care needs among women that hopefully can meet people and investigators to tailor their approaches to try to close those gaps and disparities in care. With that, let me actually turn it back to you to potentially talk about to cardiovascular risk assessments in women.

Dr Biykem Bozkurt: With the recognition of the disparities and the recent emerging trends of adverse outcomes, especially in younger women, there has been a focused attention in how to assess risk, cardiovascular risk in women. There is a very comprehensive review by Salim Virani and colleagues who's addressing the cardiovascular risk assessment for women. As our listeners will recall in 2018, ACC/AHA cholesterol professional guidelines specified risk enhancing factors such as premature menopause or preeclampsia for women. And if present, in borderline or intermediate risk patients, would elevate the 10 year risk to a higher category. But now with a recognition of many more risk factors, Virani and colleagues are proposing a more comprehensive cardiovascular risk assessment for women. And these include the risk factors that are not only identified in the 2018 ACC/AHA cholesterol guidelines, but additional such as gestational hypertension and diabetes or adverse pregnancy outcomes such as preterm delivery, small birth for gestational age or placental abruption or infarct or premature menarche or premature menopause, primary ovarian failure or pregnancy loss and additionally inflammatory disorders such as lupus, rheumatoid arthritis, psoriasis and history of cancer and cancer related therapies.

And they formulate this in a nice and well tabulated fashion. And all these risk factors are summarized table one which I think most of our listeners and readers will refer to. And they also come up with a nice approach. What shall we do? And how shall we detect that risk? First recommendation they have is that we should obtain a comprehensive obstetric and gynecological history from all women. And if these risk factors are present, then we should then screen for other traditional risk factors early and frequently and then treat for modifiable risk factors such as hypertension, hyperlipidemia, diabetes, metabolic syndrome, and also implement aggressive lifestyle modification with strategies such as management of blood pressure control, reduction of blood sugars, remaining active eating, healthy, losing weight, and not smoking. Which is summarized as life's simple seven which is an AHA initiative that summarizes healthy lifestyle as life's simple seven.

And very complimentary to Virani’s review paper, we had another wonderful paper that is titled Life's Simple Seven and health by Jacqueline Kulinski who reminds us that not only these seven factors but breastfeeding for postpartum mothers is an important approach to reduce cardiovascular risk. Breastfeeding is not only beneficial for the newborn infants but for the mother as it's been associated with reduction in risk of myocardial infarction, stroke, cardiovascular disease hospitalization rates, future development of diabetes, hypertension, and even mortality. And this paper elaborates on potential mechanisms such as increases in metabolic expenditure, enhancement of insulin sensitivity, reduction in cholesterol, greater mobilization of fat stores and reversal of elevated triglycerides and cholesterol that's seen during pregnancy.

It also emphasizes the importance of recognition and education of women because currently only about 25% of women are exclusively breastfeeding at six months and US has one of the lowest breastfeeding rates among industrialized countries. And we do have disparities according to race and income and black infants and infants living in rural areas in Southeast USA are less likely to be breastfed. And there is definitely increased recognition for importance and but it's also important to be able to accommodate and facilitate breastfeeding for mothers. Currently the paper emphasize that all 50 states now have laws allowing women to be able to breastfeed in public or private locations. But again, there definitely is a necessity for increased awareness and education.

On that end, there is also a great paper covering the news release announcing the partnership between American Heart Association and American College of Gynecology and Obstetricians in promoting risk identification and reduction of cardiovascular disease in women through collaboration between obstetricians and gynecologists. In 2018, AHA and American College of Gynecology issued a call for action for both specialists to team up and increase screening for cardiovascular disease by obstetricians and provide education and appropriate referrals. And I think this initiative is going to increase the opportunities for young women whose primary care provider solely could be an obstetrician, who potentially will get screened for cardiovascular disease and if they have these risk factors, will potentially be able to be offered lifestyle modification, message and intervention strategies.

These, I think, three very complimentary papers are enhancing our recognition for the new risk profile that needs to entail getting a comprehensive obstetric and gynecological history in all women. And in the event we recognize either of these risk factors including the traditional risk factors or obstetric and gynecological risk factors such as pregnancy related complications or preeclampsia or other additional special risk factors such as autoimmune disorders and cancer, then we will need to heighten our awareness for lifestyle modification, risk management, and earlier treatment and closer monitoring.

That brings us to another important risk profile, which is cancer for women. And Sana, I know we do have two great papers related to cancer topic. If you could elaborate on those.

Dr Sana Al-Khatib: I'm really excited about these papers. As you pointed out, Biykem, that cardio oncology is a field that is really expanding and so it was really very gratifying to get these two papers. The first paper had to do with a comparison between aromatase inhibitors and Tamoxifen in women with breast cancer in terms of their association with the risk of cardiovascular outcome. And this particular study was done in the United Kingdom and they studied women though with newly diagnosed breast cancer initiating hormonal therapy, either with everyone at aromatase inhibitors or Tamoxifen between 1998 and 2016. And the study outcomes that they were interested in included myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality.

And they actually had a sizable patient population with 23,000 plus patients included in this analysis of whom close to 18,000 initiated treatment with either an aromatase inhibitor or Tamoxifen. And they found that the use of aromatase inhibitors was associated with a significantly increased risk of heart failure and cardiovascular mortality compared with Tamoxifen and that aromatase inhibitors seemed to have a trend towards increased risk of myocardial infarction, ischemic stroke. Although those differences were not statistically significant. They actually concluded that aromatase inhibitors were associated with an increased risk of heart failure and cardiovascular mortality compared with Tamoxifen and that there were trends toward increased risks also of MI and ischemic stroke. And so they really want clinicians and patients to be aware of these findings when they are trying to make decisions about treatment for breast cancer.

We have another really interesting study, Biykem, that was actually a randomized control trial that studied the effect of exercise therapy dosing schedule on impaired cardiorespiratory fitness in patients with primary breast cancer. And so this randomized trial enrolled 174 post-menopausal patients who were randomly allocated to one of two supervised exercise training interventions, delivered either using a standard linear test or nonlinear test. And they had a control group of just stretching. They did some stretching. And they did the trial over at periods of 16 consecutive weeks and the primary endpoint was change in the VO2 level, PCO2 level from baseline to post intervention.

They had a couple of other secondary endpoints and their results were interesting. They found no serious adverse events during the trial, but they actually found that 40% of patients in both exercise dosing regimens were classified as responders. And they concluded that short term exercise training independent of dosing schedule was associated with modest improvements in cardiorespiratory fitness in patients previously treated for early stage breast cancer. Really interesting, a smaller study, not really looking at hard endpoints yet. It's still important because I believe that it is going to form the basis for more studies and more research in this important field, Biykem.

With this, I'd like to turn it over to you to talk about elevated body mass index in young women.

Dr Biykem Bozkurt: And this is another fascinating study, a large study from Sweden. It involved more than 1.3 million young women. Average age was 27. It was a national prospective cohort. The recruitment was between 1982 and 2014. What they did was they measured the baseline of weight of women in early pregnancy in the first trimester, actually the first antenatal visit before they could gain any weight related to the pregnancy. With their BMI measurement at baseline, then they followed these patients for approximately 30 years and associated this baseline BMI with future developments or dilated cardiomyopathy or any cardiomyopathy. They looked at that dilated cardiomyopathies, hypertrophic cardiomyopathies, these other cardiomyopathies such as alcoholic cardiomyopathy and others.

Interestingly, elevated body mass was associated with future development of dilated cardiomyopathy. A very similar finding was reported in former studies for adolescent men, but we didn't have this finding for young women. This study provides evidence that elevated BMI, even if it is only in the overweight range, is associated with future development of dilated cardiomyopathy. In the past we had numerous studies demonstrating overweight or obesity status being associated with future development of clinical heart failure, clinical symptoms of heart failure, but this is one of the largest scale population based cohorts demonstrating the association with dilated cardiomyopathy.

And interestingly, these women at baseline did not have the usual other confounders or comorbidities associated with future development of cardiomyopathy. The risk of diabetes and hypertension was less than 1% at baseline. Very interestingly, BMI by itself, independent of all these other variables was associated with future risk. And of course the higher the BMI was, the higher the risk was. The highest risk was for those with morbid obesity or BMI over 35 and in those patients the risk was increased by about five fold.

Sana, we talked about the disparities for women. Where are we with women participation in cardiovascular trials? And how do we looked globally overall regarding the disparity of cardiovascular diseases in woman?

Dr Sana Al-Khatib: These are really important questions, Biykem. Let me first start with a study that will be in the Go Red for Women issue on women's participation in cardiovascular clinical trials. They looked at that. Between 2010 and 2017, which is a very important topic as you know, Biykem. And so what they did here is they actually assessed the participation of women in completed cardiovascular trials that were registered in clinical trials between 2010 and 2017. And they parked calculated the female to male ratio for each trial to determine the prevalence adjusted estimates for participation of women. And so they kind of defined it as participation prevalence ratio. And so they said that they were able to identify 740 completed cardiovascular trials including more than 860,000 adults of whom 38% were women. And they talked about how the median female to male ratio of each trial was 0.501 overall and varied by age group and type of intervention and region and trial size and funding sponsors.

Actually, these are really interesting findings. In the interest of time, I'm not going to delve into all those details, but I think it would be really interesting for people to read that and look at this more carefully. But they found that relative to their presence in the disease population, the participation prevalence ratio of women versus men actually was a higher than 0.8 for hypertension, pulmonary arterial hypertension and lower for arrhythmia, coronary artery disease, acute coronary syndromes and heart failure trials. And they found that in the most recent time period, that they defined between 2013 and 2017, they saw a significant increase in the participation and prevalence ratios for stroke and heart failure trials compared to other periods. They concluded, not surprisingly, that among cardiovascular trials in the current decade, men still predominate overall, but that the representation of women actually is improving, especially when it comes to studies related to stroke and heart failure. That's what's really interesting, Biykem.

The other point that you were very nicely raised had to do with sex differences in primary and secondary prevention of cardiovascular disease. And the one study that we have in our issue, Biykem, was actually done in China. I really like this global reach of our issue. I presented a study that was done in the UK. You presented a study done in Sweden. This particular one was done in China and they conducted a community based survey of adults in seven geographic regions of China between 2014 and 2016. They really wanted to determine sex differences in the primary and secondary prevention of cardiovascular disease. And they looked at different factors in terms of age, education level, area of residence. And they had more than 47,000 participants of whom 61% were women. And they found that 5,454 had established cardiovascular disease, 57% of whom were women and 9,532 had a high estimated 10 year cardiovascular disease risk. And of those, 71% were women. And they found that only about 49% of women versus 39%, 60% of men were on any kind of blood pressure lowering medications, lipid lowering medications, antiplatelet therapy for primary and secondary prevention.

And they found that women with established cardiovascular disease were significantly less likely than men to receive blood pressure lowering medications, lipid lowering medications, antiplatelet therapy, so on, so forth. And that woman with established cardiovascular disease had better blood pressure control but less well controlled NVM cholesterol, were less likely to smoke and achieve physical activity targets. Conversely, women at high risk of cardiovascular disease were less likely than men to have their blood pressure LDL cholesterol, body weight controlled, despite the higher use of blood pressure lowering medication. Really interesting gaps in care that this study highlights that hopefully can form the basis for interventions to try to address those disparities.

And then as you know, we actually have a couple of research letters on the representation of women in editorial boards of major general and subspecialty cardiology journals, publishing clinical research. In this particular study, they actually found significant disparities where women were less represented among deputy associate editors and more so in European journals compared with US journals, general cardiology journals. Although editorial board membership was actually similar between Europe and the US, and they found that over 20 years, women deputy associate editors representation increased significantly for our journal, Biykem, Circulation. That was really very encouraging to see. And women editorial board membership increased for Circulation and for JACC without a significant change for the American Journal of Cardiology. That was really nice to see.

The one thing that was notable was in terms of women serving as editors-in-chief, we're still lagging behind in a big way, but I'm hoping that this particular study and several other studies that may get published in the future, will highlight these gaps and hopefully will lead to increased representation of women on editorial boards.

And finally we have an interesting study looking at the representation of women and men among training programs where they looked at the AAMC data and they were interested in looking at training in general cardiovascular disease medicine as well as for adult cardiology sub-specialties. And they also looked at pediatric cardiology by the way. And they found that in 2017 to 2018, among all adult cardiology trainees, only 21% were women. 79% were men. And among trainees in the different adult cardiology subspecialties, the representation was actually pretty poor in interventional cardiology, where only 10% of the trainees were women. And for electrophysiology, my own sub specialty, were only 11.6% of the trainees were women. Really interesting findings, the representation for advanced heart failure and transplant like your specialty, Biykem, women constituted 31% of the trainees and women did better when it came to adult congenital heart disease representing 47% of the training.

Really interesting trends and they concluded that in this review of ACG and the accredited training program, they found that cardiology ranked second for the most under representation of women, preceded as only by orthopedic surgery. And the sub specialty trends that I shared with you were really interesting. Hopefully as we see more of these publications, we'll be able to as a community come together and think about what are the barriers to more representation of women in these training programs? And how can we overcome these failures to encourage more women to go into this wonderful specialty of cardiology and the different sub-specialties, including procedural sub-specialties? Back to you, Biykem.

Dr Biykem Bozkurt: Thank you Sana. Very interesting findings indeed. Another fascinating study that we have in our issue is a study that provides us some insights on peripartive cardiomyopathy and potentially the role of natriuretic peptides during pregnancy.

This is an experimental study that involved natriuretic peptide receptor knockout in mice in which natriuretic peptides would not work. And the investigators demonstrated that these mice, during the postpartum lactation period, had elevated aldosterone levels, evidence of expression of pro inflammatory mediators such as IL-6, cardiac hypertrophy, fibrosis, left ventricular dysfunction, and even increased mortality. And interestingly, they were able to abrogate the effects of the lactation by use of mineralocorticoid receptor antagonists. With MRA use, there was evidence of reduction in LVH and reduction in inflammatory mediators.

There is a great editorial by Denise Hilfiker-Kleiner, who addresses the potential hypothesis of the role of unbalanced oxidative stress with prolactin in peripartum cardiomyopathy. And that the natriuretic peptides can be protected. And raises the question whether there could be a role for augmenting the natriuretic peptides further by use of sacubitril/valsartan. Or as was demonstrated in this study by you as a mineralocorticoid receptor antagonists in the postpartum period. And she also questions why in this experimental model, the detrimental effects were not seen during pregnancy but only in the postpartum lactation period.

Overall, very interesting papers. And finally we have an inspiring piece in our past or discovery section. It's an interview with Barbara Casadei, the President of European Society of Cardiology. She goes in a very detailed fashion over her career path, what she considers as the critical reasons for her success and how she envisions to shape the future of women in cardiology.

Dr Sana Al-Khatib: We would like to thank everyone who submitted their research and their work for this issue and congratulate the authors and investigators who were successful in getting their work published. Thank you very much.

Dr Biykem Bozkurt: We thank you for tuning in to our podcast. We hope that you'll enjoy our fourth issue for the Go Red for Women as we continue to highlight some of the best science for cardiovascular disease in women. Thank you.

This program is copyright, the American Heart Association 2020.


Feb 10, 2020

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

Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article this week relates to an international multi-center evidence-based reappraisal of genes reported to cause congenital long QT syndrome. But, before we get to that, how about if we grab a cup of coffee and start on our other papers? Do you have one you'd like to discuss?

Dr Carolyn Lam: Yes. My favorite part of the week. So this first paper really asks the question, "What's the association between HDL functional characteristics, as opposed to HDL cholesterol levels, and acute coronary syndrome?" The paper comes from Dr Hernáez from IDIBAPS in Barcelona, Spain and colleagues who conducted a case control study nested within the PREDIMED cohort.

Originally a randomized trial where participants followed a Mediterranean or low-fat diet. Cases of incident acute coronary syndrome were individually matched one is to two to controls by sex, age, intervention group, body mass index, and follow-up time. The authors measure it the following functional characteristics, which were HDL cholesterol concentration, cholesterol efflux capacity, antioxidant ability, phospholipase A2 activity and sphingosine-1-phosphate, apolipoproteins A1 and A4, serum amyloid A and complement 3 protein.

Dr Greg Hundley: Wow Carolyn, a detailed analysis. What did they find?

Dr Carolyn Lam: They found that low values of cholesterol efflux capacity, and levels of sphingosine-1-phosphate and apolipoprotein A1 in HDL or all associated with a higher risk of acute coronary syndrome in high cardiovascular risk individuals, irrespective of HDL cholesterol levels and other cardiovascular risk factors. Low cholesterol efflux capacity values and sphingo-1-phosphate levels were particularly associated with an increased risk of myocardial infarction, whereas HDL antioxidant or anti-inflammatory capacity was inversely related to unstable angina.

Now this is significant because it's the first longitudinal study to comprehensively examine the association of several HDL function related biomarkers with incident acute coronary syndrome beyond HDL cholesterol levels in a high-risk cardiovascular risk population.

Greg Hundley: Very nice. Carolyn. It sounds like function over just the levels is important.

Dr Carolyn Lam: Exactly, you summarized it well. Well Greg, I've got another paper and I want to pick your brain first. Is it your impression that type 2 myocardial infarction, the type that occurs due to acute imbalance in myocardial oxygen supply versus demand in the absence of atherothrombosis, do you think that this type of MI is on the rise? It seems more and more common in my country.

Dr Greg Hundley: Do we want to say it's on the rise? Certainly by measuring all these high sensitivity troponins, et cetera, we're finding, I think, more evidence of type 2 MI. So, all in all, yeah it probably is on the rise, but likely related to some of our measurement techniques.

Dr Carolyn Lam: Oh, you are so smart, Greg. Because this paper that I'm about to tell you about really addresses some of these issues and it's from corresponding author Dr Gulati from Mayo Clinic in Rochester, Minnesota. And they really start by acknowledging that despite being frequently encountered in clinical practice, the population base incidents and trends of type 2 myocardial infarction is unknown and long-term outcomes are incompletely characterized. So they prospectively recruited 5,640 residents of Olmsted County, Minnesota who experienced an event associated with cardiac troponin T greater than 99th percentile of a normal reference population, which is greater than or equal to 0.01 nanograms per milliliter. And this was between 2003 and 2012, so very careful to talk about which Troponin T assay exactly to the point you discussed earlier, Greg. The events were retrospectively classified into type 1 versus type 2 MI using the universal definition.

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

Dr Carolyn Lam: They found that there was an evolution in the types of MI occurring in the community over a decade with the incidence of type 2 MI now being similar to type 1 MI. Adjusted long-term mortality following type 2 MI is markedly higher than after type 1 MI and that's driven by early and non-cardiovascular deaths. Mortality of type 2 MI is associated with a provoking factor and is more favorable when the principle provoking mechanism was an arrhythmia compared with postoperative status, hypotension, anemia or hypoxia. And these findings really underscore the healthcare burden of type 2 MI and provide benchmarks for clinical trial design.

Dr Greg Hundley: Very nice, Carolyn. Well, my paper comes from type 5 long QT syndromes and an analysis. And it's from Dr Jason Roberts from Western University. Through an international, multi-center collaboration, improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in long QT 5 was sought across 22 genetic arrhythmia clinics and four registries from nine countries that included 229 subjects with autosomal dominant long QT five. So there were 229 of those subjects. And then 19 individuals with the recessive type 2 Jervell and Lang-Nielsen syndrome. The authors compared the effects of clinical and genetic predictors on a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter defibrillators shocks, aborted cardiac arrest, and sudden cardiac death.

Dr Carolyn Lam: Wow. What did they find?

Dr Greg Hundley: Well, several things, Carolyn. First, rare loss of function KCNE1 variants are weakly penetrant and do not manifest with a long QT syndrome phenotype in a majority of individuals. That's a little bit of a surprise. Second, QT prolongation and arrhythmic risk associated with type 2 Jervell and Lang-Nielsen syndrome is mild in comparison with the more malignant phenotype observed for type 1 Jervell and Lang-Nielsen syndrome. And then number three, all individuals possessing a rare loss of function KCNE1 variant should be counseled to avoid QT prolonging medications and should undergo a meticulous clinical evaluation to screen for long QTS phenotype.

And then finally, Carolyn, the last finding, in the absence of a long QTS phenotype, more intensive measures, such as beta blockade and exercise restriction, may not be merited.

Dr Carolyn Lam: Oh, very interesting. Well, I've got one more original paper and in this, authors describe a new cellular mechanism linking ischemia-reperfusion injury to the development of donor specific antibody, a pathologic feature of chronic antibody-mediated rejection, which mediates late graph loss. This paper is from corresponding author Dr Jane Witt from Yale University School of Medicine and colleagues who use humanized models and patient specimens to show that ischemia-reperfusion injury promoted elaboration of interleukin 18 from endothelial cells to selectively expand alloreactive interleukin 18 receptor 1 positive T peripheral helper cells in allograph tissues and this promoted donor specific antibody formation.

Dr Greg Hundley: Carolyn, here's the famous question. What does that mean clinically for us?

Dr Carolyn Lam: Aha, I'm prepared. Therapies targeted against endothelial cell derived factors like interleukin 18 may therefore block late complications of ischemia-reperfusion injury.

Dr Greg Hundley: Very nice. Sounds like more research to come. Well, how about other articles in the issue?

Dr Carolyn Lam: Well, I'd love to talk about a white paper from Dr Al-Khatib, and it's about the research needs and priorities for catheter ablation of atrial fibrillation and this is a report from the National Heart, Lung, and Blood Institute Virtual Workshop.

Dr Greg Hundley: Well, I've got another arrhythmia paper, so this is from Professor Michael Ackerman at the Mayo Clinic and its minor long QT gene disease associations by coupling the genome aggregation database. It's a harmonized database of 140,000 or more exomes and genome derived in part from population-based sequencing projects, with phenotypic insights gleaned from a large long QT syndrome registry to reassess the strength of these minor long QT syndrome gene disease associations. Next, Carolyn, in an on my mind piece, Professor Gerd Heusch from University of Essen Medical School discusses, how can the many positive preclinical and clinical proof of concept studies on reduced infarct size by ischemic conditioning interventions and cardioprotective drugs be reconciled with the mostly neutral results in regard to clinical outcomes.

The author discusses the important differences between animal models that have been used a lot in this ischemia reperfusion and infarct size reduction science, and then the clinical scenarios of STEMI in humans as well as the many aspects of coronary reperfusion. How is that affecting the myocytes? How is that affecting the microcirculation, et cetera, that must be addressed? And then finally Carolyn, there is a series of letters, one from Professor Oliver Weingärtner from Universitätsklinikum Jena and another from Professor Yasuyoshi Ouchi from Toranomon Hospital. They're exchanging letters debating the utility of lipid lowering with Ezetimibe in individuals over the age of 75 years.

Dr Carolyn Lam: Very nice, Greg. Thanks so much. Shall we now move to our future discussion.

Dr Greg Hundley: You bet.

Well, welcome everyone. This is our feature discussion and today we're going to hear more about long QT syndrome. We have Dr Michael Gollob from University of Toronto and our own associate editor, Dr Sami Viskin from Tel Aviv Medical Center. Good morning. Good afternoon, gentlemen. Before we get started with a discussion of some of the study findings and results, Michael, could you tell us a little bit about why you performed the study and what were some of the hypotheses you wanted to test?

Dr Michael Gollob: As you know, long QT syndrome is probably the most recognized channelopathy associated with sudden cardiac death in young individuals and adults. And at the present time, there are 17 genes available for clinical genetic testing in cases of suspected long QT syndrome. We simply ask the question, "Is there sufficient scientific evidence to support that each of these genes are single gene causes of long QT syndrome based on our contemporary knowledge of genetics and the human genome?

Dr Greg Hundley: Great, Michael. So, can you tell us a little bit about your study population? How did you go about this and what was your study design?

Dr Michael Gollob: We designed a methods approach that would assure that any conclusions that were made from our working group were not based on the opinions of one or two individuals. We wanted to ensure that this was a consensus conclusion with multiple experts in the field including genomic scientists, genetic counselors, inherited arrhythmia experts, and researchers in the field. We created three independent teams of genetic experts to curate the genetic evidence reported in the medical literature for each of these 17 reported causes of long QT syndrome. This was essentially an evidence-based approach using a pre-specified evidence-based matrix or scoring system depending on the level of evidence, genetic primarily, in the reported literature for each gene.

Each of these curation teams worked independently of each other and they were blinded to each other's work and they were tasked with concluding whether a gene, based on the medical literature and the resource methodologies, had sufficient evidence for disease causation. Their classifications would be one of disputed evidence, limited evidence, moderate evidence, strong or definitive evidence for claims towards disease causation. Remarkably, independently, all of these teams reached the same conclusion. In the end, their summary data was reviewed by a clinical domain expert panel with individuals with expertise, particularly in long QT syndrome and other channelopathies. So in total 19 individuals reviewed all of the literature and the data presented and came to unanimous conclusions for each gene.

Dr Greg Hundley: Out of the 17, were there some that were more important than others or was it uniformly all 17 were relevant?

Dr Michael Gollob: Well, I think the most relevant conclusions of our study are that nine of these genes, more than half of these genes, were felt not to have sufficient evidence to support their causation as a single gene cause for typical long QT syndrome. So nine genes that are currently tested by clinical genetic testing providers do not have enough evidence to support their testing in patients with suspected long QT. And to us, that is the most relevant observation because testing genes that do not have sufficient evidence for disease causation poses a significant risk to patient harm and family harm. We concluded that only three genes had very definitive evidence for causation of long QT syndrome. Those three genes were KCNQ1, KCNH2, and SCN5A. There were another four genes that were concluded to have strong or definitive evidence for unusual presentations of long QT syndrome. And by that, I mean presentations that typically occur in the neonatal period and are associated with heart block seizures or developmental delay or in the case of one of these genes, Triadin, an autosomal recessive form of the disease.

Dr Greg Hundley: So helping us perhaps what types of genes to screen for when we have someone with this condition or suspected. So Sami, can you help us put this into perspective? How does this study help us in management of this clinical situation.

Dr Sami Viskin: In Circulation, we immediately recognize the importance of the manuscript, the importance of the study because unfortunately, there are too many physicians all over who will accept the results of genetic testing essentially like gospel. Now it's in the DNA, it's in the genes, so whatever you find must be true. And too often, clinical decisions on treatment including ICD implantation have been undertaken based on results of genetic testing’s; thus are wrongly interpreted. So we recognize immediately the importance of this paper. We already had a different study by Dr Gollob and his associates. Again, reassessing the role of genes in Brugada syndrome. So we were familiar with this type of analysis.

We recognize the importance and we moved ahead to accept this paper, it went fairly easily, I think only one revision. At the same time, we were getting additional paper by other groups. So in the same issue, we have two more papers, one from Jason Roberts with the International Long QT Registry of long QT 5, reaching similar conclusions that this is a gene with very limited penetrants and another study by the Mayo clinic also showing that many of the genes who are not the major genes are overrepresented in the healthy population. So we put all these three papers together with a very nice editorial by Chris Semsarian in the same issue. So everything is put in the right perspective of how we should be looking at all the genes of these disease in a different way.

Dr Greg Hundley: So as a clinician quickly, how can I use this information in the issue, perhaps this paper and all three, in management of patients with either suspected or long QT syndrome?

Dr Michael Gollob: First off, I would emphasize that the diagnosis of long QT syndrome or any genetic base disease for that matter, should be based on clinical phenotype and not the observation of a genetic change, particularly if genes are being tested that do not have strong evidence for disease causation, as is the case for the nine genes that we've pointed out in this manuscript.

So I think clinicians need to be wary of the genetic testing panels that they are requesting be screened or used in the assessment of their patients and be knowledgeable that at this point in time, we really only have three genes with very strong evidence to support disease causation of the typical form of long QT syndrome. And that for the most part, these other genes should not be tested or should only remain in the realm of research.

I think that responsibility extends further than just the clinician taking care of the patient, but also clinical genetic testing providers, companies that offer these genetic testing services. I think they should assume a responsibility to ensure that they are only offering services for genes that have strong evidence for disease causation because when they report results in genes that are not valid for the disease, that only confuses the care of the patient and that creates a risk of harm to them if that information is misinterpreted by a physician.

As Dr Viskin or Sami pointed out, we do see patients who are inappropriately diagnosed. We remove the diagnosis of roughly 10 to 20% of cases in our own clinic. And unfortunately, many of these patients and their families have suffered undue anxiety. Some of them have ICDs in place that should not have been there. So I think overall, the field needs to be aware of what genes are relevant and what genes still are within the realm of research.

Dr Greg Hundley: Can you tell us just quickly Michael and then also Sami, what do you see as the next study in this field?

Dr Michael Gollob: We're taking a step back now. The first decade of this century saw an exponential growth in reported gene disease associations. And now in the last five or six years, we've learned a lot about human genetic variation, which has provided us an opportunity to reflect back on some of these previous and reported genes as causes for long QT and other diseases.

So I think many individuals in our field may say, "Well, you know, this is disappointing. We believed in these genes. We really thought these genes were causes of long QT." And to that point I would say, we need more research. If you believe in some of these genes that have now been considered to have limited or disputed evidence, research should continue if these remain plausible candidates for the disease.

So I think future research has to continue. There are probably still a few other genes that have not yet been discovered. I think we've got the vast majority. I think in most cases, at least in our experience, 90 to 95% of cases are explained by the top three genes. But there are probably other genes out there and it's always fascinating to learn or discover new genes, but those sorts of studies have to be done with the correct methodologies and rigid protocols. Lastly, I think in the future us clinicians and geneticists and genetic counselors need to work closely with genetic testing providers to ensure that they are offering responsible genetic testing services.

Dr Greg Hundley: Sami, do you have anything to add?

Dr Sami Viskin: Just congratulate the authors. I think they did a very great service to the medical community by pointing out the limitations of the genetic testing and the way we interpret the results, and they deserve to be applauded for reminding us that we have to be careful when we read papers about genetic results or when we get genetic testing results ourselves.

Dr Greg Hundley: I want to thank Michael from University of Toronto and Sami from Tel Aviv Medical Center for participating. And on behalf of both Carolyn and myself, wish you all a great week and look forward to chatting with you next week.

This program is copyright, the American Heart Association 2020.


Feb 3, 2020

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.

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

Dr Carolyn Lam: Greg, this issue is full of super interesting papers, many of which were presented as late-breaking presentations at the American Heart Association, like the feature paper that sacubitril/valsartan across the spectrum of ejection fraction in heart failure, where this was really analyzed across the landmark PARADIGM and PARAGON trials. I'm sure everyone's looking forward to hearing about it, but before we talk about that, I want to share some more very interesting results from a very important trial, the REDUCE-IT trial.

So, as some background, some trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. And this was the reason that there was a pre-specified subgroup analysis of the REDUCE-IT trial, which really is the reduction of cardiovascular events with icosapent ethyl-intervention trial, and this analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States.

So, Greg, do you remember what the REDUCE-IT trial was about?

Dr Greg Hundley: Well, Carolyn, I think REDUCE-IT randomized 8,179 statin-treated patients with triglycerides between 135 and 500 milligrams per deciliter and LDL cholesterol levels between 40 and 100 milligrams per deciliter and a history of atherosclerosis or diabetes to Icosapent Ethyl, four grams per day or placebo. And the primary endpoint, I believe, was cardiovascular death, nonfatal myocardial infarction, non-fatal stroke, coronary revascularization or hospitalization for unstable angina. Hah!

Dr Carolyn Lam: Wow, Greg, you pass that quiz, like maybe you had a cheat sheet answer.

Dr Greg Hundley: All right, Carolyn, tell us now what did REDUCE-IT USA find?

Dr Carolyn Lam: This was from a corresponding author, Dr Deepak Bhatt, from Brigham and Women's Hospital Heart and Vascular Center, and his colleagues and they found that in the United States Icosapent Ethyl at four grams a day produced large and significant reductions in multiple ischemic endpoints including cardiovascular death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina. Furthermore, REDUCE-IT US demonstrated that Icosapent Ethyl provided a statistically significant 30% relative risk reduction and a 2.6% absolute risk reduction in all-cause mortality. The risk benefit profile of Icosapent Ethyl was highly favorable with an overall safety and tolerability profile virtually identical to placebo.

Dr Greg Hundley: Wow, Carolyn. So, this does have important implications for us in the US, very nice. Thank you for that lovely quiz. So, Carolyn, I'm going to switch now and talk about a paper from Roddy Walsh from Amsterdam in the Netherlands. In this study, the investigators defined the frequency of rare variation in 2,538 patients with dilated cardiomyopathy across protein-coding regions of 56 commonly tested genes and compared this to both 912 confirmed healthy controls and a reference population of 60,706 individuals to identify clinically interpretable genes robustly associated with dominant monogenetic dilated cardiomyopathy.

Dr Carolyn Lam: Wow, wow. That's a huge study. So what did they find?

Dr Greg Hundley: Okay, Carolyn. So overall rare variants in 12 genes potentially explain 17% of cases in the outpatient clinical cohort representing a broad range of adult patients with dilated cardiomyopathy and 26% of cases in the diagnostic referral cohort enriched in familial and early onset dilated cardiomyopathy. And so, practically speaking, by analyzing two dilated cardiomyopathy cohorts with distinctive patient profiles, the authors were able to comprehensively evaluate the genetic basis of dilated cardiomyopathy and identify variant classes that were particularly associated with early-onset disease. By restricting analyses to validated and interpretable genes and variant classes, the authors hoped in this study to increase the accuracy and reduce the uncertainty associated with genetic testing in dilated cardiomyopathy.

Dr Carolyn Lam: Very nice, very practical information. Well, my next paper is, I have to admit a super favorite topic of mine, and that is sex differences in heart failure. Now as a reminder to everybody, women represent over half of patients with heart failure with heart failure preserved ejection fraction, and there are multiple effective drug and device therapies for HFrEF, or heart failure reduced ejection fraction, but none approved for HFpEF. Thus, there is a greater so-called failure therapeutic deficit in women compared to men. So, does the recently presented PARAGON trial provide answers?

Dr Greg Hundley: Ah, Carolyn, you were involved in the PARAGON trial. Maybe tell us a little bit about that first to help us get oriented.

Dr Carolyn Lam: I would love to. So PARAGON compared sacubitril/valsartan with valsartan in patients with HFpEF. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes, and the trial overall narrowly missed this primary outcome. However, an intriguing result in PARAGON was a significant sex-by-treatment interaction. And this was explored further in the current pre-specified subgroup analysis of outcomes by sex, which was reported by John McMurray from University of Glasgow and his colleagues.

Dr Greg Hundley: Ah, so I'm interested. What was this interaction?

Dr Carolyn Lam: Ah, so here is how the interaction work. Now, remember this was multi-variably adjusted significant in a pre-specified large subgroup of PARAGON. And what we found was that as compared with valsartan, sacubitril/valsartan seem to reduce the risk of heart failure hospitalization more in women than in men. Now, while the possible sex-related modification of this effect of treatment has potential explanations, the current study really cannot provide a definitive mechanistic basis for this finding.

Dr Greg Hundley: Very interesting. So, perhaps then, in heart failure preserved ejection fraction, sacubitril/valsartan could be very helpful in women.

Dr Carolyn Lam: Yes, and perhaps especially those with each ejection fraction in the lower ejection fraction range. And that is coming up in our future discussions, so let's not preempt it. You got another paper, Greg?

Dr Greg Hundley: Absolutely, Carolyn. My next paper is from Professor Irene Lang at the Medical University of Vienna, and it's related to microvascular disease and chronic thromboembolic pulmonary hypertension and hemodynamic phenotyping and histomorphometric assessments. So, Carolyn, pulmonary endarterectomy is the gold standard for treatment of patients with operable chronic thromboembolic pulmonary hypertension. However, persistent pulmonary hypertension after PEA or endarterectomy remains a major determinant of poor prognosis.

Dr Carolyn Lam: Ah, so are there any possible solutions to this?

Dr Greg Hundley: Well, Carolyn, today it is thought that a concomitant small vessel arteriography in addition to major pulmonary artery obstruction may play an important role in the development of persistent pulmonary hypertension and survival after pulmonary endarterectomy. One of the greatest unmet needs in the current preoperative evaluation is to assess the presence severity of small vessel arteriopathy.

Dr Carolyn Lam: Huh, that makes a lot of sense. So what did the authors do? What they find?

Dr Greg Hundley: Okay. Well, Carolyn, they had 90 patients with 49 of them receiving lung wedge biopsies for validation. So, in analyses incorporating receiver operating characteristic curves, pulmonary vascular resistance measures and larger arterial upstream resistance beds predicted persistent pulmonary hypertension after pulmonary endarterectomy, and certain values identified patients with poor prognosis after endarterectomy. Therefore, perhaps this form of analysis could be helpful in establishing prognosis in these patients and perhaps suitability for future interventions.

Dr Carolyn Lam: Wow, very interesting. Well, we were saying this issue's full of very important papers, and that also includes research letters. There's a research letter by Dr Cannon talking about evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease according to baseline HbA1c, including those with an HbA1c less than 7%. And these are very interesting results from the CREDENCE trial that was also presented at the American Heart Association.

There's a research letter by Dr Jackevicius on the population impact of generic valsartan recall in Ontario, Canada, that really highlights the potential burden and risks associated with recalls of chronic oral medications used by large populations. And in Cardiology News, Bridget Kuehn talked about cardiovascular risk biomarkers, high-sensitivity cardiac troponin T and NT-proBNP and talked about how these two biomarkers may help clinicians stratify which patients may benefit the most from therapies for hypertension or diabetes. And this was according to a pair of studies presented, again, at the American Heart Association.

Dr Greg Hundley: Well, Carolyn, that's quite a nice review. I've got just a couple more papers to discuss. There's a perspective piece from Dr Ben Levine and colleagues from UT Southwestern that discusses whether a simple physical exam and maneuvers could actually supplant tilt-table testing. He provides arguments as to whether we should continue with tilt-table testing given the high rate of false positives. And then lastly, from the Mailbag, Dr Shuyang Zhang from Peking Union Medical College Hospital and the Chinese Academy of Medical Sciences provides a letter to the editors regarding a prior publication on the clinical applicability of the awareness of androgen-deprivation therapy's effects on ventricular repolarization. And Dr Joe-Eli Salem from Vanderbilt University provides his response.

Well, Carolyn, how about onto that feature?

Dr Carolyn Lam: Let's go. Our feature discussion today is all about left ventricular ejection fraction. Ah, that measure we both love and hate in the world of heart failure, I think. And this paper is truly remarkable, in my opinion. It is the look at the effect of sacubitril/valsartan across the spectrum of left ventricular ejection fraction in the PARADIGM and PARAGON trials. And I'm just so pleased to have none other than the first and corresponding author, Dr Scott Solomon, from Brigham and Women's Hospital and Harvard Medical School, as well as our Senior Associate Editor, Dr Biykem Bozkurt, from Baylor College of Medicine as well.

Scott, could you start by telling us about this analysis and why the opportunity to do such a special analysis in this paper?

Dr Scott Solomon: This was a really fantastic opportunity because, as you know, we did these two trials, PARADIGM and PARAGON, not at the same time but essentially in series. PARADIGM was a trial of patients with heart failure reduced ejection fraction, so ejection fraction of 40%, and PARAGON was a study of patients with heart failure with preserved ejection fraction. And the interesting thing is that, with the exception of ejection fraction, the criteria for enrolling patients in these trial was virtually the same.

In other words, we enrolled patients with signs and symptoms of heart failure, some elevation in natriuretic peptides, and we followed them. So it's really an extraordinary dataset of 13,195 patients in whom we can look at heart failure across that full spectrum of ejection fraction. We haven't been able to do this really since the CHARM study, which enrolled about 8,000 patients across the spectrum of ejection fraction. And it gave us an opportunity to look at a number of things including the effect of sacubitril/valsartan across that full spectrum of ejection fraction.

Dr Carolyn Lam: Great. And, Scott, you want to tell us what you found?

Dr Scott Solomon: When we pooled 13,195 patients, and by the way, this was a pre-specified analysis that we had decided to do prior to unblinding PARAGON. We see that if we put them all together, all these patients together, and just treat them as one group, we see that for every endpoint that we looked at, whether heart failure, hospitalization and cardiovascular death, cardiovascular death, all-cause mortality, whether we look at the time to first event endpoints or the total number of heart failure hospitalizations, we see a significant benefit in patients receiving sacubitril/valsartan compared to patients receiving either enalapril in the PARADIGM study or valsartan in the PARAGON study.

Now, what we also saw though, and this is probably most important, is that there appears to be an attenuation of the treatment effect as ejection fraction rises. Now we know that patients with higher ejection fractions tend to have a lower frequency of these events such as heart failure, hospitalization and cardiovascular death. But we also see here that as ejection fraction goes up that the benefit of sacubitril/valsartan appears to wane, especially when you get over about 60, an ejection fraction of about 60%. We've looked at this in categorical ways and also looking at a continuous spline analysis throughout the entire spectrum.

Dr Carolyn Lam: Yeah, I love that, and I just need to point every listener right now to figures 3 and 4 of your paper. I have a feeling we're going to be seeing these figures in a lot of talks and cited everywhere. Biykem, could I bring you in on this? What are the implications of something like this?

Dr Biykem Bozkurt: The interesting findings from the pooled data are, first, support of what we had seen in PARADIGM, meaning the lower the EF, the more the benefit or the higher the benefits. And as we had seen in PARAGON, which did not show an improvement in the combined endpoint with treatment with sacubitril/valsartan in patients with heart failure with preserved ejection fraction. In the pooled analysis as the EF got higher, there didn't seem to be any benefit, but the interesting, perhaps group of patients that the pooled analysis allowed us to have a deeper dive into was heart failure with mid-range EF. And we can crudely perhaps define this as ejection fraction between 40 and 50%. And by certain analyses, which again this is in the post-hoc and also in a continuous analysis and a specific analysis and a cubic spline analysis, it appeared that the benefit extended into those individuals with mid-range ejection fraction.

Again, we need to keep several points in consideration. One is ejection fraction can vary over time and is not a very precise measurement. There's definitely inter-reader as well as intra-reader variability and is not a good mayor of contractile performance. And we tend to actually have a significant amount of a specific infiltrative cardiomyopathies in that EF range, which tend to be excluded from usual clinical trials. And with that caveat, having kept this in mind, it's also important to recognize from cohorts and population-based studies, about 10 to 20% of our patients currently reside in that have HeFmrEF or heart failure with mid-range EF status. And thus the findings are intriguing, hypothesis generating and also encouraging that we may see perhaps benefits with RAS antagonism in individuals that do have LV systolic dysfunction.

And probably, if this is persistent and a clear reflection of a phenotype that reflects itself as reduced ejection fraction, probably the patient may benefit. Again, these results may need to be supported by future studies, and also we need to keep in mind that infiltrative cardiomyopathies, such as amyloidosis or sarcoidosis or others, were not included in these studies.

Dr Carolyn Lam: Thank you, Biykem. Go ahead, Scott.

Dr Scott Solomon: Carolyn, I agree with many of Biykem's points. I think that this middle range, and you and I kind of coined that term, heart failure with mid-range injection fraction, a number of years ago. The problem, of course, is knowing where that range exactly is, and I think that some people believe it's 40 to 50%, but we know that these are very arbitrary cutoffs. The data from the pooled analysis in PARAGON, in particular, do suggest that the patients who have evidence of some degree of left ventricular dysfunction seem to benefit from sacubitril/valsartan. Now, this is not a completely novel finding because we saw that in patients who received candesartan in the CHARM study and in patients who received spironolactone in the TOPCAT trial that the greatest benefit was observed in the patients in that middle range of ejection fraction, again, below what we would normally consider the normal range. Normal might be 55% or 55% in men and women.

And that gets me to the other thing that I think is really worth mentioning here, which is that we found that the range of benefits does vary by sex, so that women seem to derive greater benefit to a higher ejection fraction than men. We can see that here in figure 4, looking at these two curves that there really does appear to be a difference between men and women. Women overall derive greater benefit in the PARAGON study, it appeared than in men. So I think that the fact that there's biologic plausibility here that patients with cardiac function that is not normal seem to benefit from therapies that we know benefit patients with heart failure with reduced ejection fraction, that patients with ejection fraction that was in this middle range also do appear to benefit from sacubitril/valsartan as we think they did in other studies of other agents that we know work in patients with lower ejection fraction.

Dr Carolyn Lam: Indeed, Scott. You've just pointed out my favorite figure of all, that figure 4. You know how I feel about sex differences and pointing them out. I would love to ask for Biykem's thoughts on it.

But in the meantime, just to emphasize how important findings like these are because it makes us question the cutoffs that we use to define heart failure groups, makes us question is midrange more mildly reduced ejection fraction like we're also writing about. And I think really makes us question, for example, the 2016 ESC Guidelines that say that mid-range ejection fraction should be treated like preserved ejection fraction. Well, maybe this could be really game changing here in that we actually think now this group should be treated more like reduced ejection fraction. So, really, congrats on this incredible paper.

Biykem, what do you think of those sex differences? I have to point out, I love your editorial, which everyone should read.

Dr Biykem Bozkurt: It's very intriguing, very interesting point. The benefits from sacubitril/valsartan was interestingly similar for both sexes at lower EF levels. Women's benefit compared to men's benefit for low EF was comparable; they were not different. But women seem to confer a benefit at higher EF ranges and by this continuous analysis all the way up to the 50 to 60% range, which is very, very interesting. And as to what were the phenotypes of the women compared to men at that range, women were older, had more obesity, less CAD, and of course, at all ranges they usually tend to have a higher baseline EF.

And, interestingly, even though we may state that maybe women may have more systolic dysfunction at higher EF quantification ranges or may have a different phenotype than men for HFpEF, maybe a more clear or pure heart failure phenotype, heart failure with preserved EF phenotype than men. The interesting things were the NT-proBNP levels were lower for women, though the symptoms were a little bit higher, and the benefit seemed to be higher even though the KCCQ scores were not different. So, even though we did have lesser sort of filling pressures for women and perhaps other surrogates for improvement did not seem to differ, and also biological metabolites, such as urinary cyclic GMP to creatine ratios, were not different in women.

So, if we were to think of whether there were biological differences, whether there were differences in NT-proBNP levels or delta changes over time or the urinary cyclic GMP levels, they were not different in women versus men. So, we still have many other substrates for neprilysin. I mean there could be other substrates, such as adrenomedullin or bradykinin or substance P that may be differentially metabolized for women compared to men, and we don't have the data on those. But again, it's very interesting to see this upper scale of EF benefit being higher in women compared to men. So, we don't have any other either biological or other surrogate markers for benefit for women, either for the HFpEF or HFrEF being than different than men.

Dr Carolyn Lam: Biykem, I just love the way you so carefully dissected that, and it's so reflected in that editorial that you and Justin Ezekowitz wrote entitled Substance and Substrate. So I'm going to make sure all readers look for it. We could go on forever. I mean I just was struck, that figure 4, also is really similar if we look at what normally ejection fraction is for women versus men with increasing age. We also see that women are supposed to have higher ejection fractions as they age compared to men at any age. So it's just intriguing to me, but you're right. I think hypothesis generating.

Scott, I'm going to give you the last word.

Dr Scott Solomon: I'm pretty confident that there are biologic differences between men and women. I just don't necessarily know what they are with respect to heart failure, preserved ejection fraction, but I think we're going to be spending a lot of time and effort trying to sort this out. We're pretty confident that the finding of a weighing of benefit with ejection fraction is a real one and that the benefit in this middle range is an important one to pay attention to because I agree with what you said, Carolyn. If we had been thinking about heart failure with reduced ejection fraction as something that went up to a higher level 25 years ago, we would probably have treated a lot more patients with therapies that we now know to benefit patients with heart failure with reduced ejection fraction. So, I think this data helps us rethink how we parse up heart failure and hopefully, ultimately will lead to changes how we treat patients.

Dr Carolyn Lam: Well, listeners, you heard it right here on Circulation on the Run. Thank you so much, Scott and Biykem, for joining us, and don't forget to tune in again next week.

Dr Greg Hundley: This program is copyright The American Heart Association 2020.


Jan 27, 2020

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

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

Dr Carolyn Lam: Say, Greg, you know the feature paper this week talks about the perennially hot topic now and that is transcatheter aortic valve replacement or TAVR or TAVI. It's actually data from the France TAVI Registry comparing balloon expandable versus self-expanding transcatheter aortic valve replacement.

I'm sure you want to hear more about it, but first I'm going to tell you about another paper in the same issue, this time also comparing a balloon expandable versus a self-expanding transcatheter aortic valve implantation, but data from a nationwide analysis and from corresponding author Dr Fauchier from Centre Hospitalier Universitaire Trousseau. He and his colleagues basically did a head to head comparison of the two competing transcatheter aortic valve replacement technologies that have been published but have not really been followed for long-term clinical outcomes. This was comparing balloon expandable versus self-expanding technology.

They collected information from more than 31,000 consecutive patients treated with Tavern in France between 2014 and 2018 and based this on the French administrative hospital discharge database. They did propensity score matching, which was used for the analysis of outcomes according to the Sapien 3 balloon expandable versus the Evolut R self-expanding TAVR technology and studied this as nationwide level in France.

Dr Greg Hundley: Wow. Carolyn, 31,000 patients. That's a really large study. What did they find?

Dr Carolyn Lam: They basically found that balloon expandable TAVR was associated with lower mortality rehospitalization heart failure and pacemaker implantation compared with the self-expanding TAVR. Now, that's of course a pretty big finding and this is discussed along with the feature paper that we're going to hear about in an editorial by Drs. Abdel-Wahab and Thiele from Heart Center Leipzig.

I want to tell you about another paper before I let you tell you about yours, okay?

Dr Greg Hundley: Sounds great, Carolyn.

Dr Carolyn Lam: Greg, what is your clinical impression of Impella use in the United States among patients undergoing PCI? Do you think it's increasing or decreasing over time? As a reminder, Impella was approved for mechanical circulatory support in 2008, so from then, what do you think?

Dr Greg Hundley: You know, Carolyn, I really think it's increasing, especially used more frequently rather than an intra-aortic balloon pump. How about you? What's going on in your area of the world?

Dr Carolyn Lam: My impression too, but you know, you're lucky because we now have data looking at the trends in Impella use, but in the United States, and this comes from the corresponding author, Dr Amit Amin from Washington University School of Medicine and colleagues who describe clinical outcomes and costs across U.S. hospitals in PCI patients treated with mechanical circulatory support, which is either the Impella or the intra-aortic balloon pump.

They found that among more than 48,300 real world patients undergoing PCI with mechanical circulatory support at 432 hospitals between 2004 and 2016 in the Premier Healthcare Database, Impella use was indeed found to be rapidly increasing with marked variability across hospitals and not only its use, but also in its associated adverse outcomes. When analyzed by time periods or at the level of the hospitals or at the level of the patients, Impella use was associated with higher rates of adverse events and higher hospital costs.

Dr Greg Hundley: You know, I wasn't thinking about the higher rate of adverse events. You wonder sometimes, are we using a technology in a sicker group of patients? Did this study shine any light on that?

Dr Carolyn Lam: Those are great, great thoughts. The authors concluded that the variability in Impella use, the variability in its associated outcomes, and the association of Impella use with higher adverse events and costs really, really underscore the need for better defining of the appropriate use of mechanical circulatory devices and that was what you indicated as well, Greg, and what we need there is adequately powered randomized clinical trials and prospective real world evidence, which we don't quite have yet. Until then, perhaps a more measured approach is needed in clinical practice that balances risks versus benefits in complex patients undergoing PCI who require mechanical circulatory support.

Dr Greg Hundley: That's going to be really needed, I think in this era, especially with the results from this study. Well, Carolyn, I'm going to switch over to the world of basic science and the first study I'm going to talk about is from Dr Richard Lee from Harvard University and it's a very interesting study. Just as some background, current differentiation protocols to produce cardiomyocytes from human induced pluripotent stem cells are capable of generating highly pure cardiomyocyte populations, but these cardiomyocytes remain immature and they really more closely resemble the fetal state.

As a result, they have a lower maximum contractile force, slower upstroke velocity, and immature mitochondrial function compared to adult cardiomyocytes. Also, they're prone to ventricular arrhythmias. During development, cardiomyocytes undergo a shift from a proliferative state in the fetus to a more mature but quiescent state after birth. The mechanistic target of Rapamycin mTOR signaling pathway plays a key role in nutrient sensing and growth, and Dr Lee and colleagues hypothesized that transient inhibition of the mTOR signaling pathway could lead cardiomyocytes to a quiescent state and enhance cardiomyocyte maturation.

Dr Carolyn Lam: Wow Greg, I really love the way you explained that. That's so interesting. What did they find?

Dr Greg Hundley: Among human induced pluripotent stem cell lines, transient treatment with Torin 1, an inhibitor of the mTOR pathway, shifted cells to a quiescent state and enhanced their cardiomyocyte maturity. Also, the investigative team suggests that further testing will be necessary to evaluate whether delivery of Torin 1 treated cardiomyocytes could reduce the risk of ventricular arrhythmias in newly differentiated myocytes derived from pluripotent stem cells. Really an important advance in this whole area of developing mature cardiomyocytes from our own pluripotent stem cells.

Well, Carolyn, my second basic science paper comes from Dr Calum MacRae from Brigham And Women's Hospital, also at the Harvard Medical School. Carolyn, this study used both highly purified human pluripotent stem cell derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells with human MYL4 mutations in a zebrafish MYL4 knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations associated with definitive genetic causes of atrial fibrillation.

Dr Carolyn Lam: Oh, that's really interesting. Is this new genetic predispositions that they discovered?

Dr Greg Hundley: I think the answer's yes. They found there was evidence of increased retinoic acid signaling in both human pluripotent stem cell derived cardiomyocytes and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins and loss of intracellular NAD and NADH, and thereby established a mechanistic link between the transcriptional, metabolic, and electrical pathways previously implicated in the atrial fibrillation substrate of MYL4. In the future, these data could lead to novel therapies for some patients with atrial fibrillation.

Dr Carolyn Lam: Wow. That really is fascinating, Greg. Well, let me round up by telling you about some of the other things in the issue. There is a research letter by Dr Parish on the effects of Omega-3 fatty acid supplements on arrhythmias and here, these authors reported more comprehensively on atrial fibrillation and other arrhythmias using additional data extracted from linked electronic health records in the ASCEND trial, remember, which was 1 gram of Omega-3 fatty acid supplementation daily in people with diabetes but without known atherosclerotic cardiovascular disease.

Dr Greg Hundley: Oh wow. That's fantastic, Carolyn. I've got a couple other really interesting articles in the issue. First there's an In Depth review from Dr Yvan Devaux from Luxembourg Institute of Health, and he discusses regulatory RNAs in heart failure. In a perspective piece, Dr Alejandro Lucia from Universidad European de Madrid discusses the role of aerobic and resistance training as a therapy in addition to prescribed medications in patients with resistant hypertension. Really interesting.

Then finally, Dr Ify Mordi from University of Dundee examines metformin use and clinical outcomes among patients with diabetes, with or without heart failure, kidney dysfunction observations from the SAVOR-TIMI 53 trial in which Dr Bergmark and colleagues found that metformin use was associated with a reduction in all-cause mortality and cardiovascular death, but not due to myocardial infarction or stroke, particularly in patients without a prior history of heart failure.

What could the mechanism be, if not related to presumed atherosclerosis? Dr Mordi and colleagues proposed possibilities, and Dr Brian Bergmark from the TIMI study group and the cardiovascular division of Brigham and Women's hospital at Harvard Medical School and colleagues, they write a very nice response. It's really interesting listening to how could metformin reduce events but not related to atherosclerosis? How about onto our feature article?

Dr Carolyn Lam: You bet.

Dr Amit Khera: This is Amit Khera, digital strategies editor for Circulation from UT Southwestern Medical Center joined by my colleague, Dr Dharam Kumbhani who's also an associated editor at Circulation and we're pleased to have Dr Eric Van Belle, Professor Van Belle, from Lille University Hospital to discuss the featured article today, "Transcatheter Aortic Valve Replacement Propensity Match Comparison From the France TAVI Registry." Welcome to you both.

Dr Van Belle, I'm going to start with you and we always like to hear a little bit. Perhaps you can tell us some of the background, what led up to this investigation, what led to your group pursuing this manuscript?

Dr Eric Van Belle: Nowadays, the TAVI procedure, the TAVR procedure, is becoming very prominent kind of way of treating patients without stenosis, and basically we have two different type of devices that are available to treat the patients. Once series is based on the balloon expandable concept and the other one on the self-expandable concept. These two type of devices are considered to be used primarily in every kind of patient. Theoretically, we can use any of these two devices, any kind of patient, if we follow the recommendation of the manufacturer and I'll just say that that'd been done.

These two devices are being validated against surgery, so basically, we could potentially use any kind of them. In today, there is no direct and there was no direct comparison between the two different kinds of concept, although they are very different. Again, the device is different. The way we implant the device is different. The major question that we had behind was to say, okay, what is the outcome? If it's a mean patient get one of the devices or can we expect or should we expect a different outcome? That was the main question behind it.

Dr Amit Khera: Okay, so essentially there's two valves, they're both being used fairly regularly and without any kind of direct comparisons. Tell us a little bit about the study design and what you found in this project.

Dr Eric Van Belle: For methodology, we used what is called a French study registry, basically nationwide registry with almost all patients treated in France included, and we used it as a database of patients between 2013 and 2015 with an overall group of 12,000 patients treated with either of these two kinds of devices. This is one of the aspect of this registry. The other very important aspect of this registry, and that's the mortality data survival that was obtained in all the patients in 2008 through 2016, so we have a set of 12,000 patients. It was a cool kind of device with complete mortality data by April 2016 so basically, this is the main methodological aspect. On top of this, we did the best to do some matching on the older clinical variables and all the matching valuables that we had to create pairs of patients that could be matched to one to one. We had, at the end, a group of almost 4,000 patients.

Dr Amit Khera: Okay and tell us a little bit about some of your main findings of this study.

Dr Eric Van Belle: The two main findings were those differences between the two groups of patients, that is a patient treated with self-expandable devices at a higher risk of valvular regurgitation. This was mainly a confirmation because this finding was already reported previously in previous studies trying to compare the two devices, but what was more striking was the difference in mortality. It was a difference mostly in hospital mortality but also in mortality after two years. That was significant with an absolute difference in mortality around 3% by two years.

Dr Amit Khera: Well, obviously important, as you mentioned that paravalvular leak had been seen before and this now a long-term mortality difference. Certainly an important finding and one of the main findings of your study. One of the concerns about comparative effectiveness research, essentially you're using observational data such as this is that there still could be residual confounding. There still may be patient characteristics or decisions made by interventionalists that aren't fully accounted for. How did you all really try to account for some of these components, this residual confounding to try to get the best answer that you could?

Dr Eric Van Belle: That's going to be a major comment, and everything you can do, every best way to try to control for this, there is no better answer than to do a randomized study, and probably we'll discuss on this. Let's see, indeed, we try to do our best to minimize as much as we could, all these potential confounders, so we did it in a different way, indeed.

The first way to do it was to adjust all the potential differences among group but what was very also interesting to remind is that, when you look at the 25 clinical and imaging variables and creating the aortic annulus diameter that was incorporated in the matching, that actually 21 of the 25 variables were already there. We were balanced between the two groups, existing that indeed most of the case, the operators, we are not so much directing or at least if there was selecting it was not captured but all of these valuables because again, out of 25, the correction needed to do the matching was only affecting 4 variables, mainly. Those variables were already pretty well-matched between the two populations.

The other way we did it was to look at what is called falsification endpoint, that it is endpoints that are supposed to be unrelated to the devices to verify that indeed, we have not selected a population that will have issues that are not related to the device itself. We look at, let's say, mortality by infection, mortality by cancer, to verify that, indeed, this kind of event where it did well balanced between the two groups suggesting that the mortality effects that we observed was not related to this kind of unbalance related to something else that was not captured by analysis.

Dr Amit Khera: Yeah, I think that was quite an important observation you mentioned. The first that these two groups are generally well-balanced to begin with, even before with all the matching parameters and then certainly the falsification endpoint helped to add validity to the findings.

Dharam, I'm going to turn it over to you. Maybe you can show this from an associate editor's perspective. What are some of the observations you found interesting about this study and what are some of the considerations we had in some of the discussions about it?

Dr Dharam Kumbhani: I'll just remind our listeners that this was also a late breaker at AHA last year in 2019, so this is really a very important finding. As Eric briefly pointed out, there haven't really been head to head comparisons between, the two dominant valves in the market even though TAVR has pretty much become the dominant strategy for treatment of aortic stenosis.

At the end of the day, it's an observational analysis. We have to take the findings with that in mind. At a minimum, it's first a lot of debate and discussion about the need to have randomized trials and our belief that, perhaps, TAVR is a class effect may not always be true. I think that hypothesis would certainly need to be tested and that's what this paper really sparks as far as discussion going forward.

Dr Amit Khera: Maybe I'll ask both of you. One of the challenges of any type of observational research is time period. First there was a hint towards even maybe a greater effect in the more recent time period than the distant time period. Also, there's always commonly changes in technology, especially interventional field where a study comes out and it's already obsolete because there's some new technology. There are some newer generations of valves that have come out. Do you think that it would affect these findings in any way? Maybe we'll start with you, Eric.

Dr Eric Van Belle: That's always an issue. Again, because it's a very rapidly evolving field and if you want to have strong data, you need to have really long-term follow-up. You need to have mortality data. There is some kind of contradiction between both that the field is evolving very quickly but then to have solid data, you need to have some time.

What we could say, indeed, as a study period was 2013 and 2015, but the device that we are using at that time were already really well matured and also the devices that were used at that time was usually the ones that were used for the comparison with the surgical techniques. Again, these devices are not so much obsolete since they were accepted and used again, when you need this one device study to compare with surgery.

Of course these devices have still had some evolution and change, and it is for the good of the patient, but again, as mentioned there, I'm seeing what is very, very important is that this finding is, in my view, intriguing enough to say, okay, even if it's difficult to conduct this kind of randomized study, it has to be done now because we need to really know. Let's say 80% of the patients could indeed be treated with any of the two device in this large margin of patients. Do we have to choose one or the other one to start with? This has already been well answered in a larger randomized trial.

Dr Amit Khera: Dharam, maybe I'll ask you, do you think this large randomized trial, are you optimistic that that would happen? Certainly it sounds like it's something that would be very helpful for the field. What are your thoughts on whether that's actually going to occur?

Dr Dharam Kumbhani: I know that there are some head to head trials ongoing. I don't know if they will have the sample size to really drill down, as far as hard endpoints, mortality, for example. I think the field clearly needs it. The question is, who's going to sponsor a trial like that? There's probably not much incentive for industry to sponsor something like that. Really it would fall down to whether there's a way for government agencies to partner with industry or other ways to run this. I do agree with Eric that that's really very important and hopefully we'll see that in the field going forward.

I did want to comment on the next iteration of devices as far as what we may see now. The mortality signal, I know we've talked about it. It's an observation study. It's hard to know if there's confounding, and even with all the sophisticated statistical analyses that the team did, there's always a possibility that somehow there was sicker patients that received self-expanding valves.

The signal for paravalvular regurgitation is not just in this study. We've observed it in many other studies and for other self-expanding platforms as well. Both the SCOPE trial and the St. Jude trial last year, both came around the same time. They were self-expanding platforms and both of them showed a higher paravalvular regurgitation rate compared to the balloon expandable rate. That may be a real thing, and I don't know if that is an inherent design flaw in the self-expanding platform or if there are ways that that could be mitigated going forward. Again, I think the trials, for it to be meaningful, it would be obviously important to collect and have short term and imaging markers. Really, what the field needs is long-term evaluation of these two strategies.

Dr Amit Khera: I want to take both Dharam Kumbhani and Dr Eric Van Belle l from Lille University Hospital. Thank you both for joining today.

Dr Greg Hundley: This program is copyright, the American Heart Association 2020.


Jan 20, 2020

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

Dr. Greg Hundley: And I'm Greg Hundley, Associate Editor, Director of the Pauley Heart Center in Richmond, Virginia.

Dr. Carolyn Lam: Greg, it is so good to be back. I just love doing these podcasts with you and what more when we get to feature a paper like the one that we have this week. It's all about high sensitivity, cardiac troponin and the universal definition of myocardial infarction, one of these evergreen topics that we truly need to understand better. But before we go onto that, I want to share my first paper. It's a preclinical paper and it provides an important breakthrough discovery that could protect the heart against progressive left ventricular systolic dysfunction following injury. Want to hear about it?

Dr. Greg Hundley: Absolutely.

Dr. Carolyn Lam: Okay. It's from course wanting authors, Drs Sabourin and Benitah from INSERM University, Paris, as well as Doctors Foster and Beech from University of Leeds.

Dr. Carolyn Lam: Now, whereas store operated calcium entry has recently gained attention in cardiac pathophysiology, the role of the prototypic store operated channel known as Orai1 remains elusive. So these authors used a novel genetically modified mouse that specifically disrupts the Orai1 channel in cardiomyocytes and showed that functional inhibition of Orai1 preserved alterations of calcium homeostasis, fibrosis and systolic function without affecting hypertrophy. A novel in vivo small molecule Orai1 channel inhibitor, in fact, markedly improve left ventricular systolic function and calcium handling after pressure overload without causing adverse effects.

Dr. Greg Hundley: Tell me, how does this help me as a clinician?

Dr. Carolyn Lam: All right, you always ask the tough questions. Well, these results really suggest that Orai1 inhibition has the potential for favorable hemodynamic value in the protection of the heart from maladaptive hypotrophy, and therefore might represent a new way to provide inotropic support to help relieve systolic dysfunction.

Dr. Greg Hundley: Very good. Well Carolyn, my first paper is from Dr Peter Kudenchuk from University of Washington Medical Center and this study evaluates the overall survivor after out of hospital cardiac arrest from shock refractory ventricular fibrillation or pulseless ventricular tachycardia related to the route of accessory drug administration. So to accomplish this, the investigators had 2,358 individuals that had received Amiodarone, lidocaine or placebo study drugs and randomized to an IV route.

Dr. Greg Hundley: And then they also included 661 patients that received the same medications, but they were randomized to an intraosseous route.

Dr. Carolyn Lam: So what were the results, Greg?

Dr. Greg Hundley: Well, Carolyn, while no significant effect modification by drug administration route was observed point estimates for the effects of both drugs, both the lidocaine and the Amiodarone, compared to placebo were greater for the IV, as opposed to the intraosseous route and that was across all outcomes. And they had significant increases in survival to hospital admission and discharge and favored improved neurological outcomes with the IV administration.

Dr. Greg Hundley: Unfortunately, however, the study was underpowered to examine for an interaction between the route of vascular access and drug effectiveness and thus additional studies are needed to determine whether Amiodarone in lidocaine may be lifesaving drugs in patients with shock refractory out of hospital cardiac arrest when given IV, but not necessarily intraosseous.

Dr. Carolyn Lam: Very interesting. Well, my next paper is really focused on HIV infection and asks the question, is HIV infection associated with abnormal cardiac repolarization that may contribute to a greater risk for sudden arrhythmic death? Well, corresponding author Wendy Post, our very own from Johns Hopkins University School of Medicine and her colleagues studied 1,123 men, 589 of whom were HIV positive and they were from the multicenter AIDS cohort study and they were studied using the ZioXT ambulatory ECG patch.

Dr. Greg Hundley: Wow. Carolyn, this study sounds like it's the largest study of QT variability in HIV today.

Dr. Greg Hundley: Is that right? And what did the authors find?

Dr. Carolyn Lam: Yeah, it's right. It's huge. And basically they found that HIV positive men had greater beat to beat variability in the QT interval compared to HIV negative men, especially in the setting of HIV viremia and heightened inflammation.

Dr. Carolyn Lam: Among HIV positive men, a higher QT interval variability suggests ventricular repolarization lability which could increase susceptibility to arrhythmias. However, lower heart rate variability also may signal a component of autonomic dysfunction.

Dr. Greg Hundley: Ah, Carolyn. My next paper goes back to the world of basic science and it's from Dr. Chen Yan from University of Rochester. And in this study, Dr. Yon and colleagues examine the role of cyclic nucleotide phosphodiesterase in isolated adult mouse cardiomyocytes and fibroblasts as well as in preclinical mouse models of hypertrophy and/or heart failure. And they found that phosphodiesterase 10A expression is significantly induced in mouse and human failing hearts.

Dr. Greg Hundley: It directly promotes cardiomyocyte hypertrophic growth as well as cardio fiber-blast activation, proliferation, migration and extracellular matrix production. In addition, phosphodiesterase 10A deficiency, so not as much of it, ameliorates cardiac hypertrophy fibrosis and/or dysfunction in different preclinical mouse cardiac disease models. And finally inhibiting phosphodiesterase 10A activity with a compound labeled T P 10 effectively antagonizes the pathological cardiac remodeling in LVH.

Dr. Carolyn Lam: Huh, that's interesting Greg. And now I'll ask you, so what are the clinical implications?

Dr. Greg Hundley: Well, phosphodiesterase 10A inhibitors have been evaluated in phase two clinical trials for treatment of schizophrenia, suggesting that these agents are safe, druggable, if you will, targets. And therefore the results with TP 10 suggests a potential therapeutic effect of targeting phosphodiesterase 10A on antagonizing the development of pathological cardiac remodeling. Perhaps as suggested by Dr. Ezekowitz last week, this could represent another new agent in the treatment of the adverse effects of heart failure syndromes, more pharmacological agents coming to treat heart failure.

Dr. Carolyn Lam: Wow. That is interesting. But okay, let's talk about what else is in this issue. So let me tell you about an online mine by Dr. Kalra and it's called the Cardiovascular Science India Tour. And what this talks about is a multi-pronged initiative bringing together professionals and diverse expertise to allow better understanding of the issues driving the ever-rising cardiovascular disease burden in South Asia.

Dr. Greg Hundley: Oh, very good. And from the mailbag, I've got a research letter, Carolyn from Dr. Julian Luetkens from the University of Bond, who investigates a surrogate of frailty by examining the fat fraction within skeletal muscle at the L three L four level. So it's from an axial CT that's acquired at the time of CT scanning for TAVR pre-evaluation and uses the fat muscle fraction to forecast TAVR outcomes. Well. Carolyn, that's a great wrap up. How about we get onto our feature article?

Dr. Carolyn Lam: You bet.

Dr. Amit Khera: Hi, this is Amit Khera. I am digital strategies editor for circulation and today with our featured podcast we have Dr. Andrew Chapman from the university of Edinburgh, UK who is the first author of a study entitled high sensitivity cardiac proponent and the universal definition of myocardial infarction. Welcome Dr. Chapman. Thanks for joining us.

Dr. Andrew Chapman: Good morning. It's a pleasure. Thank you.

Dr. Amit Khera: This is obviously a very interesting study and timely and on the backs of the prior work that your group has published. Maybe we can start by you telling us a little bit about the impetus, the background which led to this work.

Dr. Andrew Chapman: We've been using high sensitivity cardiac troponin in Europe now for some years, and the way that we diagnose myocardial infarction has, of course changed. We now recognize that myocardial infarction can occur in the context of an occluded coronary artery, be that a STEMI or an NSTEMI, also known as a type one myocardial infarction.

Dr. Andrew Chapman: But increasingly with the use of more sensitive cardiac troponin, we're recognizing myocardial infarction can occur in other conditions. So for example, after arrhythmia or after severe infection with hypoxia. So the real rationale and background for this study is trying to understand better the different subtypes of myocardial infarction. As proposed in the universal definition.

Dr. Andrew Chapman: And we were in quite a unique position to evaluate this as, when we implemented high sensitivity cardiac troponin testing in Scotland as part of a randomized controlled trial. We did so across different hospitals and two of our major cities, Edinburgh and Glasgow, and the trial which formed the basis for this study was called the high States trial and we enrolled 48,000 patients of who we initially used a contemporary sensitive cardiac troponin on an IRC and we then implemented a high sensitivity cardiac troponin IRC.

Dr. Andrew Chapman: And that allowed us to evaluate what impact implementing this high sensitivity test hard firstly on the prevalence of different subtypes in myocardial infarction, but also on the investigations and the treatments received. And finally of course the clinical outcomes of these patients.

Dr. Amit Khera: So obviously at a really sizable study and good forethought on your group to implement this as this step wedge type study design. As you pointed out, the goal here was to understand the different subgroups of myocardial infarction, the prevalence and implications. Tell us a little bit about what you found in this study.

Dr. Andrew Chapman: As I mentioned, we had over 48,000 consecutive patients and that was the real benefit of this step wedge design is that rather than recruiting patients between say nine and five where we had research nurses available, we enrolled all consecutive patients. So we think this is quite a representative population for our area. So of those patients, we found around 10,000 had elevation in the high sensitivity cardiac troponin concentration, and we adjudicated these diagnoses in parallel. So two independent clinicians look through every case, all the clinical information. And we had a consensus from a third when there was disagreement. So in short we found that around half of all elevations in cardiac troponin in this study were to take one myocardial infarction, that is that the blocked artery phenotype and the type two myocardial infarctions or an acute or chronic myocardial injury and myocardial injury being elevation and cardiac troponin, either acute with a rise or fall or chronic with a stable concentration with no evidence of myocardial ischemia and occurred in the other 50% of patients.

Dr. Andrew Chapman: So looking between the phases of the study, we found introducing high sensitivity troponin disproportionately increased the diagnosis of Type II MI or acute or chronic myocardial injury. So there's just an 11% increase in the diagnosis of Type I MI, and I think again that's highlighting that these more sensitive tests are finding myocardial damage in areas that previously it might not have been recognized.

Dr. Andrew Chapman: So moving forward from that, we evaluated the primary outcome of the trial, which was future myocardial infarction or cardiovascular death by subgroup. And we also evaluated unimportant non-cardiovascular death. If I may for just 30 seconds, I'll just discuss why this is important.

Dr. Andrew Chapman: So evaluating future cardiovascular events is very important and in different subgroups of myocardial infarction. However, we know patients with Type II MI and acute or chronic myocardial injury are different. So they tend to be older, they're more commonly female, they have more comorbidities, they're on more medications to start with.

Dr. Andrew Chapman: And these patients are ar increased risk of a competing events to cardiovascular death or a myocardial infarction. And that is that these patients can go on and die, will primarily from their primary illness, be an infection or a pulmonary embolism or what have you. But also they are at increased risk of death from other non-cardiovascular causes.

Dr. Andrew Chapman: So in this study we were able to evaluate future cardiovascular risks using quite advanced competing risks modeling. And I was very grateful for the input of a number of experts and we managed to find that actually, Type I myocardial infarction patients with occlusion or partial occlusion of the coronary artery were at the highest risk of cardiovascular events going forward.

Dr. Andrew Chapman: But interestingly, even despite the vast excess in non-cardiovascular death, patients with Type II MI, and acute or chronic injury also had quite a high cardiovascular risk over three folds out of patients without myocardial injury. And we noticed that these patients did not stand to receive increases in investigations or treatments for coronary heart disease and we speculate and we hypothesize that actually in a proportion of these patients there is some clinical coronary artery disease which has manifested itself during this physiological stress test of an alternative illness. We wonder and we hope that moving forward this might be an opportunity for better targeting it in an investigation and perhaps even improving clinical outcomes.

Dr. Amit Khera: Well, you just shared a ton of important findings there and I'm going to unpackage a few of them. I guess the first is this sort of type I versus type II MI, and I think one of the fears with implementing these high sensitivity troponin would be perhaps an explosion in these type II MIs. And I think, if you look, although you mentioned proportionally, the absolute numbers of increase in type I and type II MI was relatively small so it didn't seem we had this explosion that I think people had feared was implementation.

Dr. Andrew Chapman: Yes, that's a fair point. And also need to bear in mind this is a population of patients from Scotland and our high sensitivity troponin testing is quite selective. You would find differences in the impact of high sensitivity if you're testing practices were different and I know there's prior work from the United States showing that less selective testing or to put it in a different way, testing troponin in more patients. Perhaps some of them may not have symptoms of chest pain or symptoms suggestive of myocardial infarction, is likely to change the prevalence of these different groups and you are likely to pick up more secondary injury or type II MI, but I think we don't need to panic. There's no need for alarm. I don't think there is going to be an explosion in recognition of these patients. If you check a temperature, you'll find a fever, but provided we're sensible and who we're testing, then I don't think practice needs to change dramatically.

Dr. Amit Khera: That was a great way to say it. Unfortunately, we're always looking for fevers in the U.S. So as you pointed out, the prevalence increase may increase a bit, but definitely reassuring from what you're finding in your population was more judicious testing.

Dr. Amit Khera: The second point that you brought up was the event rates, type I versus type II MI. I guess this does remind us again that patients with type II have almost comparable cardiovascular deaths and MI rates as type I, so certainly a higher risk group. As you pointed out, there's many comorbidities there and this gets to your point about treatments. I guess the question is now the event rates are higher, these are higher risk group or what to do about it I think is one of the vexing problems. As you pointed out, there's, there's not a lot of secondary prevention treatments, but what should those treatments be and where do we go from here in terms of these type II MI?

Dr. Andrew Chapman: That's the million dollar question I suppose and something that we've explored in another recent circulation review under the [00:17:07] lead author is what we do for these patients. When we've looked at different strategies, it seems the most reasonable initial approach is determining, does my patient with type II MI or myocardial injury actually have a cardiac problem?

Dr. Andrew Chapman: Now I don't think we have the evidence to support routine and baited testing in this population yet and indeed that might expose patients to harm and that's one of the tensions with this diagnosis.

Dr. Andrew Chapman: For example, consider the patient with gastrointestinal hemorrhage and could it have gone forward for an angiogram. Giving them heparin might not be the best thing to do in their acute illness. However, whether or not these patients would benefit from noninvasive tests such as a CT scan to delineate the coronary anatomy and identify those that might benefit from an iron platelet agent or a statin or indeed an echocardiogram to determine which patients have left ventricular impairment and could benefit from the many number of treatments we have now for LV impairment and that would be my initial thinking is that we need to firstly risk profile these patients.

Dr. Andrew Chapman: What is their pretest probability or likelihood of coronary artery disease? It's not intermediate or high. Let's have a think about investigating their coronary arteries. In the first instance, I think a noninvasive test is going to be most appropriate for the majority of people, but we need a personalized approach. It may be that someone's just had a very brief run of an arrhythmia and that's resulted in a disproportionate level of ischemia and a very high cardiac troponin.

Dr. Andrew Chapman: Your index of suspicion for that patient having coronary disease is going to be significantly higher. So a personalized approach, I think, is where we're heading. And there are trials which are coming in this area. So yeah, two trial is being led by Derek Chu of Melbourne in Australia and they're evaluating the use of CT or invasive angiography to identify coronary disease and target treatment to see if that can improve outcomes.

Dr. Andrew Chapman: And certainly here in Scotland, we're hoping to evaluate the use of a personalized approach to target treatment in patients with type II MI and again, try and improve cardiovascular outcomes. So things are coming.

Dr. Amit Khera: Well, I appreciate that and I think as you pointed out, as we wait for these additional data and additional studies, sort of a thoughtful. algorithmic approach would be helpful and we certainly will make sure the readers and listeners look out for that paper that you mentioned in circulation.

Dr. Amit Khera: I should also point out that your paper here is an excellent editorial by David Morrow, which has a nice figure and illustration of your central findings. So we appreciate that. As we wrap up here, maybe you can tell us what are the main take homes? What should they take away from this study?

Dr. Andrew Chapman: What we've shown is that high sensitivity troponin are useful and we've shown that they increase recognition of patients who have myocardial jury or type II myocardial infarction, where in the past this may not have been found and we've shown quite clearly that these are prognostic. Not only predicting non-cardiovascular disease, but also going on to identify patients at increased risk of myocardial infarction, cardiovascular death.

Dr. Andrew Chapman: So I think moving forward, clinicians using these tests and identifying these patients should be considering investigations to identify coronary or structural heart disease. And until we have that high quality randomized controlled trial data, we need to be pragmatic and we need to evaluate secondary prevention on an individual patient basis, be that an antiplatelet agent or be that a statin as the primary ones. This may even go on to include an ACE inhibitor or a beta blocker if there's LV impairment, but our aim ultimately has to be to try and reduce the cardiovascular event rates in this population who, to date, have been under investigated and undertreated.

Dr. Amit Khera: That summarizes it quite well. And I want to thank Dr. Andrew Chapman for his excellent discussion today and that's why we do these backstage passes to get an inside look as to what the authors were thinking and some behind the scenes on their papers.

Dr. Amit Khera: Again, I'm Omnicare digital strategies editor for circulation, and thank you for joining us on this circulation on the run podcast.

Dr. Greg Hundley: This program is copyright, the American heart association 2020.

Jan 13, 2020

Dr Greg Hundley: Welcome listeners. This is Dr Greg Hundley from the VCU Pauley Heart Center in Richmond, who is in the second of his two-week stint without his dear friend, Dr Carolyn Lam who will be returning in a week or two. Our feature article this week is from Dr Mikhail Kosiborod from Saint Luke's Mid America Heart Institute and the Georgia Institute for Global Health, and University of New South Wales. And we'll review the effects of dapagliflozin on quality of life and other metrics in patients with heart failure and reduced ejection fraction. But first, let's have a look at the other articles in this issue and just like last week we've got four other original manuscripts. The first two are sort of clinically related and that very first article comes from Dr Ben Levine from University of Texas Southwestern and he serves as the corresponding author and he's examining future predictors of the development of heart failure and preserved ejection fraction or HFpEF.

His team tested the hypothesis as to whether patients with LVH and elevated cardiac biomarkers would demonstrate elevated LV myocardial stiffness when compared to healthy controls as a key marker for future HFpEF. The team recruited 46 patients with LVH. The LV septum was greater than 11 millimeters and elevated cardiac biomarkers, so the NTproBNP was greater than 40 or the cardiac troponin T was greater than 0.6. And they were recruited along with 61 age and sex-matched cohort of healthy controls. To define LV pressure volume relationships, right heart catheterization and 3D echocardiography were performed while preload was manipulated using lower body negative pressure and rapid saline infusion. They found that the left ventricle was less distensible in the LVH patients relative to the controls, that is they had a smaller volume for the same filling pressure. When preload was expressed as transmural filling pressure or wedge pressure minus right atrial pressure left ventricular myocardial stiffness was nearly 30% greater in the LVH group compared to the controls.

The author's note that although LV myocardial stiffness of LVH patients was greater than that of the healthy controls at this relatively early stage, further studies are required to clarify whether interventions such as exercise training to improve LV compliance may prevent the full manifestation of the HFpEF syndrome in these high-risk individuals.

Well, the second paper comes from Professor John McMurry of the British Heart Foundation Cardiovascular Research Center at the University of Glasgow in the United Kingdom. And the paper is somewhat similar to our feature article because it emanates from the DAPA Heart Failure dataset that we will hear about later. So in this paper, the authors examined the effects of Dapagliflozin according to age, given potential concerns about the efficacy and safety of therapies in the elderly in the prior trial. A clinical trial that as we know, demonstrated that a reduced risk of mortality and heart failure hospitalizations occurred in patients with HFrEF.

So in this current study, a total of 4,744 patients that were 22 to 94 years of age were randomized. 636 were less than 55 years of age, 1,242 we're 55 to 64 years of age 1,717 were 65 to 74, and finally 1,149 were greater than 75 years of age. Consistent benefits were observed for the components of the primary outcome of all-cause mortality and symptoms across all the age groups. Although the adverse events and the study drug discontinuation increased with age, neither was significantly more common with Dapagliflozin across any of the age groups. There was no significant imbalance and tolerability or safety events between Dapagliflozin and placebo, even in the very old population group. So we'll have more to discuss later in the feature discussion with a second paper that really looks also at the DAPA-HF study.

The next original article comes from our world of Basic Science and it reports that the deficiency of circulating monocytes ameliorates the progression of myxomatous valve degeneration in the Marfan syndrome. And this paper comes from Dr Katherine Yutzey from Cincinnati Children's Medical Center. Well, first is some background, leukocytes comprised primarily of macrophages have recently been detected in myxomatous valves, but the timing of the presence and the contributions of these cells in myxomatous mitral valve degeneration is not known. So the authors found in this study that Marfan syndrome mice recapitulated the histopathologic features of myxomatous valve disease by two months of age, including mitral valve thickening, increased leaflet cellularity and extracellular matrix abnormalities characterized by proteoglycan accumulation and collagen fragmentation.

Concurrently, disease mitral valves of the Marfan syndrome mice exhibited a marked increase of infiltrating and resident macrophages along with increased chemokine activity and inflammatory extracellular matrix modification. Likewise, mitral valve specimens obtained from gene-edited Marfan syndrome pigs as well as human subjects exhibited increased monocytes and macrophages detected by immunofluorescence. So remarkably deficiency of monocytes was protected against mitral valve disease progression resulting in a significant reduction of macrophages, had minimal leaflet thickening and preserved mitral valve integrity. So the authors identify for the first time in this interesting study from the world of basic science that monocytes are a viable candidate for targeted therapy in myxomatous valve degeneration.

The second basic science original article in this issue is entitled "Genetic IL-6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis" and the corresponding there is Pradeep Natarajan from the Mass. General is background clonal hematopoiesis of indeterminate potential or CHIP is a term that refers to clonal expansion of hematopoietic STEM cells due to acquired leukemic mutations in genes such as DNMT3A or TET2. In humans, CHIP associates with prevalent myocardial infarction. In mice CHIP accelerates atherosclerosis and increases IL-6 and IL-1 beta expression raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease risk.

So in this study, the authors observed some really exciting results. They analyzed over 34,000 samples from the UK Biobank and identified 1,079 individuals with CHIP, including 432 with large clones an LV fraction greater than 10%. During a 6.9-year median follow-up CHIP presence was associated with increased incidents, cardiovascular disease event risk with greater risk from large CHIP clones. IL6R attenuated cardiovascular event risk among participants with large CHIP clones but not in individuals without CHIP. This really exciting research results suggest that CHIP is associated with increased risk of incident cardiovascular disease. And among carriers of large CHIP clones, genetically reduced IL-6 signaling abdicated this risk. Really exciting results in an emerging area of science.

So what else is in the issue? Well, in our in depth review feature, Professor Stephan Rosencrantz from the University of Cologne Heart Center reviews the systemic consequences of pulmonary hypertension with right side heart failure. And then an On My Mind piece, our own associate editor, Dr Vlad Zaha coupled with doctors Walter Myers and Javid Moslehi from Vanderbilt discuss the impact of evolving immunotherapies for cancer and their impact on the cardiovascular system. In our mailbag, Dr Xiayan Shen from the Medical Classification Center of the Singapore Armed Forces discusses in a research letter the prevalence of Brugada Syndrome in a large Singaporean young male population. In letters to the editor, Dr Muddassir Mehmood from University of Tennessee Medical Center in one letter and Dr Goodarz Danaei from Boston in a response letter discuss the importance of diet relative to the development of HFpEF and how heart failure may be coded in by the World Health Organization when assessing global cardiovascular outcomes.

Bridget Kuhn in our cardiology news feature reports on preliminary results from the International Childhood Cardiovascular Cohort or i3C Consortium that was presented at the 2019 European Society of cardiology Congress. The i3C Consortium used data on 40,000 patients who participated in seven major longitudinal cohort studies that evaluated childhood cardiovascular risk factors from repeated measures during childhood and adolescence. And finally, our own Molly Klemarczyk at Circulation gathered and combined a very nice serial update that highlights important articles from our circulation family of journals, including electrophysiology, imaging, heart failure, and others.

Well, listeners, that's a summary of what's in the journal. But let's now proceed to our feature discussion to learn more about the rapidly emerging field of SGLT2 inhibition.

Well listeners, we are very excited for this feature discussion we have today, Dr Mikhail Kosiborod from Saint Luke's Mid America heart Institute and our own associate editor, Dr Justin Ezekowitz from Alberta, Canada. And we're going to be discussing the paper related to the effects of Dapagliflozin on symptoms, function and quality of life in patients with heart failure and reduced ejection fraction. They're going to be presenting results from the DAPA Heart Failure trial. Well Mikhail, I was wondering could you orient us a little bit to the DAPA heart failure trial. And then what was the hypothesis that you were trying to address in the current study?

Dr Mikhail Kosiborod: DAPA-HF was the first heart failure outcome trial trying to answer two critical questions about the effects of SGLT2 inhibitors in patients with heart failure and reduced ejection fraction. We knew from prior trials, outcome trials in patients with diabetes SGLT2 agents can effectively prevent heart failure inpatients, overwhelming majority of which did not have heart failure and baseline. But what we didn't know was whether these agents can also be used as therapies for patients with established heart failure, and specifically heart failure with reduced ejection fraction. And they reduce death or worsening heart failure in the patient population. And the second question was whether that effect, if in fact this medications can significantly improve outcomes in patients with heart failure reduced ejection fraction. Can they do that even in patients who do not have type 2 diabetes? Because, in a diabetes trial it appears that that heart failure protective effect may be completely independent on the hemoglobin AONC.

And so DAPA-HF was specifically designed to test those two hypotheses. It enrolled about 4,800 patients with heart failure and reduced ejection fraction about 45% of which had types 2 diabetes. And there's a majority of us, 55% did not. And the main trial results that were published prior to risk analysis showed that in fact dapagliflozin significantly reduced the risk of the composite endpoint of cardiovascular death and worsening heart failure. It was a 26% relative risk reduction and the effects were identical in patients with or without type two diabetes. So both of those hypothesis were proven to be correct. It was effective therapies for established heart failure and reduced ejection fraction, and it was equally effective regardless of diabetes status. Now what we did in this study is really trying to understand the effects not just on cardiovascular deaths and hospitalization for heart failure, but on health status, which is symptoms, physical limitations, and quality of life.

He knows that heart failure is a debilitating disease, causes high burden of symptoms, and physical limitations, has adverse impact on quality of lives. We know that two key goals of managing heart failure are to; one, reduce deaths and hospitalizations for heart failure and two to reduce the burden of symptoms and physical limitations and improve the quality of life. So, that was really the focus of this specific analysis that we're talking about today.

Dr Greg Hundley: Excellent. So I understand you use the KCCQ-12, maybe help us understand what that test is and then tell us a little bit about your methods and your study population. Did you use the whole study population?

Dr Mikhail Kosiborod: KCCQ stands for Kansas City Cardiomyopathy Questionnaire and we actually in the study we use KCCQ-23 which is the full Kansas City Cardiomyopathy Questionnaire, consists of 23 items. And it a disease-specific tools for evaluating health status and heart failure.

So it essentially assesses four key domains, which are the symptom burden, physical implementations, quality of life, and social limitations. In this particular study is a primary endpoint as a primary part of the KCCQ as KCCQ total symptom score, which is a domain that focuses on symptoms. And the idea behind KCCQ is that you have a debilitating disease, which is heart failure. That disease has impact on the patient by causing symptoms, the symptoms then translate to physical limitations. And the combination of the symptom burden physical limitations has an impact on quality of life and social limitation. So that's why are this four different domains assessing these four components of the adverse effects of the heart failure compared to health status. And just very briefly, to mention that KCCQ has been proven to be responsive to clinical change. It's highly for data predictive of death and hospitalizations from heart failure. It has been extensively validated both of them hearts failure was reduced enters and the ejection fraction.

And so we essentially focused, or the primary focus of the paper was really to evaluate the effect of dapagliflozin versus placebo on a Kansas City Cardiomyopathy Questionnaire or KCCQ level symptom score. But we also looked at other domains as well. We looked at the clinical summary score, which includes both symptoms and physical limitations and we looked at the overall summary score, which includes all of the four domains that I mentioned before.

Dr Greg Hundley: What did you find?

Dr Mikhail Kosiborod: The patients treated with dapagliflozin had a greater improvement in health status as assessed by a KCCQ total symptom score or for that matter KCCQ clinical summary overall summary score as compared to patients treated with placebo. So if you look at the mean effect, there is some improvement in the patients taking placebo. That's what we call a placebo effect. And it's very commonly seen in clinical trials. We assessed health status, but there was a greater improvement with dapagliflozin as compared with the placebo, it was statistically significant even in four months. But as the effects were further amplified to eight months and this differences were, I would say favorable when you kind of compare the effect of Dapagliflozin versus other established heart failure therapies when you look at the effects on health status.

What I think was even more important than analysis from a clinician standpoint, and then they think it's actually much more meaningful clinically is what we call a responder analysis. And that's where we look as the proportion of patients that have a clinically meaningful improvement with one type of therapy versus other in this case Dapagliflozin versus placebo.

So it's been previously established that at five-point difference or a five-point change rising KCCQ is what's considered to be clinically meaningful or minimal clinically meaningful difference. So a 5.2 grade deterioration KCCQ means it's a clinically important deterioration. And a five-point or greater improvement is a clinically important improvement. And then we also looked at the proportion of patients with moderate and large improvements in health status as well defined as STEM point of grade of two, or two point a great improvement. And essentially what we found was that significantly fewer patients treated with dapagliflozin and as compared with placebo had a clinical importance deterioration. And significantly greater proportion of patients treated with dapagliflozin has small, moderate, large improvements in health status. And the numbers needed to treat to see those differences, as the small moderate large improvements was very favorable ranging typically between 12 and 18 and over eight-months-treatment period.

Dr Greg Hundley: Outstanding. So both clinically relevant as well as statistically significant findings. Now we're going to bring in Justin, our associate editor. Justin, help us put these results into the just our perspective in looking at SGLT2 inhibitors, particularly for treatment for heart failure.

Dr Justin Ezekowitz: This is an exciting class of medications and we're eagerly awaiting these results because we saw the DAPA-HF Overall results. The majority of us treat patients with a pretty symptomatic disease and as such this quality of life is quite an important change. There's ongoing trials we're eagerly awaiting which are also going to be using other medications in the same class, but I think one question that remained was, are these simply improving symptoms by one meaning, so the total symptom score? Or the overall quality of life? And I think you nicely, elegantly portrayed that in the figures and you have. The one other part maybe Mikhail, you could expand upon, which is when you think about DAPA-HF, and the quality of life gains and across all the three different ways of looking at quality of life, where do you see this in terms of its relationship to other things that we know improve quality of life? Where we send patients, for example, CRT or put them on an RNE. Where does this fit on top of those types of changes?

Dr Mikhail Kosiborod: Thanks Justin. I think it's a really important question because it says think critical from a clinical standpoint to put it in the context of other therapies that had been previously shown to improve health status, which means again, reduced symptoms, improve physical and patient quality of life. And there are a number of perhaps the types of therapies on heart failure and LVCF that have been evaluated particularly on side this one there also have been studies with exercise training in heart failure or and the ones that you brought up, which is cardiac resynchronization therapy in patients with heart failure reduced ejection fraction and left bundle branch block. And as that perhaps, if you kind of think about it. What are some of the most effective treatments to improve the health status? That is ones that we typically would consider as such, which is CRT in patients with half RAF and a left bundle branch block.

And in fact, if you look at the mean effects dapagliflozin compares very favorably even with highly effective therapies such as TRT. Relatively few studies have previously reported to this responder in analysis. But if you look at Digoxin comparing those to dapagliflozin, one of the recent ones that I can think of is [inaudible 00:20:23], again dapagliflozin compares very favorably when you look at this types of responder analysis where again you look at proportion of patients, it was a clinically meaningful change.

So I think the beautiful thing about putting the study in the context of further studies looking at health status and also in the original main results that were published from a DAPA-HF early this year is that it's really kind of a full house if you will. So as the agent reduced deaths, reduced hospitalizations and made patients feel better and all of that, with very favorable safety profile. So, if you kind of think about risk benefit analysis and you look at numbers need to treat both for clinical outcomes such as CVS and hospitalizations for heart failure for example, where health status, it looks really impactful from a clinical standpoint.

Dr Greg Hundley: So relevance to other therapeutic interventions for heart failure is what this whole class of agents seems to be showing? So briefly, what do you see is the next important study in the field?

Dr Mikhail Kosiborod: I will waffle on this question a little bit and say there was more than one, but my views are there kind of two key components to this. One is that there are additional trials going on and heart failure with reduced ejection fraction with other agents. And so seeing what happens with those other agents in the class in a similar patient population and whether is this a class effect or not? Now the diabetes trials would suggest that these may well be class effects but I think it's nice to have validation of that. I would say that is one real important questions that hopefully we will have additional answers to in the coming year or so.

And the second and perhaps I would argue even more important question is whether these agents can also be effective in improving outcomes in patients with heart failure and preserved ejection fraction. That's a patient population that has also very high debilitating burden of symptoms that has poor prognosis and for which unlike them, half rubs, there are very few, if any medications that have been proven to be disease-modifying and actually have shown outcomes and benefit. So I would say those in my mind, are the two critical developments that we'll be seeing. And the good news is, there are the trials going on with more than one agent in a class and half to half as well. Great.

Dr Greg Hundley: And Justin?

Dr Justin Ezekowitz: Yeah, I think that there's been an explosion of therapies and Mikhail is bang on with this is the one class where we're excited about. I think the other groups of medications include Omecamtiv Mecarbil we'll know in a year or two. We'll hear more details in the spring and then there's a few other medications that Mikhail mentioned. I think this is a real good message though, that both HFrEF and HFpEF, it's the rise of medications again. Because we were on a device track for a while, but I think the medications have such more potent effect on the underlying structure and function that it's great to see that there's been such a development and explosion of medications that may obviate the need for implanted devices or advanced therapies, so we're very excited about that.

Dr Greg Hundley: Outstanding. Well, listeners, we've had the opportunity to hear from Mikhail Kosiborod from Saint Luke's Mid America Heart Institute and our own associate editor, Dr Justin Ezekowitz from Alberta, Canada, and learn more about SGLT2 inhibition and its importance in improving clinically symptomatology both in those with diabetes and heart failure, but also those with heart failure alone.

On behalf of Carolyn and myself, we wish you a great week and we look forward to running and having a coffee chat next week. Take care of. This program is copyright the American Heart Association, 2020