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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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


Dec 30, 2019

Dr Greg Hundley: Well listeners, this is Dr Greg Hundley from the VCU Pauley Heart Center in Richmond this week, who is sadly missing his dear friend, Dr Carolyn Lam, who is away for just a week or two. I hope you've experienced a wonderful holiday season and are able to embrace the new year with joy and hope.

In our feature article this week, Dr Marcelo Di Carli and colleagues are going to discuss the role of coronary microvascular dysfunction assessed with cardiac stress during PET, as well as left ventricular remodeling assessed with echocardiography and how both of those relate to clinical outcomes in patients with chronic kidney impairment. But first, let's have a coffee and chat about other articles in this issue.

We have four original manuscripts, two or more clinical papers, and two from the world of basic science. So let's go to the clinical papers first. And the first emanates from our own associate editor, Dr Sana Al-Khatib from Duke University. Her paper comes from the ARISTOTLE trial, a randomized study of 18,201 participants that compared apixaban with warfarin in patients with atrial fibrillation at increased risk of stroke. And so this sub study included 17,423 patients in ARISTOTLE without severe renal or liver disease. And the authors evaluated the risk of bleeding and major cardiovascular outcomes in patients with atrial fibrillation taking either NSAIDs with therapixaban or warfarin. The authors found that those with NSAID use at baseline, so before starting into the study or incident NSAID use, that is they began an NSAID after initiating this study were more likely, both groups were more likely to have a history of bleeding, nearly a quarter of the patients to a fifth of the patients versus only 15% that had never used NSAIDs either before or after entering the study.

In addition, the safety and efficacy of apixaban versus warfarin appeared not to significantly be altered by NSAID use. That is whether you were taking apixaban or whether you're taking warfarin, the impact of NSAID use was not different between either of those anticoagulants.

The second original clinical article comes from Dr Audrey Blewer, also from Duke University, and evaluates the variation in bystander cardiopulmonary resuscitation delivery and subsequent survival from out of hospital cardiac arrest based on neighborhood level ethnic characteristics.

As background for this research, bystander cardiopulmonary resuscitation delivery and survival from out of hospital cardiac arrest varies at the neighborhood level, was generally lower survival seen in neighborhoods predominantly with individuals from black race. Despite Hispanics being the fastest growing minority population in the United States, few studies have assessed whether the proportion of Hispanics in a neighborhood is also associated with delivery of bystander CPR or subsequent survival for an out of hospital cardiac arrest. Accordingly, the authors in this study assessed whether bystander CPR rates and survival buried by neighborhood level ethnicity. And they hypothesized that neighborhoods with a higher proportion of Hispanics would have lower bystander CPR rates and overall lower survival.

This study was a retrospective cohort and use data from the Resuscitations Outcome Consortium, or ROC Epistry across the United States. So in this study, the authors identified 18,900 cardiac arrests. And they excluded pediatric arrests, EMS witnessed arrests, or arrest occurring in a healthcare or an institutional facility. And they found overall that bystander CPR was administered in 37% of these out-of-hospital arrests. Among neighborhoods with less than 25% Hispanic residents, bystander CPR was administered in 39% of the events, while it was administered in only 27% of the events in those neighborhoods with greater than 75% Hispanic residents. Also, lower rates of survival occurred in neighborhoods with greater than 75% Hispanic residents. And so the authors conclude that these findings suggest there's an important need to understand the underlying disparities in CPR delivery and an unmet CPR training need among Hispanic communities.

Well now let's shift to our two original articles that come from the world of basic science. And the first is from Dr Ying Shen from Baylor College of Medicine and reports on the critical role of cytosolic DNA and its sensing adapters sting in aortic degeneration, dissection and rupture. So as some background for this study, recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing it after sting, a stimulator of interferon genes, plays a critical role in vascular inflammation and destruction. And so in this paper, the authors examine the involvement of this mechanism in aortic degeneration and sporadic aortic aneurysm and dissections. Just like with our other basic science papers, the authors perform both studies in a small animal model, mice, and also in human subjects. So what did they find?

The authors found that in human sporadic aortic dissection tissues, they observe the presence of cytosolic DNA in smooth muscle cells and macrophages. And they had significant activation of this sting pathway. In a mouse model, sting deficient mice showed significant reduction in challenged induced aortic enlargement, dissection and rupture in both the thoracic and abdominal aortic regions. Additional single cell transcriptome analyses were performed and provided some mechanistic understanding for the author's findings.

So in summary, for this very interesting paper from the world of basic science, the author's findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing it after, or sting signaling, is a key mechanism in aortic degeneration. And therefore future studies, perhaps targeting sting, may be performed to see if they could prevent sporadic aortic aneurysm dissection development.

The second basic original article in this issue is entitled In Vivo CRISPR CAS9-mediated gene editing and how that ameliorates atherosclerosis in familial hypercholesterolemia. It comes to us from Dr Bin Zhou from the Chinese Academy of Sciences.

So as background for this study, mutations in the low-density lipoprotein receptor are one of the main causes of familial hypercholesterolemia. The clustered regularly interspace short palindromic repeats of CRISPR and caspase-9 system is an effective tool for gene editing to correct gene mutations and thus ameliorate the disease.

So these authors tested whether in vivo sematic cell gene editing through the CRISPR CAS based nine system delivered by adeno associated virus could treat familial hypercholesterolemia caused by the LDLr mutant in a mouse model. Well, the authors ... As Carolyn would ask, so what did they find, Greg? Well, the authors observed some really exciting results. They found that the LDLr mutation was corrected in a subset of hepatocytes after the CRISPR CAS based nine treatment with LDLr protein expression partially restored. Compared with control animals, the CRISPR CAS based nine targeted SGRNA group had significant reductions in total cholesterol, total triglyceride, and LDL cholesterol in the serum while the aorta had smaller atherosclerotic plaques and a lower degree of macrophage infiltration. So this study really implicates perhaps not only a mechanism of disease, but a potential treatment. But with the relatively small numbers in this study, more research is needed to confirm and substantiate the findings from this group.

So great original articles in this issue. What else is in the issue? And let's move to those. We have a global rounds feature. Remember, global rounds are investigating how cardiovascular disease is assessed and managed in countries from all over the world. Well, in this global rounds feature Professor Ali Oto from Memorial and Cairo Hospital provides a quick reference to the control and management of cardiovascular disease in Turkey. And the next article, an on my mind piece, Dr Milton Packer explorers whether the conditions of atrial fibrillation and heart failure with preserved ejection fraction are two separate diseases that occur frequently together in patients or alternatively, whether these two adverse clinical syndromes may be parallel manifestations of the same underlying myocardial disease with atrial fibrillation affecting the left atrium and heart failure preserved ejection fraction afflicting the left ventricle.

In our what's in the mailbag series, Professor Nicholas Mills from the University of Edinburgh shares in a research letter the relationship between exercise intensity and duration on cardiac troponin release in 10 physically active healthy volunteers averaging 34 years in age. A great read for our readership that is actively exercising. And it looks like in this letter, intensity of exercise matters when evaluating post-exercise serum troponin values. I really encourage everyone to take a look at that letter.

And then finally, there's a letter to the editors from Dr Abdallah Fayssoil from the Raymond Poincare Hospital in Garches, France regarding a prior publication related to nutrition and functional tricuspid regurgitation.

Well, listeners, that sums up our summary. And I hope you had a great coffee or if you're running on your treadmill, a great run. And let's now move on to our feature discussion with Dr Di Carli. Welcome everyone to our feature discussion and we have Dr Marcelo Di Carli from Brigham and Women's Hospital who's going to be discussing with us a manuscript relating to the measurements of coronary micro circulatory function and how they may impact patients with chronic kidney disease. Also discussing today, we have our own associate editor, Dr Victoria Delgado from Leiden in the Netherlands. Well, welcome Marcelo and Victoria. We're so glad to have the opportunity to speak with you. And Marcelo, could you tell us a little bit about what was the hypothesis and some of the background of why you wanted to perform this study?

Dr Marcelo Di Carli: Chronic kidney disease represents a relatively large segment of the population. In the US alone, it's estimated that around 50 million people have the diagnosis of chronic kidney disease. And it's a disease that we all know is associated with a high risk of cardiovascular events. Even in the absence of obstructive coronary disease, it's been shown that the incidents of cardiomyopathy and the absence of obstructive disease, of coronary disease, is pretty high and that associates with a high risk of heart failure and death.

The mechanisms related to cardiomyopathy in patients with chronic kidney disease have been debated for a long time. This has been associated with LVH incidents of non-transmittal or non-ST-elevation MIs, also with microvascular disease as a measure of ischemic heart disease, but there's no clear association with how do these features of chronic kidney disease link to each other. And so our objective was to look at the associations between LV remodeling, coronary microvascular disease and adverse events. And we hypothesized that coronary microvascular dysfunction as a more integrative marker of myocardial ischemia and injury would associate with changes in cardiac structure and function and with increased risk of adverse cardiovascular events.

Dr Greg Hundley: Very nice. So tell us a little bit, Marcelo, about your study population and your study design.

Dr Marcelo Di Carli: Well, this is a cross sectional analysis of a cohort that is well-characterized in our registries. And so it consisted of a consecutive group of patients who underwent both PET scanning for measuring coronary vascular function and echocardiography within 90 days of each other. Could it not have evidence of overt obstructive coronary disease as defined by a history of prior revascularization, prior AMI or an abnormal PET scan indicating presence of obstructive disease.

We also excluded patients with severe valvular disease, cancer, severe LV disfunction to try to avoid confounding elements in the associations where we're trying to study. We used echocardiography to assess quantitatively the changes in LV geometry, diastolic function and subclinical systolic dysfunction. Most of our patients have relatively preserved LV function, LV ejection fraction. And so we looked at peak longitudinal strain, global radial strain and circumferential strain as indicators of systolic dysfunction. And of course we also looked at changes in LV mass. Patients were followed a little over four years for the occurrence of death, hospitalization for heart failure or myocardial infarction. And all of these myocardial infarctions were non-ST-elevation MIs, or people might call it type two MIs.

Dr Greg Hundley: Tell us a little bit about the results. But before you get to that, how old were these patients and what was their breakdown in terms of race and gender?

Dr Marcelo Di Carli: Yeah, so we had a population of 352 patients. The mean age was mid-sixties. not surprisingly, 60% of the patients were female. And this is because we obviously excluded obstructive coronary disease that would be more prevalent in male. They have about a 40% incidence of diabetes, a high percentage of them had hypertension. These are all the features that would typically be associated with chronic kidney disease. The rate of obesity was actually lower in patients with CKD. And we call CKD here as a GFR less than 60. That's the population we're targeting here. And so that's essentially the cohort.

Dr Greg Hundley: And what did you find?

Dr Marcelo Di Carli: Well, there were essentially three or four main findings. Number one and not very surprisingly, patients with CKD had worse myocardial mechanics that is worse diastolic function and worse systolic strain. In multi-variable models, fully adjusted for a number of clinical covariates as well as ejection fraction, we found that these abnormalities in myocardial mechanics were relatively strongly associated with abnormal coronary microvascular function as defined by PET. So this sort of suggests that the variability that we see in diastolic and systolic function are explained largely by microvascular disease, but not necessarily directly linked to GFR as a mediator.

The second finding was that patients with CKD, again, not surprisingly, it showed a higher incidence of MACE, including especially death and heart failure, more than triple the rate of death and doubled the rate of heart failure compared to those without CKD. And in multi-variable analysis, again, MACE was associated with coronary flow reserve as a measure of microvascular dysfunction but not glomerular filtration rate. And there was no interaction between coronary flow reserve and GFR. Interestingly, when we looked at the adverse events subgroup by measures of LV remodeling and we picked three measures. One is changes in LV geometry, diastolic dysfunction, and impaired global longitudinal strain, we found that the incidence of both mace as well as heart failure and myocardial infarction were significantly higher when both abnormal LV mechanics or remodeling were present and the patients also had microvascular disease. So in the absence of either one, the rate of mace was relatively low, indicating that there is a clear interaction between abnormalities in cardiac structure and function and microvascular disease.

And then lastly, we looked at mediation analysis to try to investigate a plausible pathway between impaired renal function and events and we hypothesized that coronary microvascular dysfunction might actually mediate at least part of that relationship. And indeed we found that about a third of the relationship was explained by the presence of microvascular disease. Very nice,

Dr Greg Hundley: Very nice. Very important work. So now we'll turn to our own associate editor, Victoria Delgado. Victoria, help us put this into perspective for what we know about patients with chronic kidney disease. How does the results of this study really move the field forward?

Dr Victoria Delgado: I think that this article brings new evidence on phenotyping of these patients and the factors that influence the cardiac abnormalities that we may see. There are not many studies including patients with chronic kidney disease. These patients are usually underrepresented in randomized control trials. And we know that these patients are associated with an increased mortality and morbidity and mainly heart failure hospitalizations. And I think that this study is showing another piece in the person that can help us understand why these patients are associated with much higher cardiovascular morbidity and mortality. I think that relating the coronary microvascular dysfunction is an important piece and important knowledge because then we may think how to improve the microvascular dysfunction on these patients and see if by improving these microvascular dysfunction, these abnormalities that have been described in terms of a structure and function can be reversed and see how these impacts on the outcome of these patients.

Dr Greg Hundley: So Marcelo, just briefly, what do you think is the next study that needs to be performed in this area of science?

Dr Marcelo Di Carli: I think that obviously our study has some limitations and the causation. Cause and effect cannot be inferred from our study. So I think the next steps will be to try to demonstrate whether indeed modifying microvascular dysfunction leads to improved outcomes. And I think this will be best done by intervention studies that can be targeted towards improving microvascular dysfunction. We can think of novel therapies as well that have been initially associated with improved renal outcomes. I'm talking about for example, SGLT2 inhibitors that can be potentially of benefit not only on renal outcomes but potentially on cardiovascular outcomes as has been shown in populations largely without CKD.

Dr Greg Hundley: Victoria, anything to add in terms of how noninvasive imaging could play a role in some of those next future studies?

Dr Victoria Delgado: I think that the point that Marcelo raise on the use of SGLT2 inhibitors is very timely and very appealing because we know that for patients with diabetes who have renal dysfunction and you have EGFR below 35, they may not be eligible for these therapies. But as you can see in this study, the mean EGFR of the patients with renal dysfunction was 41. So there is a wide range of patients that could be eligible for these therapies. How imaging can help to see or to detect the patients that may benefit from these therapies and see how these therapies may improve the structure and the function of the heart.

Dr Greg Hundley: Well, listeners, we've had a great discussion today with Dr Marcelo Di Carli from Brigham and Women's Hospital and Dr Victoria Delgado from Leiden. And really trying to understand some noninvasive markers of both micro circulatory dysfunction as well as abnormal echocardiographic assessments of both diastolic function as well as systolic dysfunction and how they forecast adverse events in patients with chronic kidney disease.

I want to wish you all a great week and on behalf of Carolyn and myself, I hope to see you next week. Take care now.

This program is copyright the American Heart Association 2020.


Dec 23, 2019

Dr Amit Khera: I'm Amit Khera, I'm digital strategies editor for Circulation and I'm standing in this week for Carolyn Lam and Greg Hunley. And I'm also doing the Circulation on the Run podcast, as well as Discover CircRes podcast with our two editors in chief.
This is Jane Freedman, who recently took over as editor-in-chief of Circulation Research, and Joseph Hill, who is the editor-in-chief of Circulation. So, welcome you both. We're excited to do this.
Dr Joseph Hill: Thank you.
Dr Jane Freedman: Thank you.
Dr Amit Khera: The idea behind this, there's this session here at sessions where we're learning a little bit about Circulation Research and Circulation, pulling back the cover, if you will, and seeing behind the cloak, as what happens in the Journal. So, Dr Freedman, I'll start with you. Tell me a little bit about, as the incoming editor of Circulation Research, some of your vision for the Journal, which you're excited about.
Dr Jane Freedman: Mm-hmm (affirmative). Well, I'm thrilled to be the new editor of Circulation Research. And I've assembled a fabulous team of associate editors, deputy editors and other staff and support, that are going to continue to grow what's already a wonderful journal, to be the preeminent and primary journal for basic and translational cardiovascular sciences. And also support and interact with the other HA family of Journals.
Dr Amit Khera: So obviously that starts with a great team. And it sounds like you've assembled that. Anything new that you're thinking about, and sort of the redesign of Circ Research in your term?
Dr Jane Freedman: Sure. So, we're hoping to expand the original scientific content, so we can have a larger number of articles in original science. And we can have the pages to be able to handle other areas of basic cardiovascular science to include new areas, emerging areas, things like that. We're also increasing some of our early career initiatives, so that's very important to us as well.
Dr Amit Khera: Fantastic. Fantastic. Can you talk about expanding for science? And Joe, that leads to you. I'm going to, in this session tomorrow, one of the goals is when people submit their science, it really goes into a black box and people don't know what happens on the editorial level. Can you maybe enlighten us a little, what happened?
Dr Joseph Hill: Jane and I have been friends for 20 or more years and we now have established a bi-directional, mutually synergistic collaboration where we send papers each way. We have distinct missions, but yet with significant overlap. And I think it's an incredibly exciting time for the entire portfolio of AHA Journals. So as you
say, most people that you hit send and you wait four to six weeks, and you
either get a happy note or an unhappy note.
And, what happens at both our Journals is we have a strategy of multiple
touches on every paper. The paper that first comes in, is first touched by a
senior editor, either myself or James de Lemos, and two or three others. And we
will reject without review, about 50% of the papers at that point. We publish six
papers a week, but we get 110 a week. So we don't need to review 50 of them
to pick the top six.
Out of respect to our authors to save them time, out of respect to our reviewers
who devote tremendous effort to reviewing papers, we don't send them papers
that we don't think have a shot. That said, if a paper makes it past that first
stage, there's about a 50% chance it'll get published either in our Journal, or in
one of the subspecialty journals. Probably a 50-50 chance it'll be published
somewhere in an AHA family Journal.
So if it makes it past that stage, we send it to an associate editor, of which you
are one. And we have about 50 of them. A third are in Dallas, another third are
in the U.S. outside of Dallas, and another third are in countries around the
world, 17 different countries. And that person will probably reject without
review, another five or 10% maybe. But he or she will dig into that paper, and in
parallel send it out to two or sometimes three reviewers, who are trusted and
valued advisors.
They help that associate editor make a strong recommendation. He or she
makes a decision to bring to the larger group, that is informed by those
reviewers. So already that paper has been touched by five different
investigators. Typically, that associate editor will reach out electronically within
his or her affinity group. We have an affinity group in epidemiology, heart
failure, intervention, basic science.
Asking other AEs, "Could you take a look at this paper? One reviewer said this,
one said that, I'm sort of thinking this." And then we'll have a conversation on
our weekly video conference, and then a decision goes out to the authors. So
every paper is touched by at least five, and sometimes 10 different editors and
reviewers, which we have found has been a powerful way to really dig into and
identify things that one or two people might have missed.
Dr Amit Khera: One thing I note here is, if you realize how many people touch these articles, yet
how efficient and how fast this process is, then that's a testament to sort of, the
goals of the Journal, to be really responsive and rapid for our authors. One big
part of that, and come back to Dr Freedman is peer review, right? So, associate
editors have a lot of work, and were affinity groups and so forth, but really
critical are these peer reviewers. And in the modern era, we're all so busy. Tell
us a little bit about the value of peer review, and how we enhance the value to
the peer reviewers themselves.
Dr Jane Freedman: Mm-hmm (affirmative). Well, just as you said, the peer reviewers are absolutely
central, valued and vital parts of making the Journal run correctly. And we, like
Circulation, our associate editors send them out to three different peer
reviewers, and they have a very fixed amount of time to review the articles, and
they provide these wonderful comments.
We also very heavily rely on our editorial board. They know the drill, that it
needs to be back within a fixed amount of time. And for the most part, they do
it. It's an interesting question, "What's the value to them?" I've been a reviewer
too. It's part of your pay back. It's part of educating yourself about what's new
and interesting. There's a lot of reasons for doing it. People enjoy being on the
editorial board and interacting with the Journal. But fundamentally, as an
editor, you're incredibly grateful to your reviewers. They are the unsung heroes
of making a Journal work.
Dr Amit Khera: You mentioned sending out to three, when you have sort of disparate reviews.
It's amazing when some people love it and some people hate it.
Dr Jane Freedman: Yeah.
Dr Amit Khera: How do you handle that?
Dr Jane Freedman: Yeah, well, sometimes it's apparent from the reviews why that happened.
Someone may have focused on something, that the editorial group thinks is less
important. Or they have focused on something that's addressable. The other
thing we do, similar to Joe, is we have a video conference call every single week
on Wednesdays, and that's a period where people can vet any concerns or
questions. And then my editors, my associate and deputy editors know we have
an open communication at all times. So I very frequently, when they have
questions about reviews and how to reconcile disparate reviews, we'll have an
ongoing conversation about that.
Dr Amit Khera: It sounds like, of course you're actively engaged in how this is a dynamic
process. I'll mention one thing, is digital strategies editor and I know both at Circ
Research and Circulation. We're always thinking, "How do we bring these
articles to life? How do we have the most people read them or engage with
them?" And one is traditional social media. So Twitter and Facebook, which is
incredibly important. Podcast, you have a monthly podcast.
Dr Jane Freedman: Mm-hmm (affirmative).
Dr Amit Khera: We have a weekly podcast and really hope that people listen to them because
they're really full of important information. And finally, I think what people
don't appreciate is the media. So we work with the AHA media. Some of our top
stories get over a million media impressions, go all around the world and there's
Professional Heart Daily. So, there's so many ways that we're bringing articles to
life. Joe, I'm going to finish with you. This is a Circ family. The value of having a
family of Journals and how we keep cohesion, and for authors when they're
submitting to sort of a family of Journals, what's the value and how does that
Dr Joseph Hill: Well, there has been complete turnover of all the editors in chief in the entire
family of Journals, of which there are 12. And we are all quite similar in our
personalities, and in our perspectives on the importance, the ultimate
importance of validity. The first question we ask, "Is this true?" If it's not, it's
gone. It doesn't get referred. We reject it. Even if it's going to be on the front
page of the New York Times and cited 10,000 times. And all of us hold ourselves
to that same standard. So our vectors are all pointed in the same direction. We
also care about impact, not impact factor. But does it change the way you think?
Does it matter? Is it incremental, or does it really move the needle?
So we are now in a situation, I think a wonderful situation where we all sink or
swim together. We send papers all around, as you know very well. We send
papers to the subspecialty journals. We send 20 or 30 a week, on an
extraordinarily regular basis. And we send papers horizontally to Circ Research,
or Hypertension, or Stroke and so forth. So, it is a syncytium now I would say, of
a family of journals where we are all looking out for each other. Jane cares
about our Journal and we care about her Journal. And that's really a wonderful
situation to be in.
Dr Amit Khera: Well thanks. That family and how this fluidity of articles and thought and
exchanges, is really part of the value. And ultimately the goal is for a great paper
to find a great home. And I think in this Circ family we do that.
Thank you very much. It's been a wonderful podcast. Again, I'm Amit Khera,
digital strategies editor sitting in for Carolyn Lam and Greg Hundley for
Circulation on the Run, as well as for Discover CircRes. Thank you.
Dr Carolyn Lam: This program is copyright American Heart Association 2019.

Dec 16, 2019

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

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

Well Carolyn, our feature discussion, are results from the Odyssey study and they're presented by Professor Wouter Jukema from Leiden University Medical Center, regarding the relationship between ultra-low LDL levels in both ischemic and hemorrhagic stroke. The study really seeks to answer the question related to concerns that ultra-low LDL levels, less than 15 milligrams per deciliter, in patients treated for ischemic heart disease could increase the risk of hemorrhagic stroke, but more to come on that intriguing question. Carolyn, how about your first paper?

Dr Carolyn Lam: It's from doctors Condorelli and Kallikourdis from Humanitas Clinical and Research Center and Institute of Genetic and Biomedical Research respectively in Rozzano Milan in Italy. Now, these authors used single cell RNA sequencing to map the cardiac immune composition in the standard Murine non ischemic pressure overload heart failure model. They then integrated their findings using multi parameter flow cytometry, immunohistochemistry and tissue clarification immunofluorescence in both the mouse and the human. And they found that despite the absence of infectious agents or an autoimmune trigger, induction of disease led to immune activation that involved far more cell types than previously thought. And that included neutrophils, B cells, natural killer cells, and mast cells. And this really opens up the field of cardio immunology to further investigation using toolkits that have already been developed to study these immune subsets.

Dr Greg Hundley: Ah, so Carolyn, do they have any specific examples?

Dr Carolyn Lam: Hmm, indeed they did. They found that activation lead to up regulation of key subset specific molecules such as pro inflammatory cytokine onco statin M in pro-inflammatory macrophages, and PD1 in T regulatory cells. Now these are significant because they may help to explain clinical findings such as the refractivity of heart failure patients to anti TNF therapy and cardio toxicity during anti PD1 cancer immunotherapy respectively, for the more these subset specific molecules may become useful targets for the diagnosis or therapy of heart failure.

Dr Greg Hundley: Oh, beautiful. Well Carolyn, my next article is from Ambarish Pandey from University of Texas Southwestern Medical Center and it's entitled Incorporation of Biomarkers into Risk Assessment for Allocation of any Hypertensive Medication, According to the 2017 ACC, AHA High Blood Pressure Guidelines, a Pooled Cohort Analysis.

Dr Carolyn Lam: So I suppose asking does consideration of troponin or BNP inform cardiovascular risk in those with hypertension?

Dr Greg Hundley: Great question Carolyn. So in this study, the authors included participant level data from 12,987 participants across three cohort studies, ERIC, the Dallas Heart Study and MESA. And they were pooled excluding individuals with prevalent cardiovascular disease and those taking antihypertension medications at baseline. Participants were analyzed according to blood pressure treatment group from the 2017 ACC AHA Blood Pressure Guideline and those with high blood pressure, 120 to 159 millimeters of mercury, were further stratified by biomarker status.

Dr Carolyn Lam: Okay. So what did they find Greg?

Dr Greg Hundley: Participants with elevated blood pressure or hypertension, not recommended for any hypertensive medication with versus without either elevated high sensitivity, cardiac troponin T or N terminal pro BNP, had a 10-year cardiovascular incidence rate of 11% and 4.6%, with a 10-year number needed to treat to prevent one event for intensive blood pressure lowering of 36 and 85 individuals respectively.

In addition, among participants with stage one or stage two hypertension recommended for antihypertensive medication with a blood pressure less than 160 over a hundred millimeters of mercury, those with versus without an elevated biomarker had a 10-year cardiovascular incidence rate of 15.1% and 7.9% with a 10-year number needed to treat, to prevent one event of 26 individuals and 49 individuals respectively.

Dr Carolyn Lam: Wow, Greg, those are impressive numbers. So does this mean we should be checking biomarkers in everyone?

Dr Greg Hundley: Great question again Carolyn. These results suggest that a biomarker based approach to cardiovascular risk assessment may help identify high risk individuals with elevated blood pressure or stage one hypertension who are currently not recommended for any hypertensive medication, according to the 2017 ACC AHA Blood Pressure Guideline, but who may benefit from blood pressure lowering therapy. And it seems the more we research blood pressure measures, the more we learn regarding individualizing targets for blood pressure lowering.

Dr Carolyn Lam: Very interesting Greg. Thanks. So my next paper sought to understand to what extent do drug costs, which are potentially actionable factors, contribute to medication non-adherence? A very interesting and relevant question, and this is from Dr Nasir from Yale New Haven Health System and colleagues who identified more than 14,000 US adults with a reported history of atherosclerotic cardiovascular disease in the national health interview survey from 2013 to 2017. Now participants were considered to have experienced cost related non-adherence if in the preceding 12 months they reported either skipping doses to save money or taking less medication to save money or delaying filling a prescription to save money. And they used survey analysis to obtain national estimates.

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

Dr Carolyn Lam: Listen to this. So they found that one in eight patients with atherosclerotic cardiovascular disease reported non-adherence with medications due to cost, representing nearly 1.5 million estimated patients missing doses, 1.6 million taking lower than prescribed doses and 1.9 million intentionally delaying a medication fill to save costs, all in the United States. Patients less than 65 years of age, had a three fold higher rate of medication noncompliance due to cost, with significantly higher rates in women and among patients from low income families and those without health insurance. Now the take home message I think is that the removal of financial barriers to accessing medications, particularly among vulnerable patient groups, may help improve adherence to essential therapies to reduce atherosclerotic cardiovascular disease, morbidity and mortality.

Dr Greg Hundley: Great paper, Carolyn. We've got a couple other articles in this issue. Let's just run through so our listeners get a synopsis. So Dr Javed Butler from University of Mississippi Medical Center has a nice white paper regarding heart failure endpoints in cardiovascular outcome trials of SGLT2 inhibitors in patients with type two diabetes. Dr Brahmajee Nallamothu in a perspective piece, discusses issues related to the legal prosecution of stent cases and the 70/30 rule. Remember Carolyn, the 70/30 rule, the operator may say a stenosis is 70% of an intracoronary luminal narrowing, but in review, others seem to think it's less than 30% and often these cases are prosecuted for performing coronary artery interventions on these lesions, but what Dr Nallamothu argues is perhaps, these definitions are really related to how that stenosis was measured. Are you taking approximately dilated segment or a distantly dilating segment as your reference point? Really interesting perspective piece.

The next article is from Dr Prateeti Khazanie at the University of Colorado in Denver and provides an on my mind piece with Dr Mark Drazner regarding ethical issues that arise during cardiac transplant allocation process. They review some of the pitfalls associated with current physician subjective assessments used for heart transplants in the United States. Dr Neil Kay presents another EKG challenge related to T, a new wave alternans and consumption of alcohol in association with combinations of antiarrhythmic drugs. Dr Dipan Shah from Houston Methodist provides new data in a letter, a research letter, regarding the association of extracellular volume fraction and MRI measure of interstitial fibrosis in the setting of chronic mitral regurgitation.

And finally, Carolyn, Dr Nirvik Pal and colleagues write a letter referring to an earlier publication related to LVAD adverse outcomes and cardiac transplantation. Well, shall we move on to that feature discussion?

Dr Carolyn Lam: Yeah, let's do that, Greg.

Dr Greg Hundley: Welcome everyone to our feature discussion and we're very excited today to have Dr Wouter Jukema from Leiden University Medical Center who's going to tell us about the utility of PCSK9 inhibitors on the impact of both ischemic and hemorrhagic stroke. A large study that comes from the Odyssey study. Welter, we are so glad that you're with us this morning, afternoon, evening, wherever you may be in the world. Could you tell us, what were the thoughts behind putting this study together?

Dr Wouter Jukema: As we all know that patients with acute coronary syndromes, ACS, are at an increased risk for a subsequent stroke. And we also do know that lowering of atherogenic lipoproteins, including LDL cholesterol of course, reduces the risk of ischemic stroke in chronic atherosclerotic cardiovascular disease or recent ACS.

However, concerns have been raised about very low LDL cholesterol levels and the potential risk and increased risk of hemorrhagic stroke.

So the effect of lipid lowering by PCSK9 inhibition, both ischemic and hemorrhagic stroke is actually not fully determined. So what we therefore did to better investigate this is that in the obviously outcomes trial, the main publication was of course in New England Journal of Medicine already, we did a pre-specified analysis. We was designed to assess the effect of LRO come up on the ischemic as well as on the hemorrhagic stroke in patients with a recent ACS in obviously outcomes, all patients had a recent ACS and we have hypothesized that for patients treated with LRO come up that would be one, A, a reduction in risk of ischemic stroke, B, without an increase in hemorrhagic stroke. And we also hypothesize that the results would be irrespective of baseline LDL cholesterol and the history of cerebral vascular disease.

So that was our background and objectives and we investigated this in urology outcomes trial a huge, huge trial. If you may all recall post ACS patients one to 12 months post ACS, they all had a run in period two to 16 weeks of high intensity or maximum tolerated dose of atorvastatin or rosuvastatin, and then you had to meet certain lipids criteria and then you were randomized to LRO come up circuitously every two weeks or placebo. And of course all the patients and investigators were blinded to lipid levels and treatment location. So this was a design.

Dr Greg Hundley: Wouter that was a fantastic description of why we're studying this particular series of issues as both ischemic and hemorrhagic strokes.

Tell us a little bit about your study results?

Dr Wouter Jukema: We looked at the entire population of the Odyssey outcomes trial. This is almost 19000 patients and then we looked if they had a history of prior cerebral vascular disease or we have no history of cerebral vascular disease. The majority, almost 18000 did not have a history of cerebral vascular disease and over 900 did have a history of cerebral vascular disease. And we've also looked at our baseline LDL cholesterol levels. Well, if you can of course, be sure we appreciate people with history of cerebral vascular disease or way out, there are a different study population. So that's of course what you may expect anyway. And that's what we saw.

But regardless if you have the history of a vascular disease or you didn't have that, we saw a reduction of any stroke and actually it was 28% reduction of any stroke, which is quite impressive, in my opinion, as highly significant with a P value of point 0.05 and then afterwards of course, we tried to split it in ischemic stroke and hemorrhagic strokes.

So as I told you, any stroke was reduced with 28% and if you then look at ischemic stroke, it was 27%. Also significant at the P value of 0.01. And then of course, the big question, what would happen with hemorrhagic stroke. And actually this was numerically less also in the LRO come up group. So there was not only a reduction in any stroke, but also in ischemic stroke. But also in hemorrhagic stroke, but this was 17% and then of course you are in the low numbers. So the ischemic ratio for hemorrhagic stroke was 0.83 in favor of LRO come up. And of course that by itself is not significant to the low numbers, but numerically there were less hemorrhagic strokes on top of that, there were less ischemic strokes and that was, I think a very reassuring finding. And the interesting part is that these results were more or less independent.

If you have a history of cerebral vascular disease are not, so people without a price were benefiting and with a price were benefiting. And it was also statistically independent of your baseline LDL cholesterol level. So the results were basically the same. If you had a baseline LDL starting below 80 between 80 and 100 and over 100 the results were the same. LRO come up was always better than placebo. If you look at the data, you could see that it was perhaps doing slightly even better if you had a slightly higher cholesterol from the start, which is conceivable. But the formal test returned 80 did not say show any difference. So you could say the beneficial effect of other LRO come up on stroke in post ACA patients is independent of your history of cerebral vascular disease, is independent of your baseline LDL. LRO come up is just better for ischemic strokes as well as for hemorrhagic strokes at least there was no sign.

Never mind add to that, we did even go one step further and we looked at the risk of hemorrhagic stroke in relation to the HG LDL cholesterol level. So not your baseline LDL cholesterol level, but the achieved LDL cholesterol level in the LRO come up group because there you find the, of course very low numbers and we divided them and below 25 milligrams per deciliter, which we could continue really low between 25 to 15, 15 to 17 over 17 and the numbers of hemorrhagic strokes were exactly the same, always 0.1, 0.2, 0.3%. So very low. And it was certainly not the case that they do very low numbers. We saw more hemorrhagic strokes. So this is again very reassuring data. So even at very low levels of LDL during the trial. Of course we should realize that this trial is of course only a medium duration of two per date, but we didn't see more erratic strokes.

So in my opinion, this is very reassuring data.

Dr Greg Hundley: Very good. I loved all that analysis of subgroups. I want to ask you one quick subgroup question. Was there any difference in outcomes related to gender or age?

Dr Wouter Jukema: As far as we could see there was no differential effect in gender nor in age. Of course you should realize that in very advanced age, of course the numbers get small and if you then start dividing them again in the history of stroke or not, then of course the numbers will get low. But in general there is no age or gender difference.

Dr Greg Hundley: Fantastic. So where do you think, does this field progress from here and what do you think will be the next study that we need related to PCSK9 inhibitors and adverse effects?

Dr Wouter Jukema: I think we have shown now that patients with a recent ACS and dyslipidemia, despite incentive therapy, they do benefit from the PCSK9 LRO Come up, which is reflected by a decrease in the risk of stroke. You should of course realize that this is a post ACS population, so it was not targeted in a post stroke population. This is a atherosclerotic disease population, so the results are applying for an atherosclerotic population of course, many people that have a stroke in the past may have and also from embolic processes from a FIP or whatsoever, and those results may be the same but may of course they may also be different. So that situation was not tested here. This is a atherosclerotic post ACS population. Of course you may be interested in what would happen with strokes in an embolic population with a FIP and that would of course be a very nice trial to do as well. But then you have to do an entirely new trial. And some of these trials are of course underway, but I cannot, with my publication circulation, I cannot provide you with the answer.

Dr Greg Hundley: Well listeners, we've had a great discussion on our feature article today from Dr Wouter Jukema from Leiden university medical center and really some important insights related to PCSK9 inhibitors and the fact in this study, a large study, a sub study from Odyssey that indicates really no increase incidents of both hemorrhagic or ischemic stroke in patients that receive these agents and had previously sustained acute coronary syndromes.

I want to wish you all a great week and on the half of Carolyn and myself. Hope to see you next week. Take care now.

This program is copyright American heart association 2019.


Dec 9, 2019

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

Dr Greg Hundley: And this is Dr Greg Hundley from VCU health, the Poly Heart Center in Richmond, Virginia. Well, Carolyn, this week's feature analyzed a pool cohort of all patients in partner one and partner two, both the trials and registries. Patients had severe aortic stenosis and were treated with TAVR or SAVR and then were analyzed with respect to the development of prosthetic valve endocarditis. But more to come on that later.

Dr Carolyn Lam: Let me start by telling you about my picks from this week's journal. So the first one is a really interesting natural experiment. First, do you think that a short term visit to a location with severe air pollution increases the risk of cardiovascular disease?

Dr Greg Hundley: Well, Carolyn, I would say yes.

Dr Carolyn Lam: Greg, you're too smart. But let me tell you what these investigators did. So their co-corresponding authors, Dr Araujo from David Geffen School of Medicine and UCLA, Dr Zhu from UCLA Fielding School of Public Health, and Dr Qiu from College of Environmental Sciences and Engineering in Peking University. These co-corresponding authors and their colleagues did a natural experiment by collecting urine and blood samples from 26 healthy adult residents of Los Angeles before, during, and after they spent 10 weeks in Beijing during the summer of 2014 and 2015.

Dr Greg Hundley: I am really excited to hear this. Carolyn, what did they find?

Dr Carolyn Lam: So traveling from less polluted Los Angeles to more polluted Beijing induced pro oxidative and pro inflammatory effects, which reversed after returning to Los Angeles. This is also the first human study associating exposures to polycyclic aromatic hydrocarbons with changes in paraoxonase 1, enzymatic activity, and circulating levels of hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids. Cool, huh?

Dr Greg Hundley: Absolutely. Carolyn, you did an awesome job. Very nice. Well, my article comes from the world of basic science and it's from Dr Philip Shaul at the University of Texas Southwestern medical Center. So Carolyn, in recent studies of obesity induced insulin resistance in mice with corroborating findings in human type 2 diabetics, this group, Shaul’s group, previously made the surprising discovery that the insulin resistance is driven by an altered post-translational modification in IgG that leads to enhanced activation of FCYR2B in endothelial cells. And as a result, there is an attenuation of insulin transcytosis across endothelial cells and delivery to skeletal muscle myocytes where up to 80% of glucose disposal usually occurs.

Dr Carolyn Lam: Oh. Interesting, Greg. So what did the authors find in the study and how did these findings equate with obesity and hypertension?

Dr Greg Hundley: Well, they found that hyposialyation of the Fc glycan on IgG is identified as a key contributing factor in obesity induced hypertension. And therefore low levels of IgG Fc glycan sialylation may identify individuals at greater risk of developing hypertension. In addition, the degree of sialylation of IgG may predict the relative response of an individual to any hypertensive therapy.

Dr Carolyn Lam: Nice. So my next paper is from Dr Al-Lamee from Imperial College, London, and colleagues who studied the ability of a pre-randomization stress echocardiographic score to predict the placebo-controlled efficacy of PCI within the ORBITA trial. Now as a reminder, the primary results of the ORBITA trial showed us smaller than expected effect size of PCI in comparison with placebo in single vessel stable coronary artery disease on the primary end point of change in treadmill exercise time.

Now in the current study, 183 patients underwent dobutamine stress echo cardiography before randomization, and they found that the degree of ischemia assessed by dobutamine stress echo cardiography predicted the placebo-controlled efficacy of PCI on patient reported angina frequency.

Dr Greg Hundley: Hmm. Very interesting. So help me out again, Carolyn. What's the clinical importance of this?

Dr Carolyn Lam: Ah, so this study really provides the first placebo-controlled evidence of an association between stress echo cardiography, ischemia, and the magnitude of placebo-controlled benefit attributable to PCI. And the greater the downstream stress echo cardiography abnormality caused by the stenosis, the greater the reduction in symptoms from PCI. That's the take home.

Dr Greg Hundley: Oh wow. Very interesting. You know, especially we perform so many stress echo cardiograms. What a great relationship to unfold and present. Well, Carolyn, I'm going to walk through several other important publications in this issue of the journal. The first is from Dr Peter Eckman from the Minneapolis Heart Institute, and he provides an In-Depth review of veno-arterial extra corporal membrane oxygenation, or VA-ECMO, for cardiogenic shock and it's beautifully written for the busy clinician. Robert Platt, PhD, and colleagues discuss in an On My Mind piece the fact that those with adverse cardiovascular sequelae during pregnancy may require development of new cardiovascular risk prediction models. The hypertension or the diabetes that occurs during pregnancy, perhaps we need to incorporate that into our prediction models.

Next. Our own associate editor Torbjørn Omland provides results in a research letter from the peace trial relating the relationship between smoking and high sensitivity troponin T levels. Dr Allen Sniderman from McGill University Health Center writes a letter to Welsh and Associates regarding their study of the UK bio bank database and measures of HDLC. A paper we discussed just a few weeks ago. Dr Derek Chew from the DCRI and Durham North Carolina has another EKG challenge for us. And Dr Tracy Hampton provides an updated news report regarding cardiovascular disease from several recently published articles in the world of basic science. And then finally Dr Thomas Krieg from the University of Cambridge has a nice piece regarding clinical implications of targeting succinate metabolism in ischemia reperfusion injury.

Well, Carolyn, what a great slate, but I can't wait to get to that feature discussion related to prosthetic valve endocarditis.

Dr Carolyn Lam: Me too. Let's go.

Our feature discussion today is really the first paper that describes adjudicated evaluation of prosthetic valve endocarditis in patients with transcatheter and surgical aortic valve replacement. Very unique and valuable data from the partner's trial. I'm so pleased to have with us the corresponding author, Dr Wael Jaber from Cleveland Clinic as well as our associate editor, Dr Manos Brilakis from UT Southwestern. So Wael, very unique question. Could you please tell us how you went about doing this? And I suppose in this setting, the first question on everyone's mind is how did you make this diagnosis of prosthetic valve endocarditis?

Dr Wael Jaber: Actually we saw this as an opportunity that probably we should never miss. I think this is one of the rarer instances where we can objectively not only look at SAVR data but also TAVR data. And over the past maybe seven years, eight years, we started getting here as a referral center patients with TAVR endocarditis for surgery. And we never thought we'd start seeing these weird organisms, different bugs. Of course this is a population that's frail or elderly, but we never had any idea if they behave similarly to SAVR or differently than SAVR in our previous experience with SAVR endocarditis.

So we planned this actually about maybe five years ago, but we didn't have the data because you know the partner trials were undergoing another evolution by going to lower and lower risk population. So we pose this question about a year and a half ago to CRS by asking them, can you provide us with the data on all the endocarditis in partner.

The idea was not only to answer one question but to answer multiple questions. So the first question was in the modern era, what happens in SAVR? All the SAVR endocarditis information we have so far as you will know has been from mainly single center studies or even when we learn about it from multiple centers sites, usually IN European studies, the Swedish registry, the Danish registry, and these are usually limited by the fact that there are a multicenter. The adjudication is at the site what endocarditis happened. So that was the first question. Then the second issue for us was, does TAVR, because of the unusual access to the heart and the fact that we dilate the valve, post dilate the valve, their paravalvular AI, they could be micro-fractures of the refis. This is provide a different opportunity for these bugs to form on the valve, and do they behave differently?

And the third question was, is there any difference between SAVR and TAVR incidence of endocarditis? And bugs. And the final question was what happens to patients when they develop endocarditis in the current decade. Do they do well? Especially for septic endocarditis or do they succumb to their illness? And also this is how we came up with a strategy to answer all these questions.

Dr Carolyn Lam: Very nice. So Wael, could you just expand a little bit more about how the diagnosis or adjudication of prosthetic valve endocarditis was done? And then tell us please, what did you find?

Dr Wael Jaber: All the partner patients, the records were sent to a central place. So the ECHOS first were educated at central places. We were one of those centers. Other places were Columbia University, MedStar and Quebec, the group in Quebec. So all the ECHOS were adjudicated centrally. So that's first, as far as from the echo side of calling it endocarditis or not.

On the clinical side, again, all the records and the forms were sent to a central adjudication committee, CDC group. We served at the Cleveland Clinic as the CDC for most of these trials and actually even for the current trials. So they were sent and they were adjudicated according to the Duke criteria. Which is, you know, the most, probably, reliable way still today to adjudicate these.

And then there was the CDC and the echo core labs were separate. So the people who have information from the CDC did not have access to what's going on in the core lab and vice versa. So these were independently adjudicated as far as echocardiographic evidence and clinical evidence. And then they were fed into it. So by the end, when you hold it on a Duke criteria endocarditis, the echo was fed after the fact, not before. So this is in general how it happened. So all the events were educated centrally, not at the site. And the ECHOS, the same thing, were adjudicated centrally.

Dr Carolyn Lam: Fantastic. And I would love to hear the results.

Dr Wael Jaber: The first question was, what's the incidence of endocarditis? And we decided because of the way these trials were done, to report the incidents as you would see in the results section, to report the incidents of endocarditis per 1000 person year because of the imbalances in follow up and the competing risk for death from other reasons. So we found in general that the incidents of endocarditis was 5.2 endocarditis events per 1000 patients per year in the TAVR side and 4.1 in the SAVR side with a non statistically significant difference. More importantly, we found out that once you develop endocarditis, unfortunately most of these patients succumb to the illness and are dead after the diagnosis. So the risk of dying after developing endocarditis is 4.4 times higher than patients who did not have endocarditis in the trials. In all the trials.

Now there's some caveats here. First, these are trials with different patient populations, as you well know. Starting with partner with the inoperable patients moving on to the most modern S3 trial, which was on the lowest kind of side of population. So we have totally different population groups. Some of them had prolonged hospitalizations before and after, so this should be taken with a little bit of caution.

However, if you look at some of the individual trial data, we found that incidents of endocarditis at least have a trend towards a reduction of incidence of endocarditis over time going from partner, the initial experience with partner, all the way to the modern era.

Dr Carolyn Lam: That is so great. Manos, you know, as an interventional cardiologist yourself, could you tell us how important these results are? Does it affect your practice?

Dr Emmanouil Brilakis: Thanks again, Carolyn. I would like to congratulate Wael for a phenomenal paper. I think it's a very timely study and addresses one of the common concerns there is about whether TAVR does predispose people to more risk for endocarditis. Although again, the opposite grade was kind of low at 0.5% a year. I think this may be a little more than people are commonly seeing in the setting of TAVR, and I think the paper is a good reminder that this is something we should always be mindful and watching. Although typically we'll discuss with the patient about the risk of stroke or access complications, but the risk of infection may not be as well emphasized. And based on this one question I would have is about what can we do if there is something that could potentially lower that risk? I understand the limitations of retrospective study, but are there any recommendations that you have based on the study? Should give more aggressive antimicrobial therapy? Any other biotic prophylaxis or anything else that can be done to reduce the risk of endocarditis in those patients?

Dr Wael Jaber: Actually this is the question we raised. Unfortunately we did not. So the guidelines did not catch up with what we know. So if you look right now, like I was reviewing this paper that came up last month from the Swedish Registry for Endocarditis, it came out in Europe in the European Heart Journal, and one of the questions they raised is how to address, in the editorial, how to address the risk of endocarditis and prophylaxis in this population. There are no standards for that. This is one aspect of it. We need first an update of the guidelines of how to address this issue.

The second question is we do not have any idea, unfortunately, about duration of antibiotics. How the antibiotics prophylaxis were given before the procedure, like as we do right now commonly in surgery, and after the procedure in these patients. We do not know that. Like right now, at least at our center, if you go in for aortic or mitral valve surgery or any valve surgery, you have to have a dental clearance before you start, before you go to surgery. I don't know if this was rigorously applied in the setting of TAVR, and I think it would be a good idea to apply it to make sure that there are no dental, phosphide or potential infections and things like that. So I think it's a multi-front battle to get these patients to the lowest risk possible. I don't think there's one single silver bullet here.

Dr Emmanouil Brilakis: So thanks again, Wael for addressing this. I agree that there's a lot of information to be gained understanding the intricacies of endocarditis prophylaxis. And building on this, let's say another patient develops endocarditis as you've shown in your 170 patients in the study. It was fascinating that staph aureus was actually less common than it was for surgical valves, which has been shown in other studies as well. So you think this affects the choice of the biotic prophylaxis? And then also if the patient develops endocarditis, I understand many people who are not candidates for surgery, but from the ones who did actually undergo surgery, what are the outcomes encouraging?

Dr Wael Jaber: This is a fascinating question actually. This is one of the reasons we had... There was a delay for us in getting the paper out from when we presented it as an abstract at TCT a year and a half ago, is we didn't know. We wanted to answer that question. The second part of the question is how many patients went to surgery? And unfortunately, very few patients. So less than a handful of patients end up going to surgery. And we do not know why. So this is the dilemma here. Is why the rate of referral to surgery for redo surgery was very low.

Was it because these patients were the sickest of the sick? Maybe it is because we waited too long and we did not treat them the same way. We should have treated prosthetic valve endocarditis, which is surgery to be offered as soon as possible because there's no really antibiotic cure for that. So we do not have the answer for that because these very few patients went to surgery and actually I think of those who went to surgery, even the mortality there even was similar to people who did not go to surgery. But we cannot speculate on that because the very few patients.

As far as the bug involved, I think this could be a reflection of the antibiotics given at the time of the procedure, so probably we're covering that very well. But if you notice from the paper, most of the infections happen more than 30 days after the procedure. Whether this is something that was acquired because these patients are more likely to end up in the hospital again for other reasons, whether these patients had endocarditis because they have more instrumentation down the road... Remember this is a population in general above the age of 65 which would require colonoscopies, frequent urinary tract issues, and other procedures.

So we know that we're covering very well, at least I can speculate, we're covering very well for the first 30 days because very few patients had endocarditis right after the procedure, but we're not covering probably after the 30 days. And that remains to be studied. And the worrisome thing is to try to treat these patients with prophylactic antibiotics for a long time and then end up with bug resistance and things like that. Now the CDC issued a big warning about this yesterday. I am not comfortable to speculate from this small number of patients on how to treat for prophylaxis, but I'm comfortable to say probably patients should be sent to surgery as soon as possible after developing endocarditis, especially prosthetic valve endocarditis because the outcomes are dismal.

Dr Emmanouil Brilakis: And do you think... Let's say patient is not a candidate for surgery and gets endocarditis, and I presume they get into prolonged therapy. There were some patients like this that did okay, right? So there is some hope even for those patients.

Dr Wael Jaber: I feel like I'm the cup half full here because if you look at the mortality curves here, we're talking about north of 95% death in this population. So the people who survive this must be very few people survive. So probably about seven patients who survive. So the mortality was 96% at six months versus 46%. So there are very few people who survived that event. Maybe I should go back now and figure out what was the quality of life after survival. So I don't think the picture we have right now is very rosy as far as the way we're managing endocarditis.

Dr Carolyn Lam: Manos, I'm going to give you the final parting words from this very interesting discussion. I mean what do you think are the take home messages and future directions from here?

Dr Emmanouil Brilakis: I agree that this is a phenomenal landmark study and my key takeaways are the same ones that Dr Jaber presented before. But the main thing is, on the consent process, who can tell the patients there is about 0.5% per year. So it's not zero, but it's very high either. The second thing is that this choice between TAVR versus SAVR, that should not have to do with the risk of infection because as it was shown very convincingly, it was very similar to the two groups. And number three that everything possible should be done to prevent this because if you do get infection, the outcomes are not very good.

Dr Carolyn Lam: Thank you so much Manos, Wael. Thank you so much audience for joining us today. You've been listening to Circulation on the Run. Tune in again next week.

This program is copyright American Heart Association 2019.


Dec 2, 2019

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

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

Dr Carolyn Lam: You know what, Greg, I may have a hoarse voice today and I'm a little bit scratchy, but my goodness, I couldn't be more excited about this issue. It's the TCT issue.

Dr Greg Hundley: Well Carolyn, I cannot wait to discuss with our listeners the feature article that compares Apixaban and a P2Y12 inhibitor without Aspirin, versus regimens with Aspirin in patients with AFib who have ACS, whether managed medically or with PCI, or also those undergoing elective PCI that experience regimens that include vitamin K antagonists, aspirin, or both, but more to come later. Carolyn, should I start with my first discussion article and we grab a cup of coffee?

Dr Carolyn Lam: You bet, Greg.

Dr Greg Hundley: So my first article is from Seung-Jung Park from the Asan Medical Center at the University of Ulsan College of Medicine. So Carolyn, here's our first quiz question. In terms of Ticagrelor, have studies been performed in those from Asia evaluating bleeding risk?

Dr Carolyn Lam: You know, I have to admit, Greg, I'm not totally familiar with the literature, but I do know that it's a very important question for us practicing in Asia. We have a perception that the bleeding risk, especially intracranial bleeding, may be higher in Asians.

Dr Greg Hundley: Absolutely. Well, in this multicenter trial, 800 Korean patients hospitalized for acute coronary syndromes with or without ST elevation, and intended for invasive management, were randomly assigned to receive in a one to one ratio, Ticagrelor with a 180 milligram loading dose, and then 90 milligrams twice daily, or Clopidogrel with a 600 milligram loading dose and 75 milligrams daily thereafter, and the primary safety outcome was clinically significant bleeding, which was a composite of major bleeding or minor bleeding according to the PLATO outcomes criteria at 12 months.

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

Dr Greg Hundley: Well Carolyn, at 12 months, the incidence of clinically significant bleeding was higher in the Ticagrelor group than in the Clopidogrel group. So it was 11.7% versus 5.3, and that included major bleeding and fatal bleeding. They were also higher in the Ticagrelor group. The incidents of death from cardiovascular causes, myocardial infarction or stroke, was not significantly different between the Ticagrelor group and the Clopidogrel group, although there was a strong trend toward a higher incidence in the Ticagrelor group with a P value of 0.07. So consequently, Carolyn, these results identified safety concerns regarding bleeding complications of standard dose Ticagrelor in East Asian, Korean patients with acute coronary syndromes, and therefore large adequately powered randomized trials are needed to determine the optimal antithrombotic regimen in this patient population.

Dr Carolyn Lam: Very important data for our patients, as is this next paper, which really examines the cost effectiveness of transcatheter mitral valve repair versus medical therapy in patients with heart failure and secondary mitral regurgitation. Now, these are results from the COAPT trial. As a reminder, the COAPT trial demonstrated that edge-to-edge transcatheter mitral valve repair using the MitraClip resulted in reduced mortality and heart failure hospitalizations and improved quality of life when compared with maximally tolerated guideline directed medical therapy in patients with heart failure and three to four plus secondary mitral regurgitation.

In the current paper, first author Dr Baron from Lahey Hospital and Medical Center in Burlington, Massachusetts and St. Luke’s Mid America Heart Institute in Kansas City, as well as corresponding author Dr Cohen from University of Missouri, Kansas City, and their colleagues used data from the COAPT trial to perform a formal patient level economic analysis of the COAPT from the perspective of the US healthcare system, and they found that although the follow up costs were lower with the MitraClip compared with guideline directed medical therapy, and lower by more than $11,000 per patient. However, the cumulative two year costs remain higher by about $35,000 per patient with the transcatheter mitral valve repair, and this is all due to the upfront costs of the index procedure. Now when in trial survival, health, utilities, and costs were modeled over a lifetime horizon, transcatheter mitral valve repair was projected to increase life expectancy by 1.13 years, and quality adjusted life years, or QALYs, by 0.82 years at a cost of $45,648, yielding a lifetime incremental cost effectiveness ratio, or ICER, of $40,361 per life year gained, and $55,600 per QALY gained.

Dr Greg Hundley: Very interesting. So how do we interpret these results for clinical practice?

Dr Carolyn Lam: Ah, good question. So in order to place this in context, perhaps the most comparable case is the use of transcatheter aortic valve replacement, or TAVR. So based on the partner 1B trial, the ICER for TAVR, compared to medical therapy, was $61,889 per QALY gains. So this is very similar to what you just heard as the ICER for the transcatheter mitral valve repair. The cost effectiveness is also comparable for other commonly used treatments such as the implantable cardiac defibrillators for biventricular pacing, and was interestingly substantially more than the cost effectiveness of continuous flow LVADs, for example, and this is really discussed in a beautiful editorial by Dr Bonow, Mark, and O'Gara, and in this editorial, I think it's really important that they say the cost effectiveness projections really need to be placed in the context of continuing uncertainties regarding the interpretation of COAPT compared to that of the MITRA-FR trial, which reported no benefit of transcatheter mitral valve replacement compared to medical therapy, and so they warn that the current cost effectiveness analysis is not a carte blanche for interventional cardiologists to dramatically escalate their use of MitraClip procedure, and the data do support the thoughtful and deliberate use of this potentially life lengthening procedure in carefully selected patients and under very careful circumstances. You've got to read their editorial.

Dr Greg Hundley: That sounds excellent, Carolyn. I really like that, putting that editorial that puts that data in perspective. Well, my next study really emanates from the ABSORB III trial, and it's from Dr Dean Kereiakes at the Christ Hospital Heart and Vascular Center. The manuscript addresses the long-term cardiovascular event rates among bioresorbable vascular scaffolds and drug eluting metallic stents.

Dr Carolyn Lam: Greg, remind me, what were the results of the original ABSORB trial?

Dr Greg Hundley: Right, Carolyn. So the ABSORB III trial demonstrated non-inferior rates of target lesion failure, cardiac death, target vessel myocardial infarction, or ischemia driven target lesion revascularization at one year with the bioresorbable vascular scaffolds compared with cobalt chromium everolimus-eluting stents, but between one year and three years, and therefore the cumulative to 3 year time point, the adverse event rates, particularly for target vessel myocardial infarction and scaffold thrombosis, were increased with this bioresorbable vascular scaffold.

Dr Carolyn Lam: Ah, I see. Okay, so this current study evaluated the outcomes from three to five years beyond the implantation?

Dr Greg Hundley: Exactly. So what this study did is they looked at an interval of time between three and five years out, and they found reductions in the relative hazards for the bioresorbable vascular scaffolds compared to the common coated stents, and that particularly occurred for target lesion failure, either cardiac death or target vessel MI or ischemia driven target revascularization when compared to the earlier zero to three year time period. So therefore Carolyn, the authors conclude that improved scaffold design and development techniques to mitigate that zero to three year bio resorbable vascular scaffold risk may enhance the late benefits that one sees in this three to five year time point, because of the complete bioresorption.

Dr Carolyn Lam: So that's interesting Greg. Well, my next paper is kind of related. It is the first report of a randomized comparison between magnesium based bioresorbable scaffold and sirolimus-eluting stent in this clinical setting of STEMI with one year clinical and angiographic follow-up. So this study is from the Spanish group, Dr Sabaté and colleagues from the Interventional Cardiology Department and Cardiovascular Institute in Barcelona in Spain, and they found that at one year when compared to the sirolimus-eluting stent, the magnesium based bioresorbable scaffold demonstrated a higher capacity of vasal motor response to pharmacological agents, either endothelium, independent or dependent, at one year. However, the magnesium based bioresorbable scaffolds were also associated with a lower angiographic efficacy, a higher rate of target lesion revascularization, but without thrombotic safety concerns.

Dr Greg Hundley: Wow, Carolyn, very interesting, and Dr Lorenz Räber and Yasushi Ueki wrote a very nice editorial on this whole topic of bioresorbable scaffolds, and they wonder about some of the unfulfilled prophecies. Great for our readers to put these two articles together. Now, how about in that mailbox, Carolyn? What have you got in there?

Dr Carolyn Lam: First there's a research letter by Dr Kimura entitled Very Short Dual Antiplatelet Therapy After Drug-eluting Stent Implantation in Patients with High Bleeding Risk, and that's insights from the STOPDAPT-2 trial. There's another research letter by Dr Lopes entitled The Hospitalization Among Patients with Atrial Fibrillation and a Recent Acute Coronary Syndrome, or PCI, Treated with Apixaban or Aspirin, and that's insights from the AUGUSTUS trial. A very interesting perspective piece by Dr Rob Califf entitled The Balanced Dysfunction in the Health Care Ecosystem Harms Patients, a really, really interesting read, especially those working in the U.S. healthcare system. An ECG challenge deals with fast and slow, long and shorter. I would love to give you a clue to what it is. It's got to do with the atrial ventricular nodes, but I'll let you take a look and test yourself. There’re highlights from the TCT by Drs Giustino, Leon, and Greg Stone, and finally there's Highlights from the Circulation Family of Journals by Sara O'Brien.

Dr Greg Hundley: Very nice, Carolyn. Well, I've got just a couple reviews. Richard Whitlock in a primer provides a nice historical review of anticoagulation for mechanical valves. How do we get here in anticoagulating this particular patient population? Next, Dr Mark Brzezinski from Brigham Women's Hospital in the Harvard Medical School in an on my mind piece provides very elegant figures, beautiful figures, demonstrating inadequate angiogenesis within the fibrous cap of atherosclerotic plaques, and indicates this could be a source or thought of as a contributing factor toward plaque rupture. What an issue, and I can't wait to get onto that featured discussion.

Dr Carolyn Lam: For our featured discussion today, it is a super-hot topic, and a question that comes up again and again in clinical practice. What is the right antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome, not just those treated with PCI, but also in those treated medically? Well guess what? We're going to have answers right here. I'm so pleased to have with us Dr Renato Lopes, who's a corresponding author from Duke Clinical Research Institute and our associate editor, Dr Stefan James from Uppsala University in Sweden. Wow. Very, very important question here. Renato, could you just start by outlining what is the AUGUSTUS trial?

Dr Renato Lopes: The AUGUSTUS trial was basically one of the four trials trying to give an answer, or help answering about the antithrombotic therapy in patients with anti fibrillation and/or NACS and/or PCI. So in other words, this combination of patients undergoing PCI who require antiplatelet therapy and also patients with AFib who requires anticoagulation therapy, and in summary, what the AUGUSTUS trial did was randomize patients to Apixaban versus VKA, or aspirin placebo in a double blind fashion, and this was a two by two factorial design. So these were basically the two questions that we wanted to answer. Is Apixaban better than VKA, and is it safe to drop aspirin from this treatment strategy? Remembering that everybody received a P2Y12 inhibitor for at least eight months. So this was basically the design of the AUGUSTUS trial, trying to answer two questions in the same study, a two by two factorial design.

Dr Greg Hundley: Very, very nice. And Renato, if I could, I mean I said it in the intro, but may I make sure I got it right. This is the only trial in the field that included patients with ACS that was managed medically. So that's a very important group of patients that we still don't know what the best regimen is, is that right?

Dr Renato Lopes: That is correct. The other trials, the PIONEER, the RE-DUAL PCI and the VPCI, they only included patients undergoing PCI, and when we designed the trial, we thought that it would be important to also include the whole spectrum of ACS, including not only the PCI treated patients, but also the medically managed patients.

Dr Greg Hundley: Well, super. So could you tell us now what were the results?

Dr Renato Lopes: So first, in terms of the breakdown, we found that the breakdown of the PCI, ACS versus elective PCI, was really nice. We had about 60% of the trial being ACS patients, and about 39%-40% elective PCI, and then within the PCI, I think that our results pretty much reflect practice in a lot of parts of the world, which was about 39% medically managed and about 61% PCI treated patients. So to begin with, I think a very nice breakdown that gives us power to look at these three separate groups: ACS medically managed, ACS PCI treated, and also elective PCI, which allows us to understand the whole spectrum of coronary disease in patients also with AFib, and in summary, what we showed for the primary endpoint, which was clinical major or relevant non-major bleeding. Let's start with the Apixaban versus VKA comparison, and we show that Apixaban was safer than VKA in all three groups, in the ACS medically managed, in the PCI treated patients, and also in the elective PCI patients.

There was no significant direction for those three subgroups, although it was borderline 0.052, just showing maybe a little bit less pronounced results in the elective PCI group, but nonetheless, I would say that in general, very consistent, and in terms of Aspirin for the primary endpoint, also no difference, no interaction among those three groups. In other words, as we increase substantially the risk of bleeding about two folds in all the three groups, ACS medically managed, PCI treated patients, and elective PCI patients, with about again, two fold increase in bleeding compared to placebo. If we go to ischemic events, again, that's our hospitalization and other that are ischemic events. In terms of Apixaban versus VKA, the results were very consistent with the overall trial among these three groups, and in terms of as ACS versus placebo, the results also for the ischemic events were also similar among the three groups. So again, reassuring that the main results of the trial were very consistent, regardless how patients were managed in terms of the ACS, medically or through PCI, and also included in the elect PCI group.

Dr Carolyn Lam: Thank you for explaining that so well. Stephan, I would love for you to take us under the hood. What were the editors thinking when we saw this paper, why we're highlighting it now, and what do you think are the implications?

Dr Stefan James: The AUGUSTUS trial was unique in many aspects. I think Renato highlighted a few of them. As he told, there have been several similar trials without the other DOAX, factor 10A inhibitors and the dabigatran, but the AUGUSTUS trial was larger. It includes, as you mentioned previously, patients with ACS and medical management, and it also was designed as a two by two factorial design. So it actually asks two different questions and made two different randomizations, both anticoagulation with the two different agents, Warfarin versus Apixaban, but also Aspirin versus placebo, and so it's possible from this trial to understand more of the different aspects of treating patients, these complex patients with atrial fibrillation, NACS or PCI, and gave the study group and us an opportunity to better understand all these complexities. So with that, I'd like to turn to Renato and try to, with that background that I just outlaid, and you just try to make us understand what are the clinical implications of these aspects of the trial and the treatment of Apixaban and Aspirin in these patients?

Dr Renato Lopes: I think we were in the area that we desperately needed randomized data, because basically until five years ago, the standard of care of treating these patients was the classic triple therapy with Aspirin, Clopidogrel, and Warfarin, and this was based on no randomized trials and all observational data, and we know how problematic this is, and this field has evolved tremendously almost year after year since the PIONEER trial, since the RE-DUAL trial, and this year, we had AUGUSTUS and ENTRUST and I think now, as Mike Gibson used to say, that we have about 2.8 million different combination of antithrombotic strategies to treat these patients because we have different anticoagulants, different anti-platelets, different doses, different durations, different types of stents, which makes it really impossible for physicians or for any guidelines to contemplate all these options. So we really needed a few trials to at least try to give a few options that are evidence based and not just based on low quality of data, and I think now, if you look at the Augustus results, and the totality of the data from all these trials, which now is about almost 11,000 patients all together, actually almost 12,000 patients all together.

I think that what we know today is that yes, the initial period in hospital for some time it's important to use Aspirin. I think this is an important point to highlight, Stephan, that Aspirin still needs to be used for the acute treatment, and I would say at least for the first few initial days while patients are still in the hospital, but then by the time of discharge, which sometimes might be five days, six days, seven days, I think that now the totality of data show that it's reasonable to drop Aspirin for most patients.

So based on the AUGUSTUS results, what we show is that if you're going to use anticoagulation as Apixaban at the dose that is approved for stroke preventions in atrial fibrillation, combined with a P2Y12 inhibitor without Aspirin after the initial period, you have the best outcomes in terms of lower rates of bleeding, lower rates of hospitalizations, and we don't have to pay a cost in terms of ischemic events when we actually drop Aspirin and keep only the NOAC, in this case was Apixaban, plus a P2Y12 inhibitor, which most of the time was Clopidogrel, and here with AUGUSTUS, we basically show that this is true for patients with AFib and ACS, irrespective of the management with medical managing, with medical therapy, or with PCI. So I think that's an additional piece that that is true irrespective of how we're going to treat your ACS patient, or if the patient basically underwent elective PCI, and I think we learned today that the classic treatment therapy of VKA plus Aspirin plus P2Y12 inhibitor, so in other words, the triple classic triple therapy should generally be avoided.

Dr Stefan James: Thank you Renato. I think that that was a very complete answer in this complex arena. I'd like just to mention that of course the AUGUSTUS, as well as the other trials, have their limitations, as all trials. Although it was large, it was powered for safety, for bleeding events, and it was not powered for ischemic events. Having said that, we still want to look at ischemic events and clinical outcomes, and to what degree do you think we can do that? What conclusions can we draw from an ischemic point of view because of the fact that the trial was underpowered for that interpretation?

Dr Renato Lopes: That is a great question, Stephan, and in fact, if we look at events like stent thrombosis, they are very rare, and if you really want to attack a significant difference between Aspirin versus placebo in patients having stent thrombosis, we're really going to need a trial with about 30-40,000 people, which would be not feasible and not doable. So we need to be cautious when we analyze those events in the power trial for ischemic events. Nonetheless, there was a signal, if you look at all trials, and even in the meta-analysis that we published recently, that dropping Aspirin probably increased the risk of ischemic events, not in a statistically significant fashion, but nonetheless, this trend exists. The signal exists. So probably keeping Aspirin, add some protection for ischemic events, primarily stent thrombosis and myocardial infarction. The problem is a tradeoff. The problem is that the cost of adding aspirin is too high.

So now the question to us, Stephan, is to look further into our data and in the combined data sets that we're trying to work with the other authors and try to identify, okay, Aspirin really increased the risk of bleeding, but is there a group of patients who might benefit from a little bit longer Aspirin? So that's the first question. Who are those patients? May be complex PCI, maybe bifurcation lesions, maybe multiple lesions, multiple stents, and second, if we decide to give Aspirin longer, how much longer should we give? Because again, the cost is very high in terms of bad bleeds. So we are trying now to identify what is the trade off, and who most benefit from keeping Aspirin longer, and for how long in a way the cost might be worth it to pay in exchange of potentially save some ischemic events? And with that, we can further refine the treatment that I think I highlighted before. For most patients, I think what I said before is probably reasonable. We can drop Aspirin by the time of discharge after a few days, but for a few patients, for some patients, it might be wise to keep Aspirin a little bit longer, and we are trying now to identify first, who those patients are and second, form how much longer should we keep Aspirin, since the 40,000 patient trial is very unlikely to happen.

Dr Stefan James: I like his interpretation, Renato, although I wanted to highlight that there are limitations, I think this trial is extremely informant for clinicians. We learned a lot how to treat these very complex patients with complex treatments.

Dr Carolyn Lam: No, I couldn't have agreed more. I mean quoting Mike Gibson, 2.8 million combinations. Well, at least we've talked about some of them here and had a very clear take home message, although with the caveats that we were discussing. Thank you so much, Stefan and Renato. This was really a great discussion, and thank you audience for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week. This program is copyright American Heart Association 2019.


Nov 25, 2019

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

Dr Greg Hundley: And I'm Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature article really starts to look at micro-circulatory dysfunction and abnormal coronary perfusion during exercise that can be associated with myocardial ischemia. I hear you're anxious to hear about it, but why don't we go to your article first.

Dr Carolyn Lam: Here we go. This first paper I'd like to tell you about reports a novel cardiac kinase as a potential regulator in heart failure.

Dr Greg Hundley: Now remind me, Carolyn, I got to take me back a little bit. What are cardiac kinases?

Dr Carolyn Lam: Ah, I thought you would ask. Cardiac kinases are known to play a critical role in the development of heart failure and represent potential trackable therapeutic targets. Now to identify novel cardiac kinases involved in heart failure, the corresponding authors, Dr Hind Lal from University of Alabama at Birmingham and colleagues, employed an integrated transcriptomics and bioinformatics analysis and identified homeodomain-interacting protein kinase 2 or HIP kinase 2, as a novel candidate kinase. Now this is the first study to define the role of HIP kinase 2 in cardiac biology. In essence, they performed a series of mouse experiments that showed that cardiac HIP kinase 2 expression is elevated in adults compared to embryonal and neonatal stage of mouse experiments, but down regulated in failing hearts.

Deletion of HIP kinase 2 in the cardiomyocytes led to decreased cardiac function in adulthood. The cardiac effect of HIP kinase 2 correlated to its gene expression level and impaired ERK signaling was discovered as the main driver of HIP kinase 2 deficient phenotype by enhancing apoptosis. Taken together these findings really suggest that cardiomyocyte HIP kinase 2 is required to maintain novel cardiac function via ERK signaling.

Dr Greg Hundley: All right, Carolyn, my favorite question, what does this mean for us clinically?

Dr Carolyn Lam: Two points, first since HIP kinase 2 is protective in cardiomyocytes, gene therapy using HIP kinase 2 could be a potential therapeutic method of heart failure treatment in future. Secondly, because inhibition of HIP kinase 2 has been proposed as a therapeutic approach for certain cancers and for renal fibrosis, these results suggest that caution needs to be taken for the potential cardiotoxicity of HIP kinase 2 inhibition in the adult heart. Interesting.

Dr Greg Hundley: Yeah. Very nice. Well, I'm going to switch gears a little bit Carolyn and talk about ablation for atrial fibrillation. And the corresponding author of this paper is Jason Andrade from Vancouver General Hospital. In his study, they randomly assigned 346 patients with drug-refractory paroxysmal atrial fibrillation to A, contact force guided RF ablation, B, four-minute cryoballoon ablation or C, two-minute cryoballoon ablation and they followed the patients for 12 months. Now the primary outcome was time to first documented recurrence of symptomatic or asymptomatic atrial tachyarrhythmias, whether that be AFib, aflutter, atrial tachycardia, between days 91 and 365 after the ablation or a repeat ablation procedure at any time. And the secondary endpoints included freedom from symptomatic arrhythmia and AF burden.

Dr Carolyn Lam: Interesting clinical question. What did the results show?

Dr Greg Hundley: One-year freedom from atrial tachyarrhythmia defined by continuous rhythm monitoring, was 54, 52 and 52% with each of those therapies respectively. One-year freedom from symptomatic tachyarrhythmia defined by continuous monitoring was 79, 78 and 73% with those therapies respectively. No difference statistically in either.

Dr Carolyn Lam: Right. No significant difference in those outcomes but what about AF burden or side effects?

Dr Greg Hundley: Right, Carolyn. Well, compared to the pre-ablation monitoring period, AF burden was reduced by a median of 99%, 99.9% and 98.4% in each of the three therapies. No significant difference. And serious adverse events occurred in two patients in the CF-RF group, in six patients in Cryo with four minutes and in seven patients with Cryo in two minutes. Again, no significant difference between those groups.

Dr Carolyn Lam: Greg, were there any significant difference in these techniques?

Dr Greg Hundley: Well, Carolyn, that contact force RF group at a significantly longer procedure duration but a significantly shorter fluoroscopy exposure. And the P was 0.001 versus the cryoballoon group. In summary, in this multicenter, randomized, single blinded trial, contact force RF ablation, and two different regimens of cryoballoon ablation, resulted in no difference in one-year efficacy, which was 53% by time to first recurrence, but 98% burden reduction as assessed by continuous cardiac rhythm monitoring. A new study in patients with ablations looking at these new techniques and for many reasons they're very similar.

Dr Carolyn Lam: Very interesting. My next paper also has to do with atrial fibrillation. Now we know that numerous skills exist for classification of major bleeding events in patients with atrial fibrillation who are anticoagulated. Now there are limited data comparing the most commonly used bleeding scales within a single at-risk cohort of patients with atrial fibrillation. And so Dr Bergmark from the TIMI study group and colleagues analyzed bleeding outcomes according to the ISTH, TIMI GUSTO and BARC bleeding scales in the ENGAGE AF-TIMI 48 trial of edoxaban versus warfarin. And they found that among patients with atrial fibrillation at risk for stroke, there was an approximately four-fold difference in the frequency of the most severe bleeding events across these commonly used bleeding scales. Further, the relative safety of edoxaban as compared with warfarin tended to increase with greater severity of bleeding.

Dr Greg Hundley: Interesting Carolyn. Tell me, what's the take home message from this study?

Dr Carolyn Lam: This analysis reminds us that the currently available and commonly used bleeding scales differ in important ways. The analysis shows us that one size does not fit all and that the most appropriate bleeding scale really depends on the clinical setting and the intervention being investigated. For patients particularly concerned about bleeding, these results should provide additional reassurance about the safety of the DOX. Finally, this analysis also illustrates how the differential effect of edoxaban compared to warfarin on bleeding, impacts the assessment of net clinical benefit. Now this is discussed in an editorial by John Alexander and Adam Nelson who highlight that one of the most interesting findings was the statistically significant and graded amplification of edoxaban safety compared to warfarin with more severe bleeding.

Greg, perhaps now's a good time, tell us what else is in this issue of the journal?

Dr Greg Hundley: Happy to do so. Ben Freedman from the University of Sydney discusses in a white paper concurrent thoughts from the AF, another atrial fibrillation paper, AF screen international collaboration, which summarizes existing evidence and knowledge gaps on searching for an AFib post-stroke using ECG monitoring. And Carolyn, our own James de Lemos suggests in an on my mind piece that subdividing type two MI into different based on etiology could lead to improved forecasting of events. In a perspective article, Tommy Wang from Vanderbilt revisits the polypill and discusses why we need population-based approaches in the precision medicine era.

Dr Carolyn Lam: Wow. Super interesting. And how about letters? What's in the mailbox?

Dr Greg Hundley: Oh gosh, Carolyn. It's really full this week. There are multiple letters ranging from science, to responses, to prior inquiries. It is really interesting to read these responses and the authors going back and forth and having that open discussion for us. And so Brody Slostad first has his own research letter that reviews unicuspid aortic valves, the demographics, comorbidities, and echocardiographic features and long-term outcomes. Darren Casteel from UC San Diego discusses blood pressure lowering by the antioxidant resveratrol is counterintuitively mediated by oxidation of the cyclic GMP dependent protein kinase. And there's a nice response by Dr Joseph Burgoyne from Kings College London. Finally, there's a letter by Daxin Wang and his associates from Yangzhou University regarding the article targeting filament A reduces macrophage activity in atherosclerosis and there's a corresponding response from Levent Akyürek event accurate from the Institute of Biomedicine. Great mailbox this week, Carolyn. How about now we go on to our feature discussion?

Dr Carolyn Lam: Oh boy, I can't wait. Thanks Greg.

How does coronary microvascular dysfunction relate to exercise physiology or inducible myocardial ischemia? Well, we are going to be talking all about that in the next few minutes and that's because our feature paper this week is the first study to really directly assess coronary blood flow during exercise in patients with microvascular dysfunction. And to compare these changes with high resolution perfusion imaging. We're really pleased to have with us the first and corresponding author, Dr Divaka Perera from Kings College London, as well as our associate editor Dharam Kumbhani from UT Southwestern. Welcome gentlemen and Divaka. Could you start by telling us what makes your study unique? What did you do? What did you find?

Dr Divaka Perera: As you said, microvascular dysfunction is being recognized as quite a common cause of angina. In fact, about 40% of patients who present to the Cath lab for a diagnosis of angina are found to have nonobstructive coronary artery disease, and a significant proportion of these are thought to have microvascular dysfunction. The definition of microvascular dysfunction has been based on demonstration of impaired coronary flow reserve, but what we haven't known is whether the Cath lab measurements that are made actually correlate with exercise maladaptation. Bearing in mind that these patients experience symptoms during exercise and whether there's actually demonstrable ischemia in these patients who don't have obstructed coronary artery disease. Our study's unique in that we were able to measure directly exercise physiology during cardiac catheterization and we were able to stratify patients upfront on the basis of their coronary flow reserve and then in a blinded fashion assess whether these patients who did or didn't have augmentation of flow reserve had ischemia.

Dr Carolyn Lam: Divaka, could you give us a detailed picture of what that meant? These patients were sitting with catheters and then riding bikes or give us a picture of what you did.

Dr Divaka Perera: Right. This is a setup we've been working on for the last 10 years or so to make sure that we have a reproducible and safe protocol that can be carried out in a Cath lab. A patient who was referred for diagnostic angiography, this may have been the first investigation they were having, or they may have had some form of noninvasive testing beforehand. These patients would undergo angiography via the right radial artery with their arm extended out to the side. And then during angiography when the time was right to assess this condition, they would carry out supine bicycle exercise. And that was a bike that was mounted onto the Cath lab table. During all of this, we would measure intracoronary pressure and flow velocity using this combo tipped wire which could give us distal coronary pressure and Doppler flow velocity and we were able to do this throughout the condition of exercise.

Dr Carolyn Lam: That's cool, but then how did the MRI come in then?

Dr Divaka Perera: Right. The MRI was actually done at a different visit and in that situation, we only carried out vasodilator testing. We also do exercise patients in the MR scanner, but we haven't included any of those data in this current paper. Patients would have two visits at least as part of this research protocol.

Dr Carolyn Lam: Maybe now with that background, tell us what you found.

Dr Divaka Perera: The first and most important finding was that patients are classified in the Cath lab on the basis of a coronary flow reserve below 2.5. The flow reserve threshold of 2.5, actually have demonstrable ischemia on a stress profusion myocardial magnetic resonance imaging scan. 82% of patients in the MVD group, the microvascular dysfunction group had inducible ischemia compared to just 22% of controls. This was mirrored by quantitative myocardial profusion reserve data as well, where the ability to augment overall myocardial blood flow was significantly diminished in patients with MVD. And perhaps most interestingly, their exercise pathophysiology was dramatically different to that of controls.

In the healthy heart, the heart actually becomes more efficient during exercise. We were able to quantify the proportion of accelerating and decelerating waves by carrying out a technique called wave intensity analysis on the data I've just described, on the physiology data that I've just described. And by doing that we were able to quantify the proportion of accelerating waves to decelerating wave energy. In the healthy heart, as we exercise the proportion of accelerating wave energy increases and we've termed that profusion efficiency. Now in stark contrast when you have MVD, the heart actually becomes less efficient and the profusion efficiency decreases. This is a normal finding and really told us that cath lab measurement based on the response to vasodilators seems to identify a population who have maladaptation during exercise and demonstrable ischemia on scanning.

Dr Carolyn Lam: Wow. Dharam, could I now ask you to help frame these results in the context of what's known or not known about microvascular disease?

Dr Dharam Kumbhani: I want to congratulate the Divaka and his group. I think this is very interesting analysis. It's really a new paradigm about what is now understood to be more and more of a common issue. It seems like a lot of work, even for the patient population that was enrolled. And I think done in an incredibly thoughtful way. Having said that, I guess what I'd like to understand as a card carrying interventionalist myself, I imagine that some of this may be perhaps in need of validation. And so do you think that this study and in some of the two distinct phenotypes that you describe that this will need to be demonstrated in other labs and other situations?

Dr Divaka Perera: Absolutely. I think we have demonstrated is a proof of concept that we can assess these patients in the Cath lab and then shown that firstly, the measurement of CFR and the classification of patients on the basis of CFR does identify a group with distinct pathophysiology, but that that doesn't tell the whole story because your CFR can be diminished for one of two broad reasons. That there's an abnormality of resting flow or an abnormality of hyperemic or flow at maximum stress. Now, the traditional paradigm of microvascular dysfunction has been that these patients will all have, or the majority will have, diminution of stress flow. Or that they might have an inability to reduce their microvascular resistance during stress.

What we have found in contrast is that actually two thirds of patients who have impaired flow reserve have impaired flow reserve because of an abnormality of rest perfusion. One third only conform to that traditional paradigm, and this, as you've rightly pointed out, is something that's going to need further investigation. It's very exciting and it might mean that we have a basis on which to try different therapies, for instance. That those therapies might be pathophysiologically stratified, but it needs a lot of work and I'm sure you won't be surprised to know that we've already embarked on that next stage of work to validate and take this forward.

Dr Dharam Kumbhani: Let's say you were able to validate this paradigm and you indeed are able to stratify patients with microvascular disease. What you have defined as a functional and a structural endotype. Do you believe that if this were validated and established further from a diagnostic standpoint in labs across other places, what kind of diagnostic testing do you imagine that this would require?

Dr Divaka Perera: At the most basic level Dharam, I think we need to get interventional cardiologists and any cardiologist doing diagnostic angiography to realize that the finding of unobstructed coronary artery disease isn't the final answer. It actually begins a whole chapter of investigation and if we can at least get people to think about doing a physiology study in a way analogous to what's happened when we find equivocal amounts of coronary artery disease that you'd reach for a pressure wire and do a functional test. If we can introduce that paradigm once we find normal or unobstructed coronary arteries in a patient with classical symptoms, that would be step number one. The next step will be that we'll have across the board a harmonized means of classifying these patients and by looking at microvascular resistance as well as coronary flow reserve, we might be able to identify endotypes that behave differently and need different forms of therapy. Once we've got that in place, then we have a basis to carry out large registries and large trials in a systematic fashion.

Dr Dharam Kumbhani: Let me just clarify that. You don't envision that let's say this all gets validated. Do you envision that labs that do CFR measurements would then in addition need to have the ability to do exercise testing as well?

Dr Divaka Perera: No, I don't think so. I think exercise testing requires a really carefully evolved set up and it's not practical to unleash this onto world at large. But it generates hypotheses and examines concepts which can then be translated. I think routine use of microvascular function testing will rely on response to vasodilators and these will be endothelium independent techniques such as an adenosine and possibly as a second stratum, endothelium dependent methods as well. Perhaps using graded acetylcholine infusions. But it would be vasodilator testing in the Cath lab rather than exercise.

Dr Dharam Kumbhani: Got it.

Dr Carolyn Lam: Fascinating. Wait, Divaka, just to be sure that the audience got this. You talked about the two endotypes, a structural and functional and the structural one is the one that has a low flow to begin with. The functional is the one that the hyperemic flow is the one that's mainly impaired. Is that correct? Just checking.

Dr Divaka Perera: Let me just clarify. Those patients that we've termed to have functional MVD have elevated resting flow, but actually essentially normal flow at stress. In contrast, those who have structural MVD have essentially normal resting flow but have an inability to augment their peak flow. The net result appears to be the same in the sense that they all have demonstrable ischemia on noninvasive testing, but the mechanisms are different and therefore the therapies that we direct towards these patients may also need to be different.

Dr Carolyn Lam: Very nicely put. Thank you. And if the audience, you still didn't get that, pick up the paper and read it. But say, one last question because you kind of teased us just now and said, actually we are going on with next steps and so on. What are the next steps? Maybe from you and then Dharam.

Dr Divaka Perera: I think the next step is to assess whether this sort of stratification allows us to treat patients more efficiently. To deliver subtype stratified therapy. And we need to assess this with reference to meaningful clinical outcomes, so quality of life, exercise-based indices, et cetera, before we get onto looking at large numbers and then looking at cardiovascular outcome data.

Dr Carolyn Lam: Great. And Dharam, maybe I'll let you have the closing words.

Dr Dharam Kumbhani: We're understanding a lot more about what is always been an enigma for clinicians as far as having patients who present with very typical symptoms, either stable or unstable symptoms and have no coronary artery disease. I want to congratulate the authors on really trying to dig deeper into this and helping us with this very difficult patient population.

Dr Carolyn Lam: Thank you, Dharam. Thank you Divaka. And thank you listeners for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

This program is copyright American Heart Association 2019.


Nov 18, 2019

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

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

Well, Carolyn, this week's feature articles, very interesting, discussing hypertrophic cardiomyopathy and sudden death in young individuals. But, let's save all the details for later and start in on our coffee chat. So, Carolyn, have you got a paper that you'd like to start with?

Dr Carolyn Lam: I have, and it's a basic science paper. It's one that details the contribution of get this, M-C-U-B. Now this is a paralogue of the poor forming sub-unit MCU in mitochondrial calcium, uniporter regulation and function. Now, this paper shows, for the first time, MCUB's relevance to cardiac physiology, and it's from corresponding author Dr Elrod from Center of Translational Medicine, Louis Katz School of Medicine at Temple University in Philadelphia, and their coauthors, who showed, in a series of elegant work, that MCUB is absent from the uniporter complex in the homeostatic heart. But it's incorporated into the mitochondrial calcium uniporter following ischemic injury and thus represents an endogenous mechanism to limit mitochondrial calcium overload during stress.

Interestingly, the increased incorporation of MCUB into this mitochondrial calcium uniporter is too little and too late to limit acute cell death following ischemic reperfusion injury but may limit cell loss during chronic stress.

Dr Greg Hundley: So Carolyn, tell me what are the clinical implications of this important finding?

Dr Carolyn Lam: Well, simply put, MCUB represents a novel therapeutic target to modulate mitochondrial calcium uptake in disease states speech during mitochondrial calcium overload such as myocardial infarction and heart failure.

Dr Greg Hundley: Very nice, Carolyn. Well, I've got another basic science paper and it involves Protein Kinase N and how that promotes stress induced cardiac dysfunction through phosphorylation of myocardin-related transcription factor A and disruption of its interaction with actin. This comes from the corresponding author Mikito Takefuji from Nagoya University Graduate School of Medicine. So Carolyn protein phosphorylation of course, is a major and essential intracellular mechanism that mediates various cellular processes in cardiomyocytes, in response, extracellular and intracellular signals. The RHOA-associated protein kinase, or ROCK Rho-kinase, in effect, are regulated by the small GTPS RHOA causes pathological phosphorylation of proteins resulting in cardiovascular diseases. RHOA also activates Protein Kinase N, however, and the role of PKN in cardiovascular disease remains unclear.

Dr Carolyn Lam: Ah, okay. So with that background, what did these authors find, Greg?

Dr Greg Hundley: Great question, Carolyn. What they found is that PKN inhibits the binding of MRTFA to G-actin by phosphorylating MRTFA and activating SRF mediated expression of cardiac hypertrophy and also fibrosis associated genes. Also, they showed that cardiomyocyte specific PKN1 and PKN2 double deficient mice are resistant to pressure overload and ANGII induced cardiac dysfunction.

Dr Carolyn Lam: Wow. There's a lot of letters in what you just said. So could you just tell us how does this impact heart failure research and management?

Dr Greg Hundley: So Carolyn, this PKN family appears to play a role in regulating hypertrophy and fibrosis in the heart and therefore could serve as a unique target for therapeutic interventions for heart failure in the future. And so maybe it's going to make its way your way.

Dr Carolyn Lam: Well, okay, well this next paper definitely is making its way my way and it focuses on the Sodium Glucose Co-transporter two inhibitors or SGLT-2 inhibitors, which we know lower cardiovascular events in patients with type two diabetes, but whether they promote direct cardiac effects as in that we can see in cardiac structure and function actually remained unknown until today's paper. And this is from Dr Subodh Verma and Dr Kim Connelly, these co-corresponding authors from St. Michael's Hospital and University of Toronto and their colleagues.

And they sought to determine if empagliflozin causes a decrease in left ventricular mass in patients with type two diabetes and coronary artery disease. So this was a six month double blind randomized placebo controlled trial. If individuals with type two diabetes, coronary artery disease and relatively normal left ventricular mass index. The primary outcome was six month change in left ventricular mass index to body surface area from the baseline and measured by cardiac magnetic resonance imaging and they found that the empagliflozin allocated group exhibited a significant reduction in left ventricular mass index compared with the placebo group.

Dr Greg Hundley: Wow, Carolyn. We have been hearing a lot about empagliflozin in the last several issues. How does this article differentiate what we do or maybe even change our practice?

Dr Carolyn Lam: Well, you know what? It enhances our understanding which is important. We knew about the events. Now we perhaps understand a little bit more of what it may be doing actually to the heart in terms of cardiac structure and function. The so the decrease in left ventricular mass associated with empagliflozin may explain and contribute to the cardiovascular benefits observed in patients with type two diabetes and coronary artery disease who are treated with SGLT-2 inhibitors. Now it's interesting the way we've gone like reverse translation in this, haven't we? Observing the events and then trying to find the mechanism. And this is in fact discussing an editorial by Mark Petrie and titled SGLT-2 Inhibitors: Searching for Mechanisms in the Wake of Large Positive Randomized Trials.

So Greg, after that, maybe you could tell us what else resides in this week's issue.

Dr Greg Hundley: Oh my goodness, Carolyn. Well, there's quite a bit. First Paola Erba from Pisa, Italy provides a nice In-Depth review of the use of echocardiography, radioisotope imaging and computed tomography for the assessment of patients with endocarditis. In another article, Wayne Batchelor and Rebecca Ortega and their colleagues discuss a Perspective piece, several strategies to improve enrollment of racial and ethnic minorities into clinical cohorts and trials addressing cardiovascular disease.

And of course we have our mailbox. And first is Dr Diamantis Tsilimigras from The Ohio State University, and he responds to a letter by Moris et al regarding the article: Effects of Arteriovenous Fistula Ligation, or cardiac structure and function in kidney transplant recipients.

Barry Borlaug from Mayo clinic discusses the importance of right ventricular volume loading and high output heart failure with arteriovenous fistulas.

And Carolyn, our own Joe Hill and a first author Dan Tong coauthor a letter pertaining to whether female sex is protective in a preclinical model of heart failure with preserved ejection fraction.

And then finally Toby Coates from Australia responds to several inquiries related to a prior publication regarding a published article involving the effects of arteriovenous fistula ligation on cardiac structure and function, again in kidney transplant recipients.

There's an On My Mind piece from Dr Heinrich Taegtmeyer from McGovern Medical School at The University of Texas Health Science Center at Houston, or UT Health, relating to characteristics of past prominent investigators. What makes them tick? What contributes to their long-term success and sharing their catch with others? And it's interesting Carolyn, because he compares the vast community of cardiovascular investigators to those that are like anglers or fisherman. Their passion is kind of like the allure of catching just one more. And in so doing, they like to share their catch with others.

Dr Carolyn Lam: That is hilarious. I don't think I've ever wanted more to be a fisherman or angler myself. Well that's great, Greg. Thanks and let's carry on with our feature discussion, shall we?

Dr Greg Hundley: Absolutely.

Welcome everyone to our feature discussion and we're going to discuss hypertrophic cardiomyopathy and sudden cardiac death and the relationship to exercise. And our study comes from Ontario and our lead investigator is Dr Paul Dorian from St. Michael's Hospital, and we also have our associate editor Mark Link from Dallas, Texas. Welcome gentlemen. And Paul, I'll start with you, tell us a little bit, what was the hypothesis and what were the aims that you were trying to accomplish with this particular study?

Dr Paul Dorian: Our hypothesis was that the likelihood of sudden death in patients with hypertrophic cardiomyopathy may be less than has previously been supposed. In brief, the community that looks after patients with HCM, we'll call it for short, is faced with a major challenge in knowing what the actual rate of sudden cardiac death is and it seems to be a little bit of a moving target. Over the last decade, I think that most clinics that look after these patients were faced with what appears to be a less and less frequent likelihood of sudden death in these mostly young patients that we follow. And because we have the opportunity to study this using a well-established prospective coroner database with autopsy results in all sudden deaths in Ontario in young individuals, that we have the opportunity to test our hypothesis that this sudden death rate is lower than had previously been suspected.

Dr Greg Hundley: It sounds like younger patients and trying to investigate the cause of sudden cardiac death. Can you tell us a little bit more about your study population and what was your study design?

Dr Paul Dorian: We had the fortune of being able to use the Coroner of Ontario database. Ontario has about 13 million population and by the longstanding design, almost all patients under the age of 45 who suffer out of hospital, sudden cardiac death receive a full coroner investigation and then 90% of them, it's an autopsy which includes a cardiac autopsy by a qualified forensic pathologist. And in the case of cardiac hypertrophy, the cases are re-reviewed by a specialized cardiac forensic pathologist. So we have very extensive, if you like, detective work, CSI-type information on virtually everybody who dies out of hospital suddenly including those individuals among them who have hypertrophic cardiomyopathy.

And what we did was we reviewed every single case of unexpected sudden death, looking for the specific diagnosis of cardiac hypertrophy or HCM. We verified the accuracy of our numbers by also using, for at least portions of our follow-up, the complete emergency medical services database for about 7 million people, mostly from Toronto. And this included all patients who had a 9-1-1 call for documented cardiac arrest. So we were able to verify that we missed essentially no patients without a hospital cardiac arrest who then died suddenly.

Dr Greg Hundley: Give us a little bit more about the numbers. So what was the age range of your study population, perhaps the gender and breakdown, things like that?

Dr Paul Dorian: We looked at individuals under the age of 45 but the median age was 36 for all of our patients. About 85% of the patients with documented HCM were male, 83% to be precise. And a pretty small minority of them. Had comorbidities that we would expect including hypertension, diabetes, et cetera. 11% were on beta blockers, and a small proportion had atrial fibrillation. So these are generally healthy individuals, or at least they had had relatively little interaction with the healthcare system and about half of these individuals had previously been diagnosed clinically with HCM and the rest had not been diagnosed as far as we could tell, or at least there was no medical record of them having been diagnosed with HCM.

Dr Greg Hundley: And what was the total number of individuals in this study? And then tell us a little bit about your study results.

Dr Paul Dorian: The total number of individuals who had definite HCM was about 45 we had 31 patients who were not known to have HCM who had definite HCM, which we defined as having myocardial disarray on cardiac microscopy and another 13 who are not known to have HCM. And then we had about another 10 patients who we thought had possible HCM because they had autopsy with hypertrophy but didn't have disarray. And a few patients that were diagnosed with HCM but didn't have autopsy. So the total population was approximately 50 patients and this is out of a total population of estimated population of about 140,000 HCM person-years using the widely estimated prevalence of HCM of one in 500.

Dr Greg Hundley: And what did you find?

Dr Paul Dorian: The bottom line, if you like, is that the annual incidence of unexpected sudden death, this would be out of hospital sudden death, was many folds lower than would've been expected based on prior publications and on prior risk calculators that are used by many physicians who for these patients. If your readers or the listeners just want single numbers, the total number of both definite probable and possible HCM related sudden death, this is the most sort of conservative estimate, would be approximately 0.4 per thousand person-years. So this would be less than one per thousand. This would be one half of one 10th of 1% so less than one per thousand per year. Patients with HCM will have sudden death. If we take the most conservative definitions.

Dr Greg Hundley: Now, could you tell whether these sudden deaths were related to exercise? That was sort of one of the feature questions.

Dr Paul Dorian: Absolutely. That's how we were of course, very interested so we defined both exercise as somebody died or doing sport or observed during exercise. I should emphasize that the coroners do extremely careful digging if you like into the circumstances. They interview paramedics, police, they have the police and paramedic report, they interview physicians, relatives, so they do a very thorough assessment of course as best as could be told after the fact. 65% of the sudden deaths occurred at rest and 18% occurred during light activity and about 10% occurred during exercise.

Dr Greg Hundley: Very good. I want to turn over to Mark now. This is Dr Mark link from University of Texas Southwestern in Dallas. Mark, how can we put the results from this study in the context of other studies relating to implementation of defibrillators in patients with hypertrophic cardiomyopathy?

Dr Mark Link: This study brings up a lot of issues and I want to applaud Paul and his gang for doing this. The data is very good. The autopsies are very good. So the quality of the data is excellent and the incidence of sudden death for a hypertrophy is lower than any other study that we've seen. And there are a number of possible reasons for that. Well, you know, one is that the Toronto group was using autopsied determined HCM or most other studies were kind of a mixed bag of clinical and autopsy and newspaper reports and all sorts of things. So the Toronto data is going to be probably the most accurate. The other issue, or the other question I think that could lead to a low incidence, is the denominator, in that there were estimated to be more hypertrophy in Toronto than there actually are. They use the commonly accepted one in 500 and I think that's a reasonable number across all sorts of populations that we see, but is it possible that maybe the one in 500 number isn't true for Toronto?

You know, I've heard one person explain this is that patients with HCM can't stand the cold weather. So they left Toronto, but it is a much lower number than we've seen in regards to sudden death. A couple of other things I think are very interesting in this study. One is that if you looked at the individuals that got ICD shocks for ventricular arrhythmias is there was about as many people as died suddenly, arguing that the Toronto physicians can actually in many ways predict who would benefit, predict which hypertrophy would benefit from an ICD. Since many of these hypertrophies didn't have appropriate ICD shocks. And I also found fascinating that more of the deaths occurred during rest or light activity than exercise. We all tend to think that HCM causes its sudden death with exercise. And what this study's telling us is that's not true that more sun deaths are during rest and light activity. So there's a lot of very interesting insights that come out of this manuscript in this data.

Dr Greg Hundley: Just following up on your last point, are there any inferences regarding activity in this patient population that we should take away from these study results?

Dr Mark Link: I think if you look at the early newspaper reports and they're in there as reports of the incidence of HCM, sudden deaths during sports. So it was because of that, that everyone associated HCM with death during sports. But you have to remember those studies didn't include athletes that died at night. Athletes that died during dinner. They only included athletes that died during sports. So we were missing a large percentage of the hypertrophs dying. And I think we sort of infer that it was exercise that was dangerous, but in fact there's really not that much data that would support that exercise is dangerous for patients with HCM.

Dr Greg Hundley: Interesting. So I'll maybe ask Mark first and then come back to you, Paul. Do you think there are tools that could be available, either blood testing or perhaps other imaging that could help identify which HCM patients may benefit from a defibrillator? Do these results help us in any way make that decision?

Dr Mark Link: Unfortunately, I don't think this study offers us any clues into which patients should get defibrillators. And clearly there are other data that look at risk factors for sudden cardiac death in hypertrophic cardiomyopathy. And one of the things that has come out over the last 10, 15 years is that magnetic resonance imaging, and in particular the scar burden magnetic resonance imaging may actually offer additional prognostic information to our traditional respect for stratification grade CM.

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

Dr Paul Dorian: Just a couple of things if I may. I think on that last point I completely agree with Mark. Of course we didn't have data on MRI, but the greater the scar burden, the greater our index of suspicion. It is interesting that 57% of the cases of sudden death had asymmetric septal hypertrophy, so we can at least hypothesize that it is possible that patients with septal hypertrophy as opposed to concentric hypertrophy may be at higher risk.

The one thing I might want to highlight for the listeners is that it would seem to me based on our data and based on our suspicions, is that there's probably a difference in the risk in patients who are discovered incidentally. In other words, somebody has an echocardiogram or an ECG for reasons unrelated to their heart and then HCM is discovered and these might be asymptomatic patients as opposed to patients that tend to be followed in specialized clinics who often are sent there because they have some symptoms or there's some specific signal that they have a clinically evident HCM. So I wouldn't want listeners to conclude that the risk is necessarily this low in patients that are transferred to a clinic because of disarray or atrial fibrillation or electro regurgitation or some other manifestation of a hypertrophic cardiomyopathy.

Dr Greg Hundley: Paul, I want to start with you first. What study do you think should follow yours? What's the next study?

Dr Paul Dorian: What I'd like to see, and this is technically feasible although practically challenging, is to use the big data approach and combine in one large database, all echocardiograms done in a large geographic area. All electrocardiograms done in a large geographic area with supplemented with clinical information and do, over a long period of time, a prospective study looking at all patients with cardiac hypertrophy, particularly asymmetric hypertrophy or suspected to have HCM to look at the long-term outcomes. And this should be feasible because most echocardiograms today are uploaded if you like, into a database.

Dr Greg Hundley: Very nice and Mark, how about you?

Dr Mark Link: I have similar opinion. Any one of the most important things in HCM is being able to predict who would benefit from a defibrillator, and currently our ability to risk stratify is woefully inadequate. It lacks sensitivity and specificity. And so with a larger population of HCM patients, and I think Paul's correct followed prospectively, not retrospectively, with the kind of data that we would want to be complete, including echo. Now, MRIs would be fantastic, but there's just no way that's practical, but to have echoes and EKGs and clinical factors and be followed prospectively really to hone down which patients would benefit from a defibrillator, and which patients would not benefit.

Dr Greg Hundley: Well listeners, this has been a great discussion and we want to thank Dr Paul Dorian from the St. Michael's hospital for providing this paper to Circulation and sharing these results with us and also our associate editor, Dr Mark Link from Dallas, Texas and both have emphasized in this study that those individuals with HCM, while we often see them on the sports programs and whatnot, having their, experiencing their event during activity, they also occur within activity.

For Carolyn and myself, we wish you a great week, and we look forward to talking with you next week in our next chat. Bye now.

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


Nov 11, 2019

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

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

Dr Carolyn Lam: Greg, we are going to have a great discussion coming right up regarding intensive versus standard ambulatory blood pressure control and its effects on cerebrovascular outcomes in older people. It's the INFINITY trial, but that's all I'm going to tell you for now because I want to hear all about your picks for this week's journal first.

Dr Greg Hundley: Absolutely Carolyn and I can't wait to hear about that discussion regarding hypertension. My first paper though is about titin and it comes from Dr Charles Murry from the University of Washington. The giant sarcomere protein titin is important in both heart health and disease as mutations in the gene encoding for titin are the leading cause of familial dilated cardiomyopathy. The uneven distribution of these mutations within titin motivated the authors of this article to seek a more complete understanding of this gene and the isoform it encodes in cardiomyocyte sarcomere formation and function.

Dr Carolyn Lam: Cool. What did these investigators find?

Dr Greg Hundley: Using genetically engineered human induced pluripotent stem cell derived cardiomyocytes, the authors experimentally confirmed that the gene encoding for the giant sarcomere protein titin includes an internal promoter and start site. This internal start site encodes for the isoform Cronos, which the authors demonstrate support some sarcomere formation in these human induced pluripotent stem cell derived cardiomyocytes.

Dr Carolyn Lam: Oh, nicely summarized. What are the clinical implications Greg?

Dr Greg Hundley: Well, Carolyn identification that Cronos titin, a previously unstudied form of titin is necessary for normal human cardiomyocyte function could be contributing to some of these titinopathies that are relevant for some patients with dilated cardiomyopathy.

Dr Carolyn Lam: Cool. Mine has to do with heart failure as well and presents new results regarding heart failure and heart failure related outcomes from the EXSCEL trial.

Dr Greg Hundley: Carolyn, what was the EXSCEL trial? What did it find?

Dr Carolyn Lam: Ah, so as a reminder, EXSCEL was the largest glucagon-like peptide-1 receptor agonist or GLP-1 receptor agonist trial reported to date where once weekly, exenatide had a neutral effect on hospitalization for heart failure with no differential treatment effect on major adverse cardiovascular events or MACE, by baseline heart failure status. However, the question remains, what about exenatide's effects on secondary endpoints based on the heart failure status? This is from Dr Rob Mentz and colleagues from Duke Clinical Research Institute who aim to explore the effects of exenatide on secondary outcomes in patients with and without baseline heart failure and test the effects of exenatide on recurrent heart failure hospitalization events.

Now they found that out of more than 14,750 EXSCEL participants, 16% had heart failure at baseline and when stratified by the presence or absence of baseline heart failure, there was no observed reduction in all cause death with exenatide in patients with baseline heart failure. While the risk of mortality was reduced with exenatide in the no heart failure group. And that was a significant interaction P value of 0.031. Similar results were observed for the combined outcome of all cause death or heart failure hospitalizations.

Now regarding recurrent heart failure hospitalizations, 450 patients experienced at least one hospitalization for heart failure, but there were 713 hospitalization heart failure events in total. The effect estimate that included the recurrent events was separately, statistically significant while the primary analysis based on just first events was not.

In conclusion in EXSCEL, the use of exenatide in patients with or without heart failure was well tolerated, but the benefits of exenatide on reduction in all cause death and first heart failure hospitalization were attenuated in patients with baseline heart failure. Now this is accompanied by a great editorial by Bruce Neil and Claire Arnett who caution against using post talk subgroup analysis, but the interaction of exenatide tout with baseline heart failure, it's interesting, although should be treated with caution until confirmed by findings from another trial.

Dr Greg Hundley: Very nice Carolyn, especially a nice issue regarding heart failure and I'm going to steer a little bit away from that and talk about atrial fibrillation duration and CHA2DS2-VASc scores. Putting those two together and this article comes from Rod Passman from Northwestern University. Studies of patients with cardiovascular implantable electronic devices show a relationship between atrial fibrillation duration and stroke risk though the interaction with a CHA2DS2-VASc score is poorly defined. The objective of their study was to evaluate rates of stroke and systemic embolism in those patients with cardiovascular implantable electronic devices as a function of both the CHA2DS2-VASc2 score and A-fib duration.

Dr Carolyn Lam: Interesting. What did the authors do?

Dr Greg Hundley: They had 21,768 non-anticoagulated cardiovascular implanted electronic device patients from the Optum electronic health record, de-identified database from 2007 to 2017 and they link those to the Medtronic CareLink TM database of CIEDs capable of continuous AF monitoring. Now the age averaged about 69 years and 63% were men and they found that increasing a fib duration, and of course increasing CHA2DS2-VASc2 score were both significantly associated with annualized risk of stroke and systemic embolism. These rates were low however, in those individuals with CHA2DS2-VASc2 scores of zero to one, regardless of the device detected a fib duration.

Dr Carolyn Lam: Ah. Were there any particular threshold values that seemed important?

Dr Greg Hundley: Great question, Carolyn. Yes, the stroke risk crossed an actionable threshold defined as greater than 1% per year in those with CHA2DS2-VASc2 score patients of two or more with greater than 23 and a half hours of a fib or those patients with CHA2DS2-VASc2 scores of three or four with greater than six minutes of a fib duration or finally in those individuals with CHA2DS2-VASc2 scores greater than five even if they had no atrial fibrillation.

Dr Carolyn Lam: Wow. Very nice clinically relevant conclusions here. Thanks Greg. I'm going to tell you what else is in this issue. There's also a research letter by Dr Rosenmeier entitled, “Aerobic Exercise Induces Cardiac Fat Loss and Alters Cardiac Muscle Mass Through an Interleukin 6 Receptor Dependent Mechanism.” And this is a cardiac analysis of a double blind randomized controlled trial in abdominal obese humans. We have an on my mind paper by Dr Delbridge entitled “HFpEF, It's Time to Explore the Role of Genetic Heterogeneity in Conferring Phenotypic Variability.” And this discusses among other things, the role of induced pluripotent stem cells and functional studies of bioengineered HFpEF patient derived cardiac micro tissues that could potentially enable several important questions to be answered for the first time. There's an ECG challenge as well by Dr Naru Kanya, and it's really interesting. It's a hiccup artifact. If you haven't heard about that, you should take a look. And finally cardiology news by Dr Kuhn and it's entitled, “Nourishing Native American Communities by Increasing Access to Traditional Food.” A very interesting paper right there.

Dr Greg Hundley: Carolyn, I have a few papers. Robert Gerszten provides a perspective piece regarding emerging affinity reagents for high throughput proteomics, sort of an emerging field, everyone doing proteomic studies, we have to pay a special attention to the reagents that are being used. And then Andrew DeFilippis from University of Louisville as well as Johns Hopkins reviews important concepts related to the definition of MI.

Dr Carolyn Lam: Is this pertaining to that fourth universal definition of MI?

Dr Greg Hundley: Yes, Carolyn. Absolutely. And basically in this white paper, the authors review the epidemiology, risk factor associations and diagnostic tools that may assist in differentiating between non-ischemic myocardial injury, type 1 MI and type 2 MI. And then finally from Suowen Xu from the University of Rochester, there's a letter discussing the CCN family of matricellular proteins CCN 1, CCN 2 and CCN 3, that are mechano-sensitive proteins that are differentially regulated by sheer stress, the frictional force exerted by blood flow in our vessels. Well Carolyn, that's a great issue. How about we move on to our feature article?

Dr Carolyn Lam: Let's go Greg.

For our feature discussion today we are talking about intensive versus standard ambulatory blood pressure control and that effect on cerebral vascular outcomes in older people or the INFINITY trial. Very, very important stuff and I'm so pleased to be with the corresponding author, Dr William White from Calhoun Cardiology Center in University of Connecticut School of Medicine. Dr White, thank you so much for being here. Could you maybe set up already the background of what you were thinking when you started this trial? Especially given the results that we know from SPRINT and SPRINT mind. Could you perhaps comment on how this INFINITY trial is different?

Dr William White: We started work in this area about 15 years ago and we initially were interested in interactions among vascular risk factors including ambulatory blood pressure, lipids and other sort of thrombotic factors and so forth with the development of small vessel disease in the brain that led to these fairly classic images on MRI called white matter hyperintensity lesions. And we learned from a prospective cohort study that we started about 15 years ago, that there was a very strong relationship between ambulatory blood pressure and the development and progression of these white matter hyperintensity lesions on MRI, but not very nice relationship with the clinical blood pressures measured in the standard office practice.

We decided to pursue a clinical trial, a randomized clinical trial in which we would evaluate different levels of ambulatory blood pressure versus the development of the small vessel disease as imaged by MRI, but very importantly we also wanted to link it to functional outcomes because this was in older people, typically in their late seventies, eighties and even nineties in which cognitive impairment begins to develop. There's problem with mobility, bladder function and things of that nature. And since our funder was always the National Institute of Aging of the NIH, there's a great deal of interest in more than just the vascular risk factors and even the cerebral vascular disease that we would detect on the MRI. That was the background of why the study got developed the way it did.

Dr Carolyn Lam: That's so interesting. You've already pointed out ways that this was very different from SPRINT OR SPRINT MIND in looking at ambulatory instead of clinic blood pressure and I suppose in the population you selected, out of curiosity, you mentioned that your prior work showed a relationship between white matter hyperintensity on MRI and perhaps future dementia. In which direction? And is there any basis to suspect low, too low blood pressure may also be bad in these older people who already have microvascular brain disease?

Dr William White: Absolutely. Very important point. When we look at our prospective cohort which was about a 100 older people, we followed for four years without any intervention. This was just a mixture of normal tensive and hypertensive individuals. Some on meds, some not on meds. But we did show that when you got too low or if you stay too low during those four years with a systolic blood pressure of under 115 on a 24-hour blood pressure monitor, it seemed like there was an almost like U shaped relationship with progression of white matter disease. Below 115 there was more accrual of white matter disease. Above 150 there was a systolic blood pressure, there was also a greater accrual, but in between about 125 and 145 we weren't really sure if there was going to be a difference. And that there was the target is that everybody's talking about for clinical measurement, so we decided to pursue that in this study to determine if we could figure out whether or not there was a sweet spot for the desk blood pressure without getting into trouble with hypotensive symptoms.

Dr Carolyn Lam: Nice. Thank you for drawing that up so nicely. Now I get it that you chose the targets that you did, which just for everyone, just a reminder, it was a 24 hour mean systolic blood pressure by ambulatory blood pressure control and the two targets were 130 millimeters mercury and less versus 145 millimeters mercury and less. With that, could you please tell us the results?

Dr William White: Right. We called the 130 or less systolic group, the intensive treatment group and the 145, the standard group. We focused on the primary endpoint was changes in mobility parameters in conjunction with changes in white matter hyperintensity lesion growth. And after a period of about three to four months of randomization, post randomization, we achieved a 24-hour systolic blood pressure about 128 millimeters of mercury in the intensive treatment group and 144 in the standard group. And we maintained a pretty good separation in blood pressure, ambulatory blood pressure throughout the three years of treatment. Now the changes in gait speed, which was one of our primary parameters for mobility actually turned out not to be different between the treatment groups. That is intensive versus standard. However, the changes in the accrual of light matter hyperintensity volume was smaller in the intensive treatment group of a 0.29% versus a 0.48% in the standard treatment group. That was significant at a P value of 0.03.

We actually also had a pre-specified sensitivity analysis, sort of a per protocol analysis that allowed us to look at people who stayed in their sort of assigned treatment groups based on blood pressure throughout the three years of the trial. And in that circumstance, there was actually a stronger separation because these are people who stayed clearly at 130 or less than about 145 throughout the three years and now the differences were approximately 0.23% in the intensive group and 0.58% in the standard group. And now the P value is smaller, .0028.

I think we proved in the study that maintaining a systolic blood pressure on the ambulatory recorder over 24 hours of 130 or less benefited patients by reducing the accrual of white matter hyperintensity lesions by about 40% relatively speaking compared to a standard ambulatory blood pressure value of a 145. One of course caveat is that after that happened within three years, but we did not see the expected benefit on mobility or on most of the cognitive parameters either. And while we were a little bit surprised about that, when we went back and analyzed our situation with where people started from as far as this particular cohort of patients, they might've been a little on the healthy side compared to some other studies. A very educated group, very compliant with everything that they did. And probably three years was just not long enough to show the result of this white matter hyperintensity benefit on some of the functional outcomes.

Dr Carolyn Lam: That's really interesting and I'm glad you sort of tackled head on that sort of apparent dissociation between the clinical end points and the MRI end point. Could I also ask, wouldn't those findings also be consistent with SPRINT and SPRINT MIND?

Dr William White: In many ways our results were consistent with SPRINT MIND, a sub-study on the SPRINT MRI sub-study. Of course, just let me mention the differences between the two studies. Of course, SPRINT was very large but there are sub-studies were not as large as the parent study. The MRI study had about 300 plus patients randomized into it, but the measurement of blood pressure was done in the standard clinical fashion and used that digital device that was able to take measurements without somebody present in the exam room. Though they were a bit lower than what I would have seen on an ambulatory monitor during the day time. And their goals were 120 systolic versus 140, whereas ours were an ambulatory systolic of 135 and 145.

But the results were actually comparable because they showed a benefit with regards to lesser accrual of white matter hyperintensity volume in the intensive group versus this banner treatment group. But they also showed no differences after 3.4 years in the incidence of dementia. And they also showed in a separate study, no differences in gait speed in the population who are in intensive versus standard treatment. One would say that results were really actually comparable despite the age differences and the blood pressure measurement differences. And I think both studies really point to the fact that lower systolic blood pressures in older people should be our target because it's safer actually then than maintaining people in the 140s.

Dr Carolyn Lam: Maybe the follow-up period was not long enough. Could it be possible too that maybe blood pressure control should start earlier in life. Could that be it? And then also, could you give us an idea of the kinds of changes, the magnitude of the change on MRI that you see for those of us that don't think about this all the time, is this a big change considered for your cohort or is it a little change?

Dr William White: I think it's true that these people started out around 81 years old in this trial and so by the time they got to that age and had systolic hypertension for probably as many as 20 years, that some of the damage that was done was obviously permanent and we don't really know how long it took for that to accrue. What we did know is that with three years of intensive treatment, we benefited patients by reducing the continued growth or confluency of these small vessel lesions in the brain. Now the range in the amount of damage varies from about half a percent of the overall brain volume to about 5%, so a 10-fold magnitude difference in our cohort.

And as a result of that, certainly somebody who's got about two to 3% of their brain occupied by better hyperintensity lesions or damage is going to have a great deal more functional disability than somebody who's .5%. I think we have to look at the outliers as well as the mean and median changes that we saw. The mean changes are not huge. The difference between 0.2 and 0.6% for example, in our protocol analysis, 0.4% to me it's clinically relevant because I know that that means that there are some people who went up by a percent or two over the years versus the standard versus the intensive treatment group. That's a big difference in an individual over that period of time.

Dr Carolyn Lam: Yeah, I'd hate to think that I'm losing 1% of my brain.

Dr William White: Yeah. Plus it's also where it's located because the lesions are typically around the ventricles of the brain and it's exactly where neurons are going sort of posteriorly to anteriorly to transmit information. For example, from the visual center to the sort of spatial motor cortex. And when those are interrupted, even if it's in one or 2% of the tissue, it can cause substantial difficulties for people. And it's for both the flow of cognitive information as well as this flow of a mobility and balance. I think that it is very relevant, but the gray matter is affected much less by this compared to the white matter. But there are still studies that show that gray matter sort of follows in line with that so that of course also enhances thought processes and cognitive function as well.

Dr Carolyn Lam: Wow. I love the way you explained that. Very important question would of course be the safety and tolerability of this more intensive approach. Any comments there?

Dr William White: Our sponsor, the National Institute of Aging did recruit a data safety monitoring board that was independent from the study for all the years. Impressively over the course of this trial, even though there wasn't a large sample, it was a 199 people, we saw a significant benefit in the intensive group for cardiovascular events, so there were less admissions for heart failure. There were less myocardial infarctions, there was less strokes. All these kinds of things that we worry about in our patients as they get older with vascular disease was reduced by about 75% in the intensive treatment arm versus the standard arm. As far as the events that we were concerned about, such as falls and syncope and presyncope and things of that nature, they were virtually identical in the intensive treatment group and `the standard treatment group. When you take that into consideration, along with the fact that you're reducing the accrual of small vessel disease in the brain, it's clear that this population, even though they're older, would benefit from a lower systolic blood pressure.

Dr Carolyn Lam: Oh my goodness. Thank you so much, Dr White. That was a beautiful summary. That is the take home message right there.

Listeners, I'm sure you agree with me. Thank you so much for joining us this week, and don't forget to tune in again next week.

This program is copyright American Heart Association 2019.


Nov 4, 2019

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

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

Dr Carolyn Lam: Greg, this issue is super exciting. It's the ESC simultaneous publication issue, isn't it? So the original papers were simultaneous publications at the European Society of Cardiology meeting this year.

Dr Greg Hundley: Oh, wow. Carolyn can't wait to get to these. So Carolyn, later we're going to listen to the authors of this feature discuss the association between ICD use and all-cause mortality in a contemporary heart failure reduced ejection fraction cohort and examine relevant subgroups. So Carolyn, I'm going to get started with my first paper and it's a randomized trial of one hour, one-hour deponent T protocol and suspected acute coronary syndromes and it's a rapid assessment in emergency rooms and it's from professor Derek Chew from Flinders Medical Center. High sensitivity troponin assays promise earlier discrimination of MI, yet the benefits and harms of this improved discriminatory performance when incorporated within rapid testing protocols with respect to subsequent testing and clinical events has not been evaluated in an in-practice, patient level, randomized study. So this multicenter study evaluated the non-inferiority of a zero to one hour, zero to one-hour, high sensitivity troponin T protocol compared with a more traditional zero to three-hour mask, high sensitivity troponin T protocol in those suspected with ACS.

Dr Carolyn Lam: Interesting. So what did the study show?

Dr Greg Hundley: So participants in the zero to one-hour arm were more likely to be discharged from the ED quicker and that would be expected. So 45% versus the standard arm, which was 32%. Also their median ED length of stay was shorter, and we would expect that. Four and a half versus five and a half hours. Those randomized to the zero to one-hour protocol were less likely to undergo functional cardiac testing. The zero to one-hour high sensitivity troponin T protocol was not inferior to standard of care and among patients discharged from the ED, the zero to one-hour protocol had a negative predictive value of 99.6% for 30-day death or MI. So Carolyn, how about your first study?

Dr Carolyn Lam: Well, from MI risk stratification to heart failure risk stratification. I'm going to tell you about a paper describing the TIMI Risk Score for heart failure in diabetes, which is a novel integer base clinical risk score for predicting hospitalization for heart failure in patients with type two diabetes. This is from Dr Mark Sabatine and the TIMI study group who developed a clinical risk score for heart failure hospitalization in more than 8,200 patients with type two diabetes in the placebo arm of saver TIMI 53, as well as externally validated this score in more than 8,500 patients with type two diabetes in the placebo arm of declare TIMI 58.

They found that five clinical variables were independent risk predictors of heart failure hospitalization. These were prior heart failure, history of atrial fibrillation, coronary artery disease, estimated GFR, and urine albumin-to- creatinine ratio, a simple integer base score from zero to seven points. Using these predictors identified a more than 20 full gradient of heart failure hospitalization risk in both the derivation and validation cohorts with high SES statistics. Although the relative risk reductions with dapagliflozin were similar for patients across the risk scores, the absolute risk reductions were greater in those with higher baseline risks.

Dr Greg Hundley: Wow, Carolyn. So tell us what are the clinical implications of this really thorough study?

Dr Carolyn Lam: In summary, the risk score had excellent discrimination in two large clinical trial cohorts. It was well calibrated, and it identified a strong gradient of increasing absolute reduction in risk of heart failure hospitalization with the SGLT two inhibitor dapagliflozin. So by using this TIMI Risk Score for heart failure in diabetes, which is a simple validated clinical risk score, clinicians could better educate patients about their risk for heart failure hospitalizations and could perhaps better identify those patients who have a greater absolute risk reduction in heart failure risk with SGLT two inhibitors.

Dr Greg Hundley: Very good, Carolyn. Well, I'm going to go back to the world of troponins and talk about a paper from Nicholas Mills from University of Edinburgh. And in this study, they evaluated the safety and effectiveness of risk stratification thresholds of high sensitivity troponin in patients with suspected acute coronary syndrome. 48,282 consecutive patients with suspected ACS were enrolled in a multicenter trial from 10 hospitals within Scotland and they're pre-specified secondary and observational analyses. They compared the performance of the limit of a detection of less than two nanograms per liter versus the optimized stratification threshold of less than five nanograms per liter using the Abbott high sensitivity troponin I assay. Patients with myocardial injury at presentation with less than two hours of symptoms or with ST segment elevation myocardial infarction were excluded and the negative predictive value was determined in all patients in subgroups for a primary outcome of MI or cardiac death within 30 days. And they had a secondary outcome that was MI or cardiac death at 12 months.

Dr Carolyn Lam: Nice. So Greg, which threshold of troponin was the optimal one?

Dr Greg Hundley: So the negative predictive value for the primary outcome was 99.8% and 99.9% in those with cardiac troponin I concentrations of less than five or less than two nanograms per leader respectively. At both thresholds, the negative predictive value was consistent in men and women across all age groups. Although the proportion of patients identified at low risk fell with increasing age. Compared to patients with cardiac troponin I concentrations of greater than five nanograms per liter but less than the 99th percentile, the risk of MI or cardiac death at 12 months was 77% lower in those with less than five nanograms per liter and 80% lower in those with less than two nanograms per liter. So in conclusion, use of risk stratification thresholds for high sensitivity cardiac troponin I identified patients with suspected acute coronary syndrome in at least two hours of symptoms at low risk presentation irrespective of both age and sex.

Dr Carolyn Lam: Very nice. Well, more risk stratification in this next paper, which really evaluated the application of the 2018 ACC AHA Cholesterol Management Guideline recommendations for additional lipid lowering therapies in patients with established atherosclerotic cardiovascular disease and residual dyslipidemia despite maximum tolerated Statin who were enrolled in the ODYSSEY OUTCOMES trial. Now, just as a reminder, the 2018 US Cholesterol Management Guidelines recommend additional lipid lowering therapies for secondary prevention in patients with LDL above 70 or non-HDL above a hundred despite maximum tolerated Statin therapy.

Such patients are considered at very high risk based on a history of more than one major atherosclerotic cardiovascular disease event or a single event and multiple high-risk conditions. So in this paper from Dr Matt Roe from Duke Clinical Research Institute and colleagues, they found that in the ODYSSEY OUTCOMES trial, patients classified as very high risk by these 2018 ACC AHA guidelines and either because of a history of multiple atherosclerotic cardiovascular events or a single event, which is a trial qualifying acute coronary syndrome and multiple high risk conditions, these very high risk patients had more than double the risk of recurrent cardiovascular events as compared to patients classified as not very high risk.

 They further looked at the association of Alirocumab with outcomes and found that Alirocumab was associated with a consistent relative risk reduction in both risk categories. But the absolute risk reduction for major adverse cardiovascular events was numerically greater, although not statistically different, in the very high-risk group versus those not at very high risk and among patients at very high risks with multiple prior events versus a single prior event.

Dr Greg Hundley: Wow, Carolyn. Can you put all this together? This is a lot of information in this study.

Dr Carolyn Lam: Yes, so it would appear that the application of the new ACC AHA 2018 guideline recommendations for risk stratification and the use of additional lipid lowering therapies in patients with established cardiovascular disease clearly identifies patients at very high risk of recurrent cardiovascular events after an acute coronary syndrome and these patients may derive substantial benefit from additional lipid lowering therapy, for example, with a PCSK nine inhibitor.

Dr Greg Hundley: Very nice, Carolyn. Well, let me just finish off with what other articles we have in this ESC featured issue of our journal. So Jonathan Stamler and John Lundberg in separate letters discuss findings related to whether hemoglobin beta 93 cystine is not required for export of nitric oxide bio activity from the red blood cell. And in additional separate letters, Doug Lewandowski and Heng-Chen Yao discuss preservation of ACL CoA and attenuation of pathological and metabolic cardiac remodeling through selective lipid trafficking. In a perspective piece, Blake Thomson from the University of Oxford discusses what Medicare for all in the United States can mean for US medical research and provides lessons from the United Kingdom. In a letter from the United States, Gregory Marcus from University of California San Francisco discusses incident atrial fibrillation among American Indians in California and then both Marco Bergonti from University of Milan and Derek Chew from University of Calgary present two separate cases in our ECG challenge feature. Well, Carolyn, what a great issue and how about we turn to our feature discussion?

Dr Carolyn Lam: Yes, let's go. Thanks, Greg.

Dr Greg Hundley: Welcome, everyone, to our feature discussion today we have Gianluigi Savarese from Karolinska Institute in Stockholm, Sweden and our own associate editor, Sana Al-Khatib from Duke University. We're going to be discussing implantable cardioverter defibrillators in their mortality and looking at a more recent take on this relative to some of the previous published studies. So Gianluigi, I'd like to start with you. Could you tell us a little bit about the hypothesis and why you wanted to perform your study?

Dr Gianluigi Savarese: Yes. Basically we design our study based on three main considerations. First one is recent studies show that the advance in heart-failure therapies have impact patients' risk profile leading to roughly 40% reduction risk of sudden cardiac death in HFrEF and RCTs on ICD use for primary prevention of sudden cardiac death and rural patients more than 20 years ago and thus, nowadays the beneficial prognostic effects of ICD may be different due to the improved risk profile in this population.

The second consideration was that efficacy of ICD patients with heart failure with non-ischemic cardiomyopathy patients receiving a contemporary heart failure therapy as being a question in Danish trial and the third consideration is that efficacy of ICD in elderly is still debated due to findings again from the Danish trial showing a significant reduction in all-cause death associated with ICD use in patients age younger versus older than 70 years old. Based on these considerations, we decided to assess the use of ICD for primary prevention propose in a contemporary and selected FRF population and to assess the association between ICD use and outcomes in such a population.

Dr Greg Hundley: So it sounds like we're doing an update on the utility of ICDs. Can you tell us a little more about your study population and your study design and then let's hear a little bit about your results.

Dr Gianluigi Savarese: Sure. First of all, I would like to first highlight of course the observational natural of this study. Our analysis is performed using data from the Swedish Heart Failure Registry, which is a large enough select court of heart failure patients, enrolling patients regardless of ejection fraction. So today we have roughly around 70,000 patients. And of course for the current analysis we select the patients with HFrEF. There were around 15,000 patients with the HFrEF who were eligible for ICD use for primary prevention according to the ESC guidelines. A study design, we used propensity score matching design in order to try to address the issue of potential compounders. Of course this is a very important point in observational studies. So basically, we amassed patients receiving the ICD versus those not receiving ICDs. And we assessed the association between ICD use and all-cause death and cardiovascular death and we accessed one year and five-year outcome.

Dr Greg Hundley: And so what were some of those results?

Dr Gianluigi Savarese: What we observed is that there was a statistically significant 25 relative risk reduction in all-cause mortality in ICD recipients versus those who didn't receive an ICD within one year and there was also a 12% reduction erased within five years. And we also serve a statistically significant 29% reduction in risk of cardiovascular mortality within one year. But we were not able to observe any association for cardiovascular mortality within five years. We thought it was particularly relevant to have subgroup analysis in our studies since there are so many questions regarding ICD use in specific subgroups, which are, for example, older versus younger patients, those with versus without ischemic heart disease, males versus the females and so on. So what we observed was that results in terms of all-cause mortality were consistent in all of the subgroups considered such as patients older versus younger than 70 years old, versus those without history of ischemic heart disease and those with versus without concurrent CRT use.

Dr Greg Hundley: What about the frequency of implanting ICDs? Was the frequency expected in your results?

Dr Gianluigi Savarese: We add that only 10% of our patients received an ICD at the baseline. This person's age is quite low in particular. If we compare these with other studies in US for example, or also in other European countries and basically, we can only speculate about the underuse of ICD in primary prevention propose. First of all, a certain proportion of ICD underuse may be explained by the fact that we could not assess whether life expectancy was longer than one year, and this is one of the eligibility criteria for ICD according to the guidelines.

Then another point is that in Sweden, the majority of heart failure patients are seen by primary care physician and general practitioners who may have less knowledge and acceptance of device therapy and then higher perception of contraindication. In our previous analysis, we showed that patients not seen by cardiologists have lower likelihood of receiving an ICD and use of devices is higher in centers who do implants, CRT, ICD. So this may be some of the explanation that I can anticipate that some more analysis will follow where we will try to assess the predictors for an under use of ICD for primary prevention.

Dr Greg Hundley: Well, thank you very much. Sana, now we're going to turn to you and help us put this study in perspective to what we have already found or observed in other prior studies related to implantation of cardio defibrillators.

Dr Sana Al-Khatib: As was mentioned earlier, I was the handling associate editor for this paper, so I really enjoyed the handling it and writing an editorial on it. The main points that I wanted to touch on are number one, the significantly low or reduced utilization rate of ICDs. So as was mentioned, the 10% of this patient population received a primary prevention ICDs. Even if you account for some of the new ones is that you can't estimate life expectancy. You can't capture granular clinical data on these patients. So of course some of the non-use of ICDs may have been appropriate. I think 10% by anyone's definition is still pretty low and I'm very encouraged to hear that there are plans to look at predictors of non-use, the characteristics of those patients and hopefully the office can build on their findings and try to implement some strategies to improve the utilization of this life saving therapy.

The other thing that I wanted to touch on is clearly the results are positive in favor of the implantable cardioverter defibrillator. Showing that it significantly reduces all-cause mortality within one year, within five years, certainly reduces cardiovascular mortality within one year. As was mentioned, the reduction in cardiovascular mortality within five years was not significant and to me that is probably mostly explained by competing causes of death in this patient population, but I also cannot rule out the possibility of some mis-classification of causes of death, which is not uncommon. I do want to commend the authors for the great and robust methods that they applied in their analysis. As was mentioned, this was a comparative effectiveness research using observational data. These kinds of analyses can be pretty challenging, but the authors defined their patient population very clearly. They used propensity score matching. In fact, they took it a step further by doing a negative control analysis, meaning looking at hospitalizations for renal failure, for pneumonia, respiratory infections, things like that that you don't expect to be affected by the ICD and they found no difference in that.

And that is amazing to kind of see this level of analysis that I believe really lends their results more credibility. It is important though to keep in mind that when you have 10% of patients getting an ICD, I suspect that this was a highly selected patient population and most likely people who were thought to benefit the most from ICDs were implanted with an ICD. And yet, as I said, that given the robustness of the methods that they use, I actually believe the results. I think the results are credible.

The one last point that I want to comment on is the subgroup analyses that were mentioned. Absolutely important subgroups to look at from a clinical perspective. But I point out the fact that when you start looking at subgroup analyses, and especially when you have a smaller sample sizes and lower event rates that it makes you start thinking about, "Well, are these results valid? Are they believable?" I mean, even honestly, in the setting of a randomized clinical trial, I look at subgroup analyses as hypothesis generating. So I liked that they included those just to kind of really emphasize the importance of looking at these subgroups. But I certainly would not put too much weight on the subgroup analysis results, but overall great results and congratulations to the authors.

Dr Greg Hundley: Fantastic overview, Sana and Gianluigi. So on behalf of Carolyn Lam and myself, we wish you a great week and we look forward to speaking with you next week.

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


Oct 28, 2019

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

Dr Greg Hundley:  I'm Greg Hundley, Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article today involves bleeding and new cancer diagnosis in patients with atherosclerosis and it emanates from Dr John Eikelboom from McMaster University who addresses the question of whether incident GI or GU bleeding when treating cardiovascular disease with anticoagulation is associated with incident cancer. Now, that's a common occurrence that we see frequently clinically, and I'm really interested to hear those results.

Dr Greg Hundley:  How about we start with our articles. And Carolyn, maybe I'll go first this time and my first paper is on mapping and ablation of ventricular fibrillation associated with early repolarization syndrome and it's from Professor Nademanee from Chulalongkorn University. Carolyn, this multicenter study evaluated mapping and ablation of ventricular fibrillation substrates and VF triggers in early repolarization syndrome, also called ERS or J wave syndrome, JWS, among 52 ERS patients for women who are averaged age 35 years with recurrent ventricular fibrillation episodes. Ablations were performed on one. VF substrates defined as areas that had late depolarization abnormalities characterized by low-voltage fractionated late potentials and two VF triggers.

Dr Carolyn Lam:  So... What did they find?

Dr Greg Hundley: So first there were two phenotypes of ERS/JWS. Group one included those with late depolarization abnormalities with the underlying mechanism of high-amplitude J wave elevation that predominantly resided in the right ventricular outflow tract and the right ventricular inferolateral epicardium. They served as excellent targets for ablation. And two, the other was with a pure ERS devoid of VF substrates, but with VF triggers that are associated with Purkinje sites. The catheter ablation of the arrhythmogenic substrates with late depolarization abnormalities was very effective in preventing VF recurrence in group one patients and ablation of VF triggers emanating from the Purkinje system was effective in treating the group two patients.

Dr Carolyn Lam:  Wow, thanks Greg. My first paper is a first randomized double-blind placebo-controlled trial examining the early effects of SGLT2 inhibitors on clinically important endpoints in patients with heart failure and reduced ejection. Recall that outcome trials in patients with type 2 diabetes have demonstrated reduced hospitalization for heart failure with SGLT2 inhibitors. However, few of these patients had heart failure and those that did were not really fully well characterized.

Dr Carolyn Lam:  So DEFINE-HF was an investigator-initiated multicenter randomized controlled trial of heart failure patients with left ventricular ejection fraction less than 40, New York Heart Association Class II to III, GFR above 30, and elevated natriuretic peptides. This DEFINE-HF was published by Dr Kosiborod from St. Luke's, Mid America heart Institute and colleagues. In total, 263 patients were randomized to dapagliflozin 10 milligrams daily or placebo for 12 weeks. There was a dual primary outcome and the first was mean NT-proBNP and the second proportion of patients with a five or more point increase in heart failure disease specific health status on the Kansas City Cardiomyopathy Questionnaire or KCCQ overall summary score or a 20% or more decrease in NT-proBNP.

Dr Carolyn Lam:  So here's what they found. There was no significant difference in average six and 12 weeks adjusted NT-proBNP with dapagliflozin versus placebo. However, for the second dual primary outcome of a meaningful improvement in KCCQ overall summary score or NT-proBNP, significantly greater proportions of patients treated with dapagliflozin experienced clinically meaningful improvements in heart failure-related symptoms, functional status, and quality of life or natriuretic peptides compared to placebo, and these results were consistent among patients with or without type 2 diabetes.

Dr Greg Hundley:  Wow, Carolyn, another sort of feather in the cap for SGLT2 inhibitors. What are the clinical implications specifically for this study?

Dr Carolyn Lam:  Yeah, I couldn't agree with you more Greg, and these findings in particular suggest that dapagliflozin may have a favorable effect on improving disease-specific health status after 12 weeks of treatment in patients with heart failure and reduced ejection fraction. These beneficial effects of dapagliflozin may potentially extend to patients with or without type 2 diabetes. Interesting that the first primary outcome of NT-proBNP was not significantly different. I'm sure we'll hear more.

Dr Greg Hundley:  Very good. Well, my next paper comes from Dr Jeffrey Saffitz from Beth Israel Deaconess Medical Center and it really relates to therapeutic modulation of the immune response in arrhythmogenic cardiomyopathy. Carolyn, inflammation is a prominent feature of arrhythmogenic cardiomyopathy, but whether it contributes to the disease phenotype is not really known. So in this study, the authors sought to define the role of inflammation and the pathogenesis of arrhythmogenic cardiomyopathy by characterizing NF kappa beta signaling in ACM models both in vitro and in vivo and in cardiomyocytes from patient-induced pluripotent stem cells.

Dr Carolyn Lam: Wow, that sounds like a lot of work. So what did they find?

Dr Greg Hundley:  First they found that NF kappa beta signaling is activated in cardiac myocytes in arrhythmogenic cardiomyopathy. Second, BAY 11-7082, a small molecule inhibitor of NF kappa beta signaling prevented development of major features of the disease phenotype. And third, cardiac myocytes express large amounts of inflammatory cytokines and chemotactic molecules in arrhythmogenic cardiomyopathy, reflecting activation of an innate immune response in the heart.

Dr Greg Hundley:  So Carolyn, clinically important features of ARVC or arrhythmogenic cardiomyopathy, myocardial injury and arrhythmias are driven by activation of an immune response in the heart. And the results of this study suggest that Anti-inflammatory drug therapy should be studied to determine if it could be an effective mechanism-based strategy to reduce myocardial damage and risk of sudden death in patients with arrhythmogenic cardiomyopathy.

Dr Greg Hundley:  So Carolyn, how about the other articles in this issue? Can you tell us a little more about them?

Dr Greg Hundley:  Oh, I would love to. We have a primer from Dr Weissgerber entitled Reveal, Don't Conceal Transforming Data Visualization to Improve Transparency, and this primer really outlines strategies for selecting the correct type of figure based on a study design, sample size, and type of variable. It examines techniques for making effective dot plots, box plots, and violin plots and illustrates how to avoid sending mixed messages by aligning the figure structure with the study design and statistical analysis. A really nice primer.

Dr Greg Hundley: We also have a perspective from Dr Verma entitled More Credence for SGLT2 Inhibition. Talk about even more feathers in the SGLT2 inhibitor cap.

Dr Greg Hundley: There's an On My Mind article from Dr Godier on specific antidotes for direct oral anticoagulant reversal. Is it a case closed or a cold case? Dr Godier really concludes with saying that the availability of specific antidotes provides in itself reassurance, but whether DOAC reversal translates into clinical improvements remain unknown and this leaves clinicians in kind of an awkward position and the case is not closed. Read more. It's a very nice piece.

Dr Greg Hundley: We also have a research letter from Dr Mills very interestingly showing that endothelial progenitor cells do not are originate from the bone marrow. Very interestingly, Dr Mills systematically studied the origin of endothelial progenitor cells in people with sex-mismatched bone marrow transplantation using two complimentary methods and found that all the clones formed from single cells were actually derived from the recipient rather than from the donor bone marrow, thus suggesting that endogenous neovascularization in the heart is driven by tissue resident endothelial progenitor cells without a direct contribution from bone marrow cells. A very important piece because it goes against prior pieces and it's consistent with others, so do read this research letter.

Dr Greg Hundley: Finally, there's a cardiovascular key series from Dr Uriel and title It's All About the Tissue and it's a rare case of acute cardiogenic shock.

Dr Greg Hundley: Wow, Carolyn, what great summaries and articles we have in this issue, but how about now we go and learn a little bit more about that GI tract in our feature article?

Dr Carolyn Lam: You bet, Greg.

Dr Greg Hundley: Welcome everyone to our feature discussion and today we're going to meet with Dr John Eikelboom from McMaster University in Ontario, Canada and our own associate editor, Dr Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. The feature discussion paper focuses on the development of lower gastrointestinal bleeding or genitourinary bleeding that may occur in patients with cardiovascular disease that are receiving anticoagulant therapy.

Dr Greg Hundley: So first John, I was wondering, could you tell us a little bit about the hypothesis and why you wanted to conduct this study?

Dr John Eikelboom:  Intriguingly, we set out to do a trial of antithrombotic therapy in cardiovascular disease and our intent originally was not to look at cancer specifically in relation to bleeding. In fact, normally in our cardiovascular trials we don't even collect cancer. But the background story is that there is a hypothesis and there are data that aspirin protects against gastrointestinal cancer and in the COMPASS trial we were testing a regimen that omitted aspirin. So we were concerned that by omitting aspirin this might lead to an increase in cancer. So as a safety measure we very carefully collected all types of cancer during this trial. We were very much reassured that none of the antithrombotic regimens were associated with an increase in cancer, but then we noticed there was a very high rate of cancer diagnosis, about 4% during the course of the trial, and cancer was as common as cardiovascular events. This observation prompted a secondary analysis to see who was having the cancer and in particular with our interest in bleeding where the bleeding identified patients who were subsequently diagnosed with cancer.

Dr Greg Hundley: Can you tell us a little bit about the design of your study and your study population?

Dr John Eikelboom:  The COMPASS trial was designed to test whether an antithrombotic regimen containing rivaroxaban might be more effective than aspirin in preventing cardiovascular events. We included people with chronic coronary artery disease or peripheral artery disease who were randomized to one of two rivaroxaban regimens or aspirin. The results of this main analysis have been previously published the rivaroxaban regimen was associated with more bleeding than aspirin and in particular more gastrointestinal bleeding. Of course, it was more effective than aspirin in reducing the composite of cardiovascular death, stroke, or myocardial infarction. So in this analysis, we then drilled down on the bleeding story and in particular on the gastrointestinal or genitourinary bleeding because bleeding into a hollow viscus has previously been identified as a marker of cancer risk.

Dr Greg Hundley: And who did you include in this study?

Dr John Eikelboom:  We included people with chronic coronary or peripheral artery disease, that is people who were some time away from an acute event. They were more or less stable, although the term chronic is probably better. They were on effective secondary prevention strategies. They'd be your typical patient that a cardiologist, an internist, a vascular specialist, or a neurology would see in their outpatient clinic, an ambulatory patient, where the focus of the clinician would be on cardiovascular prevention.

Dr Greg Hundley: And how many subjects were in your study? Was this a large study?

Dr John Eikelboom:  The study included 27,395 patients from 33 countries and 602 centers, so yes, a large study with a very broad inclusion criteria. This result therefore also is very widely applicable to the secondary prevention cardiovascular populations.

Dr Greg Hundley: So what did you find? What were your results?

Dr John Eikelboom:  We found that there are several highlights. The first, as I've already alluded to, new cancer diagnosis was found in one of 25 people of comparable frequency to the composite of cardiovascular death, MI, or stroke. So that's the first finding. The second funding was that bleeding was very common, that is any bleeding, major or minor, about 10% of the population during an average of two years of follow-up. Then the third and the most relevant finding to our report is that bleeding was a powerful predictor of a new cancer diagnosis.

To describe that a little bit more carefully, among those with bleeds about 10% were diagnosed with a new cancer of any type. And then when we look specifically at gastrointestinal bleeding, it's again around the same proportion of those with GI bleeding who are diagnosed with gastrointestinal cancer but compared with those who did not have gastrointestinal bleeding, those with gastrointestinal bleeding had a twentyfold increased hazard. In other words, the GI bleeding was a very powerful predictor of news GI cancer diagnosis.

Likewise, genitourinary bleeding was a very powerful predictor of new genitourinary cancer diagnosis, about a thirtyfold increased hazard. And when we separated out the urinary bleeding that was the most powerful predictor about a hundredfold increase. And the converse, if we look at bleeding in other areas, they was an association with cancer, but it was much weaker, and this really focuses the attention on bleeding into a hollow viscus, GI tract, the genitourinary tract, and in particular the urinary tract, and it sends up a red flag for clinicians if you bleed into these areas there is a very great increase in the hazard of new cancer diagnosis.

Dr Greg Hundley:  Fantastic, John. So just two quick points and then we wanted to ask Shinya to help us put this study in perspective. The average age of the patients, what was that in this study, what was the gender breakdown, and then did you find any more frequent association of cancer with genitourinary bleeding in men versus women?

Dr John Eikelboom:  The average age was 68 and about one fifth where women, so that is pretty typical of cardiovascular trials, although an area of separate interest because women were relatively underrepresented. Of course, that's another story. In terms of cancer prediction, we didn't separately explore this in men and women and indeed the cancers were dominated by the urinary tract and the GI tract with far fewer genital tract cancers. So we're not really in a position to answer that question. I do accept that very important consideration because clearly, we're going to investigate differently in a man compared with a woman if they have genitourinary tract bleeding.

Dr Greg Hundley:  Well, Shinya, we appreciate having the opportunity to speak with you as an associate editor of Circulation. How do we implement or interpret this data in the context of administration of both aspirin as well as other anticoagulant strategies?

Dr Shinya Goto:  This paper is very important. I mean, that we are cardiologists, we believe we are very away from that cancer, but John and COMPASS group demonstrated cancer is much commonly occurred than we expected, almost similar rate as cardiovascular death within two year in patients recognized coronary artery disease and peripheral artery disease. They are on antiplatelet or anticoagulant agent aspirin, 2.5 milligram b.i.d. of rivaroxaban, plus over 5 milligram b.i.d. of rivaroxaban alone. So CAD/PAD patient on antithrombosis, we have to care about cancer.

And as John beautifully pointed out, if the patient experienced bleeding, like GI tract bleeding, we have to care seriously about hidden GI tract cancer. If a CT scan found GU bleeding, it is an important sign of concealed genitourinary tract cancer. We are very close, so it's a kind of bridging discipline. Cardiology should be close to oncology. As John pointed out, the patient at 68 average age, not so old, it's typical of age of the patient treated by cardiologist. But you know, the message is strong: We have to be careful about the cancer and we have to be careful especially if we found anything in GI tract or GU, so the message is clear.

Dr Greg Hundley:  Well, thank you Shinya. Shinya, I wanted to ask you, what do you think is the next study to be performed in this area of investigation?

Dr Shinya Goto:  If we conducted a cardiovascular trial, it would be nice to add cancer as an endpoint, especially for long-term trial.

Dr Greg Hundley:  John, do you have any perspectives? Where do you see your research going in this area over the next five years?

Dr John Eikelboom:  In addition to the very important point raised by Shinya, I think there are two additional considerations. The one is we need to better understand whether the apparently earlier diagnosis of cancer that can be achieved by exploring bleeding in these cardiovascular patients can improve clinical outcome. We certainly hope that this is good news for patients because we hope to be able to diagnose cancer earlier. The second big question is if we were more diligent in screening for bleeding and in particular occult bleeding in the cardiovascular patient, would that lead or help us to diagnose the cancer earlier?

Dr Greg Hundley:  Well listeners, we've had a great discussion from Dr John Eikelboom from McMaster University in Ontario, Canada, and our own Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. They have highlighted to us this important study result indicating an association of detection of cancer when we observe gastrointestinal and genitourinary bleeding after treatment with both anticoagulant and antithrombotic therapy.

And so for Carolyn Lam and myself, Greg Hundley, we wish you a great week and we look forward to catching you On the Run next week.

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

Oct 21, 2019

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

Dr Greg Hundley:             And I'm Dr Greg Hundley, associate editor for Circulation, from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article, this issue reminds us of the importance of the physical exam in patients with heart failure and reduced ejection fraction involving those that were enrolled in the PARADIGM-HF. Remember a trial of sacubitril/valsartan versus ACE inhibition in those with a reduced ejection fraction? Can't wait to hear more of the discussion of the importance of that physical exam. Carolyn, how about you talk about your first article?

Dr Carolyn Lam:                I will because this first paper reports a novel ventricular tachycardia or VT ablation strategy guided by a voltage independent mapping display during sinus rhythm.

Dr Greg Hundley:             Well, Carolyn, since many of us don't do VT ablations every day, how about a little background on this one first?

Dr Carolyn Lam:                Substrate modification during sinus rhythm is actually the mainstay ablation strategy for scar related VT. With the recent trend being more extensive ablation, aimed to homogenize the entire scar region. These authors are led by Dr Tung from the University of Chicago Medicine Center for Arrhythmia Care, and colleagues. They had hypothesized that a greater understanding of the nature and characteristics of the scar would be most prone to reentry, may actually improve the precision and yield of ablation. Now, they had previously demonstrated that sites critical for reentrant VT localized to regions of activation slowing during sinus rhythm or so-called deceleration zones rather than regions with latest activation. In the current study, they aim to prospectively assess the outcomes of VT ablation guided primarily by targeting these deceleration zones identified by propagational analysis of ventricular activation during sinus rhythm.

Dr Greg Hundley:             Interesting. What did they find, Carolyn?

Dr Carolyn Lam:                They studied 120 patients with scar related VT who are prospectively enrolled in the U Chicago VT ablation registry between 2016 and 2018, who underwent 144 ablation procedures for scar related VT. They performed high density mapping during baseline rhythm and identified the deceleration zones which all localized to successful termination sites in 95% of cases. The median total radio frequency application duration was 29 minutes to target the deceleration zone, representing ablation of 18% of the low voltage area. At a mean of 12 months, 70% freedom from VT recurrence was achieved with an overall survival rate of 87%. A novel voltage independent high-density mapping display may further identify the functional substrate for VT during sinus rhythm and guide targeted ablation thus obviating the need for extensive radio frequency delivery.

Dr Greg Hundley:             Fantastic, Carolyn.

                                                Well, my first paper is from Professor Mark Nicolls from Stanford University. It's entitled Phenotypically Silent Bone Morphogenic Protein Receptor 2 or Bmpr2 mutations, that predispose rats to inflammation induced pulmonary arterial hypertension by enhancing the risk for neointimal transformation. While being the most common inherited risk factor for pulmonary arterial hypertension, Bmpr2 germ line mutations only result in disease in 20% of mutation carriers. A finding that suggest a second hit is required to elicit vascular pathology. Transgenic mouse models of Bmpr2 mutations were developed in this study to better understand the relationship between these phenotypically silent gene mutations and the predisposition to pulmonary arterial hypertension.

Dr Carolyn Lam:                Huh. What did they find Greg?

Dr Greg Hundley:             In this new two hit model of disease, Bmpr2 mutant rats subjected to pulmonary inflammation, developed severe pulmonary arterial hypertension with vascular remodeling and the pulmonary arterial endothelial cell transformation that occurred did so in three phases. An initial apoptosis phase induced by exogenous LTB4. Second, a proliferative phase relying on P38 mediated noncanonical TGF-beta signaling. And then finally a terminal inflammatory phase in which pulmonary arterial endothelial cells utilized the canonical TGF-beta pathway, expressed mesenchymal markers and produced LTB4, IL6 and NF-kappa beta signaling molecules. The clinical implications include that in phenotypically silent Bmpr2, haploinsufficient individuals, a second hit of pulmonary inflammation may put them at risk for subsequently developing pulmonary arterial hypertension. And this lung inflammation while usually self-limited may cause durable and inflammatory vascular lesions in these genetically susceptible patients.

Dr Carolyn Lam:                Wow, that is super interesting. Thanks Greg for that great summary.

                                                Well, my next paper really looks at the temporal trends in survival after pediatric in hospital cardiac arrest in the United States. This is from Dr Holmberg from Beth Israel Deaconess Medical Center and colleagues who performed an observational study of hospitalized pediatric patients who received CPR from January 2000 to December 2018 and were included in the Get With the Guidelines resuscitation registry.

Dr Greg Hundley:             Carolyn, what did they find?

Dr Carolyn Lam:                They found that survival has improved for pediatric events requiring CPR in the US with a 19% absolute increase in survival for in hospital pulseless cardiac arrests and a 9% absolute increase in survival for non-pulseless events between 2000 and 2018. However, survival from pulseless cardiac arrest appeared to have reached a plateau following 2010. The increase in survival over time is reassuring and perhaps provides some evidence for the progress of quality improvement efforts. However, given the plateau and survival following 2010, there is a continued need for clinical focus and new interventions to improve outcomes of pediatric in hospital cardiac arrests. And Greg, are you now going to tell us what's in the mailbag?

Dr Greg Hundley:             Absolutely Carolyn. Professor Wei, from Harvard, provides a new perspective on using the restricted mean survival time difference as an alternative to the proportional hazards model and hazard ratios for analyzing risk in clinical cardiovascular studies. In another article, Eric Peterson from Duke provides a white paper discussing randomized clinical trials versus EMR extracted data to inform new therapies in cardiovascular disease. And he really reviews what are the issues we need to overcome using these EMR strategies? And on my mind piece from Dr Glenn Levine from Baylor, discusses the role of psychological wellbeing as it relates to cardiovascular disease. And then we have a large series of letters in this issue.

                                                First, Otmar Pfister and Kari Nytrøen, each have letters regarding high intensity interval training. Dong-Vu Nguyen, asked for several points of clarification regarding the utility of BNP assessments in syncope and whether other metrics incorporating clinical information could be useful. There's a corresponding response from Christian Müller from the PRICIPLE study with great discourse. And then finally an important research letter from Dr Rodés-Cabau in Quebec, evaluates the left atrial occlude or thrombus occurrence among eight centers in Canada and in this letter provides data that suggests thrombi can occur in those that have implanted left atrial occluders and raises considerations for anticoagulation of these patients. Great set of letters in this issue of the journal.

Dr Carolyn Lam:                Absolutely Greg and thanks for sharing that. Let's go onto our feature discussion.

Dr Greg Hundley:             You bet.

                                                Welcome everyone to discussion of our featured article and today we have Senthil Selvaraj from University of Pennsylvania and our own Mark Drazner, associate editor at Circulation from the University of Texas Southwestern and we're going to be discussing some very interesting results regarding the physical exam as they've been generated from the PARADIGM heart failure trial. And remember that's a prospective comparison of an Angiotensin Receptor-Neprilysin inhibitor with an angiotensin converting enzyme inhibitor to determine the impact of those two therapies on all-cause mortality and also morbidity in heart failure. Senthil, welcome to this discussion. We're very excited to have the opportunity to discuss your article and I wonder before we get started, could you tell us a little bit about the background and the hypothesis for why you wanted to perform the study and then afterwards tell us a little bit about the study population and the methods.

Dr Senthil Selvaraj:          I think the impetus for this study torn out of the fact that we do the clinical exam so often, and I think like many cardiology clinicians in the community, we perform this so often, but we don't know what the actual impact is of performing the clinical exam. What I wanted to understand and the primary motivation was to really understand what the change in the physical exam meant in terms of subsequent prognosis. Does decreasing congestion actually relate to improved cardiovascular outcomes? I think this is an area that is hard to study by randomized controlled trials. In my opinion I think there is not so much equipoise in performing a trial of decongestion versus no decongestion. I think this is sort of one way that we can understand epidemiologic methods, whether lowering congestion improve outcomes.

                                                I had a number of other interesting analysis. I think the first is we've had a number of studies that have evaluated the physical exam, but I think that an updated analysis in a population receiving contemporary management was particularly important, particularly given the fact that the risk rad versus insignificantly in the past couple of decades essentially related to improvements in therapy. The second is we formed the physical exam in conjunction with a number of other additional forensic markers in the use of validated risk scores that to understand those and have utility above and beyond this. For instance, can I just check a natural aside and will that be doing a physical exam. And I think while that's easier, I don't know that that necessarily is the right thing to do. And that was another motivation.

Dr Greg Hundley:             What was your overall study design and your study population?

Dr Senthil Selvaraj:          The overall study design was to use the PARADIGM-HF cohort. And in our analysis, we did a time updated analysis, which is different than many other analyses previously done. That means that every single point that a patient goes into a clinical trial visit, we updated their physical exam, possible because the study investigators did perform an exam at each of these visits. And so what we did was we used the physical exam and number of signs of congestion as the time bearing covariate and looked at its relationship to outcomes, but also just as importantly why might think decreasing congestion or changing congestion has really stuck out as very important about to want to feel better. And I anything quantifying that relationship while it's intuitive I think is also very important.

Dr Greg Hundley:             And just remind us who's in PARADIGM heart failure? Well what was the study population? And just very quickly the randomization arms?

Dr Senthil Selvaraj:          PARADIGM-HF was a randomized controlled international multicenter trial of patients with heart failure ejection fraction which has been defined in this study as less than or equal to 40%, near two, three or four symptoms, elevated natriuretic peptides, depending on the trial compared an angiotensin converting enzyme inhibitor and Angiotensin Neprilysin inhibitor to control valsartan.

Dr Greg Hundley:             Tell us what were your study results? And how did they pertain to the outcomes that were gathered in PARADIGM-HF?

Dr Senthil Selvaraj:          We first divided our cohort based upon the total number of signs and as might imagine increasing congestion was associated with a number of adverse clinical features. We then looked at the association between the number of signs and the efficacy outcomes, which included a primary composite outcome of time to heart failure, hospitalization as well as cardiovascular mortality and then we individually looked at those as well as all-cause mortality. And as we show in our paper, there was really a striking relationship between time updated times of congestion as well as all of the efficacy adjusted for baseline natriuretic peptides which are available in all of our participants in PARADIGM-HF as well as MAGGIC risk score and New York Heart Association class to get at the question of whether improving congestion, where the relationship congestion above and beyond symptoms is still valid.

                                                The other thing that we did is because we only looked at natriuretic peptides at baseline is that we've formed a sub study where we evaluated, since you had natriuretic peptides during follow-up as well at the one month visit and eight month visit and compare the utility of signs of congestion and outcomes and you can still see that there was a significant relationship in this sub analysis. The participants would complete NP data. We further looked at relationship and congestion and quality of life and there is a significant relationship such that for every sign of congestion that you decrease, there is a five-point increase in KCCQ, the quality of life score which some have considered to be a clinically significant increase in times of congestion.

                                                We also looked at the relationship between the treatment arm and reduction of congestion as sacubitril/valsartan was associated with significant reduction in clinical congestion, which has mirrored its impact on natriuretic peptides as well. And finally to understand whether reducing congestion was actually associated with improved outcomes, we entered both the baseline congestion and change of congestion into models that looked at the relationship with outcomes and found that change of congestion was a very strong predictor of outcomes even after baseline congestion, which we interpreted to mean that reduction in congestion was a mutable factor, and that reducing congestion is actually associated with improved outcomes.

Dr Greg Hundley:             Signs of congestion on the physical exam, you had JVD, peripheral edema, rales, and then an S3 and so you're adding those up and making a score. And so when one of those particular findings dropped off in terms of score, that's what you're indicating by change in congestion, is that correct?

Dr Senthil Selvaraj:          That's really correct. We analyzed this in two methods. The first is a dichotomous presence of a physical exam science. As you said, the presence or absence of JVD, the presence or absence of a DMO rales and an aspirate. The investigators also graded two of those signs of congestion, which included a DMN rale that we formed a complimentary analysis where we created a sign score where we gave partial credits to gradations of the physical exam and we saw very similar outcomes as well.

Dr Greg Hundley:             Mark Drazner at UT Southwestern has done a lot looking at the importance of our physical exam and assessing patients with heart failure. Mark, how do you feel the results of this study compare with previously published works?

Dr Mark Drazner:             Thanks Greg. First, always a pleasure to join you on this and I do want to congratulate Dr Selvaraj and his team on this outstanding paper to generate considerable enthusiasm among the editorial team and reviewers I'd say. It's a really interesting study for several fold and you've heard a lot of the important methods by Dr Selvaraj already. I would just highlight there've been a number of previous studies that have looked at markers of congestion from physical exam and showed that they had prognostic utility, but a major question that has been addressed to me personally and I think in the field, does that add any independent information beyond just sending BMPR natriuretic peptide level measurement?

                                                And this analysis here as you've heard, one of the big advances was that they were able to adjust for natriuretic peptide levels and showed that the exam or the markers of congestion did add independent prognostic information. I think that's an important step forward, as is bringing the relevance again about the markers of congestion and prognostic utility to patients being receiving the most modern-day therapy including ARNI therapy, which is unparalleled opportunity because of the PARADIGM trial to look at that question. I think those two are really set this paper. I think this is going to be a standard, this is the standard for assessing prognostic utility congestion in heart failure by far in the literature in my opinion.

Dr Greg Hundley:             What we're saying is that our following the patients and identifying these physical exam changes during an initiation of ARNI therapy can be really helpful in determining that particular patient's long-term prognosis. Coming back to both of you, maybe first Mark and then we'll come back to Senthil, what do you see is the next study in this field? Both in terms of new therapies in heart failure and the relationship of physical exam and then also perhaps just briefly some thoughts on ARNI therapy.

Dr Mark Drazner:             I think this paper highlights the incredible importance of congestion in modern day therapy. And there are a number of other studies that looked at this recently, including there's an analysis of TOPCAT preserved heart failure showing again congestion being linked to adverse outcomes. I think that question is resolved that even in modern day therapy. The next step in my opinion is to understand why clinical congestion, the pathway from clinical congestion to adverse outcomes. What are the links? Can we target those links to try to interrupt that cycle? And what is the most effective way to achieve decongestion? We heard that now ARNI appears to be a mediator of decongestion and we need more work on that I think. I would say looking at the pathway from congestion to adverse outcomes and then what is the optimal way to decongest our patients.

Dr Greg Hundley:             Very good. Senthil, do you have anything to add to that?

Dr Senthil Selvaraj:          I think that's great. I completely agree with Dr Drazner on this. I think one question would be to understand truly as Dr Drazner said, the optimal way to decongest patients and so for instance, the way that we have traditionally done this is by increasing diuretic. There are a number of experimental and novel ways that we can decongest patients. I think one unanswered question actually is does increasing a diuretic potentially at the expense of activating the renin angiotensin aldosterone access, actually afford benefit if you decongest patients. It's an analysis that I think is ripe and timely and not been adequately addressed. I think that that would be one potential way to go. And the second is, I think as you mentioned in clinical trials, I think clinical congestion may not be an outcome, a pre-specified outcome of course. But I do think that it is an important outcome aside from just looking at decreases in other surrogate markers such as natriuretic peptides. It's easy to perform. It's collected on many investigator visits during these trials and therefore these are ripe analyses.

Dr Greg Hundley:             Listeners, we look forward to speaking with you next week and have a great week.

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


Oct 14, 2019

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

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

                                                Well, Carolyn, we've got a great feature article to discuss later in our interview today. We're going to compare surgical versus percutaneous aortic valve replacement, but now with coronary artery revascularization. So, very exciting results from the SURTAVI trial.

                                                So, Carolyn, do you have a couple papers to discuss?

Dr Carolyn Lam:                For sure. Actually, it's exactly a couple, and it's a couple of GWAS papers. The first is a GWAS of the cardiac magnetic resonance imaging derived left ventricular phenotypes of the UK bio bank. It comprises almost 17,000 European-UK bio bank participants without prevalent myocardial infarction or heart failure. So this was led by professors Petersen and Monroe from Queen Mary University of London, and colleagues who found that prognostically important left ventricular imaging phenotypes were highly heritable, with a heritability of 22 to 39%. A total of 14 genetic susceptibility low PSI, eight of which were unique, enriched in the cardiac developmental pathways and regulation of contractile mechanisms were discovered, and the polygenic risk scores of left ventricular phenotypes were predictive of heart failure events independently of clinical risk.

Dr Greg Hundley:             Well, Carolyn, knowing me and MRI, something I really am interested in. So tell us a little about what are the clinical implications?

Dr Carolyn Lam:                Well, the findings not only enhance our understanding of the genetic basis of prognostically important left ventricular phenotypes in the general population, but they also underscore the intricate genetic relationship between these endo phenotypes and the pathogenesis of heart failure. The prioritized genes in the genome whites significant load size should be followed up in the functional studies to aid the development of potential novel therapies in future. The polygenic risk scores of left ventricular phenotypes may have a role in personalized risk stratification. But this, of course, is dependent on further validation of the clinical robustness in future studies.

                                                I want to skip onto my second GWAS paper, and this time dealing with bicuspid aortic valve. So, first a little reminder that bicuspid aortic valve disease is a congenital defect that affects 0.5 to 1.2% of the population, and is associated with comorbidities including ascending aortic dilatation and calcific aortic stenosis. To date, while a few causal genes have been identified, the genetic basis for the vast majority of bicuspid aortic valve cases remains unknown. Today's paper from Dr Lipschultz from Medical University of South Carolina reports novel human genetic based models, which developed bicuspid aortic valve and aortic stenosis with high penetrance.

Dr Greg Hundley:             Very interesting. So, how did the authors do this, Carolyn?

Dr Carolyn Lam:                Yeah, it is interesting. What they did is they performed a GWAS and replication study using cohorts of more than 2,000 patients with bicuspid aortic valve and more than 2,700 controls, which identified the primary Celia genes as associated with the bicuspid aortic valve phenotype. Specifically the most associated snips were identified in or near genes that are important in regulating Ciliogenesis through the exocyst, which is a shuttling complex that chaperone Celia cargo to the membrane. Genetic dismantling of this exocyst resulted in impaired Ciliogenesis through the XO CIS, disrupted Ciliogenic signaling, and resulted in a spectrum of cardiac defects in zebra fish and aortic valve defects including bicuspid aortic valve, valve stenosis, and Velveeta calcification in murine models as well. So this data really supports that the exocyst is required for normal Ciliogenesis during aortic valve morphogenesis and really implicates the disruption of Ciliogenesis, and its downstream pathways may contribute to bicuspid aortic valve and its associated comorbidities.

Dr Greg Hundley:             Wow. Very interesting. Learning more and more about bicuspid valves through our journal. I'm going to shift Carolyn and talk about an article from Dr Marc Sabatine from the TIMI study group at Brigham and Women's hospital. This study performed a systematic review and a trial level meta regression analysis of three classes of lipid lowering therapies that reduce triglycerides to a greater extent than they do LDLC. Fibrates, Niacin, and Marine derived Omega-three fatty acids and key inclusion criteria were a randomized, controlled trial that reported on major vascular events. The study also incorporated data from a previous Meta-regression of 25 Statin trials, and the main outcome measure was the risk ratio for major, vascular events associated with absolute reductions in lipid parameters.

Dr Carolyn Lam:                Oh, very interesting. So did the study show that it was beneficial to lower triglycerides or not?

Dr Greg Hundley:             Let me tell you a little more about it. The study encompass 374,358 patients that sustained 46,180 major cardiovascular events, and in their multi-variable Meta-regression model, that included terms for both LDLC and triglyceride surrogates for LDL and VLDL. The risk ratio was 0.8 per one millimole per liter reduction in LDLC, and 0.84 per one millimole liter reduction in triglycerides. Therefore, a reduction in non-HDLC, a measure of atherogenic LDL and VLDL particles, is strongly associated with lower risk of major vascular events regardless of the lipid lowering drug class, and triglyceride lowering is associated with a lower risk of cardiovascular events, but to a lesser extent per absolute amount of reduction then with LDLC. Interesting, Carolyn one study reduce it and impacted the study results, and nearly all non-statin trials did not achieve significant non-HDLC lowering to detect a clinical difference in major vascular events. Now how about in regards to Omega- three dose?

                                                Well, each one gram per day of EPA administered was associated with a 7% relative risk reduction in major vascular events, whereas there was no significant reduction in major vascular events with DHA. So the benefits of Marine-derived Omega-three fatty acids, particularly high dose EPA, appear to exceed their lipid lowering effects.

Dr Carolyn Lam:                Wow. Interesting. So Greg, take it home for us. What should we do clinically about this information?

Dr Greg Hundley:             Carolyn, developing drugs that achieve large reductions in VLDL and triglycerides and are targeting patients with high baseline levels of triglycerides would likely increase the probability of showing a meaningful clinical benefit, and fibrates could be considered in patients needing further non-HDLC lowering, being mindful of side effects, as they should offer clinical benefit proportional to the degree of non-HDLC lowering, and if a disproportionate relationship between lipid lowering and cardiovascular risk reduction is validated in ongoing high dose Omega-three fatty acid trials, it will support the hypothesis that confers a unique benefit of this class of agents beyond simply their lipid lowering.

                                                How about that?

Dr Carolyn Lam:                Very nice Greg and I think very balanced and good clinical take home messages. Tell us what else is in the mailbag.

Dr Greg Hundley:             We have so many interesting articles in Circulation and let me just run through a quick list of those that are also in this issue. First, Dr Jere Mitchell, from UT Southwestern, reviews the 50th anniversary of the Dallas Bedrest Study that involve five 20-year-olds that underwent several weeks of bedrest, and he discusses how this informs many of our thoughts regarding the benefits of activity today, and one of his major coauthors is Dr Ben Levine. Our own Josh Beckman reviews the ongoing efforts of physicians to understand the role of paclitaxel coated stents for those undergoing peripheral arterial interventions. Dr Berlinde von Kemp, in our case series, identifies that not all cardiomyopathy, after delivery, is simply postpartum cardiomyopathy. In another article, Dr Anurag Agrawal discusses what's on their mind regarding the use of spirometry as a cardiovascular disease risk assessment tool, should it be incorporated into existing cardiovascular disease risk models.

                                                Then, we have a great letter back and forth discussion from Dr Junfeng Wang, Dr Daxin Wang, and our own Naveed Sattar in three separate letters that discussed the relevance of age of onset for type two diabetes relative to cardiovascular risk. Then, finally our own Carolyn Lam reviews the role of biomarkers in heart failure and preserved ejection fraction.

Dr Carolyn Lam:                Let's hop on to our feature discussion, shall we?

Dr Greg Hundley:             Absolutely.

Dr Greg Hundley:             Welcome everyone to the discussion of our featured article today where we're going to review an excellent study comparing TAVR versus SAVR in patients with aortic stenosis, but also now considering simultaneous coronary artery revascularization. Discussing our article today we have Dr Thomas Engstrøm and then our own associate editor, Dharam Kumbhani. Well Thomas, welcome to our podcast featured article discussion. I wonder if you could start us off with a little background regarding your study. What were your hypotheses, and then tell us a little about your study population and your methods.

Dr Thomas Engstrøm:     Now, as you know, up to 50% of patients that are treated for aortic stenosis have coronary artery disease, and this may be considered as a bystander disease to develop disease, but definitely also adds to the prognosis for the patients. A priority guideline recommends that if you do SAVR, you'll also have significant coronary artery disease. What we don't know is if the complete percutaneous approach is as good as a surgical approach. Maybe do TAVR plus PCI comply with fiber plus CABG. That's the background for the study.

                                                Now, the population involved in this study is the population from the search TAVR trial, which as you know compared TAVR to SAVR in patients that were clinically at intermediate risk and in patients that had severe aortic stenosis. If patient had additional coronary artery disease with a syntax called Bob 22, they were excluded from the trial. We are talking about intermediate risk patients with low syntax score. Of the patients in the TAVR trial, 20% had additional coronary artery disease and were resterilized. In the paper, we compare TAVR plus PCI versus SAVR plus CABG in those patients with significant coronary artery disease.

Dr Greg Hundley:             How did you define the presence or absence of coronary disease? Just real quickly before we get to your results.

Dr Thomas Engstrøm:     This was at the discretion of your operator to define where the patients had coronary artery disease or not. In the paper, patients were defined as having significant diseases. More than 70% of stenotic lesions were present in one or more coronary arteries.

Dr Greg Hundley:             And so can you tell us, Thomas a little about the results of your study?

Dr Thomas Engstrøm:     First of all, the patients that had additional coronary artery disease had a poor prognosis than those that only had valve substitution, which is probably not a surprise. Within those that also had coronary artery disease, TAVR plus PCI appeared to be as good as CABG plus SAVR in terms of the primary endpoint, which was all because mortality or disabling stroke after two years. Then, if you dive more deeply into the endpoint and the number of secondary endpoints were pre-specified, there were no differences regarding any stroke myocardial infraction and in total no differences between what you could call major heart end points. If you look more into detail of the secondary endpoint, there are subtle differences. Patients that were in the SAVR plus CABG had more atrial fibrillation as they also had more acute kidney injury following that treatment. Whereas, in the TAVR plus PCR, more patients had vascular complications and of course had the need for pacemaker implantation. There are differences between the outcome in the two groups, but not in regard of pre-specified primary and more important secondary endpoints.

Dr Greg Hundley:             Dharam, I was wondering if you could help us think about what this means for the field in terms of both from aortic valve replacement, and then also the concomitant management of coronary disease in patients that require aortic valve replacement.

Dr Dharam Kumbhani:   As Thomas just pointed out, I think this is a very important question. This comes up all the time in patients with severe aortic stenosis, being evaluated for best options, and the guidelines have stayed true to this that if somebody has concomitant coronary artery disease, then the guidelines typically would recommend SAVR as the first option because then they can have CABG at the same time. This study really seeks to address a very important knowledge gap in the field, and as he very well pointed out, this does restrict itself a little in terms of the population, because they couldn't have a high syntax score, actually an intermediate or high syntax score, and they need in the trial...I think the main syntax score was eight or nine. I think that is important, but having said that, more than 50% of the patients had multi-vessel disease, and it was really impressive that nearly 15 or 17% still had three vessel PCI even in this arm.

                                                I think it's important for people to recognize that although this was the lowest syntax score, multivessel PCI was still pursued. I think that's definitely an important takeaway from the strike. It's a really important trial. It's one of the very few pieces of information that we have that is prospectively done under the auspices of a big trial like SURTAVI, and with low risk approval in and what this means for patients going forward I think will be very exciting to see how this few devolves.

                                                Thomas, as this field matures, could you walk us through, in terms of did you do the valve first and then the coronaries, or where the coronaries worked on first and then the valve? That's sort of the first question. Can you walk us through how you make those decisions?

Dr Thomas Engstrøm:     It was up to the discretion of the operator whether to do a concomitant procedure, both PCI and TAVR, or to state the procedures in that way that PCI was done first, and this could be done up to seven days before the TAVR. If you compare those two groups, and now numbers become a little bit few, so we can't be conclusive here. It appears that patients that had stage procedures did poorer than those that had concomitant procedures done. Of course, it raises some questions. The prioritization as to do it in one way or the other was that through concomitant procedure, you may introduce too much of stress to the patient. Otherwise, if you do a stage procedure, it's best to do the PCI first, because the actual appearance of the valve may make it more difficult and cumbersome to address the coronary arteries. To sum this up, in the patients that we have, it appeared that a concomitant procedure is safe.

Dr Greg Hundley:             Dharam, tell us, what do you think is the next step forward for this field? What do see as the next study moving forward here?

Dr Dharam Kumbhani:   I think this study really sets the stage for, I think future trials where perhaps we would have... So I'm doing this in this trial. The stratification was done based on whether or not they need to revascularization. I think going forward, again with LOTUS approval here and proliferation of the number of TAVR procedures that are being offered everywhere, I think it will be helpful. This study would set the stage for future studies, where I think you would prospectively have patients with needing an aortic valve replacement and perhaps even complex revascularization, and how that was kind of actually the randomization, which is the stratification strategy, which again was very helpful. These are really among the first few data that we have of this, but I think this kind of sets the stage for future investigations in this space. And then as I briefly alluded to, I think this may help evolve or this may help in the evolution on the guidelines as well.

                                                Thomas, would you like to add anything to that?

Dr Thomas Engstrøm:     Yeah, I completely echo that. Going back to the old syntax trial, it would be very interesting to see if PCI holds through, even in high tunes, syntax scores with newer drug eluting stents, and also of course the question of the diabetics is totally unsolved in this cohort. CABG plus SAVR may turn out to be the best solution, but we still are waiting to see data that can support any of the two strategies in those patient cohorts.

Dr Greg Hundley:             We want to thank Thomas Engstrøm and also our own Dharam Kumbhani. We look forward to seeing you next week.

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


Oct 7, 2019

Dr James de Lemos:        My name is James de Lemos. I'm the executive editor for Circulation and I'll be filling in today for Carolyn Lam and Greg Hundley, and delighted to host the podcast for the annual cardiac surgery themed issue. I'm joined today by Tim Gardner from the University of Pennsylvania who leads the surgical content in Circulation year-round, as well as by Dr Marc Ruel, who's the guest editor for this issue and the Chief of Cardiac Surgery at the University of Ottawa and has really led the development of this issue. Marc, Tim, welcome.

Dr Timothy Gardner:      Thank you.

Dr Marc Ruel:                    Thank you. Good afternoon.

Dr James de Lemos:        And Marc, thanks for all you've done to bring this issue home again this year. It's really wonderful to see this thing develop. Why don't you start us off and tell us how this issue came together and what the purpose of this is? Why do we publish a specific issue focused on cardiac surgery?

Dr Marc Ruel:                    We're really delighted that Circulation has taken the stance as the cardiovascular community's premier cardiovascular journal. I think as an important piece of this is the fact that cardiovascular surgery already has a resurgence intermediate with importance despite new percutaneous options and medical therapies available. There's more and more patients who find himself in need advance path if you will, of an advanced cardiovascular disease and surgery can be performed with safer and better outcomes constantly.

                                                So, I think this issue obviously aims to gather the very best of cardiovascular surgery, not only including cardiac surgery, but also there's actually one of the papers on peripheral vascular surgery.

Dr James de Lemos:        We'll start Tim with you if you don't mind. I'd like to talk about two papers. One from Stanford that focuses on inter-facility transfer of Medicare patients with Type A dissection and then a research letter that studies hospital volume effects with abdominal aortic aneurysm surgery from Salvatore Scali and colleagues at the University of Florida. Can you walk our readers through these papers and lead the discussion on these?

Dr Timothy Gardner:      The first paper focused on inter-facility transfer of Medicare recipients with Type A dissections. First off, underlines the fact that this is a very difficult, serious condition with mortality rates in this series there ranging between about 22 and 30%. And the purpose of the study was to analyze how these Medicare patients with acute aortic Type A aortic dissections are managed and whether the effect of high or low volume hospital experiences influences the mortality. As I think we might expect, patients who receive care at high volume aortic surgery centers have a lower mortality. Then the question is, what is the effect of transfer from a low volume or from a hospital without aortic surgery capabilities? What is the net effect there? The benefit of care and a high volume hospital is pretty clear. The mortality rate is significantly lower and the need to transfer or the actual fact of transfer does not increase the risk to the patient.

                                                It's an interesting challenge because we do know that patients with acute aortic dissection, if their repair or surgery is delayed, we'll have a predictable accumulating mortality. However, what this study shows is that the benefit of transfer and the importance of experience with this complicated aortic surgery. And it really brings up this very challenging issue of regionalization, of acute care or specialized care.

                                                We really struggle with this in so many aspects of surgical care, medical care in general, but especially procedural care. We realize that we need to be able to provide emergency care in many areas and we don't want to suggest that that smaller hospitals may not be able to care for patients with acute complex illnesses. But on the other hand, if transfer can be accomplished and if the availability of high volume experience can be achieved, that this is something that we really need to look at carefully. I think that this study brings that into pretty good view.

Dr Marc Ruel:                    James, I think that Tim has already captured the essence of this paper. The results are impressive in this excellent series and the really carefully led analysis. This is an important paper and it's very thought provoking.

                                                There’re two clans among surgeons. Those that believe that every cardiac surgeon who was named as such should be able to perform safely aortic dissection repair and another client and somewhat sustained or supported by the data from this paper that says that this is a special expertise that should be or regionalized and put through centers of excellence. So this paper would support the latter theory.

Dr James de Lemos:        The next paper, which was a research letter, sort of adds fuel to this fire of regionalization, doesn't it? At least insofar as we're talking about the more complex procedures.

Dr Timothy Gardner:      Yes, this paper studies the hospital volume effects on surgery for abdominal aortic aneurysms, an even more common and somewhat less lethal, but very morbid condition. And this analysis of center volume for care of these patients is complicated even a little bit more because as we know, endovascular repair of abdominal aortic aneurysms is now the most common form of treatment.

                                                Interestingly, in looking at the outcomes in a variety of centers with varying volume procedural volumes, there was no difference in outcomes when endovascular repair was done, but there was inverse relationship between volume and outcomes after classical surgical repair. This really highlight a change that's occurring in vascular surgery where, with endovascular repair being done more commonly, surgeons are having less exposure unless experience with open repairs. This is particularly a challenge for training programs where you have a surgical resident or fellow for two years and he or she may experience relatively few open repairs.

                                                So, this again, the data seems to suggest that higher volume vascular surgery centers, where the numbers of open repairs are done, have better results and that this is not nearly as much, in fact, it wasn't an issue for endovascular treatments, but it again highlights the procedure of volume outcomes relationship. I think this is something we're going to have to deal with both in terms of optimizing patient care, even considering when we're training new or young avascular surgeons, they may have to move to different centers to ensure that they have the kind of exposure to classical surgical treatment for those complex patients who are not candidates for endovascular repair.

Dr James de Lemos:        Let's change gears. We've been talking about two systems of care issues, but let's get back to the complicated patient themselves and talk about a paper Mark from Kato and Pellikka from Mayo Clinic, focusing on hemodynamic and prognostic impact of concomitant mitral stenosis in patients undergoing surgery or TAVR for Aortic Stenosis.

Dr Marc Ruel:                    As you say, this is an intricate clinical problem that we not uncommonly meet when we provide care for patients who have severe aortic stenosis. These are not young patients. These patients in this particular series of 190 patients with severe aortic stenosis, they also had some significant degree of mitral stenosis. These are patients that had a mean age of 76 years. I think we've all encountered these patients estimations, so someone has severe aortic stenosis and has some form of calcific mitral stenosis. And indeed in this series, more often than not, the vast majority of those patients had calcific MS as opposed to a Rheumatic MS. So, a different type of pathology probably to what we see in the elderly patients coming in with some degree of inflow obstruction.

                                                So, the authors took their 190 patients, mostly from the Mayo clinic, but also from Tokyo, about five patients contributed from Japan, and matched in one to two with some controls who also had the same degree of severe aortic stenosis, the same age, same gender, same left ventricular ejection fraction, but didn't have mitral stenosis. And then compare their fate over a couple of years. Essentially, what the authors found is that in patients with severe MS, which was defined as a trans-mitral gradient of equal or higher than four millimeters of mercury, the midterm survival was decreased. The hazard of death was increased by about 90% or so. And there was also a classification, the sub classification based on the fate of the patient with regards to the echocardiographic findings, as to whether the patient truly had mitral stenosis at the time of presentation. So prior to the aortic valve replacement or whether the patient had pseudo-mitral stenosis. How the authors classify this, is those patients in whom the mitral valve area remained less than two centimeters square before and after aortic valve replacement were classified as having true mitral stenosis.

                                                The authors provide a number of maybe predictors, if you will, or correlates perhaps a more appropriately termed as such, of patients who would be generally believed as having true mitral stenosis. And these included, for instance, in the mitral valve area was less than 1.5 centimeters square at the time of presentation, if calcium involved at both the anterior and the posterior leaflet on echo. And there was also the concept of Andler excursion. So, basically the distance between the apex and the analyst of the mitral Valve, half of the patients had true mitral stenosis and the other half saw an increase in the mitral valve area above two centimeters squares after aortic valve replacement.

                                                I think still that we don't have an answer to the question as to whether the mitral valve should already be intervened upon in this series. It was an observational series, so there's no arm where the mitral valve was actually intervened on, and we know that often this intervention is not easy to do if it's by TAVR, there's not a lot we can do on the aortic valve and if it's at surgery, often these patients may have extensive mitral annular calcification, which is not an easy undertaking to fix at the time of surgery.

                                                So, whether these patients, even the ones with true MS are better served by just addressing the aortic valve or adding a mitral valve intervention in addition to the AS treatment still remains an unresolved or unanswered question. But I think this paper helps tremendously with regards to identifying patients who may have the true mitral stenosis concomitant problem at the time of presentation with a severe AS.

Dr James de Lemos:        This was news for me actually. The high prevalence of pseudo MS in this context, I think many of us are very familiar with this with aortic stenosis and low output, but to see this in the context of serial valve lesions was really instructive for me. Tim, what are your thoughts?

Dr Timothy Gardner:      I think this is a really important observation to remind ourselves of in this TAVR era. If you have the heart open and you're doing the aortic valve replacement and you notice this, you can get a picture of this severity of the mitral stenosis or the mitral valve involvement, but I think that in the TAVR era, this finding, this possibility of significant mitral stenosis related to a more severe aortic stenosis has to be accounted for and taken into account.

Dr James de Lemos:        Excellent. The next paper I'd like to talk about is another original article from Shudo and Joe Wu at Stanford. Remarkable series really of almost a thousand heart-lung transplants that were done and reported in UNOS. Tim, can you walk us through this paper and its implications?

Dr Timothy Gardner:      heart-lung transplantation was done first at Stanford and actually by one of my close colleagues. Bruce Reitz in 1981. It was a really an operation and in the tradition of the innovation there in transplant surgery at Stanford. The operation, primarily for patients with end stage lung and heart disease, was done reasonably often at adventuresome and well-experienced transplant centers in the eighties and nineties and it's used less often today because we found that even in patients with end stage lung disease and concomitant ventricular failure that many of those patients can be treated successfully with double lung transplantation.

                                                So, that has resulted in a decline in use of heart-lung block transplantation. The other problem is that as they mentioned in the article that a donor becomes available and you can get two or three patients treated by taking the individual lungs and the heart for three recipients rather than using the whole block for one. That's been another reason why it's been harder to get these heart-lung blocks. But for some patients with end stage heart disease and irretrievable lung disease, this is a great option. There's a few patients with end stage congenital heart disease who have developed irretrievable Eisenmenger's complex with severe pulmonary irreversible form of hypertension who are still candidates for this, but this analysis of the 30 year experience at Stanford and using the UNOS database as well is very interesting and shows the importance of donor selection as a really significant effector of outcomes.

Dr James de Lemos:        Yeah, well I was also struck by the recipient factors too. It looks like selection in both directions is so important. The group that was remarkable to me was the markedly poor outcomes in the group that had heart-lung transplant after ECMO, that five times increase in mortality. That really struck a chord, particularly given what we're seeing now with ECMO accelerating somebody's status on wait lists. I don't know Mark or Tim, do you want to comment?

Dr Timothy Gardner:      That's a very useful observation and where an individual patient ends up on the acuity list as a potential recipient with UNOS rules, it is ECMO support does get them to a higher level of urgency and yet, as is shown in this series, the morbidities or co-morbidities associated with a patient who requires ECMO support prior to transplantation is pretty consequential. And as you said, those were the features of the recipient, the degree of co-morbidities or co-morbidity complications also impact the outcome.

                                                We're still struggling to find the best way to deal with rescue patients both with mechanical support and with transplantation, organ transplantation, and even in the case of heart failure, with destination therapy with mechanical devices, we're still struggling in an area where the challenges are high, and the best practices are not always as well clarified as we would like.

Dr Marc Ruel:                    And I would echo those concerns. I think the prohibitive results that we see after ECMO reflect the reality that there's not a lot of intermediate therapies available for patients who require heart-lung transplants. We have them for the heart now. We can move from ECMO and not go directly to an LVAD or to a transplant because we have implantable axial devices that can be put in percutaneously and basically can arrest the inflammatory response and the major cascade derangements that we see with ECMO.

                                                Unfortunately that is not available to replace both the heart and lungs, so I think there's still some medical advances, surgical advances that are necessary to bridge the gap because that gap right now is real and it's not a gap, it's a cliff.

Dr James de Lemos:        Great discussion gentlemen. Let's talk next Marc, about a research letter that was a case series from Cleveland Clinic from Donnellan and Desai, focusing on a fairly large group of individuals that had received mediastinal radiation therapy previously and then underwent valve surgery for radiation-induced valve disease.

Dr Marc Ruel:                    We were happy to receive this research letter from the Cleveland Clinic because clearly that institution, and maybe a few others around the world, have a special expertise in dealing with the uncommon, but very, very challenging issue of patients with the surgical radiation-induced mitral valve disease. And in fact, radiation-induced carditis. On average, these were patients who were seen about 17 years after their chest irradiation and I guess the main message that can be seen from this paper is that there's often multiple cardiac issues in those patients. They don't just have, for instance, a single valve, in this case the mitral valve, being affected. But the vast majority all tolled of around 80, 85% of patients required not only either another valve, but valve plus bypass or bypass surgery to be performed as well.

                                                So, there are clearly patients where there's been a lot of physical/irradiation damage, not only to the mitral valve, but to the entire heart. It's also, when you look at this series of these 146 patients, you can see that many had an increase in the right ventricular systolic pressure on echo and probably some degree of RV dysfunction as certainly we've seen episodically in our practices.

                                                So, hospital mortality outcomes are pretty good, but the results are humbling. 51% mortality at 2.8 years. And these patients were on average 60 years of age. So looking at U.S. life tables, when someone's 60 years, I've made it to 60, they usually have at least another 20 years on average to live. But these unfortunate patients, despite their cardiac operation performed, having been performed safely, have about an 18% death rate per year.

                                                I think the jury's still out as to which are clear indications to offer these patients surgeries with the humbling results that we see even at a center of excellence by the Cleveland Clinic. But I think this is a foray into a very difficult cardiac problem for which there was limited literature before and certainly that's something that's very relevant as we refer to very advanced cardiac surgical therapies for patients with advanced disease.

Dr James de Lemos:        Mark, you're actually a coauthor on our State-of-the-Art piece, evaluating arterial grafts and CABG, reviewing after the publication of art and radial. What were the main conclusions from your review and interpretation?

Dr Marc Ruel:                    Essentially, there's a discrepancy right now with regards to the use of multiple arterial grafting. The observational series have almost uniformly showed that patients who receive multiple arterial grafts live longer and do better, et cetera, but I think this has to be taken for what it is. There's an inherent indication bias or confounding by indication that goes into allocating that therapy to patients who are perceived to have the potential to do well in the long-term. There may also be an expertise bias at the institutions that provide this and those patients may be receiving better secondary medical therapy or guidelines directed medical therapy, etc. So, maybe a halo effect that comes into play.

                                                In counterpart, the randomized control trials of which the latest was the arterial revascularization trial. Now available with data at 10 years, have shown essentially very little difference which regards to the use of multiple arterial grafts on long-term outcomes. Even looking at cardiac-specific outcomes like myocardial infarction. Actually the more compelling data came from their Radial Alliance, also led by Mario Gaudino who is the author of this, State of the Art paper.

                                                The conclusion of the article is that we need a trial and we need to include the radial artery. The answer may not necessarily lie with the use of mammary arteries, but it may be that the radial artery is more user friendly and more robust. So the new ROMA trial has been designed with that in mind. Comparing one arterial graft versus as many arterial grafts, as long as it's more than one in the test group that the surgeon wants to use. And the surgeon, she or he can use the right internal thoracic artery or radial artery in order to complete the revascularization.

                                                That trial is ongoing. Enrollment is on track and hopefully should provide answers to this very relevant question.

Dr James de Lemos:        You know that discussion about the limitations of clinical trials, Tim, I think leads really nicely into the frame of reference you received from Eugene Blackstone and Cleveland Clinic, doesn't it?

Dr Timothy Gardner:      Yeah, and it was really an article worth everybody reading. It's a short opinion piece and he points out the fact that we really have competing standards for choosing therapy. Sort of the standard traditional evidence based medicine, evidence-based medical care versus precision medicine which focuses on individual patients risk factors and so on. It's sort of the average treatment effect that we may be able to demonstrate well in randomized clinical trials versus real world experience with various therapies based on the risk profile of the patient. It's a really excellent article and as many of us know Gene Blackstone is a very thoughtful student of statistics in surgery and this is, I think, an excellent article. I'm really grateful for his doing this opinion piece for us.

Dr James de Lemos:        The last opinion piece we have is from Mike Farkouh in the group in Toronto. Can you just give the readers and listeners a bullet about what they might expect in that piece?

Dr Marc Ruel:                    I think it's one of the remaining big questions, if you will, in myocardial revascularization as to what should be done with diabetic patients in multi-vessel coronary artery disease who have an acute coronary syndrome and require revascularization. A very well written piece and certainly that instructs what probably the next five years we'll see in terms of big study questions in coronary REVASC.

Dr James de Lemos:        First I'd like to recognize Sarah O'Brien from the Circulation Editorial Office for her tremendous work for pulling this issue together. She's really the glue that brings this issue together every year and thank as well Marc, for your leadership again of this effort and Tim for your ongoing leadership at circulation with our cardiac content and vascular content as well as liaisoning with our surgical colleagues.

                                                Dr Marc, you get the last word. Can you please summarize the thoughts you'd like to leave our listeners with?

Dr Marc Ruel:                    Thank you, James, for your generous comments and also for your support of cardiovascular surgery in and of the team issue. I think again, we have a fantastic issue this year and we really want to gather the very best of cardiovascular surgery and we want to get the highest impact papers. Circulation is home for the best data, the best outcome, say the most interesting answers to important clinical questions that are around cardiovascular surgery.

                                                There's definitely an editorial desire to help with the best of cardiovascular surgery science. And I think I want to again launch a call to cardiac surgical investigators and cardiovascular and surgical investigators in general to consider circulation as your home.

Dr Timothy Gardner:      Yes. And if I could just add to that, not only are we interested in a surgery-themed issue annually that really highlights some of the best articles that we have to publish, but we also want some of the best surgery science during the course of the year. And just remind our surgeon colleagues that the particular advantage to having a paper published in circulation is the exposure of that study to a broad cardiovascular community. Not just surgeons, the predominant readership obviously of circulation, or cardiologists and other cardiovascular specialists. So that's the big advantage you get by having your best work published in circulation. We'd love to see more of it.

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


Sep 30, 2019

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

Dr Greg Hundley:             And I'm Greg Hundley, associate editor at Circulation and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, have you ever wondered about instead of coding a stent, coding balloons with paclitaxel? Well, the feature article day is going to look at mortality assessments of paclitaxel-coated balloons in a meta-analysis from the ILLUMENATE clinical program, the three-year outcomes. Do you have a paper you want to start us off?

Dr Carolyn Lam:                I sure do. First of all, we know that diabetes impairs atherosclerosis regression following cholesterol lowering in both humans and mice. Now in this process of plaque regression, what's the role of functional high density lipoprotein or HDL, which is typically low in patients with diabetes?

                                                Well, this first paper that I chose looks just at that and it's from Dr Fischer from New York University School of Medicine and colleagues, who aimed to test if raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages and enhances atherosclerosis regression following cholesterol lowering. So to do this, the authors used aortic arches containing plaques, which were developed in LDL receptor null mice, and these were transplanted into either wild type or diabetic wild type or diabetic mice transgenic for human APL lipid protein A1, which have elevated functional HDL.

Dr Greg Hundley:             So Carolyn, what did they find in this interesting study?

Dr Carolyn Lam:                Well, diabetic wild type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. The benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte neutrophil production capacity. ACL also suppressed the general recruitability monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2 phenotype, which is an atherosclerosis resolving state. There was also a decrease in plaque neutrophil extracellular traps or nets, which are atherogenic and increased by diabetes. So raising apolipoprotein AI and functional levels of HDL promoted multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques in diabetic mice after cholesterol lowering. And this may represent a novel approach to reduce cardiovascular risk in patients with diabetes.

Dr Greg Hundley:             Really interesting, Carolyn. Well, I'm going to talk to you a little bit about a large study in patients with valvular heart disease and it's a contemporary presentation and management study and it's from the Euro Observational Research Program Valvular Heart Disease II, Roman numeral two, survey. And the corresponding author is Professor Bernard Iung from Bichat Hospital. So the VHDII survey was designed by the Euro Observational Research Program of the European Society of Cardiology to analyze actual management of valvular heart disease and compare practice with guidelines.

                                                Now in short, patients with severe and native valvular heart disease or previous valvular intervention were enrolled prospectively across 28 countries over a three-month period in 2017. Indications for intervention were considered concordant if the intervention was performed or scheduled in symptomatic patients corresponding to class one recommendation specified in the 2012 ESC and in the 2014 American Heart Association American College of Cardiology valvular heart disease guidelines.

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

Dr Greg Hundley:             Okay, so there's 7,247 patients. 4,483 were hospitalized, and 2,764 were outpatients, and they were included across 222 centers. The median age was 71 years and 1,917 patients were over the age of 80, and 3,400 were women. Now, aortic stenosis was present in 2,000 plus patients, aortic regurgitation in 279, mitral stenosis and 234, mitral regurgitation in 1,114. And multiple left-sided valvular heart disease was present in 1,297, right-sided valvular heart disease in 143, and 2,028 patients had prior vascular intervention.

                                                So the decision for intervention was concordant with class one recommendations in symptomatic patients with severe single left-sided valvular heart disease in 79.4% of those with AS, 77% with aortic regurgitation, 68.5% for mitral stenosis, and 71% for primary MR. Valvular interventions were performed in 2,150 patients during the survey. Of them, 47.8% of the patients with single left-sided native valvular heart disease were in New York Heart Association class three or four, and transcatheter procedures were performed in 38.7% of the patients with AS and 16.7% of those with MR.

Dr Carolyn Lam:                Wow, Greg. So what are the take home messages? That was a lot of numbers.

Dr Greg Hundley:             Yep. Lots of data there. And so couple things. First, recommendations for interventions in symptomatic patients with severe valve disease are better applied today in this paper than in the previous European survey conducted in 2001, particularly for those individuals with aortic valve disease. Second, multi-modality imaging is now more frequently used, but stress testing remains underused in asymptomatic patients. And finally, transcatheter therapies are now widely used in patients with stenotic valve disease, and we would expect that, particularly for the use in the elderly.

Dr Carolyn Lam:                Great, Greg. So what are the clinical implications?

Dr Greg Hundley:             Okay, so Carolyn, first, late referral for intervention shows the need for increasing awareness of valvular heart disease by general practitioners and cardiologists. Second, the high burden of elderly patients highlights the need for multidisciplinary heart team approaches to assess the risk benefit ratios of the different modalities of valvular interventions. And finally, number three, echocardiographic quantification of regurgitation should be more accurate and pay more attention to quantitative measurements. Those are the main take homes from this large registry analysis.

Dr Carolyn Lam:                Nice. Thanks, Greg. My next paper is the characterization of the first transgenic mouse model of ARVC 5. Now, that is the most aggressive form of arrhythmogenic right ventricular cardiomyopathy caused by a specific mutation in transmembrane protein 43. So this paper's from co-corresponding authors, Dr Lara-Pezzi from CNIC in Madrid and Dr Garcia-Pavia from Hospital Universitario Porto de Hero in Madrid, and with their colleagues, they generated transgenic mice over expressing transmembrane protein 43 in either it's wild type or that specific mutant form in postnatal cardiomyocytes under the control of alpha-myosin heavy chain promoter.

                                                And they found that these transgenic mice expressing the specific mutant in transmembrane protein 43 showed fibro fatty replacement of the myocardium and died at a young age. The model confirmed that transmembrane protein 43 is mostly localized at the nuclear membrane and provides new information regarding the pathophysiological mechanisms underlying ARVC five. One of them is that the GSK3 beta signaling pathway plays an important role in this disease.

Dr Greg Hundley:             So that's great, Carolyn. Sounds like we have a new model that's been created by this group and certainly this disease has spread. It's something we definitely worry about. Do you see any therapeutic implications for their work?

Dr Carolyn Lam:                Great question, and indeed the authors tested two new therapeutic approaches for ARVC five. In the first they found that targeting fibrosis really had no beneficial effect. But in the second, they found that inhibition of GSK3 beta improved cardiac function and survival, thus opening the way to a new therapeutic approach focused on GSK3 beta inhibition in patients with ARVC five.

Dr Greg Hundley:             Very good. So we look forward to seeing what the results of that study will be. How about now we talk about some of the other articles in this issue?

Dr Carolyn Lam:                I love that. I think it's a great idea to tell everybody about this amazing issue. So we start with an article from our Global Rounds, and this time from Argentina, so a great status update and future strategies for cardiovascular disease in Argentina. We also have a perspective paper and that's on the new World Symposium on Pulmonary Hypertension guidelines, really questioning some of the cutoffs that we've taken for granted and asking, "Should 21 be the new 25?" Intrigued? Well, you really need to pick this one up and read it.

                                                And then there's a white paper, and this is a report from the 2018 NHLBI workshop that really talks about unlocking the secrets of mitochondria in the cardiovascular system and asking if this may be a path to cure in heart failure. We also have a research letter, and I love these. They're so succinct and really contain an important message. And this one talks about the evolution of Medicare formulary coverage changes for antithrombotic therapy after the guideline update. So very topical subject.

Dr Greg Hundley:             Very good, Carolyn. So I've got a couple. There's a Paths to Discovery article that John Rutherford did discussing with Paul Zimmet regarding reflections of the evolving global diabetes epidemic. Second, there is a very nice On My Mind piece from Samuel Tretheway from Birmingham, England who discusses medical misinformation, kind of like medical fake news. And he discusses how this occurs and it depends on the motivation of both authors and publishers, and he reviews responsibilities of all of us, how to avoid generating this type of material. And then finally, a really interesting Cardiology News piece by Bridget Kuehn, who discusses diet and microbes in heart failure, and with that there's a very nice piece of artistry work that would be great for your office. So that's all included in the journal.

Dr Carolyn Lam:                Oh, you got us all curious. Finally, I just want to highlight, we have a section called Highlights from Major Meetings, and this time from my part of the world with Dr Aijun Sun and Dr Junbo Ge summarizing the 13th Oriental Congress of Cardiology takeaways. Cool issue, isn't it?

Dr Greg Hundley:             Absolutely. So how about onto our feature discussion?

Dr Carolyn Lam:                You bet, Greg.

Dr Greg Hundley:             Welcome everyone to our feature discussion. And this afternoon or this morning, wherever you may be, we are going to have an opportunity to discuss the utility of paclitaxel-coated balloons in terms of management of patients with peripheral arterial disease. And our article today comes to us from Bill Gray and colleagues from Mainline Health in Philadelphia, Pennsylvania. And we have our own Josh Beckman, associate editor from Vanderbilt, who will be joining us in the discussion. Bill, welcome to Circulation. We really appreciate you sending us this article. Can you tell us a little bit about the background of why you wanted to perform your study and also, what was your study design, study population?

Dr William Gray:               The study was really prompted by a prior report by Katsanos et al in JAHA about nine months ago. When we started this study, it was much more fresh. And what we did was we realized we had data from multiple studies using the Stellarex drug-coated balloon that we could use to address some of the issues raised with the Katsanos paper. Just to review that briefly, the Katsanos paper suggested that there was a significant mortality signal in patients who were randomized to drug-coated balloons using paclitaxel versus PTA or patients randomized to drug eluting stent versus PTA or other stents. That signal was seen late at two years and at five years, and so we sought a given the data, the tightly controlled and well-reported data and this experience to see if we could see a signal as well.

                                                The study design really involved taking all the data from the randomized trials, and there were two, which comprised an aggregate of about 600 patients, unequally randomized, about 400 in the drug-coated balloon arm and about 170 or 200 patients in the PTA arm. And then we also looked at all the poolable data, which was controlled data, so we had two randomized control studies I mentioned just a minute ago, as well as three single arm studies in one registry. Now, these had quality oversight and data reporting. And then those data were adjudicated for adverse events, including death, by a blinded third party CEC, and then those data reported out by Kaplan–Meier estimates as well, and then we do a multi-variable analysis looking at predictors of death, and then I can talk about that in a moment. Importantly, the data here has followed out to three years. As I mentioned before, the original paper which incited the concern had reported unequal deaths at two and five years, so we're somewhere splitting that difference. That's the genesis of the study and the study design.

Dr Greg Hundley:             So Bill, tell us now about the results.

Dr William Gray:               It turns out the baseline characteristics were largely similar between these trials and the patient arms, even though they weren't strictly speaking the same trials, except that the drug-coated balloon arm was a bit younger and smoked more frequently, so they were at a little bit more risk. In the randomized control analysis, which was done first, there was no difference in all-cause mortality between the PTA patients and the patients who received paclitaxel drug-coated balloons. That was true at one year, two years and three years. When we looked at the pooled analysis, which included not only the drug-coated balloon randomized trial patients, but also all the single arm studies and registries, we also found that there was no differences between those treated with drug-coated balloons in those additional studies and the control group of 170 patients in the randomized trial arm of PTA alone.

                                                Interestingly, when we started to look at the multi-variable analyses, we did something that we ordinarily would not do, but because of the pressing issue around paclitaxel mortality, we actually did a standard covariate analysis looking at predictors and then we forced drug and drug dose into the model to see if they would come up positive as a predictor of outcome. As you might expect, not surprisingly, we found that age, congestive heart failure, diabetes and renal insufficiency were the four major predictors of mortality in a group of patients who were largely claudicates with significant peripheral vascular disease. No surprise there. We all know the patients don't die of claudication, they die of cardiovascular disease, and this I think bears that out.

                                                When we force drug into the model, in point of fact, not a dose nor the presence of drug had any impact on death rates in the model, so there was no predictive value there whatsoever. Those are the results. Again, they're out to three years, and I think one of the important things that we have to recognize is that the numbers are relatively small and the follow-up is relatively limited and by itself, although it doesn't show any signal, it probably doesn't stand on its own to refute a larger meta-analysis, but does I think contribute to the dataset that is becoming more evident that the individual analysis do not appear to show mortality effects.

Dr Greg Hundley:             Very good. So this is Dr Josh Beckman at Vanderbilt University. Josh, could you talk to us a little bit and put this paper in perspective relative to the prior published literature in terms of how you manage patients with peripheral arterial disease?

Dr Joshua Beckman:        I have to say first, I'm really glad that we're able to publish this paper from Bill Gray and his group. We are, and I'm going to put this in really muted terms, in extraordinary times. I have never seen what is going on now happen with any other technology or really even medical therapy in the 20 plus years I've been a practicing physician. I think for the audience, it's really important to understand what is going on right now because if you don't pay attention to this space, you may not realize what's really been happening. Bill did a nice job at telling you why he did the study, which was this Katsanos aggregate level meta-analysis that was published in JAHA back in December.

                                                On the basis of this paper, there has been a rapid development of worry and concern that these devices may be associated with late mortality. This concern has spread to the Food and Drug Administration, which has now put out three letters to healthcare professionals, each of them basically suggesting that you should choose non drug-coated either balloons or stents first, and if you want to use these, you have to have an extended conversation with the patients discussing the risks. And so in response to this aggregate level meta-analysis, which had an extensive number of lost to follow-up patients and didn't account for crossovers and the usual problems with this kind of information, I have been really impressed by the community of people who are interested in this topic and work with these kinds of devices.

                                                And by that, I mean, the response has not just been a series of editorials. The response has really been, "Let's find every single piece of data that we can find to see whether or not this signal holds up," because as evidence-based physicians, we take one piece of data and say that it is one piece of data, and then we have to put it into the context of all of the other pieces of data that were published. And so I know that Dr Gray is old enough to remember 10 years ago when these devices were being used in the coronary arteries with drug eluting stents. And as far as anybody can tell with studies that were two to three times larger or meta analyses two to three times larger than the study published in December, there was no mortality signal.

                                                It should be made clear that in doses that dwarf the doses from these devices, when these medications are given to pregnant women who have breast cancer, not only is the mother fine but the fetus is fine. And so I think paper that we are discussing this morning in particular, but the group of investigators in the space has really stepped forward to publish as much data as possible to fill out our understanding and place the original study in the correct context. And so when you understand what's happening in the community, and there's been a significant reduction in the use of these devices on the basis of that one publication at the expense of patients for whom these devices are really much better at limb outcomes, then you can understand why we were so interested in the paper by Dr Gray.

                                                This is another brick in creating the foundation to really have a fuller and better understanding of any possible relationship between the use of these devices and a nonspecific increase in mortality two to five years later, which as far as I can tell, I've never seen something that may end up being a poison that doesn't have a specific mechanism of causing morbidity or mortality. And so when we got this paper, I was really happy to be able to work with Bill and bring it to the level that it is now so that when it's published in October, it's going to be another really important contribution and I just want to congratulate the authors for doing that work. I will say, and I'd like to get Bill's perspective on how he thinks the information that's now being published is going to help us understand what to do with these devices.

Dr William Gray:               Yeah, that's a great question, and I want to emphasize something you brought up, which I did not, which is at the aggregate level data that Katsanos used to publish his analysis was really all he had access to, which means that he had some numerical data from prior published publications but did not have patient level data. And so what Josh is referring to appropriately is the concept that each individual holder of those data, those patient level data, are now coming forward with their own analysis of those data at a patient level, which allows us to look more granularly and more clearly at the causes of death. For example, in this study, the causes of death did not cluster around cancer. They were largely cardiovascular, and they were not dis-equally distributed or unequally distributed between the two groups.

                                                So I think that patient level data, to get back to your original question, Josh, the patient level data will be incredibly important from each of the experiences with the various drug-coated balloons and drug eluting stents on the market because it does allow us to look more closely at the mechanism of death and whether there's any putative cause that might be assigned to paclitaxel. As you mentioned, the pharmacology of this is not understandable. The only type of pharmacology that would work like this was if paclitaxel was radioactive and accumulated a hazard along the way, but we know that's not true.

                                                I think extend your question, it's important to say that both the FDA and other independent groups like VIVA have looked closely at the meta analytic data both from a patient level and aggregate level data set, and they have seen a signal at five years. The problem with that is that data starts to winnow down very quickly at five years. There's not a lot of numbers, so that's the first problem, and the meta-analysis that have followed the publication by Katsanos. The second problem is, as Josh alluded to, there's a lot of missing data. Either patients withdrew or got lost to follow-up, and that didn't happen at an equal distribution between the control and the active arms, so there's some ascertainment bias there.

                                                And lastly, there's a crossover, that is patients who are in the control arm crossed over near as we can tell at a rate of about one in five or one in four to an active arm in the first year alone, which means they need to be reassigned to a risk pool that includes the original assignment of paclitaxel randomization. My sense is that those data will not get any better in the near-term future because the problems I just listed are not going to go away anytime soon. And so we are left with these individual patient level data and other big data, like Medicare analyses of tens of thousands of patients or Optum insurance analyses of again, tens of thousands of patients, which actually show no difference between the treatment with paclitaxel in the real world and patients treated with non-paclitaxel devices. So while we are comfortable and happy to publish these data and we think that are meaningful in terms of contributing to the larger dataset, we recognize the flaws and the limitations in the meta-analysis, which will not be solved soon or quickly.

Dr Joshua Beckman:        So, I totally agree with what you just said. I will also say that every time data like this is published, it adds to the picture to make our understanding clearer. And you are responding directly to the Food and Drug Administration, who basically said they are not settled on this question either. It is noted, they are worried about it, and what they've really asked for is for more data to be published. And so when people analyze data like these, I think it is really helpful to the rest of us to create a fuller and more granular picture of the overall state of the field.

Dr Greg Hundley:             We want to thank again both Josh for his time and Bill for his time. Hope you have a great week, and both Carolyn and I look forward to sharing with you again next week. Take care everyone.

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


Sep 23, 2019

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

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

Dr Carolyn Lam:                Greg, what do you think is the association between preeclampsia and hypertensive diseases of pregnancy and cardiovascular disease and future? Well, we're going to find out in a large U.K. pregnancy cohort of linked electronic health records, the CALIBER Study, but that's a feature discussion that's coming right up.

                                                I think we need to start by discussing this week's hot issue. For the first paper, we know that the incidents of acute cardiovascular complications are highly dependent on the time of day. Greg, have you ever wondered what mechanisms drive the rhythmicity of ischemic vascular events?

Dr Gregory Hundley:       You know what, Carolyn, I had a dream about that and I think that somehow maybe it might be something to do with leukocytes.

Dr Carolyn Lam:                Good guess, Greg. Well, Dr Christoph Scheiermann and his colleagues from University of Geneva looked at this and they examined the role of rhythmic leukocyte adhesions and what those play in different vascular beds. They did this by evaluating leukocyte recruitment in vivo with real time, multichannel fluorescence intravital microscopy of a TNF alpha induced acute inflammation Murine model.

                                                Now, they also used ablation of sympathetic nerves or adrenergic receptors to assess their relevance for these rhythmic leukocyte adhesions. Basically what they found was that leukocytes adhere to arteries and veins following a circadian rhythm in mice, with adhesion peaking in the arteries in the morning and in the veins at night.

                                                These peaks in leukocyte adhesion at different times in the two vascular beds were associated with increased vascular inflammation and shortened times to local basal occlusive events occurring out of phase between the arteries and the veins. The differences in cell adhesion molecules and leukocyte adhesions were ablated when disrupting the sympathetic nerves, thus demonstrating their critical role in this process and the importance of beta2-adrenergic receptor signaling. Neat, huh?

Dr Gregory Hundley:       Really neat. It's interesting how that ties together sympathetic nerve activity and leukocyte adhesion.

Dr Carolyn Lam:                You got a paper?

Dr Gregory Hundley:       I've got a paper to discuss and it's from Dr John Cooke at the Houston Methodist Research Institute. It's involving nuclear S-nitrosylation and how that defines an optimal zone for inducing pluripotency, the ability to generate induced pluripotent stem cells or I.P.S.C's from somatic cells as it enhanced the field of regenerative medicine.

                                                It has facilitated studies of development in differentiation, promoted insights into pathobiology, and generated a novel platform for drug discovery and testing. In fact, work in this area has been sufficient to induce nuclear reprogramming to pluripotency and galvanized our whole scientific community. Recently in 2012, this work was recognized by the Nobel Prize for physiology or medicine.

Dr Carolyn Lam:                Wow. What did this week's paper show in this area?

Dr Gregory Hundley:       Well, Carolyn, in this study, the team identified an optimal zone. They call it the Goldilocks zone of innate immune activation for nuclear reprogramming to pluripotency. The authors believe that this Goldilocks zone for nuclear reprogramming may have broad relevance for epigenetic control, for regenerative processes, and for the pathobiology of cancer and even other diseases.

                                                Consequently, the results from this study may help to develop methods that identify whether a patient or tissue is in an optimal zone of inflammatory signaling to improve surgical and medical therapies. In addition, they may provide a method to detect early inflammatory signaling and DNA accessibility and thereby reverse these processes to guide cancer prevention.

Dr Carolyn Lam:                Oh wow, Greg. It sounds like a real landmark paper. Everyone, you've got to pick that one up. As with this next paper, it is the first randomized trial comparing internal cardioversion by commanded shock and external cardioversion in patients with ICD's who present in atrial arrhythmias.

                                                Dr Lüker and colleagues from University Hospital Cologne randomized 230 consecutive patients with ICD's undergoing elective cardioversion for atrial arrhythmias at 13 centers and they randomized them to either internal or external cardioversion. The primary safety endpoint was a composite of lead or device malfunction and conversion of the atrial arrhythmia to sinus rhythm was the primary efficacy endpoint. Myocardial damage was studied by measuring troponin release in both groups.

Dr Gregory Hundley:       I really like where this study's going. What did they find?

Dr Carolyn Lam:                They found that external cardioversion was superior for the restoration of sinus rhythm, with shock efficacy of 93% in the external cardioversion group compared to 65% in the internal cardioversion group. There were three cases of preexisting silent lead malfunction that were unmasked by the internal shock resulting in lead failure. Troponin release did not differ between the groups.

                                                In summary, these findings suggest that external cardioversion may be considered as the first line approach to electrical cardioversion in patients with ICD's and atrial fibrillation. Because silent lead malfunction may be present in some ICD patients, internal cardioversion may be considered in select patients to detect it and with no difference in adverse events associated with internal or external shocks. That's a good sign but needs to be evaluated in larger randomized trials.

Dr Gregory Hundley:       Oh, very nice, Carolyn. Well, my next paper is entitled the Androgenic Effects on Ventricular Repolarization and it's a translational study from the International Pharmacovigilance Database to iPSC-cardiomyocytes. The corresponding author is Dr Joe-Elie Salem from Vanderbilt University Medical Center.

                                                Male hypogonadism arising from a range of ideologies, including androgen deprivation therapies and other things, has been reported as a risk factor for acquired long QT syndrome, as well as torsade de pointes. The authors searched the International Pharmacovigilance Database, VigiBase, for men and they had 6,560,000 plus individual case safety reports presenting with long QT syndrome, torsade de pointes, or sudden death associated with androgen deprivation therapies.

                                                In cardiomyocytes derived from induced pluripotent STEM cells from men, they also studied the electrophysiological effects of androgen deprivation and dihydro testosterone.

Dr Carolyn Lam:                That's super interesting. What did they find, Greg?

Dr Gregory Hundley:       It's one of these combinations of a clinical study as well as basic science. Of the 10 androgen deprivation therapies examined, seven had disproportional association reporting odds ratios of one four to four seven with long QT syndrome, torsade de pointes, and sudden death. The minimum medium times to sudden death were from 0.25, a quarter of a day, to 92 days respectively. The androgen receptor antagonist, enzalutamide was associated with more deaths than any other androgen deprivation therapy used for prostate cancer.

                                                In the basic science experiment, in induced pluripotent STEM cells acute and chronic enzalutamide at 25 micromolar, a. Significantly prolonged action potential durations, b. Generated after depolarizations and activity, c. Inhibited delayed rectifier potassium currents, and d. Chronically enhanced late sodium currents.

                                                Interestingly, dihydrotestosterone at 30 nanomolar reversed the enzalutamide electrophysiologic effects on these induced pluripotent STEM cells.

Dr Carolyn Lam:                Again, really interesting approach from this Pharmacovigilance Database as well as bench work and clinical work, but what do we do with this information?

Dr Gregory Hundley:       Couple of key points, Carolyn. One, men receiving androgen deprivation therapy are at increased risk for drug induced QT prolongation and torsade de pointes. Two, in men developing acquired long QT syndrome or torsade de pointes, a diagnostic workup might include evaluation of testosterone blood levels, androgen deprivation therapy intake, and evaluation for endocrine conditions associated with hypogonadism. Three, in men treated with androgen deprivation therapy for example, for prostate cancer, other risk factors for torsade de pointes should be sought and corrected to avoid any accumulation of risk. And finally number four, in men treated with androgen deprivation therapy, the role of electrocardiographic monitoring to detect QT prolongation really requires an additional study.

Dr Carolyn Lam:                Cool, Greg. What else in the journal did you find cool?

Dr Gregory Hundley:       Yeah, this is great, Carolyn. We're going to start now with sort of a new format where we go through all the other wonderful information. We're just going to trade back and forth.

                                                The first one I'm going to tell you about is a letter from James Tisdale who is from the College of Pharmacy at Purdue University, and he demonstrates in a small randomized controlled trial that transdermal testosterone attenuates drug induced QT lengthening in older men. Really kind of links back to that study I just told you about.

Dr Carolyn Lam:                Nice. Well, I want to highlight an on my mind paper and it's entitled, Chronic Severe Aortic Regurgitation, Should we Lower Operating Thresholds? This is from Dr Desai at Cleveland Clinic and he considers newer EchoMRI methods to assess the severity of aortic regurgitation and determine suitability for valve intervention. It's a large study and just a really nice read of a short on my mind paper.

Dr Gregory Hundley:       Excellent. Well, you know we also highlight excellent reviews in circulation and the one I'm going to discuss briefly is from Schuyler Jones from Duke and he revisits the role of primary aspirin for primary prevention of cardiovascular disease.

                                                He talks about the indications, that there are really few indications for aspirin in those with diabetes mellitus, community dwelling elderly individuals, and patients without diabetes who are at intermediate risk for atherosclerotic events. Also, he discusses the role of aspirin and reviews very nicely the role of aspirin in primary prevention including the optimal drug formulations, different dosing schedules, weight-based dose selection, and the interplay between sex and treatment response. It's a great review.

Dr Carolyn Lam:                Ah, and then from a nice in-depth review we also have a perspective, a nice short read. This one is from Dr Simari from Kansas who discusses diversity in clinical trials and you know, his title is actually a question, when will clinical trials finally reflect diversity? Really lovely paper. He points out that to increase the diversity of enrollment, we need to consider expanding the diversity of investigators. So, a nice piece there, too. Thanks, Greg. That was a super chat. Shall we go on to our feature discussion now?

Dr Gregory Hundley:       Absolutely. Welcome everyone to discussion of our featured article focusing on hypertensive disorders in pregnancy, and then the subsequent long-term outcomes related to that. For our author discussion, we have Fergus McCarthy from Ireland and the Irish Center for Fetal and Neonatal Translational Research at Cork. Then, we also have our associate editor, Sharon Reimold.

                                                Fergus, could you tell us a little bit about what was your thinking behind starting this study? What type of questions were you trying to answer? And then after that, tell us a little bit about the study design.

Dr Fergus McCarthy:       I'm an obstetrician by trade and we have this funny paradox where a lot of us know that pregnancy is not just about the nine-month periods that a woman is pregnant and then ultimately delivers, that what happens in pregnancy can influence long-term maternal health. But despite this, we have this paradox whereby a woman becomes pregnant, the pregnancy may be complicated by hyper pressure in pregnancy, the woman delivers her baby, goes home and often doesn't see a healthcare practitioner for possibly another 10, 20 years.

                                                Even though we know if a pregnancy is affected by high blood pressure, we don't really do a huge amount about it and we deal with this funny situation. We know that high blood pressure in pregnancy affects two to 8% of pregnancies, depending on the population studied. What we wanted to do was examine specifically the impact of hypertension or high blood pressure in pregnancy on long-term maternal health.

                                                But importantly, what we also wanted to try and determine was is there any factor that may be modifiable that may be ultimately able to improve or reduce the long-term morbidity associated with having hyper pressure in pregnancy? So, if you have high blood pressure in pregnancy, is that it or is there anything that we maybe could make women aware of that may ultimately improve their long-term health?

                                                Also as I said, despite research documented in the association between preeclampsia, which is high blood pressure in pregnancy and major cardiovascular disorders later in life, but we felt also that there was a lot of limitations with the evidence that's there.

                                                Firstly, a lot of the evidence is focused on more composite endpoints and secondly, over the past several decades, the pattern of initial presentation of cardiovascular disease has changed significantly. And thirdly, a lot of the studies that are out there have been unable to adjust for post-pregnancy factors such as hypertension. We wanted to see whether that was a significant factor. But that's the thought process behind why we undertook this study.

                                                Then we had a great opportunity with the collaboration with the Fire Institute in London and University College London, whereby we were able to use a database which is called CALIBER. What CALIBER stands for is cardiovascular research using linked bespoke studies and electronic health records, bit of a mouthful. But what CALIBER is, is basically it's a combination of the GP database in the U.K., which is called the Clinical Practice Research Database, hospital episodes, statistics, and the Office for National Statistics cause specific mortality records. What that does is basically it combines a lot of pregnancy data with long-term really well phenotyped cardiovascular disease.

                                                In particular, what CALIBER is very strong for is they have phenotypes, 12 cardiovascular phenotypes, in an extremely strong robust way. So, we were able therefore to examine the impact of pregnancy using the GP database, using the CPRD with these 12 cardiovascular phenotypes as our outcomes.

Dr Gregory Hundley:       Tell us a little bit about your study population and what were some of the results of your study?

Dr Fergus McCarthy:       What we did was we used electronic health records from a period of 1997 to 2016 and we looked at a U.K. population core of about 1.3 million women. The mean age of delivery of these women was about 28 years of age and they had about just under 2 million, 1.9 million completed pregnancies.

                                                Over the 20-year study period, we were able to observe just over 18,000 cardiovascular disorders, 65% of which had occurred in women under the age of 40. Again, this was quite surprising because using cardiovascular disease, you think a much older group, and when we looked at the pregnancies that were affected by hypertension in pregnancy, we were able to see that compared to women without hypertension in pregnancy, women who had one or more pregnancies affected by preeclampsia had increased hazard ratio for stroke, atherosclerotic events, heart failure, atrial fibrillation, cardiovascular death, and for chronic hypertension.

                                                What was particularly interesting was that the differences in the cumulative incidence curves that we were able to see. According to preeclampsia, we were able to see these differences within one year of the first index pregnancy. So again, this was quite fascinating from our point of view because I think prior to this study, maybe we thought that it was happening a bit earlier than we thought in women's lives, but actually, to see something so soon occur after pregnancy was quite interesting.

                                                The other thing that, and one of our motivations to do this was to say, okay, well is there anything we can do about it? Is there anything that might be modifiable here? What we were able to do within our study was we were able to examine, is this just because women are leaving hospitals with high blood pressure and this high blood pressure is not being treated? What we were able to do was we were able to adjust into our models this concept of having postpartum hypertension. If we were able to adjust for the mediating effect of post-pregnancy hypertension, we observed a 35% reduction in the point estimates of the hazards ratio for any cardiovascular disease event.

                                                One of the things I think that this study shows is that it is critically important that women have appropriate medical follow-up after their pregnancy. It's a very difficult period. People have young babies, they may be going home to more children at home, and often the neglected person in this situation is the mother. What we're saying is that actually even if we could focus on that one factor which is post-pregnancy adequate control of hypertension, we may be able to reduce the hazards ratio of developing a cardiovascular disease by approximately 35% is what the study is suggesting.

Dr Gregory Hundley:       Really interesting results, Fergus. Sharon, I wanted to turn to you a little bit. How do the results of this study change for us the way we might practice in terms of managing this patient population?

Dr Sharon Reimold:         This study, I think, is very interesting because of the large population and the significant number of unfortunately adverse outcomes and the ability to compare those with and without preeclampsia and hypertension. I think that we end up with two or three different issues or ways that we think about dealing with them.

                                                First of all, just as Fergus alluded to is we need to make sure that we take hypertension seriously in pregnancy and since it's a small, but significant number of women leave the hospital and will remain hypertensive, we need to assure that they are getting care. The other thing that I think is important in this group, but you would never be able to capture in the current study is my approach is also to think about, well, what other risk factors does this woman have other than just high blood pressure? Is she at risk to be a diabetic? Does she smoke? Is she getting enough exercise? What other things can we do to modify their long-term risks?

                                                This points out a method to identify those patients pretty easily. Are they hypertensive early post-pregnancy, and then it's up to the medical community to really develop strong guidelines and training that emphasizes using prevention in the outpatient setting.

                                                The two things I found very interesting about this work, first of all, the rapid separation of these curves. I know that they had some very young women that gave birth and then some obviously women of what I guess would be termed advanced maternal age. But we do think of a woman who has a child at 30 maybe being at higher risk when she's 50 or 60, but the risk is much earlier, and patients are really not aware of this.

                                                Then, the ultimate thing is how do we identify these women early in their pregnancy or before they're pregnant, so we can help avoid these complications altogether? I guess the take home message is if somebody has hypertension or they're going home hypertensive, they need early follow-up and we need to be aggressive about their treatment.

Dr Gregory Hundley:       Both of you have emphasized the point that this paper makes of early identification of hypertension. In the paper, it talks about hypertensive disorders of pregnancy. I think many of us understand about preeclampsia or eclampsia and relatively high blood pressures, HELLP syndrome, et cetera. Are there other issues that we need, like what blood pressure ranges are we thinking about?

                                                If I'm picking up a chart of a woman in their early forties, late thirties what should I be looking back for retrospectively in terms of blood pressure levels? Do I follow the new guidelines and I'm looking for blood pressures above 120 systolic? Can either of you give us some guidance on what to look for, how I would set up a program, what the timing would be, when I need women to come back? Just practical things like that.

Dr Sharon Reimold:         I believe that is still in the obstetric world that the older guidelines are really what are used and whether those shift over time to lower thresholds for the diagnosis of hypertension is not clear, but usually it's 140 over 90. You want to try to get the patient history and differentiate between those people that perhaps were hypertensive prior to their pregnancy, people who had isolated short-term hypertension during their pregnancy, and those people who then left pregnancy remaining hypertensive. But I'll ask Fergus since he deals with this a lot more than I do with the pregnancies, what they use as the cutoff in the U.K.

Dr Fergus McCarthy:       In general, we had the CHIPS Study, which was published several years ago. That advocated, certainly during pregnancy, that a tighter control of blood pressure was associated with an improved pregnancy and improved maternal outcome. That type of control generally aimed for a systolic blood pressure of under 135. In general, when we are managing our patients, that's usually what we're aiming for, to keep the systolic blood pressure under 135.

                                                I think the other thing that is becoming apparent from a lot of the work that's been done is that it's maybe not just about the pre-eclamptic woman, which is generally the woman with hypertension and proteinuria that gestation and hypertension, which often is nonproteinuric by definition, is also playing a significant part.

                                                Certainly, when you look at populations where I previously worked in the U.K. and London, women with chronic hypertension, pregnancy is becoming a huge issue, both with increasing obesity and certain ethnic groups, and with advanced maternal age women coming into pregnancy with chronic hypertension is really becoming a major issue for us, as well, and is associated with a much worse pregnancy outcome. But to answer the question, that's usually where we're aiming for and we're trying to, where possible, run as tight a control of blood pressure as possible.

Dr Gregory Hundley:       Thank you very much, and we look forward to talking and discussing with you with Carolyn next week.

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


Sep 16, 2019


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

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

Dr. Carolyn Lam: Greg, you know I'm vegetarian and any paper on plant-based diet will always interest me, and of course, we have one as a featured paper this week, very interestingly talking about changes in plant-based diet quality, meaning that there could be good plant-based diets and not so good plant-based diets. I mean we all know that potato chips, for example, are still plant-based. But, anyways, so this feature paper discusses the changes in these plant-based diet quality and association with total and cost-specific mortality. Neat, huh?

Dr. Greg Hundley: Yeah. I can't wait to hear about that one. I know that's a favorite topic of yours. How about if we have a sip of coffee and jump into our other articles?

Dr. Carolyn Lam: Sure. I'm sipping away, and have already picked my first paper. This talks about mutations in plakophilin 2, which are the most common cause of gene-positive familial arrhythmogenic right ventricular cardiomyopathy.

Dr. Greg Hundley: No quizzes for me on plakophilin 2, please.

Dr. Carolyn Lam: All right, well, let me tell you all about it. Plakophilin 2 is classically defined as a protein of the desmosome, which is an intracellular adhesion structure. Studies though have suggested that plakophilin 2 also translates information at the initiation. Recent studies have also shown that plakophilin 2 translates information initiated at the site of cell to cell contact into intracellular signals that maintain structural and electrical homeostasis. Now, the important thing is that mutations in plakophilin 2 associated with most cases of gene-positive arrhythmogenic right ventricular cardiomyopathy or ARVC. However, the molecular and cellular mechanisms responsible for arrhythmias in ARVC remain unclear.

Dr. Carolyn Lam: In today's paper, Doctors Delmar and Cerrone from New York University School of Medicine and their colleagues studied the role of cardiomyocyte plakophilin-2 expression in cardiac function. To do that, they utilized a cardiomyocyte-specific, tamoxifen-activated, plakophilin-2 knockout murine line. They found that loss of plakophilin-2 expression caused, as an early event and predominantly in the right ventricle, a non-transcriptional and likely arrhythmogenic, connexin-43-dependent disruption of calcium homeostasis.

Dr. Carolyn Lam: The phenotype included accumulation of calcium in three intracellular compartments, the junctional sarcoplasmic reticulum, the cytoplasm, and the mitochondria. Right ventricular myocytes also showed increased eagerness of ryanodine-receptor-2 channels to release calcium from the sarcoplasmic reticulum. Intrinsic ryanodine-receptor-2 properties were also modified further contributing to the pro-arrhythmogenic state. In summary, the authors postulated that disruption of calcium homeostasis in the right ventricle is a major arrhythmia trigger in patients with ARVC. The data identified both the ryanodine-receptor-2 channel and the connexin-43 hemichannel as targets for antiarrhythmic therapy in this population.

Dr. Greg Hundley: Very interesting that ARVC is such a worrisome concern, and gathering this mechanistic information is just so helpful.

Dr. Carolyn Lam: Exactly.

Dr. Greg Hundley: I have a basic science paper, but it was actually interesting because of the conduct was in many, many human subjects. It emanates from the large Million Veteran Program. There are a whole list of coauthors that are recognized as equal contributors, but Scott Damrauer actually serves as the corresponding author from the VA Medical Center. What it's addressing, about 13% of African American individuals carry two copies of the APOL1 risk alleles, G1 or G2, that are associated with a one and a half to two and a half fold increase in the risk of chronic kidney disease.

Dr. Greg Hundley: There've been conflicting reports as to whether an association exists between these APOL1 risk alleles and cardiovascular disease independent of the effects of the APOL1 on kidney disease. Here, the investigators thought to test the association of these G1 and G2 alleles with coronary artery disease, peripheral arterial disease, and stroke among African American individuals in the Million Veterans Program.

Dr. Carolyn Lam: Seems like a great study population and designed to look at this. What did they find?

Dr. Greg Hundley: Among 30,903 African American Million Veterans Program participants, 3,941 or about 13% carried the two APOL1 risk allele, high-risk genotype. Individuals with normal kidney function at baseline with the two risk alleles had a slightly higher risk of developing coronary artery disease compared to those with no risk alleles. Similarly, modest associations were identified with incident stroke and peripheral arterial disease. However, when modeling both cardiovascular and renal outcomes, APOL1 was strongly associated with incident renal disease while no significant association with the cardiovascular disease endpoints could be detected. In conclusion, what the authors are indicating is that the APOL1 risk variants display a modest association with cardiovascular disease, and this association is likely mediated by the already previously known association of APOL1 with chronic kidney disease.

Dr. Carolyn Lam: Interesting.

Dr. Carolyn Lam: My next paper also has to do with chronic kidney disease and this time looking at metformin use and clinical outcomes in patients with diabetes with or without heart failure or kidney dysfunction. We know that metformin is the first-line therapy for type 2 diabetes, although its effects on the cardiovascular system are actually, not fully proven. In this next paper, the authors examine metformin use in the SAVOR-TIMI 53 Trial.

Dr. Greg Hundley: Tell us a little bit about that SAVOR-TIMI 53 Trial. How is that organized?

Dr. Carolyn Lam: Just as a reminder, the SAVOR-TIMI 53 trial was a multinational, randomized, controlled cardiovascular outcomes trial that compared the dipeptidyl peptidase-4 or DPP4 inhibitor, Saxagliptin, with placebo, enrolling almost 16,500 patients with type 2 diabetes and cardiovascular disease or elevated cardiovascular risk.

Dr. Carolyn Lam: Now, in the current paper led by Dr. Bergmark from TIMI study group in Brigham and Women's Hospital and Harvard Medical School, the authors performed the post hoc analysis and looked at patients in SAVOR-TIMI 53 with baseline biomarker samples of whom there were more than 12,000 patients and classified these patients as ever versus never taking metformin during the trial period. The associations between metformin exposure and outcomes were estimated using inverse probability of treatment weighting, Cox modeling.

Dr. Carolyn Lam: They found that among patients with type 2 diabetes and high cardiovascular risk in the SAVOR-TIMI 53 trial, metformin use was associated with lower rates of all-cause mortality including after adjustment for clinical variables and biomarkers, however not lower rates of the composite endpoint of cardiovascular death, MI or stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease.

Dr. Greg Hundley: Excellent.

Dr. Greg Hundley: I'm going to transition to another clinical trial and this one is looking at ezetimibe in elderly patients and looking at efficacy for preventing cardiovascular-related events. The paper comes from Yasuyoshi Ouchi from Toranomon Hospital in Japan. Evidence regarding the primary prevention of coronary artery disease events by LDL-C/lipid-lowering therapy in order individuals that are above the age of 75 years, is somewhat incomplete. This trial tested whether LDL-C lowering with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. They implemented a multicenter, prospective, randomized but open-label, blinded, endpoint, however, evaluation design conducted among 363 medical institutions in Japan.

Dr. Greg Hundley: In the study, there're 3,796 patients that are aged greater than 75 years with elevated LDLC without a history of coronary artery disease that already were receiving dietary counseling. They're randomly assigned one-to-one to receive as ezetimibe 10 milligrams once daily versus usual care with their randomization stratified in a block design on age, sex, and baseline LDL-C. The primary outcome is the composite of sudden cardiac death, myocardial infarction, coronary revascularization, and stroke.

Dr. Carolyn Lam: Ooh, so tell us the results.

Dr. Greg Hundley: There were several patients that had to be excluded, so what ended up happening, there's 1,716 and then 1,695 that are included in each of the two respective arms for the primary analysis. What they found is that as ezetimibe reduced the incidents of the primary outcome. Then, regarding some secondary outcomes, the incidents of composite cardiovascular events and coronary revascularization were lower in the ezetimibe group than in the control group. But, there was no difference in the incidents of stroke, all-cause mortality, or adverse events in the two different groups.

Dr. Carolyn Lam: Can you sum it up for us, Greg? What should we take home regarding ezetimibe and what further do we need to do?

Dr. Greg Hundley: Good point, Carolyn. I think what we can take away from this study is that LDL-C lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals greater than 75 years of age with an elevated LDL-C. However, remember, it was open label, so I think a placebo, controlled, randomized clinical trial will be required to validate the data that were obtained in this study. I think another study is probably going to be needed.

Dr. Carolyn Lam: Thanks, Greg. Well, let's move on to our feature discussion, shall we?

Dr. Carolyn Lam: Today's feature paper is of personal interest to me and I'm sure of widespread interest to everybody. Why? It's on plant-based diet. We've heard a lot about it. I'm vegetarian and very, very loudly self-confessed, but does the quality of a plant-based diet actually matter? Such an important question.

Dr. Carolyn Lam: I'm so pleased to have the authors of this very remarkable paper, Dr. Megu Baden as well as Dr. Shilpa Bhupathiraju, both from the Harvard T.H. Chan School of Public Health; and our associate editor, Dr. Mercedes Carnethon from Northwestern University Feinberg School of Medicine. Welcome, ladies. What a nice chat we're going to have on this very personal topic to me as well.

Dr. Carolyn Lam: First of all, maybe, could I ask, Shilpa, do we need another study on plant-based diet? Could you tell us the rationale for what you did this time?

Dr. Shilpa Bhupathiraju: Like you said, when we talk about plant-based diets and what people usually think is, well, it's vegetarian or not. But, I think there's much more to a vegetarian diet. It's the quality that matters. Previous studies really then differentiate the quality of a vegetarian diet.

To this extent, we developed plant-based diet indices, which actually capture the quality of a plant-based diet, so we have an overall plant-based diet index which captures the amount of plant-based foods; a healthy plant-based diet index, which captures the quantity of healthy plant-based foods; and again, the unhealthy plant-based diet index, which captures the quantity of unhealthy, plant-based foods.

Dr. Carolyn Lam: Thanks. Meg, if you don't mind, I know everybody is asking this as they're listening. Could you give us some examples of what an unhealthy plant-based diet index would consist of compared to healthy? Then, perhaps, tell us a little bit about your study and what you found.

Dr. Megu Baden: First of all, let me explain again. In this study, we use three versions of plant-based diet indices that can assess the quality of plant foods in general population. The first index is an overall plant-based diet index, PDI for short. A second one is a healthful plant-based diet index, HPDI. The third one is an unhealthful plant-based diet index, UPDI. In order to create these indices, we divide all food groups into three larger categories. One is the healthy plant foods, which contains whole grains, fruits, vegetables, nuts, legumes, vegetable oils, tea, and coffee; less healthy plant foods such as fruits juice, refined grains, potatoes, sugar-sweetened beverages, and sweets or desserts; and animal foods, which is animal food, dairy, eggs, fish, meat, miscellaneous animals-based food.

Dr. Megu Baden: We investigated the association between preceding trailblazing changes in these indices and subsequent total and cause basic mortality in two large US cohorts. We found that compared with participants whose diet remained stable, the hazard ratio for total mortality, among those risks, the greatest increase in PDI was 0.95; for the greatest increase in HPDI, the healthful versions of the PDI was 0.90; and the greatest increasing in unhealthful PDI was 1.12. In contrast, the hazard ratio among participants with the greatest difficulty is in PDI, was 1.09; the greatest decrease in healthful PDI was 1.10; and the greatest decreasing in unhealthful PDI was 0.93. For CVD mortality, the risk was 7% lower for our 10 point increase in PDI, and 9% lower for HPDI and 8% higher for UPDI.

Dr. Megu Baden: In summary, we found that improving plant-based diet quality over a 12-year period was associated with a lower risk of total and CVD mortality, whereas increased consumption of unhealthful plant-based diet was associated with a higher risk of total and CVD mortality.

Dr. Carolyn Lam: Could I ask, Shilpa, to maybe add a line of ... have you applied this information in any way yourself or with patients, or is there an overwhelming take-home message you'd like people to remember?

Dr. Shilpa Bhupathiraju: Yeah, I'm not a clinician myself, but I'm a public health researcher. I'm in India currently and I'm giving a talk to South Asians and the emphasis on vegetarianism. But, again, the quality of the vegetarianism is important. Being a vegetarian is not enough, but what goes into it is really important. If it's a white rice and sugar-sweetened beverages, it's not good, so really the emphasis should be on whole grains, consuming more nuts and legumes. I think that's important.

Dr. Carolyn Lam: Oh, that's great. Mercedes, we've discussed this paper as associate editors, so proud to be publishing this in circulation. Could you share some of your thoughts on the implications of these findings?

Dr. Mercedes Carnethon: The authorship team has done an outstanding job of clarifying a very complicated issue. I think what we really like about this and the ways in which it really adds to the literature, what you point out, that every vegetarian diet isn't the same. I was very impressed with the thought that went into classifying vegetarian foods as healthy or unhealthy. I would be interested in hearing more from the authors, particularly, since I feel they did a good job of how they dealt with complicated foods or mixed foods. I think one example given was a pizza, which has tomato sauce, but it also has other things, so I would love to hear from the authors how they classified complicated foods.

Dr. Shilpa Bhupathiraju: The decision to classify pizza as an animal food was somewhat, I would say, arbitrary. I do agree that there's lots of tomato sauce, but again, I think the decision that went to it, it does have a ton of cheese, processed cheese, I think that's why we classified that as an animal food. The other complicated foods are mixed dishes that we struggled with were cream soups. We thought about what the base was or what the general preparation of that would be. Given that heavy cream is a major ingredient, so those were again, classified as animal foods.

Dr. Mercedes Carnethon: I think there's a lot of logic in that and I really like the thought and care that you put into that. The other questions I have, I feel that you did a really nice job of, are even portion sizes. Tell me how you handled portions.

Dr. Megu Baden: We basically take the information from our food frequency questionnaire. All of them are per the serving sizes, so we considered how participants reported how often on average they had consumed each food of our standard portion size in the past year. I know it's difficult to indicate the portion size. Shilpa, would you add something for the portion size for that?

Dr. Shilpa Bhupathiraju: Yes. Like Megu said, we use standardized portioning sizes, so a cup of fruit, a cup of vegetables, an eight-ounce, or a cup of tea or coffee, so that's how we use what people use in general. The portion sizes are all specified on the food frequency questionnaire, so the nurses or the health professionals, they understand exactly what they're reporting. Is it a glass of fruit juice or half a glass? Then, we can word those frequencies into standardized serving sizes onto servings per day.

Dr. Carolyn Lam: Great. Shilpa, could I follow up from Mercedes very important question? How does the index account for portion size too, as an is too much of even a good thing become a bad thing? You know what I mean?

Dr. Shilpa Bhupathiraju: The index itself is a score. The way we capture it, as you know, everything is converted from frequencies into servings per day for each participant. Then, what we did was we divided the participants based on the distribution of the data into quintiles. Those in the highest category of the healthy plant foods received the highest points. The scoring varied a little bit based on which index we were calculating. But, in general, what we did was we divided everybody into five groups or quintiles. Then, the scoring varied depending on what we were calculating. For the HPDI, which is the healthy plant-based diet index, those in the fifth group or the highest intake received the maximum number of points, which was five. For the unhealthy plant-based diet index, those people received the reverse scoring, so they received zero points. Essentially, the participants were divided into quintiles and the scoring was done accordingly.

Dr. Carolyn Lam: Maybe I could ask you a question on a different track, and I'm not sure if you have some answers here, but I noticed that your study population was impressive, almost 49,500 women from the Nurses' Health Study, almost 26,000 men from the Health Professionals Follow-up Study. Did you find any sex differences?

Dr. Shilpa Bhupathiraju: We didn't find any sex differences. We did some sensitivity analysis by cohort and we didn't find a statistically significant interaction, which is I think good to note because we would expect the effects to be similar in men and women.

Dr. Carolyn Lam: I think both men and women need to hear that. None of us are excused from, I suppose, trying to gear towards a healthy plant-based diet. I think that's what I'm hearing. Mercedes, do you have more thoughts to add?

Dr. Mercedes Carnethon: I do. One thing I really like about this particular paper is the way the you acknowledge some of the limitations that we face when interpreting findings from observational studies, particularly observational studies of a health behavior when we know that health behaviors often cluster or correlate with other health behaviors. Can you tell us a little bit about some of the cautions and interpretation that you certainly acknowledged and presented very well?

Dr. Shilpa Bhupathiraju: Sure. Our primary analysis was looking at changes, so long-term changes. When people change a diet or their lifestyle, they change something else. As you can see from our paper, those who improve the plant-based diet quality, we're also, in general, tended to be healthier. This being an observational study, we tried to control for those as to the greatest extent possible, but again, they could be residual confounding. We maybe failed to measure for certain things that we were unaware of or that we did not measure. I think we really can't get at causality, but I think the consistency of the evidence from our previous papers and from this paper point to a suggestion that improving plant-based diet quality is definitely associated with better health outcomes and a lower risk of death. But, again, it is important to know that this is observational and there could be changes in other health behaviors that we did not measure that could explain this association. But, we did as well of a job as we could in trying to control for these changes and other behaviors, lifestyles or even health conditions.

Dr. Mercedes Carnethon: Thank you.

Dr. Carolyn Lam: Thank you so much, Meg and Shilpa. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

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

Sep 9, 2019


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

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

Dr. Carolyn Lam: Greg, I'm so excited about the feature paper this week. You know it deals with machine learning. It's such a hot topic now, and this one particularly deals with machine learning and the prediction of the likelihood of an acute myocardial infarction. So everyone's going to want to listen to it. Let's discuss a couple of papers and get to it, shall we?

Dr. Greg Hundley: Absolutely Carolyn, would you like to go first?

Dr. Carolyn Lam: I sure would. So my first pick is the first study to investigate the overall importance of translational regulatory networks in myocardial fibrosis. This is the study from doctors Rackham and Cook from Duke NUS Medical School here in Singapore.

Dr. Carolyn Lam: What they did is they generated nucleotide resolution translatome data during transforming growth factor beta one, or TGF beta one-driven cellular transition of human cardiac fibroblasts to myofibroblasts. So this technique identified the dynamic changes of RNA transcription and translation at several time points during the fibrotic response, revealing transient and early responder genes.

Dr. Carolyn Lam: Now, very remarkably about one third of all the changes in gene expression in activated fibroblasts was subject to translational regulation and dynamic variation in the ribosome occupancy, affected protein abundance independent of RNA levels. Ribosome occupancy in the hearts of patients with dilated cardiomyopathy suggest that the same post-transcriptional regulatory network, which was underlying cardiac fibrosis. Now key network hubs included RNA binding proteins such as PUM2 and QKI that worked in concert to regulate the translation of target transcripts in the human disease hearts.

Dr. Carolyn Lam: Furthermore, the authors showed that silencing of both PUM2 and QKI inhibited the transition of fibroblasts towards profibrotic myofibroblast in response to TGF beta one.

Dr. Greg Hundley: You know, Carolyn, this whole aspect of fibroblasts and how they turn on and turn off, become myofibroblasts, such a hot topic in heart failure. What are the clinical implications of this work?

Dr. Carolyn Lam: Yes, I agree. Well, threefold. First, these authors identified previously unappreciated genes under translational control, which could be novel candidates for disease biology and therapeutic targets.

Dr. Carolyn Lam: Number two, they found that critical fibrosis factors impacted cellular phenotypes at a protein level only, and hence these cannot be appreciated using single cell, or bulk RNA sequencing approaches. So that was significant. Finally, RNA binding proteins was shown to be central to the fibrotic response and represent unexplored gene expression regulators, and of course potential diagnostic or therapeutic targets.

Dr. Greg Hundley: Very nice Carolyn. Well, my next paper is also from the world of basic science, and it comes from Dr. Joseph Hill. Have we ever heard of him? Well of course, he's our Editor in Chief. He's going to discuss, he and his team investigated Polycycstin-1. Well, what is Polycycstin-1? It's a trans membrane protein, originally identified in autosomal dominant polycystic kidney disease, where it regulates the calcium permeate cation channel polycystin-2. So autosomal dominant, polycystic kidney disease patients develop renal failure, hypertension, left ventricular hypertrophy, atrial fibrillation and other cardiovascular disorders. These individuals harbor PC1 loss of function mutations in their cardiomyocytes, but the functional consequences of this are relatively unknown.

Dr. Greg Hundley: Now PC1 is ubiquitously expressed in its experimental ablation in cardiomyocyte specific knockout mice reduces contractile function, and in this paper the authors set out to determine the pathophysiologic role of PC1 in these cardiomyocytes.

Dr. Carolyn Lam: Huh--very interesting. I liked the way you laid that out. So what did they find?

Dr. Greg Hundley: What the investigators identified is that PC1 ablation reduced action potential duration in cardiomyocytes. They decreased calcium transients and therefore myocyte contractility. PC1 deficient cardiomyocytes manifested a reduction in sarcoplasmic reticulum calcium stores due to reduced action potential duration and circa activity, an increase in outward potassium currents decreased action potential durations in cardiomyocytes lacking PC1. PC1 coimmunoprecipitated with a potassium 4.3 channel and modeled PC1 C terminal structure suggested the existence of two docking sites for PC1 within the end terminus of K4.3. Supporting a physical interaction between the cells. Finally, a naturally occurring human mutant PC1 manifested no suppressive effects on this potassium channel activity. Thus, Carolyn, Dr Hill and colleagues' results help uncover a role for PC1 in regulating multiple potassium channels, governing membrane repolarization and alterations in circa that reduce cardiomyocyte contractility.

Dr. Carolyn Lam: Oh wow. What a bonanza of really interesting papers in this week. Now my next pick is a secondary analysis of the reveal trial. It hinges on the hypothesis that was generated from prior trials that the clinical response to cholesterol ester transfer protein or CETP inhibitor therapy may differ by ADCY9 genotype. So in the current study, authors Dr. Hopewell and colleagues from Nuffield Department of Population Health, University of Oxford examine the impact of ADCY9 genotype on the response to the CETP inhibitor Anacetrapib within the reveal trial.

Dr. Greg Hundley: Tell me, I've forgotten a little bit, but can you remind me a little about what was the reveal trial?

Dr. Carolyn Lam: Yes, of course. So the randomized placebo controlled reveal trial actually demonstrated the clinical efficacy of the CETP inhibitor Anacetrapib among more than 30,000 patients with preexisting atherosclerotic vascular disease. Now, in the current study, among more than 19,000 genotyped individuals with European ancestry, 13% had a first major vascular event during four years median follow up. The proportional reductions in the risk of major vascular events did not differ significantly by ADCY9 genotype. Furthermore, the authors showed that there were no associations between the ADCY9 genotype and the proportional reductions in the separate components of major vascular events, or any meaningful differences in lipid response to Anacetrapib.

Dr. Carolyn Lam: So in conclusion, the reveal trial being the single largest study to date to evaluate the ADCY9 pharmacogenetic interaction provided no support for the hypothesis that ADCY9 genotype is materially relevant to the clinical effects of the CETP inhibitor Anacetrapib. The ongoing dal-GenE study, however, will provide direct evidence as to whether there's any specific pharmacogenetic interaction with dalcetrapib.

Dr. Greg Hundley: Oh, very good. So we've got some results coming from dal-GenE.

Dr. Carolyn Lam: Mm.

Dr. Greg Hundley: Well, Carolyn, my last selection relates to a paper regarding the incidence of atrial fibrillation among those that exercise, and I mean really exercise.

Dr. Carolyn Lam: Ooh.

Dr. Greg Hundley: So the paper comes from Dr Nicholas Svedberg from Uppsala University, and studies have revealed a higher incidence of atrial fibrillation among well trained athletes. The authors in this study aim to investigate associations of endurance training with the incidents of atrial fibrillation and stroke, and to establish potential sex differences of such associations in this cohort of endurance trained athletes. They studied all Swedish skiers, so 208,654 that completed one or more races of the 30 to 90 kilometer cross country skiing event called the Vasaloppet from 1989 through 2011, and they had a matched sample of 527,448 non-skiers, and all of the individuals were followed until their first event of either atrial fibrillation or stroke.

Dr. Carolyn Lam: Wow. What an interesting and what a big study. So tell us, what are the results and especially were there any sex differences?

Dr. Greg Hundley: Well, interesting that you ask about those sex and gender differences. So female skiers had a lower incidence of atrial fibrillation than female non-skiers, independent of their finishing time and the number of races, whereas male skiers had a similar incidence to that of non-skiers. Second, skiers with the highest number of races or fastest finishing times had the highest incidents of the AFib, but skiers of either sex had a lower incidence of stroke than non-skiers independent of the number of races and finishing time. Third, skiers with atrial fibrillation had a higher incidence of stroke than skiers and non-skiers without atrial fibrillation. That's true for both men and women. We would think that. Finally after one had been diagnosed with atrial fibrillation, skiers with atrial fibrillation had a lower incidence of stroke and a lower mortality compared to non-skiers with atrial fibrillation.

Dr. Carolyn Lam: Very interesting. Could you sum it up for us? What's the take home?

Dr. Greg Hundley: Couple things. One, female endurance athletes appear to be less susceptible to atrial fibrillation than male endurance athletes. Second, both male and female endurance athletes have a lower risk of stroke independent of their fitness level. Third, after the diagnosis of atrial fibrillation, participants in a long distance skiing event with atrial fibrillation had a 27% lower risk of stroke and a 43% lower risk of dying compared to individuals from the general population with the diagnosis of atrial fibrillation.

Dr. Greg Hundley: So there's some clinical implications. Although very well trained men have a higher incidence of atrial fibrillation than less trained men, the incidence is on par with that of the general population and not related to a higher incidence of stroke at that group level. This indicates that exercise has very beneficial effects on other risk factors for stroke. Then lastly, atrial fibrillation in well trained individuals should be treated according to our other usual guidelines for the population at whole.

Dr. Carolyn Lam: Wow. What a fantastic study to end our little coffee chat on, but it's time to move on to our feature discussion.

Dr. Carolyn Lam: Today's feature discussion touches on super-hot topics. First of all, the perennially interesting and hot topic of the prediction of acute myocardial infarction, or should I say the more precise predictions that we can do these days. The second part of the hot topic is machine learning. Oh my goodness. This is creeping into cardiovascular medicine like never before. So I'm so glad to welcome to this discussion corresponding author of the featured paper Professor Nicholas Mills from the University of Edinburgh, as well as our Associate Editor Doctor Deborah Diercks from UT Southwestern. So welcome both, and Nick, if I could start with you, tell us about MI Cubed.

Prof Nicholas Mills: First thing to say, it was a major international collaboration, involved researchers from over nine different countries and we got together to develop and test an innovative algorithm that estimates for individual patients the probability when they attend the emergency department with acute chest pain that they may or may not have had a myocardial infarction.

Prof Nicholas Mills: Machine learning is a really new area in cardiovascular medicine as you say. Our algorithm called MI Cubed uses a fairly simple algorithm which is a decision tree. It takes into consideration really important patient factors such as age, sex, troponin concentration at presentation, and troponin concentration on subsequent testing, and the change in troponin in between those two tests in order to estimate or calculate the probability of the diagnosis. One of the really interesting aspects of this is it's not just an algorithm for research, it's a clinical decision support tool as well. So what we've done is taken the output from that algorithm and translated it into something that is meaningful for clinicians. We've kept it quite simple. It gives an output between zero and a hundred, which is directly proportional to the likelihood of the patient having a myocardial infarct. We also provide estimated diagnostic metrics. So sensitivities and specificities that relate to that individual patient. It's really going to change the way we think about the interpretation of cardiac troponin in clinical practice.

Dr. Carolyn Lam: Indeed, and first audience please, please look up the beautiful figures of this paper. I think it summarizes it all. The algorithm shows you what MI Cubed is and then compares it to the ESC three hour algorithm, one hour algorithm. Then I love the last figure, where you actually show us that very important component that you just said. As a clinical support tool, how it's going to work. So we actually have pictures of your cell phone and showing you the pictures that you're going to get from it. So super cool. Beautiful paper.

Dr. Carolyn Lam: Now I just have so much to talk about, first the machine learning bit, always sexy sounding, but a bit scary for clinicians. So I really like the fact that you broke it down to actually say what components go in so that people aren't afraid of this black box. We don't know what's going on. Is there like a set time between samples, or how does this work? Do you need to have it within a certain timing? How does that fall in? Is it a particular type of troponin, what are some of the specs of the model that a practicing clinician needs to know?

Prof Nicholas Mills: Well, in order to answer that question, I might explain to you the rationale for developing it. So when you're assessing a patient in the emergency department, we all recognize in our daily practice that patients differ. So interpreting troponin has been challenging. One threshold for all may not be the right way to approach this really important clinical diagnosis. Troponin concentrations differ in men and women. They differ by age, and as a surrogate of the presence of comorbidities. They differ depending on the timing of when you take that sample and when you repeat that measurement, and that has introduced some complexity. So many interesting pathways have been developed for guidelines which try and apply fixed thresholds and fixed time points, and it's pretty tough to deliver in the real world setting of a super busy emergency department. So the premise for developing this algorithm was we wanted something that was really flexible, that recognized that patients are different, they're not all the same.

Prof Nicholas Mills: That's why we went for a machine learned approach rather than a more conventional statistical model. So you asked about the specification. You can do your two troponin tests whenever you like. So I had across the 11,000 patients huge variation in the timing of samples, but that is okay for MI Cubed. If you repeat the test within an hour, two hours, three hours, six hours, it still provides the same diagnostic performance. I think that's really important.

Prof Nicholas Mills: You also mentioned specification about the assay. This algorithm has been developed using a particular high sensitivity cardiac troponin assay developed by Abbott Diagnostics. It will be effective for other high sensitive troponin assays, but it's unlikely to be as effective using a contemporary assay. So if your hospital uses a contemporary or conventional cardiac troponin assay, this might not be the right algorithm for you.

Dr. Carolyn Lam: Great. Thank you for breaking down the issue so beautifully and practically. It really makes me think, oh my goodness, this paper's just far more than about MI. Because you know, natriuretic peptides, you could say the same thing. A prediction of heart failure is the same thing, you know? So the whole approach is novel. Deb, could you please share your thoughts and perspectives on where this is going perhaps?

Dr. Deborah Diercks: I think this study is terrific because I think it does, as Dr. Mills stated, reflect reality. We don't draw measures at zero, exactly at zero, and exactly at one and exactly at three, especially in a busy emergency department. So I think it provides flexibility to the physician and provider in using it to be able to interpret values in a world that doesn't fit complete structure like the guidelines are written out. What I find really interesting about this study, and I'd love to hear more about, is how you decided the thresholds of where low risk and high risk were cut at. It mentions by consensus, and I guess I would have loved to have been a fly on the wall to hear how those discussions went, and would love to hear more from you Dr. Mills about that.

Prof Nicholas Mills: Fascinating discussions amongst all the investigators on this project as to how we would define that. The first point I would make though is we designed the algorithm to provide a continuous output, a continuous measure of risk. So your MI Cubed score is between zero and a hundred. You don't have to apply a threshold, but we are used to in clinical practice having processes that support our triage of patients, and identifying people as low risk and high risk. Therefore we felt upfront that we should evaluate specific low risk and high risk thresholds.

Prof Nicholas Mills: So low-risk, we were completely unanimous on how to define that, and it was based on some really nice work done by emergency physicians in New Zealand. Martin Fan, who's the first author on this paper, surveyed many emergency physicians and asked about their acceptance of risk. They came up with the concept that an algorithm to be considered safe in emergency medicine would be acceptable if the sensitivity was greater than 99% or the negative predictive value was greater than 99.5%.

Prof Nicholas Mills: So we agreed up front that we would hold our low risk thresholds to those bars. Those metrics. Where there was less agreement was how you defined high risk. That didn't surprise me hugely. The positive predictive value of troponin is one of the most controversial topics around. Most cardiologists [crosstalk 00:20:52] of troponin has been difficult for them in clinical practice because with the improvements in sensitivity we are seeing lower specificity and lower causative link to value. If I put it into context, just measuring troponin and using the 99 percentile in consecutive patients gives you a positive predictive value of around about 45 to 50% in most healthcare systems for the diagnosis of type one myocardial infarction. Therein lies the problem. So one in every two patients has an abnormal troponin result but doesn't have the condition that we have evidence based treatments for, and whom cardiologists who are often quite simplistic in their approach to the assessment of these patients know how to manage.

Prof Nicholas Mills: Every second patient we don't know how to manage, and therefore we wanted an algorithm that would help us identify those patients who can go through our often guideline-based pathways and treatment pathways for acute coronary syndromes more effectively. We eventually agreed that a positive predictive value of 75% would be ideal. So three out of every four patients would have the diagnosis that we knew how to manage and treat. That was our target. We got pretty close to it in our test set. I think the actual positive predictive value at the threshold of around an MI Cubed value of 50 was 72%, so pretty effective. Certainly a lot better than relying on a kind of binary threshold such as the 99 percentile to identify high risk patients.

Dr. Deborah Diercks.: Thanks for that great answer. My next question is how do you think MI Cubed is going to integrate, or will it even replace the need for other risk stratification tools that we often use the emergency departments such as TIMI or the heart score?

Prof Nicholas Mills: Fabulous question. In this analysis, we haven't specifically compared the performance of MI Cubed with TIMI or heart, so my answer is going to be a little speculative. You can forgive me hopefully. Both those scores were developed prior to the widespread use of high sensitive cardiac troponin tests. I think what we've learned since the introduction of high sensitive cardiac troponin is that we're using this test as a risk stratification tool, and a lot of the power of the MI Cubed algorithm comes from the way that it identifies extremely low risk patients with very low and unchanging cardiac troponin concentrations way below the diagnostic threshold.

Prof Nicholas Mills: TIMI and heart simply consider troponin as a binary test, a positive or negative test, and do not take advantage of the real power of the test to restratify patients. All the evidence to date that has compared TIMI and heart with pathways that use high sensitive troponin in this way, both to restratify and diagnose patients show that these risk tools add very little in terms of safety, but do make pathways more conservative. So they identify fewer patients that are lower risk and permit discharge of those patients.

Prof Nicholas Mills: So my concern about using an algorithm like MI Cubed with an existing tool like heart is that it will undermine much of the effectiveness of this tool which identifies around about two thirds of patients as low risk. If you were to combine that with a heart score, you would reduce the effectiveness. I don't think you get a gain in performance, but further research is required to do a head to head comparison with these sorts of traditional restratification tools.

Dr. Carolyn Lam: I'm so grateful for this discussion, both Nick and Deb. In fact, I was about to ask what are the next steps and I think Nick you just articulated it. Deb, I want to leave the final words to you. Do you have anything else to add?

Dr. Deborah Diercks: I think this study represents a real change in how we can practice medicine, where we can actually take our biomarkers that actually have really strong value and utilize them in a manner that is pragmatic. It can actually introduce and take full advantage of them, and so I think this is a great opportunity for us to rethink our usual approach, which frankly, especially for troponin has really been very binary and very static. Thank you so much Dr Mills for the innovation and the willingness to look into this area.

Dr. Carolyn Lam: Thank you so much. This paper is like a sneak peak into the future of what we'll be practicing medicine like. Well, audience, you heard it right here on Circulation on the Run. Don't forget to tune in again next week.

This program is copyright American Heart Association 2019.

Sep 3, 2019

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

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

Dr Carolyn Lam:                So Greg, have you ever wondered what is the clinical significance of exercise induced cardiac troponin eye release with regards to mortality and cardiovascular events?

Dr Greg Hundley:             Well, being a runner, and you are too, I actually have wondered about that.

Dr Carolyn Lam:                Well guess what? I'm not going to tell you the answer because you're going to have to wait for our feature discussion coming right up after we chat about a few wonderful papers in this week's issue. And I want to start. So the first paper I chose really sought to discover new and effective drug treatments for ischemic stroke. And it did this by integrating genetic and proteomic data through Mendelian randomization analysis.

Dr Greg Hundley:             So Carolyn, what is Mendelian randomization analysis?

Dr Carolyn Lam:                Well, I would have loved to quiz you on that, but since you already asked me, I'll tell you. So Mendelian randomization is a statistical genetics framework that's used to assess causality between an exposure and an outcome. So similar to how randomized controlled trials randomly allocate an intervention to test its causal effect on an outcome. Well, Mendelian randomization represents a sort of natural randomized control trial that leverages the random allocation of exposure influencing genetic alleles.

                                                Now previously, this technique of Mendelian randomization was applied in a hypothesis driven manner to assess causality of selected biomarkers on stroke risk, for example. However, there has been no systematic scan of the human proteome for novel causal mediators of stroke. And beyond drug target prioritization, Mendelian randomization can actually also be applied to predict target mediated side effects to reveal unanticipated adverse effects and opportunities for drug re-purposing. Hence, in the current paper, the authors led by Dr Paré from Hamilton Health Sciences, McMasters University and colleagues, use Mendelian randomization to firstly systematically screen 653 circulating proteins to identify novel mediators of ischemic stroke subtypes.

                                                Secondly, examine the relationship between identified biomarkers and the risk of intracranial bleeding. And thirdly, predict target mediated side effects through phenome wide analysis. They found that among these 653 proteins, seven were causal mediators of ischemic stroke, including two established targets, apolipoprotein allele and coagulation factor 11. As well as two novel mediators of cardioembolic stroke, which were scavenger receptor class A5, or SCARA5, and tumor necrosis factor weak inducer of apoptosis.

                                                They further showed that targeting SCARA5 was predicted to also protect against subarachnoid hemorrhage with no evidence of it for side effects. Some biomarkers mediate at risk of multiple non-stroke disorders. So in summary, integrating genomic, proteomic and phenomic data through Mendelian randomization facilitated discovery of drug targets and their side effects. Their findings provide confirmatory evidence for pursuing clinical trials of coagulation factor 11 and apolipoprotein allele. Furthermore, SCARA5 represents a new therapeutic target. Neat, huh?

Dr Greg Hundley:             You bet. Well, my basic paper, Dr Carolyn Lam, focuses on the border zones of infarcts. And it comes to us from Vincent Christoffels from the Academic Medical Center in Amsterdam. So surviving cells in the post infarction border zone is subjected to intense fluctuations of their microenvironment. We can imagine that. And recently border zone cardiomyocytes have been specifically implicated in cardiac regeneration. Here in this study, the investigators define their unique transcriptional and regulatory properties and comprehensively validated new molecular markers, including NPB or encoding B-type natiriuretic peptide after infarction.

                                                So, in the study, transgenic reporter mice were used to identify the NPB positive border zone after mitochondrial infarction, and transcriptome analysis of remote border and infarct zones, and of purified cardiomyocyte nuclei was performed using some RNA sequencing. Top candidate genes displaying border zone spatial specificity were histologically validated in ischemic human hearts. So like these great papers we have in basic science, there is a fundamental mouse and then human subject validation.

Dr Carolyn Lam:                 Nice. A lot of work. So what did they show?

Dr Greg Hundley:             So Carolyn, the investigators identified the border zone as a spatially confined region transcriptionally distinct from remote myocardium. The transcriptional response of the border zone was much stronger than that of that remote ventricular wall involving acute downregulation of mitochondrial oxidative phosphorylation, fatty acid metabolism, calcium handling and sarcomere function, and activation of the stress response program.

                                                Analysis of infarcted human hearts revealed that the transcriptionally discrete border zone is conserved in humans and led to the identification of novel conserved border zone markers including NPBB and a whole list of others. So in conclusion, cardiomyocytes in a discrete zone bordering the infarct switch gene expression programs, this post switch program is conserved between mouse and humans, includes the NPPB expression, which is required to prevent acute heart failure after infarction.

Dr Carolyn Lam:                Wow, really interesting. Well, my next paper is also really just novel information, and it's a promising clinically-relevant approach for immune modulation in transplantation medicine. And that is by selectively targeting notch one.

Dr Greg Hundley:             Tell us a little bit about notch signaling.

Dr Carolyn Lam:                Well, I'm glad you asked me before I asked you again because notch signaling is a highly conserved pathway, pivotal to T cell differentiation and function, rendering it a target of interest in efforts to manipulate T cell mediated immunity. Now this is relevant in transplantation since, despite advances in immunosuppression, long-term outcomes remain suboptimal and is hampered by drug toxicity and immune mediated injury, the leading cause of late graph loss.

                                                So, the development of therapies that promote regulation while suppressing effector immunity is imperative in improving graph survival and minimizing conventional immunosuppression. In today's paper, Dr Riella and colleagues from Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts investigated the pattern of notch one expression and effector and regulatory T cells in both murine and human recipients of a solid organ transplant. They further examine the effect of notch one receptor inhibition in full murine cardiac and lung transplant models as well as in a humanized skin transplant model, and also in T regulatory cells. They found that notch one is a potent novel target to modulate aloe immunity. Blockade of notch one signaling prolongs allograph survival and enhances tolerance in animal transplant models in a regulatory T-cell dependent manner.

                                                So, in summary, these data suggests that notch one signaling pathway is a potentially clinically relevant target to control effector function and promote immune regulation after transplantation.

Dr Greg Hundley:             Oh wow. A lot of intense work, and I learned about notch pathways. I am going to switch and talk about a clinical situation that's really emerged over the last five years, particularly in our scientific literature. And that's tricuspid regurgitation. And this paper comes to us from Dr Jeroen Bax from Leiden University Medical Center in the Netherlands. So in patients with moderate and severe tricuspid regurgitation, the decision to intervene is often influenced by right ventricular size and function. And right ventricular remodeling in significant secondary TR however been under explored. And so in this study the investigators characterize right ventricular remodeling in patients with significant secondary tricuspid regurgitation, and they investigated its prognostic implications.

Dr Carolyn Lam:                 Indeed, very important topic. So please tell us what they found.

Dr Greg Hundley:             Okay, so they use transthoracic echo-cardiography, and it was performed in 1,292 patients with significant secondary tricuspid regurgitation with patients having an average or median age of 71 years. Half were men, half were women. They had four patterns of right ventricular remodeling, and they were defined according to the presence of RV dilation with the tricuspid annulus of greater than 40 millimeters and RV systolic dysfunction. So pattern one was normal RV size and normal RV systolic function. Pattern two was a dilated RV with preserved systolic function. Pattern three, normal RV size with systolic dysfunction. Pattern four was a dilated RV and systolic dysfunction.

                                                So the primary end point was all caused mortality and event rates were compared across these four patterns of remodeling. So what did they show, Dr Carolyn Lam? The five-year survival rate was significantly worse in patients presenting with either pattern three or pattern four remodeling compared to pattern one, which was normal. And they were independently associated with poor outcome in multivariable analysis. Thus, in patients with significant secondary tricuspid regurgitation, patients with RV systolic dysfunction have worse clinical outcomes regardless of the presence of the magnitude of RV dilation. So really helps us as we're trying to decide what going to do with that tricuspid valve and modifying the severity of tricuspid regurgitation. Very nice work.

Dr Carolyn Lam:                 Yeah. Very interesting. Now let's get to our feature discussion.

Dr Greg Hundley:             You bet.

Dr Carolyn Lam:                Our feature discussion today is all about cardiac troponin increases after endurance exercise. Is it a new marker of cardiovascular risk? What should we think of it? Is it associated with cardiovascular events? Now I know many of us has thought of this many times and we're going to get some beautiful answers with today's feature paper. I'm so glad to have the corresponding author, Dr Thijs Eijsvogels, from Radboud Medical Center that's in Nijmegen. And I also have our associate editor and editorialist for this paper, Dr Torbjørn Omland from University of Oslo. So welcome gentlemen, and if I could please start. Thijs, I think a good place to start would be for you to tell us about this four-day march of Nijmegen. Tell us about that and how your study builds on that.

Dr Thijs Eijsvogels:           The Nijmegan four-day marches is actually the largest walking march in the world, so it's hosted every year in July in the Netherlands, and about 45,000 people walk for four consecutive days. And this gave us the opportunity to collect some research data during this great exercise event. What we did over the past couple of years is that we've collected blood samples and participants of this Nijmegan marches. We did a before exercise and also directly after exercise. Within those blood samples we determined the concentration of cardiac troponin eye, which is a marker of mitochondrial damage. And what we subsequently did is that we followed this group of walkers over time and we collected data about diverse events that occurred, and also whether they survived or whether they died over time.

Dr Carolyn Lam:                Thijs, it's such a clever setup for a study. Now give us some idea though. We're saying walking for four days; how many kilometers is covered? And when you say before and after your troponin sampling, give us an idea of how many hours of walking that would be. Because I believe you did it only on the first day, right?

Dr Thijs Eijsvogels:           Yeah, that's correct. So the distance that they must cover is dependent on sex and on age. So for example, if you're a male older than 50 years old, you can walk 30 kilometers per day, but then for four days in a row. But if you are a young individual like me, then you have to cover 50 kilometers per day. So that's a lot more. Typically, they walk about four to five kilometers per hour. So that means that if you walk the shorter distances then you are done within six to seven hours of walking. But if you walk for a longer period of time, then you need 10, 11, and sometimes even 12 hours to complete the distance.

Dr Carolyn Lam:                Okay, there you heard it everybody. So we've got a stress test of a mean, I'm reading from your paper, 8.3 hours of walking at almost 70% of maximum heart rate. So that's really cool. Now before you go on further too, tell us a little bit about the population because everybody's wondering, oh no, does this apply to me?

Dr Thijs Eijsvogels:           So the population participating in this walking event, I would almost say it's about a representation of the general population. So we have very healthy and very trained individuals. So you could say athletes. But we also have people with cardiovascular disease or cardiovascular risk factors. And even obese individuals. So it's a very mixed population, and it's not like the typical athlete population that you see at a runner’s event, for example.

Dr Carolyn Lam:                Great. That's important. So now with that backdrop, please tell us your main findings.

Dr Thijs Eijsvogels:           We measured this cardiac troponin and eye concentration, and we determined the number of individuals that were above the clinical threshold, which is the 99 percentile. And then we've compared the event rate. So major at first cardiovascular events and mortality with those walkers who had a cardiac troponin above the 99 percentile and those below it. And then we found that it was way higher in the walkers with the high troponin concentration. So they had an event rate of 27%, whereas the reference group they only had an event rate of 7%. So that was quite a marked difference.

Dr Carolyn Lam:                That's huge. So first data of its kind and it's so scary because I think, Torbjørn, as you discussed in your editorial, a lot of us have sort of excused the rises in troponin that we know have been reported at the marathons and all that. So how do you put it all together, Torbjørn? what are your thoughts?

Dr Torbjørn Omland:      So I would just like to congratulate Dr Eijsvogels with a very interesting article. And the findings are, as you say, very novel and significantly enhances our understanding of the prognostic implications of exercise induced increase in cardiac troponins. That transient increase in cardiac troponin concentrations may occur in many circumstances, and it's usually considered to reflect acute mitochondrial injury. And thus it has been considered to reflect harmful pathophysiological processes.

                                                But there has to be in one notable exception and that has been the rise in cardiac troponin after endurance exercise, which has commonly been considered a benign phenomenon. But until this study, definitive data relating post exercise troponin concentrations, or the magnitude of the cardiac troponin response following exercise have been lacking. So with Dr Eijsvogels' study we now have clear data showing that these are associated with increased risk.

Dr Carolyn Lam:                That's amazing. So thank you for that in context. Thijs, do you agree? I mean that is a beautiful summary, but what is the take home for listeners? What should we be thinking about now first pertaining to our own exercise I suppose, but also then how do we interpret this clinically?

Dr Thijs Eijsvogels:           I think that Dr Omland made a great point. So for a long period of time we thought that it wasn't a benign phenomenon, that everybody had those increases in cardiac proponents following exercise and also the pattern that was way different from what we see in clinical populations. So we thought, it's just a physiological phenomenon and it doesn't hurt the heart. But clearly our study now shows that there is an association between high post-exercise troponin concentrations and clinical outcomes. So this is an important finding.

                                                And basically there are two hypothesis I guess that could explain those findings. So first of all, it could be that participants with higher troponins have subclinical or underlying disease. And due to this walking exercise, that could be a stress test for the heart. And then those with vulnerable hearts, they demonstrate a greater increase in cardiac troponins. On the other hand, we should also acknowledge the hypothesis that even though it's moderate intensity exercise, it could be some damage to cardiomyocytes. And those individuals with the greatest or the highest troponin concentrations, they could have more cardiomyocyte damage compared to individuals with lower troponin concentrations. And if you then have repetitive exposures to exercise bouts, it could be harmful in the long run as well.

Dr Carolyn Lam:                And so, Torbjørn, you discuss this along with several different mechanisms by which troponin could be increased. Do you have anything else to add to that?

Dr Torbjørn Omland:      No, I think it's very right what the Dr Eijsvogels point out. So on one hand we can consider this like a stress test. And there are some data suggesting that that could be the main effect, in that those who had the higher baseline troponin in the trifocal study also demonstrated the highest increase. So in one way you could consider this as a long-term exercise test. Of course that makes it less applicable in clinical practice. So because we can't have exercise test that last for so many hours, but I think that should be an impetus to have more standardized tests that could be applied to the clinical practice.

Dr Carolyn Lam:                There's also a comment that you made about the kind of troponin tests that we're applying here, that people should understand that we're using the high sensitivity ones, right? Is that correct?

Dr Torbjørn Omland:      Actually, it is not the high sensitivity, but it is a contemporary essay, but it had quite good sensitivity even though it is not classified as a high sensitivity test.

Dr Carolyn Lam:                Thank you for clarifying that. I know you made a point about that, that we should know what kind of tests we're talking about. The other thing is what are the remaining unanswered questions then? Like you said, we can't do an eight-hour walking test. Should we be measuring troponins now in our exercise stress? Which kinds? What time? No, it's not time yet? What are the next steps? I'd like to hear from both of you, actually.

Dr Thijs Eijsvogels:           First of all, indeed it's not possible in clinical practice to do an eight-hour tests whatsoever. But I think that it could be interesting to explore that maybe with some small modifications to current stress tests, if we do it maybe on a little bit lower intensity. For example, moderate intensity exercise, but we do it for a fixed amount of time and then collect blood sample to determine a highly sensitive correct proponents., then maybe also the Delta, so the increase in proponents could be predictive sign of underlying disease. Because what you see in studies that have been published so far is that the duration of most stress test is too short to induce any substantial changes in aortic troponin concentrations. So I think if we modified a protocol a little bit, we can see greater increases in cardiac troponins, and that could provide us with more information, of course.

Dr Torbjørn Omland:      I completely agree. And I think like all great studies, this study raises many new questions, and of course how we should use this clinically is very important one. And as such Eijsvogels pointed out, standardized tests will be required. And I think how much the Delta information we get from measuring the Delta to just the baseline should be one topic for future studies.

                                                And then of course we know that the cardiac troponin increase is a risk factor. But what we also would like to know is whether the at risk is modifiable in some way. So there are some studies that have suggested that increasing your physical activity over time can actually decrease your sort of chronic cardiac troponin concentration. And it would be interesting to see whether increased physical activity over time will also reduce the increase that you observe after a stress test like in Nijmegan march.

Dr Carolyn Lam:                That's such great points. And if I could add too, not to forget that the study population here, would I be right to say the majority are middle aged individuals and they do have cardiovascular risk factors or even prior cardiovascular disease in a sizeable proportion? So to what extent these findings generalized to a really, like the young, athletic, competitive, athletic population? Could you comment on that Thijs?

Dr Thijs Eijsvogels:           I think that's a very good point, that we cannot compare this population where the fit population competing in running events or cycling events or triathletes or whatsoever. So I think we definitely need follow up studies that reproduce our findings in different cohorts with different training modalities, with different age categories, and so on. So that's definitely a topic of interest for future studies.

Dr Carolyn Lam:                Thank you so much. I mean, you've inspired me on so many levels. You've been listening to Circulation On The Run. Don't forget to tune in again next week.

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


Aug 26, 2019

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

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

Dr Carolyn Lam:                In just a moment, we will be discussing further results from the CREDENCE trial. That's canagliflozin in patients with type 2 diabetes and chronic kidney disease, this time focusing on the cardiovascular outcomes as well as both primary and secondary prevention groups. Really exciting stuff, huh, Greg?

Dr Greg Hundley:             Absolutely, Carolyn. Got any papers you want to have a coffee chat about?

Dr Carolyn Lam:                Absolutely. So my first pick really tells us that allele-specific RNA silencing of human alleles may be effective in treating inherited cardiomyopathies. Want to hear more?

Dr Greg Hundley:             You bet.

Dr Carolyn Lam:                So, this is a study from Dr Ashley and colleagues from Stanford University School of Medicine who performed a selective allele-specific silencing of the human restrictive cardiomyopathy, a specific mutation of asparagine to lysine in the regulatory light chain, which is encoded by MYL2. So they did this in a humanized transgenic mouse model using an adeno-associated virus RNA interference approach. Using this approach, they showed that an interfering RNA treatment ameliorated disease phenotypes by specifically reducing the cardiac expression of the mutated allele, hypertrophic carb biomarkers and intramyocardial fibrosis. In fact, isolated cardiomyocytes from the treated animals showed normalization of contraction and relaxation dynamics with partial restoration of calcium re-uptake dynamics.

Dr Greg Hundley:             Boy, Carolyn, sounds like improvement in cardiovascular function, but were there any adverse effects?

Dr Carolyn Lam:                Great question. Well, they also performed cardiac genome-wide transcriptome profiling, which showed a reduction in the hypertrophic program without significant off-target effects, so that's important. So in summary, these results show the feasibility, efficacy, and safety of RNA interference therapeutics directed at human restrictive cardiomyopathy. A really promising step towards targeted therapy for a prevalent disease.

Dr Greg Hundley:             Very nice. Carolyn. So I'm going to start my discussion also with a basic science paper that's going to focus on ischemia reperfusion injury and looking at the mechanism by which mitochondrial dysfunction can be avoided. So, the paper emanates from Dr Yu-Lin Li from Beijing Anzhen Hospital at the Capital Medical University in Beijing. The study from Dr Li identifies an important mechanism of this myocardial ischemia-reperfusion injury in a mouse model and found, in human subjects, a biomarker that was predictive of adverse cardiovascular events after those individuals had sustained an MI.

Dr Carolyn Lam:                Oh, interesting. So tell us more, Greg.

Dr Greg Hundley:             Yeah, so the authors utilized a dynamic transcriptome analysis of mouse hearts exposed to various myocardial ischemia-reperfusion periods to identify a new inflammatory molecule that they termed S100A8/A9, and it was an early mediator. And then they measured this new inflammatory molecule level in patients, human subjects, after myocardial infarction, before and after they had undergone percutaneous intervention. So this S100A8/A9 was identified as the most significantly up-regulated gene during the early reperfusion stage and knockout of that molecule markedly decreased cardiomyocyte death and improved heart function, whereas hematopoietic overexpression of the molecule exacerbated myocardial ischemia-reperfusion injury.

                                                The authors then demonstrated that the levels in patients significantly increased day one post-PCI in anterior MI patients and elevated molecule levels were associated with the incidents of future MACE. So perhaps, in the future, targeting this molecule-initiated signaling may represent a novel therapeutic intervention for myocardial ischemia-reperfusion injury.

Dr Carolyn Lam:                Interesting and very nicely explained. Now my next paper, the title says it all. Three Public Health Interventions Could Save 94 Million Lives in 25 Years. So we know that preventable noncommunicable diseases, which are mostly cardiovascular diseases, are responsible for 38 million deaths annually. So, these authors who are Dr Danaei and colleagues from Harvard T.H. Chan School of Public Health in Boston, Massachusetts, quantified the global mortality impact of three high-impact and feasible interventions. One, scaling up treatment of high blood pressure to 70%, two, reducing sodium intake by 30% and, three, eliminating the intake of artificial trans fatty acids.

                                                So, they used global data on mean blood pressure levels and sodium and trans-fat intake by country, age and sex from a pooled analysis of population health surveys and regional estimates of current coverage of antihypertensive medications as well as cause-specific mortality rates in each country, along with projections from 2015 to 2040. They used the most recent meta-analysis of epidemiologic studies to derive the relative risk reductions for each intervention.

                                                And, in summary, they found that the combined effect of the three interventions delayed 94.3 million deaths during 25 years. Increasing the coverage of antihypertensive medications to 70% alone would delay 39.4 million deaths, whereas reducing sodium intake by 30% would delay another 40 million deaths and eliminating trans-fat would delay an additional 14.8 million deaths.

Dr Greg Hundley:             Aha. So controlling blood pressure, cutting salt, eliminating trans fats, but are there any regional differences around the world, Carolyn, your part of the world versus United States?

Dr Carolyn Lam:                Good question as always. So the authors also estimated the impact in different parts of the world and found that the estimated impact of trans fat elimination was largest in South Asia. Sub-Saharan Africa had the largest proportion of premature delayed deaths out of all delayed deaths. National and international efforts therefore need to scale up these interventions and this should be a focus of cardiovascular disease prevention programs.

Dr Greg Hundley:             Oh, my. Really interesting. Well, I'll tell you what, Carolyn, my next article is going to take us to space, the unified efforts of all these countries in the world trying to examine the effects of prolonged space flight. So this article, it's headed up by Dr Ben Levine at University of Texas Southwestern Medical Center, but it has a very large group of coauthors and examines the impact of prolonged space flight on orthostatic tolerance as those astronauts return to earth.

                                                So, as we know, astronauts returning to earth usually demonstrate reduced orthostatic tolerance, especially when you assess them on a tilt table. But no studies to date have evaluated sort of the post-flight return to earth effects of orthostatic on activities of daily living, and those are most clinically relevant. So in this study, ambulatory blood pressure variability, that's already been known to be associated with orthostatic intolerance in other patient populations and can capture clinically significant orthostatic hypertension during activities of daily living. So, in the study, ambulatory beat-to-beat blood pressure was recorded using a portable device for multiple 24-hour time periods before, during, and after six months of space flight in 12 astronauts, four women, age averaged 48 plus or minus five years.

Dr Carolyn Lam:                Fascinating. What a clever study. So what did happen to the astronauts when they returned to earth?

Dr Greg Hundley:             So, in contrast to previous studies which employed the tilt tables or the stand test, no astronaut experienced orthostatic intolerance or hypertension during activities of daily living before or after space flight. 24-hour systolic blood pressure decreased in space as we might expect, but it returned to normal upon landing and diastolic blood pressure was unchanged during and following space flight. Systolic and diastolic blood pressure variability remained the same before, during, and after space flight. Given the current countermeasures that include exercise, training in flight, volume resuscitation on return, no astronauts experienced orthostatic hypertension or intolerance during routine, for landing day, activities in the initial 24 hours after landing, following six months in space. And prolonged exposure to space fight, therefore, had little impact on systolic blood pressure variability and its distribution. Though the latter showed just a transient change in space and that might be expected. It returned, however, to preflight values when we got back to earth. Very nice work.

Dr Carolyn Lam:                Yes, indeed. Very clever. But let's carry on with our feature discussion, shall we?

Dr Greg Hundley:             You bet. Welcome everyone to our featured article discussion, and we're going to learn more about primary and secondary cardiovascular-related events from the CREDENCE trial and we have with us, Dr Ken Mahaffey from Stanford Medical Center in California and our associate editor, Professor Naveed Sattar from Glasgow in the United Kingdom. Welcome to you both and we feel very honored to be able to discuss this paper today with you, Ken.

                                                Can you just refresh our memories a little bit about the CREDENCE trial? What were its primary results? I understand they had patients with diabetes and chronic kidney disease. Maybe tell us a little bit about how that was defined and then transition to what were the hypotheses in your study that you were going to test?

Dr Kenneth Mahaffey:   So, the CREDENCE trial was a trial of an SGLT2 inhibitor, canagliflozin, in patients with diabetes who had chronic kidney disease with albuminuria. And it was the first of any of the SGLT2 inhibitor trials that was done in a dedicated renal population with a primary outcome that was a composite of renal outcomes along with cardiovascular death, and the trial was stopped early by the data safety monitoring board on an interim analysis when they found overwhelming efficacy. And, at the end of the day, the final results showed that canagliflozin compared with placebo showed a 30% reduction in the composite renal outcome as well as important reductions in cardiovascular outcomes without any evidence of increase in amputations.

                                                Now, the study that we're talking about today is a pre-specified, pre-planned subgroup analysis from CREDENCE where we wanted to look at how canagliflozin worked in people or participants who had known cardiovascular or cerebrovascular or peripheral vascular disease and those who did not. And one of the reasons this was an important analysis was that in previous studies of SGLT2 inhibitors, there has not been a consistency in the message about whether the drug worked in both primary and secondary-prevention populations.

                                                And what we found here in this analysis was that in the primary-prevention participants, which actually was 50% of the overall trial recruitment, had very similar reductions in renal outcomes and cardiovascular outcomes compared with those who were a secondary-prevention cohort. So a very different results and a very important result in this patient population.

Dr Greg Hundley:             Really interesting. So in terms of the patients that you evaluated in this sub study, were they any different than the whole cohort and, in terms of participants and compliance with the therapy, was there any difference with the placebo versus the study drug that you noticed and can you infer from that any particular groups of patients that may benefit more or be able to take the therapy more? Just more about compliance.

Dr Kenneth Mahaffey:   First of all, you asked how the primary and secondary-prevention groups in the study were different and they were, as one would expect. Those participants who did not have prior atherosclerotic cardiovascular disease tended to be younger. They were more often women. They had shorter durations of diabetes and they were less often treated with cardiovascular preventive medications, in terms of staph and antiplatelet therapies. All the patients were on an ACE or an ARB.

                                                In terms of overall compliance with canagliflozin, it was very good. Now, the SGLT2 inhibitors, as a class, have a number of important side effects including genital mycotic infections in both men and women. They do cause some hypovolemia and volume depletion, but we found overall in the CREDENCE trial that fewer participants stopped the study drug prematurely in the canagliflozin arm than in placebo arm. So we feel that we had a very, very good comparison of the two therapies in the overall trial and in the primary and secondary-prevention analyses.

Dr Greg Hundley:             And so just general thoughts of how do you think this might impact the results of your study, or treatment, when we see patients with diabetes and chronic kidney disease?

Dr Kenneth Mahaffey:   I think there's potentially a big impact moving forward. Now, the SGLT2 inhibitor classes were approved based on the early cardiovascular outcome trials, did not enroll participants with lower EGFRs. So once these data are reviewed by the FDA and if they accept these findings and change the label, then the proportion of patients with diabetes who also have EGFRs down to 30 would be potential candidates for this therapeutic intervention. And it's important to point out that the CREDENCE trial that showed this reduction in renal events in patients with type 2 diabetes and chronic kidney disease, this is the first positive trial in 20 years of an intervention and 20 years ago we had both ACEs and ARBs based on large outcome trials, but we've had nothing since then that could be a therapeutic intervention to improve outcomes in this very important patient population.

Dr Greg Hundley:             Thank you so much, Ken. And, Naveed, I would like to just turn to you and ask you a couple things. One, can you put this study on the SGLT2 inhibitors with all the other information that's coming out related to potential benefits, not only in controlling blood sugar, but impacting cardiovascular disease-related events? How does this fit in to all of the other studies that we're learning about in such rapid fashion?

Dr Naveed Sattar:            This comes on the back of the three major trials and extends the evidence based so that, yes, I think we now show clear evidence that these drugs work in people with impaired renal function down to a level of 30 which I think is very important, so that will extend the guidelines. Yes, they seem to work in primary prevention. Of course. I think Dr Mahaffey would accept that these are probably high-risk primary prevention individuals because you also have evidence for chronic kidney disease and I suspect a lot would probably have subclinical cardiovascular disease if we went to look for it.

                                                Nevertheless, I think it will extend the guidelines in the sense that physicians are not only going to be potentially using these drugs in people with existing cardiovascular disease but also patients like those in CREDENCE with chronic kidney disease or a very high risk of cardiovascular disease without having had an event. So I think that's also very reassuring as well and exciting. And I think also the benefits of kidney outcomes is, as we said beautifully, that this is a game changer. Over the last few decades we've not really had any major trials to excite the renal community. But now we have. This trial extends the promise that we saw in the three previous trials and takes it a bit further, that these drugs have substantial and meaningful benefits in prevention of important kidney outcomes in our patients with diabetes. It looks like those benefits appear across the spectrum of diabetes. Whether they've existing disease, chronic kidney disease, or even a primary prevention when previous colleagues looked at it in a meta-analysis.

                                                So, I think that's exceptionally exciting and I think, therefore, given the profile of these drugs and as we're improving our safety in the sense we're able to use these drugs better in groups and also advise how to reduce side effects. I think really they're changing the paradigm of how we care for many of our patients with diabetes and I'd be interested to see what Dr Mahaffey thinks about those comments. My sense is this is really exciting.

Dr Greg Hundley:             Ken, any thoughts?

Dr Kenneth Mahaffey:   I think it was nicely articulated, some of the important observations here. I do agree that the patient population here that has chronic kidney disease but no known atherosclerotic disease and therefore primary prevention, it had higher risk. The event rates in CREDENCE were much higher than event rates in the CANVAS trial where the mean eGFR was much higher and so I agree that these patients may have some subclinical atherosclerotic disease, but they are clearly at higher risk of developing it.

Dr Naveed Sattar:            Again, this would be interesting to take Ken's take. But if people have chronic kidney disease, they are, in a sense, revealing themselves to have evidence of end organ damage or be at the level of the kidney but not necessarily the heart. So my sense is there's still people with evidence of disease and it's just that we're seeing it in a different way. I don't know what Ken thinks about that as a kind of interpretation.

Dr Kenneth Mahaffey:   Again, I think they're at high risk and we know that people who have kidney disease often are at higher risk of having cardiovascular disease during their lifetime and where we are in the spectrum of those new disease processes. We don't necessarily have the data in CREDENCE to understand that at a very granular level, but I think it's an important area that we need to evaluate sooner and it raises that issue of treatment for primary prevention should occur earlier and what we're seeing now is that when people develop type 2 diabetes and we notice that they have chronic kidney disease with microalbuminuria, that is the time to intervene, intervene soon. We now have a single therapy that's safe and effective and reduces the metabolic derangements with improved glucose control, improved blood pressure control, improved weight. It also has an important impact on the renal outcomes and important impact on cardiovascular outcome. So it's really a trifecta from a single therapy that can be prescribed easily.

Dr Naveed Sattar:            I agree. And all those means of treatments were very, very favorable as well across the board, which I think is also important.

Dr Greg Hundley:             So, Ken, what are some key clinical aspects related to your study that you feel we need to address?

Dr Kenneth Mahaffey:   What we need to think about carefully is we now have a new therapy. These types of patients are actually seen by a whole host of clinicians in our healthcare systems, at least in the United States. They're seen by diabetologists, cardiologists, nephrologists, and primary care. And we need to think of ways that we can educate all four of those groups of clinicians about these important data and provide learning and other mechanisms to integrate these therapies into clinical care. It's a message I've been trying to get out.

Dr Greg Hundley:             Well, listeners, what a great discussion between Ken and Naveed on this very important topic, the emergence of SGLT2 inhibitors and the results of these primary and secondary cardiovascular prevention group analyses from CREDENCE.

                                                We want to thank each of you for listening with us this week. Carolyn and I look forward to talking with you next week. Take care now.

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


Aug 19, 2019

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

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

                                                Well, Carolyn, this week's feature is from Professor Carl Lindstrom from Helsinki University Hospital and the University of Helsinki and evaluates whether administration of simvastatin via nasogastric tube in brain-dead individuals prior to cardiac transplant donation improves transplant recipient cardiac-related outcomes. It is a randomized trial using an inexpensive therapy, and I look forward to that discussion with Professor Lindstrom. How about we grab a cup of coffee and start off our discussion today.

Dr Carolyn Lam:                All right, so here goes. The first paper that I want to discuss really looks at the question, is DNA methylation related to incident coronary heart disease? Well, Dr Agha from Columbia University in New York and colleagues looked at this and profiled epigenome-wide blood leukocyte DNA methylation in 11,461 individuals from nine population-based cohorts in the United States and Europe using the Illumina Infinium 450K microarray and prospectively ascertained coronary heart disease events.

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

Dr Carolyn Lam:                Well, they found that differences in blood leukocyte DNA methylation at 52 cytosine phosphate guanine sites were associated with incident coronary heart disease or myocardial infarction with a false discovery rate of less than 0.05. Several of the differentially methylated loci mapped to genes related to calcium regulation and kidney function. Exploratory analyses with Mendelian randomization supported a causal effect of DNA methylation on incident coronary heart disease at loci in active regulatory regions with links to noncoding, RNAs and genes involved in cellular and tissue structural components.

                                                Very nice Caroline. So what's the summary for us clinically?

Dr Gregory Hundley:       So, these findings really provide the first evidence that genomic regulation via epigenetic modifications in kidney function and calcium homeostasis related pathways may be involved in the development of coronary heart disease. The findings of epigenetic, loci related non-coding RNAs highlight pathways that have not immersed in genome-wide studies of coronary heart disease and therefore represent novel therapeutic targets, which thus far have not been explored.

Dr Carolyn Lam:                Very good, Caroline. Well, I've got a basic paper that I want to present and it's from professor Xander Wehrens from the Baylor College of Medicine. And this study addresses factors that promote atrial fibrillation. The investigators found that reduced levels of protein phosphatase-1 regulatory subunit R3A in human atria are causally linked to abnormal calcium handling and atrial fibrillation pathogenesis.

                                                In the absence of protein phosphatase-1 regulatory subunit R3A reducing binding of PP1 catalytic subunit increases phosphorylation levels of the ryanodine receptor, R2 calcium release channel, and phospholamban. Complex zone, profiling, a technique that combines native gel electrophoresis with mass spectrometry to obtain the composition of multi protein assemblies revealed that PP1 R3A is part of a macro molecular protein complex containing the ryanodine calcium release channel and the circuit 2APLN calcium uptake transporter.

Dr Gregory Hundley:       Wow. Complex zone profiling. That's so cool, but what does it all mean for us clinically, Greg?

Dr Carolyn Lam:                Well reduced levels of PP1 regulatory subunit contribute to abnormal calcium release and re-uptake and atrial monocytes, thereby promoting atrial fibrillation pathogenesis. And thus normalizing levels of PP1R3A phosphatase sub unit may represent a novel therapeutic approach to manage atrial fibrillation.

Dr Gregory Hundley:       That's so cool. I next have a preclinical paper which contributes really to the understanding of molecular basis of pathological myocardial remodeling in heart failure. And this is from co-corresponding authors, doctors, Jung, Liu, and Lin-Jung from Shanghai East Hospital Tongji University School of Medicine in China. And the paper really focused on Forkhead box transcription factor P1 or Foxp1 in endothelial cells.

Dr Carolyn Lam:                So Foxp1 Carolyn, tell me a little bit more about that.

Dr Gregory Hundley:       Is it good that you asked before I asked you. Forkhead box proteins P or Foxp are large modular transcription repressors that bind to DNA via their highly conserved Forkhead DNA binding domains. Fox p1 is highly expressed in vascular endothelial cells and it's essential for normal cardiac development.

                                                So, these authors found significantly down regulated Fox P1 expression in cardiac endothelial cells during cardiac remodeling induced by to angiotensin 2. Endothelial cell Fox P1 loss of function resulted in cardiac dysfunction following angiotensin 2 infusion and in the transverse aortic constriction model with severe cardiac fibrosis and mild adaptive cardiac hypertrophy.

                                                Whereas endothelial cell Foxp1 gain of function protected against pathological cardiac remodeling and improved cardiac dysfunction transforming growth factor beta 1 signals were identified as Foxp1 direct target genes in endothelial cells which mediated the pathological cardiac fibrosis through cardiac fibroblasts proliferation and myofibroblast formation and maladaptive cardiac hypertrophy through TGF beta 1 promoted endothelial one expression during pathological cardiac remodeling.

Dr Carolyn Lam:                Wow. Carolyn, this was very sophisticated work. What do we take away from it clinically?

Dr Gregory Hundley:       These data really identified endothelial Foxp1 mediated TGF beta 1 signal pathway involvement in the promotion of cardiac fibrosis and cardiac hypertrophy via TGF beta 1 induction of the endothelin one pathway. So targeted delivery of TGF beta 1 silencing RNA or small interfering RNA to inhibit endothelial cell specific TGF beta 1 for the improvement of pathological cardiac remodeling may actually represent a future novel therapeutic strategy in managing this maladaptive cardiac fibrosis and hypertrophy during progression of heart failure.

Dr Carolyn Lam:                That was an excellent summary of a very technical but informative basic science paper. I'm going to shift gears a little bit and talk a little bit about a study relating to clopidogrel and aspirin from the point study.

                                                This study comes from Claiborne Johnston at the Dell Medical School and University of Texas. And in patients with acute minor ischemic stroke or high risk transient ischemic attack enrolled in the point trial. The combination of clopidogrel and aspirin for 90 days reduced major ischemic events but increased major hemorrhage compared to aspirin alone. This current paper is a secondary analysis of Point and involves 4,881 subjects in which the investigators assess the time course for benefit and risk from the combination of clopidogrel and aspirin.

                                                The primary efficacy outcome was a composite of ischemic stroke, myocardial infarction or ischemic vascular death, and the primary safety outcome was major hemorrhage. Risks and benefits were estimated for delayed times of treatment initiation using left truncated models.

Dr Gregory Hundley:       So, what did the study show Greg?

Dr Carolyn Lam:                Well through 90 days, the rate of major ischemic events was initially high, then decreased markedly while the rate of major hemorrhage remained low but stayed constant throughout the study. Using a model based approach the optimal change point for major ischemic events was 21 days with a hazard ratio of 0.65 for clopidogrel aspirin versus aspirin at a P value of 0.0015 compared to later at 22 to 90 days. Where that hazard ratio was 1.38 and the P value only 0.24.

                                                And the models showed benefits of clopidogrel aspirin for treatment delayed as long as three days after symptom onset. So Carolyn, the authors conclude that the benefit of clopidogrel aspirin occurs predominantly within the first 21 days and outweighs the low but ongoing risk of major hemorrhage. When considered with the results of the CHANCE study, a similar trial treating with clopidogrel aspirin for 21 days and showing no increase in major hemorrhage. The combined results suggest limiting clopidogrel aspirin use to 21 days may maximize benefit and reduce risk after TIA or minor ischemic stroke. Very practical paper.

Dr Gregory Hundley:       Indeed. Thanks Greg. That was nice.

Dr Carolyn Lam:                You bet.

Dr Gregory Hundley:       Welcome everyone to our podcast and we're very pleased today to have Dr Antti Nykänen from Helsinki University in Finland as well as an associate editor, Justin Ezekowitz from Edmonton, Canada to discuss a very interesting randomized clinical trial related to the administration of simvastatin in those that are donors for heart transplantation and looking at subsequent outcomes in the patients that received the transplants. Antti, we're very excited for you to bring this to circulation. This particular paper and I wonder if you might outline for us what were your hypotheses that you are trying to test and what was your overall study design.

Dr Antti Nykänen:            These things are routinely admitted to heart transplant recipients starting one to two days after transplantation. As previous clinical studies show that recipient that treatment has beneficial long-term effects on mortality and cardiac allograft vasculopathy. So in this clinical study, we basically tried to answer the question whether having the statin effect on the board even earlier before the transplant procurement by giving statins to the organ donor, if that would protect the transplanted hearts.

                                                And this question was based potential rapid vascular and cardioprotective effects of statin and when our previous experimental study showing that treating the organ donor with statins will decreases vascular profusion injury in a heart transplant model. So basically we went on the test donor simvastatin clinically and randomize brain dead heart transplant donors either to a control group or to receive a signal 80 milligram dose of simvastatin before organ procurement.

Dr Gregory Hundley:       I'm imagining that you would administer the simvastatin through either an intravenous mechanism or perhaps an NG tube, something like that. Maybe tell us a little bit about how you accomplish this and then what were your study results?

Dr Antti Nykänen:            So, the simvastatin was administered to the donor via a nasogastric tube so there is no intravenous simvastatin formulation available. It needs to be absorbed and then activated through the liver so that can form. So, what we did in our previous experimental study was that we included a few clinical human brain-dead donors and basically investigated whether by giving simvastatin through the nasogastric tube would be metabolized and if you could detect that in in the donor plasma.

                                                And that was actually the case. So in a few hours we saw up-regulated levels of simvastatin and also the active form in the donor or so basically showing off that treatment in a clinical brain dead donor of situation would be feasible. So we went on to use that method, clinical study and basically our primary outcome was plasma levels of cardiac injury biomarkers after transplantation.

                                                And interestingly by treating the donor with simvastatin decreased and recipients for troponin INT levels six hours after transplant's profusion. Therefore, it seems that organ donor’s statin treatment reduces biomarkers of myocardial injury after transplantation in a clinical setting.

Dr Gregory Hundley:       And did you examine any other functional measures of these patients? For example, ejection fraction by echo or anything, or was it primarily a biomarker study? That's the first question. Second question. Do you have any other information on other organs that also may have been donated? Would the statin have impacted, for example, liver transplantation?

Dr Antti Nykänen:            That's a good question. So we did follow up cardiac function and the routine and serial measurements with the echocardiographic and we did not find any changes in the left ventricle. It took some traction after transplantation.

                                                We did however find the decrease in proBNP levels into recipients. And that was maybe then at one week after transplantation and then it's leveled out after that.

                                                And then regarding the next question about other transplanted organs. So once he was in a multi organ donor situation, so the same donor could have donated kidneys or livers, lungs, pancreas. So we did a follow up of the close recipients also. And I can say that there was no adverse effects, no decline in the survival or primary function of the transplanted organs. And interestingly we did find in the liver recipient that if the recipient received the liver from a donor simvastatin treated the liver function tests were better at day seven post-transplant.

Dr Gregory Hundley:       Very interesting. And then lastly, just another outcome related question. Sometimes I know these patients undergo assessments for rejection by biopsy. Any information that you can share with us on outcomes related to biopsies.

Dr Antti Nykänen:            We took routine biopsies, myocardial biopsies from the recipients and we did not find any significant differences in the biopsy program rejections either at 30 days or one year after transplantation. We did also monitor, we checked some treatments, so during the first 30 days there was significant decrease in the amount of rejection treatments for hemodynamically rejects it about not for the first year.

Dr Carolyn Lam:                Wow. Just fabulous results. Thank you so much Antti. So Justin, I wanted to turn the conversation over toward you. Tell us about post-transplant management of these patients and then how do you see these study results integrating into our current standards of care.

Dr Justin Ezekowitz:        Thanks Greg and Dr Nykänen and thanks for also letting us look at your work, which is terrific and extremely hard to do from the translation of your original 2011 circulation publication in animals and moving forward into the current publication years later. And thinking forward into the next few years of how we translate this into practice so that the current management after transplantation obviously involve multiple anti-rejection medications and many activities around detecting rejection is one of the key ways in which patients are managed other than their hemodynamics and other things that happen early.

                                                What I was interested in is the generation of the idea where the simvastatin will really affect the clinical outcomes on the recipient and thinking that into the practice environment is, it's a very simple intervention to think about that would be easily applicable in, I think, most hospitals that do transplantation as either the recipient or the donor.

                                                And Dr Nykänen, when you think about translating this into practice over either Europe or in Finland, I don't sense that this is going to be very difficult. Statins are well tolerated. The cardiology and other communities are very familiar with using a statin. But do you anticipate any barriers to translating this into practice as I think the guidelines may pick this up as something of interest.

Dr Antti Nykänen:            Yes, I think we can show that it's feasible and we did a result on the biomarkers, so indicating that the damage the heart undergoes during the transplantation was smaller after donor statin treatment, so it is feasible, it's very cheap and it generally has a good safety profile. The timeframe for the treatment also feeds into the window of creating a brain dead organ donor. So in that sense it would be applicable in a donor treatment situation.

Dr Justin Ezekowitz:        Right. And so I think this is the key point is even though it's a smaller trial in terms of the cardiology thinks about its trials. This is an area that doesn't have a lot of clinical trials were randomized clinical trials and so any evidence of benefit with a known, generally considered safe medication such as a statin, you would think that we should be able to broadly apply pretty quickly even on what are often not hard outcomes that are softer outcomes.

                                                Because the benefit to risk ratio is generally favorable here. Dr Nykänen, my only other question to you is to think about the team getting this done must have been incredibly hard, but do you think there is a need for a larger trial to test this hypothesis on clinical outcomes or do you think this is really as far as you can go in the transplant world for an RCT.

Dr Antti Nykänen:            So, it's been a long road from artery to single center clinical trial, which took time, so the patient numbers are fairly small in our study. We had 42 in the control group on 42 in the treatment group. I agree the risk benefit ratio is probably beneficial. But for sure it would be very nice to see larger studies that would look at the biomarker effects, but also would look at the other clinical end points.

Dr Justin Ezekowitz:        Right, and that's a great point. It's only 84 patients, but a continued study of the area's important while perhaps implementation studies could go on to take what you found in both an animal translation into humans in a single center RCT and now translation into a larger population of recipients and their donors. I think that's probably the key next step in the transplantation world which has a tougher time getting larger number of patients into clinical trials for a variety of reasons.

                                                So, congratulations to you and your team in getting this one to the point where we could probably apply this in a reasonable way with reasonable safety and an expected benefit to a broader group of patients.

Dr Gregory Hundley:       Well this has been a fascinating discussion, Antti as well as Justin and what a relatively simple, clever idea that could have profound outcomes for this transplant population. We certainly want to thank you Antti for bringing this to circulation and sharing it with our readership. Are there any few last words you'd like to share with us before we close today?

Dr Antti Nykänen:            Very nice to see how things evolve after this. We will for sure try to look more closely at the mechanisms and follow up the patient population for a long term follow up. And I hope this will stimulate some other experiments in the field.

Dr Gregory Hundley:       Justin, any parting comments from the editorial team?

Dr Justin Ezekowitz:        This is a great example of a full clinical trial that is mechanistic, but also has MR outcomes, and I just want to congratulate the authors on providing a very full picture of all the pieces that it takes to do in a clinical trial environment. Plus also collecting genetic and other biomarker material and imaging material. So, my compliments to the authors both to yourself, Dr Nykänen, but also the team that you assembled over the last six or eight years of doing this project, which we know was a huge task and my congratulations to you and your team.

Dr Gregory Hundley:       We want to thank Dr Nykänen and his team from Finland and Justin Ezekowitz. We look forward to chatting with you next week.

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

Aug 12, 2019

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

Dr Greg Hundley:             And I'm Greg Hundley, associate editor from the Poly Heart Center at VCU health in Richmond, Virginia. Carolyn, oh, this is going to be an exciting featured article today, and we're going to discuss the combination of agents or their administration et al that are best suited for managing both anticoagulation and antiplatelet therapy and those with coronary disease, peripheral arterial disease and heart failure. And, we'll speak with Dr Kelley Branch from the University of Washington.

Dr Carolyn Lam:                And me!

Dr Greg Hundley:             Yes. How am I going to interview you? And, we'll discuss the utility of Rivaroxaban with or without aspirin in patients with heart failure or peripheral arterial disease from the compass trial.

Dr Carolyn Lam:                Well, I'm not going to let you get there until I tell you about this first basic paper I've chosen because it focuses on the unfolded protein response.

Dr Greg Hundley:             What's that?

Dr Carolyn Lam:                Well, Greg, I was really hoping you'd ask. The unfolded protein response is a cellular adaptive process to cope with protein folding stress. Now, approximately 40% of human proteins are predicted to be either transmembrane or secretory. The synthesis, the folding, the cellular transportation and location of these proteins rely on proper functioning of this secretory pathway. Numerous studies have established that the unfolded protein response plays versatile roles during development and under physiologic and pathophysiologic conditions. However, the role of this unfolded protein response in the regulation of cardiomyocyte growth is unclear.

Dr Greg Hundley:             That's fantastic, Carolyn. I've already learned something here. So, what did this paper show?

Dr Carolyn Lam:                This is from Dr Wang and colleagues from UT Southwestern, and basically, they use both gain and loss of function approaches to genetically manipulate spliced X-box binding protein one or XBP1, which is the most conserved signaling branch of the unfolded protein response in the heart. In addition, primary cardiomyocyte cultures were employed to address the role of XBP1S in cell growth in a cell autonomous manner. They found that XBP1S expression was reduced in both human and Rhode and cardiac tissues with heart failure deficiency of XBP1S lead to decompensation and exacerbation of heart failure progression under pressure overload. On the other hand, cardiac restricted over expression of XBP1S prevented the development of cardiac dysfunction. Mechanistically, they found that XBP1S stimulated adaptive cardiac growth, your activation of mechanistic target of rapamycin or MTOR signaling which is mediated via the FK-506 binding protein 11, which is a novel transcriptional target of XBP1S. So in conclusion, this study really showed a critical role of the XBP1S FKB or FK-506 binding protein 11 and MTOR axis in coupling the unfolded protein response and cardiac cell growth regulation.

Dr Greg Hundley:             Boy Carolyn, you explained that so well, and I learned a lot from that. I hope I can do as well with this next article from Professor Johann Backs from the University of Heidelberg. Now paradoxically, some glucose lowering drugs have been shown to worsen heart failure, raising the question of how glucose mediates protective versus detrimental cardiac signaling, and this study from his group focused on one of the class two histone deacetylases or HDAC's namely HDAC-4, which functions as an important epigenetic regulator by responding to upstream stress signals, and linking them to downstream gene regulatory programs involved in among other things, metabolic regulation.

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

Dr Greg Hundley:             What they found is that HDAC4 acts as an important maintenance factor of cardiac function in diabetes and O-glycine-N0acetylglucosamine of HDAC4 at searing 642 induces the production of cardio-protective HDAC F-end terminal fragment and attenuates cardio detrimental Cam kinase two mediated phosphorylation of HDAC4 at searing 632. Vice versa, Cam kinase two mediated phosphorylation of HDAC4 at searing 632 attenuates HDAC-4 n terminal production. Thus, these findings lay the ground for the development of novel therapeutic strategies for diabetic patients with heart failure by inhibiting Cam kinase phosphorylation at CIHR 632 or enhancing o-glycine and escalation at searing 642.

Dr Carolyn Lam:                Fascinating, Greg. Well, my next paper is a subgroup analysis of EUCLID and is the first to assess acute limb ischemia in the context of a large-scale clinical trial studying a primary peripheral artery disease population.

Dr Greg Hundley:             So Carolyn, reminded us what was the EUCLID trial.

Dr Carolyn Lam:                Okay, so EUCLID stands for Examining Use of Ticagrelor in Peripheral Artery Disease, and this was a randomized clinical trial that included acute limb ischemia as an adjudicated outcome in a primary peripheral artery disease population randomized to ticagrelor versus clopidogrel. Now in EUCLID ticagrelor was not superior to Clopidogrel for the prevention of cardiovascular events in patients with stable peripheral artery disease. However, a EUCLID subgroup analysis of patients with and without prior limb revascularization demonstrated significantly higher risk for acute limb ischemia hospitalization in patients with prior low extremity revascularization.

Dr Greg Hundley:             So Carolyn, that's interesting. So, what did they find related in this study that focused on the acute limb ischemia?

Dr Carolyn Lam:                Right. So, today's paper is from Dr Hess and colleagues at University of Colorado School of Medicine and CPC, clinical research in Aurora, Colorado. And, they found that acute limb ischemia occurred in 1.7% of almost 13,900 randomized patients with a median time to hospitalization for acute limb Ischemia of 320 days after randomization. In this population, prior lower extremity revascularization, atrial fibrillation and lower ankle brachial index identified patients at higher risk for acute limb ischemia. Hospitalization for acute limb ischemia was associated with subsequent cardiovascular and limb ischemic events. So, the take home message is providers should monitor for signs and symptoms of acute limb ischemia in patients with stable symptomatic peripheral artery disease, particularly those with prior lower extremity revascularization, atrial fibrillation, and lower ankle brachial index.

Dr Greg Hundley:             That's very instructive, Carolyn. Fantastic message. So, I'm going to ask you if you could select one lipid biomarker to forecast future adverse cardiovascular events, which would you select? Total cholesterol, HTLC, non-HTLC, direct and calculated LDLC, APO-A1, or APO-B?

Dr Carolyn Lam:                Well, I'm traditional. I would have chosen LDL.

Dr Greg Hundley:             Okay. Well, the authors of this study led by Dr Paul Welsh at the University of Glasgow attempted to answer this question by studying participants from the UK Biobank without baseline cardiovascular disease and not taking statins with relevant lipid measurements. They had 346,686 participants. An incident fatal or nonfatal cardiovascular event occurred in 6,200 participants of which 1,656 were fatal, and they occurred over a median time of 8.9 years. So, the associations of non-fasting lipid measurements, total cholesterol, HDLC, non HDLC, direct and calculated LDLC, APO-a1, and APO-B with cardiovascular disease were compared using Cox models, adjusting for classical risk factors and predictive utility was determined by the C-index and net reclassification index. Also, prediction was tested in 68,649 participants taking a statin with or without baseline cardiovascular disease, and that group experienced 3,515 cardiovascular events.

Dr Carolyn Lam:                Okay, so drum roll. What did they find?

Dr Greg Hundley:             So, measurement of total cholesterol and HDLC in the non-fasted state is sufficient or was sufficient to capture the lipid associated risk in the cardiovascular disease prediction with no meaningful improvement from addition of APO lipoproteins, direct or calculated LDLC. And, similar findings were reproduced in those taking a statin at baseline.

                                                As such, the authors feel like calls for widespread use of APO lipoproteins are not warranted given the negligible difference in risk prediction beyond total cholesterol in HDLC. And, direct LDLC is also not required for risk prediction. Non HDLC is a cheaper or equivalent predictor of risk on and off statins without the requirement of one of us being fasting. This is an excellent article for our listeners to review or download.

Dr Carolyn Lam:                Wow, that is so cool. So, from one excellent paper to another excellent paper in our feature discussion. Let's go, shall we?

Dr Greg Hundley:             Welcome everyone to discussion of our featured article. We have Dr Kelley Branch from the University of Washington and our own Carolyn Lam, and they're going to be discussing the compass trial. So Kelley, could you tell us a little bit about the rationale for compass as opposed to the previously published commander study?

Dr Kelley Branch:              So, in order to understand compass and compare it to commanders, we're going to have to go back a little bit in time here. And recall, you know well over 20 years ago that when we used anticoagulants in coronary artery disease, that was actually shown to be more beneficial than aspirin alone, but because of the excess bleeding risk, warfarin or vitamin K antagonists not used, and aspirin won. Fast forward a number of years, and now we have the non-vitamin K anticoagulants, and the was potentially that we could find the goldilocks, if you will, the good balance of benefit as well as less bleeding maybe used to these new agents. So, the compass trial was really born from an atlas ACS one and Atlas ACS two, which found that a low dose of, in this case, Rivaroxaban 2.5 milligrams VAB as well as five milligrams VAB were shown to be beneficial in patients after acute coronary syndrome.

                                                And then, it was thought what happens if we treat these patients with now chronic coronary disease as well as arterial disease? And from this 27,000 patients, 47,395 patients were tested, and our study very specifically looked at patients with a baseline or a history of heart failure when they answered compass. Compass were shown to be beneficial with specifically the use of aspirin plus Rivaroxaban, 2.5 milligrams BAD. And, our idea was to test this in patients with this baseline or history of heart failure. Now, this is in real contradistinction to what the commander tried to do. And the reason why encompass, we actually excluded patients with severe heart failure. This was defined as a New York Heart Association class three or four or an ejection fraction less than 30%. Now if you looked at patients with commander, these patients had ejection fraction less than 40%. That was a criteria to get in. And of course, these patients had to have a recent hospitalization for heart failure. So, these are very different patient populations. Well, both of them, yes, they did have coronary artery disease, but really very different patient populations.

Dr Greg Hundley:             Very good. So Kelley, tell us specifically, what were your treatment group assignments and the doses and the outcomes that you were going to follow, and then lead us into what did you find? What were the outcomes of your study?

Dr Kelley Branch:              Sure, so compass was actually developed as a partial three by two factorial. The arm that we're going to be talking about is the rivaroxaban arm. There was also another arm that tested the use of Proton pump inhibitors, and that actually was shown to not be as beneficial as we thought to decreased bleeding. But specifically for rivaroxaban, the baseline was aspirin, and this was on top of guideline based medical therapy. And then patients were randomized to either aspirin alone plus placebo or Rivaroxaban, five milligrams BAD, plus placebo. So, no aspirin at all or aspirin, a hundred milligrams daily, plus Rivaroxaban, 2.5 milligrams BAD. Those were really the three treatments. Patients were going to be followed for about three to four years. That's what we expected to get our 2200 events , an event-driven trial. But, because of the overwhelming benefits at 23 months median follow up, this trial was actually stopped early, so we only had a little over 1300 events at that time.

                                                And with that we saw substantial reduction in major adverse cardiovascular events, about 24% mortality was reduced 18%, and there was a bleeding risk along with this, major bleeding, little different way of actually measuring major bleeding, but that was increased by about 70%, and that was the overall trial results. So, looking at the patients with heart failure, though, there was actually a relatively large proportion of patients, so 5,902 patients, about 22% of patients, actually had either baseline heart failure or had a history of heart failure coming in. Now, this was defined specifically by the PI's. These were not rigorously defined as compared to say commander, but these were patients where the PI said this patient has history or has chronic heart failure. So, with these 5,902 patients, we looked specifically at the outcomes of major adverse cardiovascular events similar to what we saw with compass and that is cardiovascular death, myocardial infarction, or any stroke, that combination. And then, looked at some others exploratory analysis like mortality.

                                                And, what we found is that in patients with heart failure, the baseline rate was substantially higher for a mate's. Not too surprising because this tends to be a higher risk patient population. But, what we found is that the hazard ratio was about 0.68, so pretty similar to what we've seen the 24% relative risk. In this case, this was a 32% relative risk reduction in those patients with heart failure. Now, if we looked at a patients without heart failure, the hazard ratio is 0.79, so fairly similar and the [conference intervals 00:16:33] overlap. No statistical heterogeneity or no difference between those, but what we did see if we looked at the absolute risk reduction, was an absolute risk reduction in heart failure of 2.4% reduction. That means a number needed to treat of about 42. If you look at the absolute risk reduction for those patients without heart failure, that was 0.9 to 1.0 depending on what the rounding was. We took 1.0 so that means the number needed to treat of 103. So, these were slightly different relative risks, but overall, what we saw is that the hazard ratio is very consistent with the overall effect of compass in the same direction.

                                                Interestingly, and actually I think even for me it was surprisingly, we actually looked at the hazard ratios for bleeding, and when we looked at the hazard ratios for bleeding, we fully expected that because it's the higher risk patient population, we actually expected that to go up. What we saw is that the bleeding actually was no difference at all, and if anything in the heart failure population was slightly lower. And, this was fairly surprising to us because we thought that the patients with heart failure, the bleeding would actually trend up because this was a higher risk patient population. So it looks like it's something can be used and really no substantial increase in bleeding.

Dr Greg Hundley:             Very good. Well Carolyn, as someone that's managing patients with heart failure, what do you see are the clinical implications of this study?

Dr Carolyn Lam:                That is a beautifully simple, direct question but is not as easy to answer as I may have thought. And, that's because the commander trial that Kelley did describe a bit earlier was neutral on its primary outcome. And, the commander trial is what we would traditionally think of as a heart failure trial. And why? Because those were patients that we rigorously define heart failure, including a naturally acid peptide inclusion criteria. And, because we really wanted these to be severe heart failure patients, we recruited them very close to their hospitalization or decompensation event. So, I just want to reiterate what Kelley has already so beautifully described that commander was neutral, whereas this heart failure subset of compass showed very impressive results that were consistent with the very impressive positive results of the overall compass trial.

                                                So, how do we reconcile all of it? Well, first of all, I have to humbly remind myself that this heart failure subset of compass, the entire subset was actually bigger in numbers than the entire of the commander trials. So, this is not a small little subgroup analysis. This is a huge subgroup analysis. And that's why a paper like this, we're so proud to be publishing in circulation.

                                                So, how do I apply it? Well, when I have a compass like patient, which means it's a stable coronary artery disease or peripheral artery disease patient who happens to have some mild heart failure. I think of this patient as a compass patient and I think that the combination of aspirin and low dose Rivaroxaban has been shown to be effective in these patients. So, in such a patient, I continue the aspirin rivaroxaban combination. However, if I have a new patient coming in with decompensated heart failure, a very low ejection fraction and has some coronary artery disease, by the way, I see that as a commander patient, and I just want to make sure that in such a patient I'm not trying to reduce their overall mortality by treating them with a combination of aspirin Rivaroxaban because commander has shown that I don't impact their overall survival with this combination, even though we may still have beneficial effects on their thromboembolic thrombotic events.

                                                Kelley, would you agree?

Dr Kelley Branch:              I would completely agree. That was actually born out very, very well by Barry Greenberg who had a really a wonderful sub analysis which he looked at the thrombotic events published in Jama cardiology and really showing that yes, you can affect the thrombotic events, but I mean really what it comes down to is we want to save lives. We want people to be better. There's just an overwhelming risk for these patients with heart failure that is really non thrombotic, primarily. And so, you're really not going to move the needle very much. You may prevent a stroke here, you may prevent some cardiovascular death from a thrombotic problem, but overwhelmingly pump failure, arrhythmia, et cetera. Those are really going to be the drivers for the commander like population.

Dr Carolyn Lam:                But Kelley, this comes up a lot when we've chatted, but if you have a compass patient who has heart failure and then gets admitted with heart failure, what would you do then?

Dr Kelley Branch:              That's a really interesting question, right? It depends on what the overall goal is. So, if the patient gets admitted for heart failure, now has it decreased ejection fraction sick. So has an MI, now decreased the ejection fraction. What's the end game? Right? Well you know, you may not be affecting mortality in this case because there's now competing events. However, if the goal was to decrease stroke, we've seen that. Still this goal is to decrease MI to some extent than we see that also. So, it would be reasonable to continue in order to prevent those events. But, just knowing full well that there's many other medications which actually do much better for the patients with decreased ejection fraction. And, those would probably be considered first line, but it's reasonable to continue. But, I would never start it.

Dr Carolyn Lam:                Kelley, I couldn't agree more. And here I think the, your data showing that the bleeding risk is not significantly increased in this patient matters a lot. So, if I had a patient, a compass patient who was already on the combination and then gets admitted with heart failure, I too, if there's no additional bleeding risk, I would continue the combination as well.

Dr Kelley Branch:              Couldn't agree more.

Dr Greg Hundley:             Well listeners, this was a fantastic discussion, and we look forward to seeing you next week. Have a great week.

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


Aug 5, 2019

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

Dr Gregory Hundley:       And I'm Greg Hundley, associate editor from the Pauley Heart Center in Richmond, Virginia at VCU Health. Our feature article today really invokes thought regarding LVAD bridging to heart transplantation. I really look forward to the conversation with Dr Veli Topkara from Columbia University, the corresponding author and our associate editor, Dr Mark Drazner from UT Southwestern. And it's regarding the outcomes from their study, evaluating patients waiting for transplant that are bridged with an LVAD versus not. But before we get to that, let's dive into some of our other original articles with our little coffee chat. Do you have an article that you'd like to discuss?

Dr Carolyn Lam:                You bet I do Greg and I have my coffee here. Have you ever wondered, does microvascular disease, in any location in the body, increase the risk of lower limb amputation? Well, this was looked at in the paper that I chose first today. It's from Dr Beckman from Vanderbilt University Medical Center in Tennessee and his colleagues, and they basically examined 125,674 participants in the Veterans Aging Cohort Study from 2003 to 2014 and analyzed the effect of prevalent microvascular disease defined as retinopathy, neuropathy and nephropathy and peripheral artery disease status on the risk of incident amputation events, of which there were 1,185 amputations over a median of 9.3 years.

Dr Gregory Hundley:       Wow, Carolyn. What did this study find? What did Josh and his colleagues find?

Dr Carolyn Lam:                They found that the presence of microvascular disease increases the risk of amputation significantly in the absence of peripheral artery disease. As many as one in six below knee amputations may result from microvascular disease, even without peripheral artery disease. Microvascular disease also potentiates the amputation risk in persons with peripheral artery disease to more than 20-fold, compared to persons with neither peripheral artery disease nor microvascular disease. Further research is really needed to understand the mechanisms by which this occurs. And in the meantime, clinicians should bear this increased risk in mind when screening for and managing lower extremity disease.

Dr Gregory Hundley:       Ah. Well Carolyn, my first paper is somewhat related because we're going to talk about triglycerides. And this paper is from Zahid Ahmad from UT Southwestern Medical Center. He's the corresponding author. And can you imagine Carolyn an antibody that could correct elevations in serum triglycerides?

Dr Carolyn Lam:                Tell us about it, Greg.

Dr Gregory Hundley:       Well, I'm going to give you a little background first. Low levels of triglycerides and other lipids are observed in individuals with loss of function mutations in angiopoietin-like protein 3 which inhibits lipoprotein lipase activity, increasing triglycerides and other lipids, and providing a rationale for development of a monoclonal antibody therapy.

Dr Carolyn Lam:                Interesting. What did this study do Greg?

Dr Gregory Hundley:       It evaluated evinacumab. They looked at the safety of this. This is a fully human angiopoietin-like protein 3 antibody, and it was compared with placebo, with no serious treatment emergent adverse events, no events related to death or treatment discontinuation was reported. They did two phase one studies evaluating single and multiple ascending doses. In addition, substantial and sustained percent reductions from baseline versus placebo were observed and triglycerides with absolute levels reaching about 50 milligrams per deciliter for several of the evinacumab doses at specific time points in both studies. And therefore, the data from these two phase one studies in this one paper support further clinical evaluation of this new antibody in larger studies of hypertriglyceridemic individuals.

Dr Carolyn Lam:                Definitely a space to look out for. Well Greg, my next paper is a basic paper. Genome wide association studies have identified chromosome 14 Q32 as a locus for coronary artery disease. The disease associated variants fall in a hitherto uncharacterized gene called Hedgehog Interacting Protein Like 1, or HHIPL1. the function of this gene and its role in atherosclerosis has previously been unknown, well, until today's paper. But Greg, here's your quiz. What do you know about the hedgehog proteins?

Dr Gregory Hundley:       Well, I know hedgehogs are friendly little animals and I know they must have great proteins because they're so friendly.

Dr Carolyn Lam:                Why did I expect that? Oh, let me tell you a little bit about them. The mammalian hedgehog proteins like sonic hedgehog, desert hedgehog, and Indian hedgehog are secreted molecules that exert a concentration and time dependent effect on target cells following binding and complex signal transduction pathways. They induce the transcription of target genes, primarily involved in cell proliferation, survival, and fate specification.

                                                Now in adults, the hedgehog signaling is involved in the maintenance of adult vasculature and ischemia induced neovascularization, including after myocardial infarction. Today's authors, however, including Tom Webb from University of Leicester and colleagues, report the first experimental investigation of HHIPL1 and the present evidence that it is a secreted proatherogenic protein that regulates smooth muscle cell proliferation and migration. So, that's novel.

                                                Through a series of experiments involving coronary artery disease, relevant human cells and mouse models, they showed that HHIPL1 is a secreted protein that interacts with sonic hedgehog and is a positive regulator of hedgehog signaling. In murine models, HHIPL1 deficiency attenuates the development of atherosclerosis by reducing smooth muscle cell proliferation and migration. The clinical implications are two-fold. First, this study supports HHIPL1 as the causal gene at that 14 Q32 coronary artery disease locus that we did not really understand previously. And secondly, HHIPL1 is a promising therapeutic target that affects a pathogenic mechanism not addressed by current mechanisms for coronary artery disease. Room for novel development.

Dr Gregory Hundley:       Very interesting Carolyn. Well, I've got another basic science paper, and this is from Dr Kenneth Walsh at University of Virginia and it's going to look at the role of neutrophils, not necessarily macrophages but neutrophils and their role in pressure overload induced cardiac dysfunction. While the complex roles of macrophages in myocardial injury is widely appreciated, the function of neutrophils in nonischemic cardiac pathology has received relatively little attention. This study examined the regulation and function of neutrophils in pressure overload induced cardiac hypertrophy as mice underwent treatment with Ly6G antibody to deplete neutrophils and then subjected them to transverse aortic constriction or TAC.

Dr Carolyn Lam:                Huh? What did they find?

Dr Gregory Hundley        Caroline, the study revealed that neutrophils played a critical role in the hypertrophy of the left ventricle that results from pressure overload in this murine model of heart failure and identified that a non-canonical Wnt protein is essential for the recruitment of neutrophils to the injured myocardium.

Dr Carolyn Lam:                Hmm. What do you think are the clinical implications of this?

Dr Gregory Hundley        This study demonstrates how neutrophils contribute to the hypertrophy of the left ventricle under conditions that do not involve ischemia or myocardial necrosis. Also, since cardiac hypertrophy is a risk factor for the development of heart failure, this study implicates WnT5a mediated neutrophil infiltration as an early step in the progression of this disease.

Dr Carolyn Lam:                Wow, thanks Greg. That was so cool. But let's hurry on to our feature discussion, shall we?

Dr Gregory Hundley        You Bet.

Dr Carolyn Lam:                Bridge to transplant with left ventricular assist devices is a mainstay of therapy for heart failure in patients awaiting heart transplantation. The criteria for heart transplantation listing does not differ between patients medically managed versus mechanically bridged to heart transplant. However, are there differences in post-transplant outcomes between medically managed and mechanically bridged patients? Well, today's paper provides important data to address this question. So pleased to have with us the corresponding author, Dr Veli Topkara from Columbia University Medical Center, New York Presbyterian as well as Dr Mark Drazner, associate editor from UT Southwestern. Welcome gentleman. Veli, this is an important question. Could you please tell us how you addressed it and what you found?

Dr Veli Topkara:                We decided to visit an old question of whether bridging with LVAD confers at risk for post-transplant mortality. Because the field and pump technology has been rapidly changing. There has been a significant increase in utilization of devices nationwide to the extent that more than 50% of patients already have an LVAD in place by the time they receive a heart transplant. And patients also wait much longer on these pumps before they could get a heart.

                                                Currently, available devices provide continuous flow and patients essentially live without a pulse for many months to years waiting for a heart. And with this unique physiology, they also have unique complications such as RV failure and there has also been pre-survey reports including one from our center suggesting an increase in the primary graft failure rates after heart transplant. And mostly seen in patients who were bridge to transplant with an LVAD.

                                                To address some of these questions, we took advantage of the UNOS database, which is the largest prospective transplant data registry in the United States. We were able to identify more than 14,000 patients who are either medically or mechanically bridged to transplant. We then derived a cohort from patients who were LVAD baseline by propensity score and we looked at their outcomes.

                                                And what we found was that patients who were mechanically bridged to transplant with an LVAD, had 9.5% mortality at one year, compared to 7.2% in patients who were medically bridged. And this is more than 30% increase in relative risk of death for LVAD patients. When we looked at the specific cause of death at one year, LVAD patients had a higher number of cardiovascular death secondary to primary graft failure, confirming findings of the recent studies at a larger scale.

                                                Next, we looked at whether mortality risk factors were similar in the mechanical versus medical bridged patients. And this is a very important question clinically because the criteria for transplant listing do not distinguish between the two patient cohorts. For example, at my center age cutoff transplant listing is less than 72 years of age and that is whether or not patients are on VAD support. And same applies for example, GFR cutoff for renal function or PVR cutoff for pulmonary hypertension. And all the cutoffs that are utilized are essentially identical for transplant candidates irrespective of the bridging strategy.

                                                But what we found in this paper, however, what's quite different that if we apply the same thresholds for mechanical versus medical bridged patients, for some of these risk factors, you end up having outcomes that are remarkably different. For example, for patients with a normal renal function, the mortality risk is similar going into transplant with or without an LVAD, but for patients with borderline renal function observed mortality has more than doubled for those going into transplant with an LVAD, as opposed to medical therapy.

                                                And we also observed similar trends for recipient age, BMI and PVR, in which numerical increase in these factors would translate to high risk of mortality in LVAD patients going into heart transplant. Despite the limitations of this large registry analysis, I think these findings suggest that we may need to think of it differently when it comes to listing or transplanting patients who are on LVAD. And there seems to be a group of patients who are perhaps maybe better served by staying on an LVAD as opposed to moving on to heart transplant and we need to better identify who these patients are.

Dr Carolyn Lam:                Oh Wow. Veli, thank you. First, congratulations on a very important paper and also how you beautifully summarized. Mechanically bridging patients associated with a higher risk of early post-transplant mortality and even providing data on the cause and risk factors associated with that mortality. Mark, could I bring you in here? Not just as AE (associate editor), but as a doc[tor] who manages many of these patients. What were your perspectives?

Dr Mark Drazner:             As I step back and as Veli said, there's an increasing number of patients who are being bridged with a VAD, so the question clearly is important, and we don't really have any randomized data available to us in terms of how the bridging strategy may impact outcomes. When you look at the groups of patients who are supported with VADs or not, they're very different and so you need to do some statistical manipulation which here they did propensity matching, to try to come up with equal groups as you look at their outcomes. That was nicely done.

                                                And then theoretically I think you could argue there may be reasons why patients bridged with VADs may do better or they may do worse. They may do better because you may restore their functionality, you may improve renal function and, but they may do worse because they have coagulopathies, the VAD itself may lead to complications and so it's a question you can't really answer just logically. You really need some data which is I think the best study that's been brought forward so far as the one we're discussing today. Veli, let me ask you because the obvious question then is why do you think the outcomes are worse among the patients who are bridged?

Dr Veli Topkara:                I think they are doing worse for multiple different reasons. Having an LVAD is clearly an additional surgery which technically makes the second transplant surgery more complicated. But when we looked at the risk factors for primary graft failure at our institutions, the predictors of primary graft failure in LVAD patients were also very similar to factors we identified in this nationwide analysis which included renal failure, RV dysfunction, as well as trans-transplant and increased time on device support. I think it's clear that some subset of LVAD patients who have these risk factors are at higher risk for increased post-transplant mortality for some of the mechanistic reasons are unclear at this point.

Dr Mark Drazner:             Do you think their continuous flow exposure is part of it?

Dr Veli Topkara:                That's clearly one of the hypotheses that we have been talking about because as we discussed, these patients are exposed to continuous flow for a long time and one of the concerns is whether they lose their peripheral arterial venous-reactivity over time. And this could potentially also be the reason why patients who are on pump support for longer times are at higher risk for PGF. That's a possible underlying mechanism. But in this data set, we didn't have fair data with regards to pulse pressure and pulsatility, which could have helped answering this question.

Dr Mark Drazner:             And just for clarification for the listeners, this was pre-HeartMate 3 data, is that correct?

Dr Veli Topkara:                Yes. This analysis doesn't include any HeartMate 3 patients.

Dr Carolyn Lam:                And Mark, if you don't mind, could you also clarify for the listeners why you specifically pointed out HeartMate 3 in the setting of the pulsatility?

Dr Mark Drazner:             There is some degree of pulsatility reintroduced with the HeartMate 3, whether that has any physiological consequences is not yet known. Certainly, in terms of the impact of transplants. But as Veli said, the dataset available didn't yet include the HeartMate 3 so that's, remains an unanswered question for us currently, but certainly an important one.

Dr Veli Topkara:                We would probably be able to do this analysis now that we have accumulated more patients with HeartMate 3. At the time of the study we didn't have any HeartMate 3 patients in the registry. In terms of primary graft failure, we have implanted over 160 patients with HeartMate 3 at my center, but we still see primary graft failure in HeartMate 3 patients going into heart transplant, but that would clearly be an interesting follow up project.

Dr Mark Drazner:             Yeah, for sure. Another point that people, as they looked at your paper and asked me, is in terms of the impact of the VAD complications, whether the patients who are doing worse or those who, because they are patients who had VAD who have had complications and then went on a transplant and the impact of that, in terms of your findings. I know you did some analyses on that. Could you just clarify that for our listeners as well?

Dr Veli Topkara:                Sure, so we wanted to look at for the LVAD patients, if there were any VAD related factors that would impact the posttransplant mortality and one of the things that we looked at was, their specific complications on LVAD support and were able to pull that data by looking at their reason for 1A upgrade status which clarifies the complication pipe. And when we looked at, based on complication type, we didn't see any impact of complication on the post LVAD mortality. In other words, the other patients who are transplanted with an infection or they were transplanted because of device thrombosis, they did not have any difference in terms of their posttransplant mortality.

                                                We also compared patients who were supported by axial flow devices versus centrifugal flow devices and again, there was no significant difference in terms of posttransplant mortality. One factor that we found that was significant was the duration of the LVAD support and patients who stayed on the LVAD for longer times clearly had increased higher risk of posttransplant mortality. And this is also something that we had found in our institutional data.

Dr Mark Drazner:             And Veli that would potentially speak to the impact of the continuous flow if duration of VAD is a risk factor.

Dr Veli Topkara:                That's our hypothesis Mark. And I think we all tend to think that continuous flow is not natural, and we have pulse style flow for a reason. Now it's possible that if our bodies and end organs and vessels are exposed to continuous flow for a long time, that may be potentially a reason for, increased risk of PGF or raise of PGF after heart transplant. But I don't think we have enough data yet.

Dr Mark Drazner:             Veli, one of the other interesting findings was the lack of impact on long-term outcomes. I'd be interested in your thoughts about that, why there was an impact on the first year but not long term.

Dr Veli Topkara:                Absolutely. And that was a critical part of the findings and when we looked at our survival, when we visually looked at the curve, it seemed like the curves really separated early on and they sort of remain parallel to each other after one year. And for that reason, we did a conditional survival analysis starting from one year and then we compared starting for one year. There was actually no difference between the LVAD versus medical group. Again, confirming that the adverse impact of survival was really early, within the first year after transplant and I think that really has to do with primary graft failure as well as vasoplegia which are, typically seen early posttransplant. And I think the reason the VAD support is increasing mortality is most likely through increasing risk of PGF as well as vasoplegia. Now that's my read on the early risk rather than the late impact.

Dr Mark Drazner:             Do you think that speaks to maybe not as big an impact on the immunological milieu of VADs as one might anticipate?

Dr Veli Topkara:                Certainly, I mean the immunology, one thing we know is that LVAD patients have higher HLA sensitization going into transplant. However, primary graft failure is typically very early after transplant. And in general, we don't find, obviously we don't see any rejection in these patients. The mechanism is not related to HLA mediated rejection.

Dr Mark Drazner:             That's interesting.

Dr Carolyn Lam:                Well Mark and Veli, thanks so much. This is such an important and interesting discussion. Could I wrap it up now by asking each of you, you've already covered possibly the important areas for future research including the pulsatile devices, but what should clinicians take home right now? Veli, if I could start with you, because you had already said earlier that perhaps these patients need to be more carefully considered. What do you mean by that? What's the take home for now?

Dr Veli Topkara:                I think the question is whether we should be listing or transplanting LVAD patients who are high-risk, and I think the research should focus on developing tools to better identify LVAD patients who are too high-risk for transplant. In this project, we only worked with a limited number of variables that were available in the UNOS registry, but there may be more specific clinical risk factors or even biomarkers predicting outcome in this unique cohort of LVAD patients potentially transitioning into transplant. I think that's an important question to figure out.

                                                And another important question is whether we should be using identical cutoffs for listing patients with or without LVAD and if not, what would be the ideal cutoff for each one of these risk factors? Because what I read from this paper is that, a creatinine level of 1.8 may signal a different risk in an LVAD patient versus another patient on a minor trump. That's another important question.

                                                And also, since October of last year, the new heart allocation policy has been in place, which now defines LVAD patients to appear status three or four based on their complication profile. And it will be interesting to see how the new allocation system would impact patients are on LVAD support waiting for an organ. And it's possible that these patients may end up waiting longer compared to patients who are with cardiogenic shock and are assigned to higher tier status. And if LVAD patients wait longer as we see from this data, they will have worse posttransplant outcomes. It's going to be very interesting to see how the new allocation policy impacts.

                                                Another point I want to make is that with the recent MOMENTUM-3 trial patients receiving HeartMate 3 LVADs, had a 13.4% mortality risk at one year and this is actually lower than 17.6% mortality at one year in high risk LVAD patients in our study. Again, questioning transitioning from LVAD to transplant in high risk patients.

Dr Mark Drazner:             I might take a step back even further. It's an important, it touches on a critical question in my mind, which is if you have a patient who needs to go into transplant and they're not crashing and burning. I'm assuming if they're crashing and burning, you need to go onto an LVAD, the following comments won't apply to that group. If you're a patient who's relatively stable, is it a better strategy to try and get them to transplant directly? Or is it better to go through and VAD and then transplant them? And ultimately that strategy question I think would require randomization to really answer that. But the data that we have discussed today, I think are opening that question and touch upon that in terms of the strategy of the impact of bridging people with VADs itself, which is why I think this is such an important question.

Dr Carolyn Lam:                Thanks again, Mark and Veli. That was an amazing discussion.

                                                Thank you, audience, for joining us. You've been listening to Circulation On The Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019.


Jul 29, 2019

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

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

Dr Carolyn Lam:                Greg, guess what? We are going to be talking later about non-inferiority trials. Now, you're going to go like, "Huh? What?," but then we see more and more non-inferiority cardiovascular trials. And do we really know the advantages and limitations of this type of trial design? Which is so important to understand, because we need to understand the factors that may impact our confidence and interpretation of these results. So, that's going to be a really important feature discussion, coming up right after our coffee chat. Greg, what are your papers?

Dr Greg Hundley:             Thanks Carolyn. Boy, I can't really wait to get to that feature discussion. That's something that we deal with all the time, and I look forward to that explanation and that discussion. I'm going to talk a little bit of basic science, with two papers right in a row.

                                                And the first one involves catecholaminergic polymorphic ventricular tachycardia through inhibition of calcium/calmodulin-dependent kinase II. The lead author is Dr Vassilios Bezzerides from Boston Children's Hospital.

                                                Carolyn, this paper focuses on treatment of catecholaminergic polymorphic ventricular tachycardia, an underlying diagnosis in at least 12% of pediatric patients who present with unheralded cardiac arrest. ICDs, as you know, are frequently implanted, but are problematic because of increased complication rates in pediatric patients, failure to convert ventricular arrhythmias, and the risk of fatal ICD-induced electrical storm. Modulating CaM Kinase II within the heart shows promise to treat this, but CaM Kinase II is essential in other tissues, most notably the brain.

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

Dr Greg Hundley:             Well, the investigator used adeno-associated viral gene therapy, which is proven to be a safe and efficient vector for sustained gene transfer into many cell types to selectively inhibit CaM Kinase II in cardiomyocytes. They were able to express the specific CaM kinase II inhibitory peptide AIP in cardiomyocytes without significant extra cardiac expression, and an inhibition of CaM Kinase II effectively suppressed ventricular arrhythmias in a murine model of catecholaminergic polymorphic ventricular tachycardia after a single therapeutic dose. So thus, in animal models, delivery of a CaM Kinase inhibitory peptide by AAV represents a novel single dose gene therapy for catecholaminergic polymorphic ventricular tachycardia. How about that?

Dr Carolyn Lam:                Wow. You've got a second paper?

Dr Greg Hundley:             I sure do. So now we're going to jump into, again, looking at polymorphic VT from engineered human heart tissue. And this article is from Kevin Parker at Harvard University, "Modeling of Human Arrhythmias Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes has Focused on Single-Cell Phenotypes."

                                                With this said, it is important to realize that arrhythmias are emergent properties of cells assembled into tissues and the impact of inherited Arrhythmia mutations on tissue level properties of human heart tissue. And therefore, newer technologies are needed to develop more satisfactory therapeutic interventions. Ones that encompass all of the tissue, not just single cells.

Dr Carolyn Lam:                Interesting. So, what did this particular study do?

Dr Greg Hundley:             So, Carolyn, in this study, the investigators report on an optogenetically-based human-engineered tissue model of catecholaminergic polymorphic VT, which as we have discussed in the previous article is promoted by mutation of the cardiac ryanodine channel 2, which is promoted by mutation of cardiac ryanodine channel and triggered by exercise. They developed a human IPSC cardiomyocyte-based platform to study the tissue level properties and investigated pathogenic mechanisms in polymorphic VT by combining this novel platform with genome editing. The authors found that engineered heart tissue, fabricated from human pluripotent stem cell derived cardiomyocytes, effectively modeled catecholaminergic polymorphic VT caused by dominant mutations in the cardiac ryanodine receptor, including induction of arrhythmias by conditions that stimulate exercise. Using selective pharmacology and genome editing, the authors identified activation of calcium/calmodulin-dependent kinase II, or CaM Kinase II, and CaM Kinase II mediated phosphorylation of ryanodine at Serine 2814 as critical events that are required to unmask the latent arrhythmic potential of catecholaminergic polymorphic VT, causing ryanodine mutations, highlighting a molecular pathway that links beta adrenergic stimulation to arrhythmogenesis in this disease.

Dr Carolyn Lam:                Wow Greg! So, two very interesting and important linked genetic papers. Well, we're going to switch tracks a little bit and talk about, well, my favorite topic: heart failure with preserved ejection fraction and the whole complex issue of the diagnosis of this syndrome. Now we know that the diagnosis is kind of complex and there is currently no consensus but several proposed definitions. So how do the clinical and hemodynamic profile of patients vary across the different definitions of HFpEF?

                                                So, this question was answered by Dr Jennifer Ho from Massachusetts General Hospital and her colleagues, who examined consecutive patients with chronic exertional dyspnea and an ejection fraction above 50% who are referred for comprehensive cardiopulmonary exercise testing with invasive hemodynamic monitoring. They applied societal and clinical trial HFpEF definitions and compared the clinical profiles, exercise responses, and cardiovascular outcomes by these different definitions. So, of 461 patients, 416 met the ACC/AHA definition, 205 met the ESC definition, and 55 met the HFSA criteria for HFpEF.

                                                The clinical profiles and exercise capacity varied vastly across the definitions, with peak oxygen uptake averaging 16.2 for those with the ACC/AHA definition and down to 12.7 in those satisfying the HFSA definition.

Dr Greg Hundley:             Wow. What a difference from these societies.

Dr Carolyn Lam:                Mm-hmm (affirmative).

Dr Greg Hundley:             So Caroline, it sounds like they looked at all comers with exertional dyspnea. Now how about those that had hemodynamic evidence of heart failure with preserved ejection fraction?

Dr Carolyn Lam:                Yeah, good question Greg. So, you caught me telling you that all these patients had hemodynamic cats as well, and a total of 243 had hemodynamic evidence of HFpEF, which was defined as an abnormal rest or exercise feeling pressure. Of these, 222 met the ACC/AHA criteria, 161 met the ESC criteria, and only 41 met the HFSA criteria. Over a mean follow-up of 3.8 years, the incidents of cardiovascular outcomes range from 75 for the ACC/AHA criteria to 298 events per thousand-person years for the HFSA criteria.

                                                The application of clinical trial definitions of HFpEF similarly resulted in distinct patient classification and prognostication. So in summary, the authors demonstrated significant diversity in the number of patients meeting HFpEF criteria. And using different HFpEF classifications variably enriched for future cardiovascular events, but at the expense of not including up to 85% of individuals with physiologic evidence of HFpEF. Comprehensive phenotyping of patients with suspected heart failure really highlighted the limitations and heterogeneity of current HFpEF definitions and may help to refine HFpEF sub-grouping to test therapeutic interventions. Now, these are all discussed in an important accompanying editorial by Michele Senni, Sergio Caravita, and Walter Paulus.

Dr Greg Hundley:             Wow Carolyn. It appears, depending upon the definition, we could really classify patients drastically differently.

Dr Carolyn Lam:                Yeah, an important paper indeed. And again, I would strongly encourage everyone to read that editorial as well. For my second pick, we're going to switch to CPR in children.

                                                So these authors, now led by Dr Rohan Khera from UT Southwestern, examined the prevalence and predictors of survival of children who progress from bradycardia to pulselessness in in-hospital cardiac arrest despite cardiopulmonary resuscitation. So they looked at almost 5,600 pediatric patients age more than 30 days to under 18 years of age, who received CPR at hospitals participating in the Get With The Guidelines - Resuscitation during 2000 to 2016 each CPR event was classified as bradycardia with pulse, bradycardia with subsequent pulselessness, and initial pulseless cardiac arrest. And the authors assessed for risk adjusted rates of survival to hospital discharge.

Dr Greg Hundley:             So Carolyn, what did they find? This is really interesting.

Dr Carolyn Lam:                Well, among hospitalized children in whom CPR was initiated, half had bradycardia with poor perfusion at the initiation of chest compressions and nearly one third of these progressed to pulseless in-hospital cardiac arrest despite CPR. Survival was significantly lower for children who progressed to pulselessness despite CPR compared to those who were initially pulseless. So, these findings suggest that pediatric patients who lose their pulse despite CPR are at particularly high risk and require a renewed focus on post resuscitation care.

Dr Greg Hundley:             Very interesting, Carolyn.

Dr Carolyn Lam:                Well, that wraps it up for our discussion. Let's go onto the featured discussion. Shall we, Greg?

Dr Greg Hundley:             You bet.

Dr Carolyn Lam:                Non-inferiority cardiovascular trials are increasingly being published and in the highest impact journals. Yet how much do we really know about these designs of the trial, of the non-inferiority trials? Well, I have to admit not much in my point of view, and I was so pleased to see our feature discussion paper really published in this week's journal, which really digs deep into non-inferiority trials and talks about time trends and perhaps some lessons that we should all bear in mind when we look at these. I'm so pleased to have the first author, Dr Behnood Bikdeli, to tell us about the study. And he is from Columbia University Medical Center, New York Presbyterian Hospital, Yale Center of Outcomes, Research and Evaluation Core, as well as the Cardiovascular Research Foundation in New York. We also have Dr Naveed Sattar, associate editor from the University of Glasgow. Behnood, could you tell us, so what made you look at this question and what did you find?

Dr Behnood Bikdeli:        For a while we've been very interested in profiling the cardiovascular trials, trying to understand a little better, what are the specific characteristics of the major child that we rely upon for research but also for clinical practice? Years ago, we did some studies for surrogate outcome trials and this, let's just say subsequent piece, where we tried to look into a randomized cardiovascular trial that use a non-inferiority design. We had a series of features in terms of quality metrics and methodological metrics that we wanted to look into. The over eight almost 27-year period, we identified 111 of these trials. Reassuringly, most of these trials inherited several important quality and methodological metrics that we were looking into. However, we also saw a significant room for improvement. There were quite a few quality or methodological metrics that some of these trials were not adhering to and we think it's important because ultimately for the design reporting and last reading of these trials, knowing these pluses and minuses would help inform people.

Dr Carolyn Lam:                That's great, Behnood. Now for those of us listening who don't think about this every day, could you give us some examples of the top errors perhaps to look out for?

Dr Behnood Bikdeli:        For example, in the typical superiority trials, when we want to test an intervention a versus intervention B, all that matters is we do a very good and adequately sized trial and rest of it is up to the study and how it goes to see whether or not something panned out. There was a significant difference between the new intervention versus the older ones, but in non-inferiority trials we have something called the non-inferiority margin and that's very highly relevant when it comes to the outcome that you're assessing when it comes to the ultimate results of the trial.

                                                If the investigators choose a very lenient y non-inferiority margin, they may end up calling an intervention non-inferior. They may give it a pass. While in reality the intervention has quite a lot of a risk or harmful profile compared with standard of care. But in the other side, as a clinical example, we have several interventional tools at hand, like transcatheter aortic valve replacement. Most of the indications where it's currently used came from large bell designed non-inferiority trials. Where they showed that it was almost as good as surgery, in some cases better, but also it had a lot of ancillary advantages.

Dr Carolyn Lam:                Thanks, Behnood. And you know here, I just want to call out to the readers. You have to look at this paper. Look at the tables and figures which are really so helpful. And Naveed, can I bring you in on this now? I mean, I just love this paper. It's such an important topic and I've never seen it addressed like this before. Could you tell us a little bit about what the editors discussed when we looked at this?

Dr Naveed Sattar:            I've been involved in a few non-inferiority trials and some of the factors that many of us discuss and some of course associated, sort of our clinical trials, and I've been involved normally in superiority trials, but increasingly we have cut our teeth in non-inferiority trials. So, some of the points that the paper picks up resonated well with us in terms of, one of the examples was Behnood and his team found that around about 40% of trials didn't even justify what their non-inferiority margin was. And that's something I've actually had detailed discussions involved in various trials with. And that's a really important point, but it isn't a, you have to be able to justify why you choose particular margin and what that margin would mean to the community. Otherwise you potentially could just pick something out there which really doesn't allow you to make a really strong non-inferiority claim. And I think that's one of the factors that you found, Behnood. Is that correct?

Behnood Bikdeli:              Absolutely. And that's a great point. Thank you. To us, there were two things about it. One was whether or not they provided any detailed justification for it exactly as you said, not that they're just picking up something because that's the sample size that they could achieve or that's the number that they felt comfortable with. But also the second piece of it, a respective of how they calculated or came up to the number, their readers have a right to know how this was calculated or were this came from, so it's the reporting part of it. Sometimes they reported both in the published paper and a study protocol or a design paper. Sometimes it was only in one of them. Sometimes as you mentioned, it was not mentioned in either, which puts the reader in a very difficult situation.

                                                So we think, and these were the best of the best trials in the highest impact journals. Probably if we look high and low elsewhere it's going to be even more challenging. So, we think there's a lot of room for improvement for the readers to expect cleaner, more comprehensive papers to come, but also for the trialist to report them with more clarity.

Dr Naveed Sattar:            And going forward, issue a nice figure that shows that the trend is that we are going to see more of these trials probably because you've got lots of better treatments now. So, you know it's getting harder, in the sense, in many areas of cardiovascular medicine to show superiority. So, there is a need for more trials which actually show benefits beyond just perhaps the main outcome in ways that you've explained in the particular paper.

                                                Do you think the FDA does enough in this particular area in terms of this helping investigators decide what the non-inferiority margins are? Or is that something in terms of the quality of the trials that needs a bit more investigation? I think your papers partly are pushed to say, "Actually we need to do these better. We need to justify them better. We need to look at them better." Because actually they do have a greater influence going forward.

Dr Behnood Bikdeli:        First, I cannot agree more. We are going to see a lot more of non-inferiority trials sort of, maybe because we have reached a ceiling effect when traditional intervention for superiority, but there's a lot of room to find interventions that are at least as safe or as good but have a lot of side advantages and ancillary benefits that's happened with some of the anticoagulants among other therapies available.

                                                In terms of the regulatory aspects, one of the things we were fortunate about was within our team, we had people with expertise on the trialist side while communicating with the regulatory bodies and also from people who were consulting to the FDA for assessment of non-inferiority trials. So, we were fortunate to look into several of the methodological or quality metrics that were being thought of and we consulted with the in-source guidelines and FDA guidelines. That said, I completely agree that, for example, the suggestions that you provided in one of the tables could hopefully help shape some of these trials in a more rigorous way. Or at least a reporting, which is also an important piece, would be more transparent ultimately for the readership.

Dr Naveed Sattar:            Absolutely. And transparency is really pivotal so that the readers completely understand what was done, what was predefined, and what was found so that they can make a proper judgment. And probably the final question I have in terms of, you make a good point that actually if the trials are not done well and there's a bit of slippage either in terms of loss of data or methodological issues, that then really pushes a trial towards a "no", in a sense you get a false reassurance of non-inferiority, but partly because the methodology wasn't robust enough. And it's really very critical for these trials, perhaps at least as critical as they are in superiority trials, but perhaps even more so. Is that a fair judgment?

Dr Behnood Bikdeli:        No, no, no. You're absolutely right. That's another very important point in the typical superiority trial, if any bias drives the results toward no difference. Investigators are naturally guarding against that because it's going to be very problematic in non-inferiority trials. Depending on the effect measure that they choose, it could actually falsely favor the intervention of interest because it might show a false assessment of non-inferiority, and there are ways to work around it. There are ways to correct for it, such as choosing both absolute and relative effect measures, which practically addresses this concern. Again, gets back to the importance of appropriate design and appropriate transparency to report the results in a robust way, both intentions to treat and has treated or per protocol, both relative effect measures and absolute effect measures.

Dr Naveed Sattar:            My sense of and getting back to you, but I think this will be a really seminal paper for the community to look at and really help us as a community to improve our conduct of such trials in the future because there will be more of these coming forward.

Dr Carolyn Lam:                And I couldn't have said that better, Naveed. I think the take home message is right there. Pick it up, have a look and especially have a look at those tables and figures. It's really going to help you read many, many journals.

                                                Thank you so much, Naveed and Behnood. Thank you audience for joining us on Circulation on the Run. Talk to you next week.

                                                This program is copyright American Heart Association 2019.


Jul 22, 2019

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

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

                                                Well Carolyn, did you ever wonder whether cardiovascular drug effects could be investigated through natural variation in the genes for the protein targets? In our feature discussion today, investigators from the British Isles, Germany, and the United States use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs. Sound interesting? Well listeners, we look forward to the results later in our program, but Carolyn, how about we chat about some of the other papers in this issue?

Dr Carolyn Lam:                You bet Greg. So, have you ever asked yourself "What is the role of protein glycosylation in regulating LDL metabolism?"

Dr Greg Hundley:             That was going through my mind when we were playing basketball just the other night.

Dr Carolyn Lam:                Well this is truly a great study from Dr Holleboom at Academic Medical Center Amsterdam and Dr Lefeber from Radboud University Medical Center, both in the Netherlands. And their colleagues will study 29 patients of the two most prevalent types of Type 1 Congenital Disorder of Glycosylation, and these are the ALG6 and PMM2 types. They also study 23 first and second-degree relatives with a heterozygote mutation and measured their plasma cholesterol levels. LDL metabolism was studied in three cell models. They found that patients with type 1 congenital disorder of glycosylation have hypobetalipoproteinemia through increased LDL receptor expression. Carriers of the mutation in glycosylation enzymes affected in this syndrome had decreased LDL cholesterol levels compared to controls, and defects in glycosylation enzymes could play, therefore, an important role in LDL cholesterol metabolism.

Dr Greg Hundley:             Boy, this is pretty insightful I think, Carolyn. So, what are the clinical implications?

Dr Carolyn Lam:                Well, given that LDL cholesterol was also reduced in a group of clinically unaffected heterozygotes, the authors propose that increasing LDL receptor mediated cholesterol clearance, by targeting N-glycosylation in the LDL pathway, may therefore represent a novel therapeutic strategy to reduce LDL cholesterol, and of course prevent cardiovascular disease.

Dr Greg Hundley:             Very interesting work. You know, we just keep learning more and more about LDL. I'm going to switch and jump back with Empagliflozin. And this is a study in diabetic mice that really has an interesting in-vivo imaging component. As an imager, I was really excited about this. The article is from Dr Kengo Kidokoro from Kawasaki Medical School. And we don't often talk about it, but listeners, if you have a chance, there's a very interesting video-enhanced file associated with this article, and if you can download it, it's really just so cool with multiple image clips demonstrating an operative mechanism of SGLT2 inhibition on renal function. And it really gives us an opportunity to revisit renal function.

                                                Quick quiz Carolyn. In diabetic kidney disease, is glomerular hyperfiltration good or bad?

Dr Carolyn Lam:                Bad.

Dr Greg Hundley:             Yeah, absolutely. So, hyperfiltration is characteristically observed at earlier stages of diabetic kidney disease and involves activation of the renin-angiotensin-aldosterone system at the efferent arteriole and tubuloglomerular feedback mechanisms, especially at the afferent arteriole. So, as they go through this, just picture in your mind that glomerulus and afferent is arriving, and efferent is leaving.

                                                So, SGLT2 upregulation in diabetes is thought to play an important role in TGF signaling by increasing sodium reabsorption at the proximal tubule, thereby decreasing distal delivery to the sodium sensing macula densa at the juxtaglomerular apparatus. This decline in distal sodium delivery is interpreted as a decline in effective circulating volume, leading to inappropriate afferent vasodilation in an effort to preserve intra-glomerular pressure and GFR.

                                                In diabetes, these TGF effects lead to intra-glomerular hypertension and hyperfiltration. You got that quiz right, Carolyn. Which promotes diabetic kidney disease progression and impaired kidney function, ultimately increasing overall cardiovascular risk and mortality. Conversely, blocking SGTL2 pharmacologically reduces renal hyperperfusion and hyperfiltration in animals and humans, which may preserve renal function, thereby reducing risk associated with diabetic kidney disease progression.

Dr Carolyn Lam:                You know what, Greg? I kind of had an unfair advantage in this quiz. I work with a lot with the SGLT2 inhibitors, but I just love that you asked us to picture it and look at that video. Anyways, so this article really allows us to review SGLT2 inhibition at the glomerular level, which is truly hot. So, tell us what did they find?

Dr Greg Hundley:             So, this is the first report of changes in renal hemodynamic function by SGLT2 inhibition using direct in-vivo visualization techniques in a diabetic animal model. The videos, they're spectacular, and they're excellent so that you can download them for educational purposes. Afferent arteriolar vasoconstriction, and reduced hyperfiltration occurred within a few hours after a single dose of a SGLT2 inhibitor. And Adenosine signaling, through tubuloglomerular feedback, is a key pathway to prevent diabetic hyperfiltration via SGLT2 inhibition.

                                                Clinically, Carolyn, now I know you would ask me about that, so I got ready, this study highlights another potential mechanism for the benefits of SGTL2 inhibition. The SGLT2 inhibitor-related mechanism's responsible for reducing cardiovascular risk in clinical trials may be due to protection against diabetic kidney disease progression, thereby attenuating risk factors for heart failure, such as volume overload and hypertension.

Dr Carolyn Lam:                Ah. That is just so cool, and really just so consistent with the clinical data that's emerging too. Thank you, Greg. So, have you ever asked yourself this other question, what role do platelets play in ischemia reperfusion injury? So, I'm not going to quiz you. I'm actually kind and loving and a good person. And so, I will tell you about ischemia reperfusion injury, which is a common complication of cardiovascular disease.

                                                Now, resolution of the detrimental effects of ischemia reperfusion injury generated prothrombotic and proinflammatory responses, is essential to restore homeostasis. Now, although platelets are known to play a crucial role in the integration of thrombosis and inflammation, their role as participants in the resolution of thrombo-inflammation is really under-appreciated. And hence, this other paper that I chose today, and it's from Dr Gavins from Louisiana State University Health Sciences Center Shreveport, and her colleagues, who used pharmacological and genetic approaches, coupled with murine and clinical samples to uncover key concepts underlying this role for platelets.

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

Dr Carolyn Lam:                Well, they found that exacerbation of thrombo-inflammatory responses occurred in ischemia reperfusion injury mouse models of middle cerebral arterial occlusion, as well as lower plasma levels of the anti-inflammatory pro-resolving protein Annexin A1. And this was a lower plasma level of this Annexin A1 among patients with acute ischemic stroke.

                                                Administration of Annexin A1 promoted cerebral protection against thrombo-inflammation and the development of subsequent thrombotic events post-stroke. Annexin A1 was also able to reduce platelet activation and thrombosis, via the suppression of integrins. So, overall, these data reveal a novel multi-faceted role for Annexin A1 to act both as therapeutic and prophylactic drug via its ability to promote endogenous pro-resolving anti-thrombo, anti-inflammatory circuits in the cerebral ischemia reperfusion injury. And collectively, these results further enhance our understanding in the field of platelet and ischemia reperfusion injury biology.

Dr Greg Hundley:             Oh wow. So, another important insight from this author group on platelet activation and thrombosis in key clinically relevant syndromes. Well, my last paper is going to be talking about a risk prediction score for life-threatening ventricular tachyarrhythmias. And they're going to study this in laminopathies, and the lead investigator is Dr Karim Wahabi from Cochin Hospital in France.

                                                To estimate the risk of life-threatening ventricular tachyarrhythmia in patients with LMNA mutations, and thus select candidates for implantable cardiac defibrillators, the investigators evaluated 444 patients of about 40 years in age in a derivation sample. And then, 145 patients that are about the same age, 38 years, in a validation sample, for the occurrence of a) sudden cardiac death or b) ICD-treated or hemodynamically unstable ventricular tachyarrhythmias.

Dr Carolyn Lam:                Oh. Very important. These laminopathies are really not that uncommon. So what did they find, Greg?

Dr Greg Hundley:             Carolyn, predictors of events included male sex, non-missense LMNA mutations, first-degree and higher AV block, non-sustained ventricular tachycardia, and LVEF. The authors developed a new score to estimate the 5-year risk of life-threatening ventricular tachyarrhythmias in patients with LMNA mutations. And compared to the current standard of care, the proposed risk prediction model offered more accurate prediction of life-threatening ventricular tachyarrhythmias, and correctly re-classified almost 30% of the patients in the study.

                                                Nicely, the authors have made this available, and the score can be derived from readily collected clinical and genetic parameters and estimated using an online calculator that's provided in the journal. But, it's

                                                Future prospective studies should focus on the estimation of the clinical benefit conferred by the use of this score in terms of sudden cardiac death prevention.

Dr Carolyn Lam:                That is super cool, Greg. But, I am so excited now to move to our feature discussion. Shall we?

Dr Greg Hundley:             You bet.

Dr Carolyn Lam:                Can we use natural variations in our genes for the protein targets as a way to look at cardiovascular drug effects? Man, this is going to be such an important and exciting discussion, because this is what our feature paper talks about. I am so pleased to have with us our corresponding author, Dr Dipender Gill from Imperial College London, as well as our Associate Editor, Dr Wendy Post from Johns Hopkins.

                                                So, first of all, Dipender, please, could you give us a background on what you did? This is really very novel in approach.

Dr Dipender Gill:               It was also a lot of fun to conduct. I think, currently, we're living in an era where there's been a recent explosion in the availability of genetic data, and this really inspired us to think about how we could use that to learn more about commonly prescribed drugs. The implementation of genetics, or genetic variance, to study drug effects isn't entirely novel. It's actually been undertaken for some years now.

                                                Most of the work has been related to lipid lowering drugs, for example, statins, where people can take genetic variance, or versions of genes, corresponding to the drug effect, and study these to investigate what effects these drugs might have, both on the intended target, but also potential side effects. To my knowledge, this hadn't previously been done for anti-hypertensive drugs. But yet, the data for this was available. And therefore, we thought that actually we could very well go ahead and do this, and perhaps find some interesting things.

Dr Carolyn Lam:                Oh, that's so interesting thing, Dipender. You know, there was this term in your abstract, and mentioned multiple times, Mendelian randomization. Now, for those of us that don't think about this every day, could you tell us a little bit what that means?

Dr Dipender Gill:               Yeah. So, I'll actually give a little bit of background. One of the main limitations of traditional epidemiological research is that any association, it's sometimes difficult to infer causation. They can be confounded by environmental factors, lifestyle factors. In the Mendelian randomization technique, what we do is we use randomly allocated genetic variants to study the effect to an exposure.

                                                So, we select these genetic variants because they are related to the exposure of interest. And because these genes are randomly allocated at conception, they're not subject to confounding from environmental or lifestyle factors. Whether you have a gene or not, is not necessarily related to your lifestyle or your environment. And therefore, the association of these genetic variants with certain outcomes isn't subject to confounding.

Dr Carolyn Lam:                That makes so much sense, and I suppose that, not to allow cause and effect to be determined. So please, tell us, in this particular case of the anti-hypertensive drugs, what did you do and what did you find?

Dr Dipender Gill:               First, we decided specifically which drugs we wanted to look at, and we thought, actually, let's start off with the most commonly prescribed anti-hypertensive drugs. So, we short-listed these based on recent consensus guidelines, and we looked at ACE inhibitors, beta-blockers, calcium channel blockers, thiazide type diuretics. And then, we went back to various online databases to identify which genes correspond to the target protein of these drugs.

                                                We took these genes, and we then identified genetic variants at their specific genetic loci, their specific region of the genome, and we identified the variants in these regions that were also related to systolic blood pressure. And in this way, we inferred that genetic variants, at the protein coding targets of these genes, that were also related to systolic blood pressure, likely represented the effect of variations in these proteins that also implicated blood pressure, and therefore, could serve as proxies, or instruments, to study the effect of these drug targets.

                                                We then went ahead to validate the selection of these genetic variants by forming Mendelian randomization, and specifically, we checked whether people that have genetic variants that correspond to, say, ACE inhibitor activity, or beta-blocker activity, or calcium channel blocker activity, if they also have correspondingly lower risk of coronary heart disease and stroke, to the same degree that we would observe in randomized control trials against placebo.

                                                And indeed, we found that actually, the results were fairly similar, and this gave us confidence. And studying these genetic variants that mimic the effect of these drugs could be used as a proxy or as a surrogate to study their clinical effect of taking these drugs. So, that was the first phase.

Dr Wendy Post:                 Dipender, congratulations to you and our team. This is a really exciting paper, and the editors were especially interested in the novelty, and the potentially impactful findings, especially of the second part of the study, which I think you'll describe briefly next. And that was using an approach that many who are listening may not have heard about too much before called PheWAS, or a phenome wide association study. And maybe you could tell us briefly what you found in that part of the analysis.

Dr Dipender Gill:               The first part, it was very cool, because it allowed us to identify versions of genes that corresponded to the effect of these drugs. But in itself, it didn't tell us anything novel. It didn't tell us anything new. So, the real question was, how could we use this new information to make progress towards helping patients? So, we went back and we thought, "So okay." So, we knew that these drugs are used for certain conditions already to prevent heart disease, to prevent stroke.

                                                But, what about their side effects? What about their repurposing potential? How could we use our new approach to study that a little bit more carefully? As you alluded to, when we used this new technique, relatively new technique called phenome wide association study, and we essentially investigated the association of our genetic variants for each respective anti-hypertensive target with all clinically relevant outcomes throughout the phenome, using the UK bio-back cohort, which was the main population used for this PheWAS, this phenome wide association study.

                                                We were actually able to rapidly investigate over 900 disease outcomes, and their association with our genetic risk score for these drugs. And this was very exciting for us, because it allowed us to very rapidly, efficiently, and cost-effectively explore the potential repurposing opportunity and side effects of these very commonly prescribed drugs, which to our mind, offered significant advantage over previous approaches.

                                                We all know that sometimes randomized control trials can be very expensive and time-consuming, and of course, traditional observational research can be limited by reverse causation, assessment-vise confounding. And so, what we were able to do here had several important advantages, and not to mention the efficiency by which it allowed study of these outcomes.

Dr Wendy Post:                 Dipender, tell us what you found in your PheWAS study.

Dr Dipender Gill:               We identified genetic variants for 3 commonly prescribed anti-hypertensive targets. The first were ACE inhibitors, second, beta blockers, and the third were calcium channel blockers. When performing PheWAS for all of these drug targets, we identified associations with common cardiovascular disease that are related, or implicated in hypertension, specifically hypertension itself, but also circulatory diseases, things like atrial fibrillation, coronary heart disease. They all came up.

                                                And this actually gave us a lot of confidence because that's exactly what we'd expect. We know that these medications prevent or reduce risk of these diseases, and therefore, this served as kind of a positive control that our approach was doing it what it was supposed to do. The novel finding came when we investigated the genetic risk score, or the genetic variants for calcium channel blockers, in this PheWAS approach.

                                                And we actually identified an association which we weren't expecting. We showed that blood pressure reduction through the genetic risk score for calcium channel blockers was an association with an increased risk of diverticulosis, a condition not conventionally thought to be associated with blood pressure. We were very excited and interested by this, and we went on to investigate it further using some other techniques as well.

Dr Wendy Post:                 The really impactful part of this, many things, but especially this association with diverticulosis. So, maybe you can briefly summarize what you think the potential clinical implications are, and what the next step should be.

Dr Dipender Gill:               The first question we had was whether this was related to blood pressure alone, the effect of calcium channel blockers, or perhaps some other effect of these drugs. We investigated the genetic risk score for systolic blood pressure generally and found that this itself wasn't associated with risk of diverticulosis, which suggested that the effect isn't really mediated by blood pressure alone, but it's some other property of calcium channel blockers.

                                                We know that sometimes calcium channel blockers can be associated with constipation, and it may be through this mechanism that they're having consequent effects on risk of diverticulosis. Other possible mechanisms might be through effects on blood flow, through the vasa recta in the bowel. But, what was very interesting was that we went forward with this finding, and investigated, observed, drug use in the UK bio-bank.

                                                Specifically, we looked at people taking non-dihydropyridine, and dihydropyridine calcium channel blockers at baseline, and found that those taking non-dihydropyridine calcium blockers only were known to have a higher risk of diverticulosis as compared to those taking other anti-hypertensive classes, which further added support for our findings. The interesting point here is that looking at the genetics doesn't allow us to discriminate between these drug classes.

                                                That was only possible with the observed data, and that was because the genes for these drug classes were the same.

Dr Carolyn Lam:                Well, congratulations. Wow. I'm just so intrigued listening to all of this. Wendy, I would love if you could help put all of this in context for us. The US, the novel information, and the approach that could potentially go way beyond just anti-hypertensive.

Dr Wendy Post:                 So, this is a very exciting new approach to doing genetic studies that can help us to understand potential targets for therapy in the future, and understanding more about causality, which as Dipender explained, can sometimes be confusing, as it may be confounded by environmental factors. So, using these genetic approaches through Mendelian randomization, and what we heard about today, which is PheWAS, or phenome wide association study, we can learn much more about how the potential observational analyses can be related to new discoveries through mechanisms, or potential side effects, as we heard about here of calcium channel blockers.

                                                So, wanted to congratulate Dipender again with his impactful paper here.

Dr Carolyn Lam:                Thanks, Wendy. And then if I could, I'm just going to steal minutes here, because this is so interesting. Where do you think the field's going to go next? And Dipender, with these findings of diverticulitis and diverticulosis, what next? How do we apply this?

Dr Dipender Gill:               There's 2 main points to cover here. The first is what we do specifically with the findings we got for calcium channel blockers and diverticulosis. I should emphasize that on their own, I don't think that this should currently change practice. But, I think it should inspire and capitalize further research into this association. If we're able to replicate and validate it further, then perhaps there might be some implications for the drugs that we prescribe with patients at risk of diverticulosis.

                                                The second point I wanted to make is more generally, what does this mean for research, and particularly, genetic research. I think we're living in very exciting times, and there's a lot of really great work that's going to come out using these types of approaches. I think 2 areas that we could expand further is what else we can do with our genetic instruments, or our genetic variants that proxied these drugs. How do we look at other targeted refocusing potential? Can we try and explore other side effects? Can we investigate efficacy for other disease outcomes? Specifically, for these anti-hypertensives.

                                                And the other thing is, which other drugs can we identify genetic variants to proxy? We've been thinking about looking at diabetes medicines. There's a variety of other drugs that correspond to specific gene targets, and proteins. And in theory, these could also be studied using genetics. So, there's a lot more work to come out from this.

Dr Carolyn Lam:                Thanks so much, both of you, for joining us today. This was just such an exciting discussion.

                                                Thank you for listening to Circulation on the Run. Don't forget to tune in again next week. This program is copyright American Heart Association, 2019.


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