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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Now displaying: July, 2016
Jul 25, 2016

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore. I am so excited to be joined in just a moment by Dr. Andrea [inaudible 00:00:21] and Dr. Wendy Post to discuss the feature paper this week about leisure-time physical activity and the risk of coronary heart disease in young women. First, here's the summary of this week's issue.

The first paper, by Dr. Bohula and colleagues at the TIMI Study Group at Brigham and Women's Hospital in Boston, Massachusetts, aim to test the hypothesis that an atherothrombotic risk stratification tool may be useful to identify high-risk patients who have the greatest potential for benefit from more intensive secondary preventive therapy such as treatment with Vorapaxar following a myocardial infarction. As a reminder, Vorapaxar is a first-in-class anti-platelet agent that inhibits thrombin-mediated activation of platelets via the protease activator receptor 1. The authors studied almost 8,600 stable patients with a prior myocardial infarction followed for a median of two and a half years.

In the thrombin receptor antagonist and secondary prevention of athrothrombotic ischemic events, TIMI 50 trial. They identified nine independent risk predictors which were age, diabetes, hypertension, smoking, peripheral artery disease, prior stroke, prior coronary bypass grafting, heart failure and renal dysfunction. A simple integer-based scheme using these predictors showed a strong graded relationship with the rates of cardiovascular death, myocardial infarction or ischemic stroke. Moreover, the net clinical outcome was increasingly favorable with Vorapaxar across the risk groups.

In summary, this paper provides a practical strategy that could be used by clinicians to assist with risk stratification and therapeutic decision-making regarding Veropaxar use for secondary prevention after myocardial infarction.

The next paper is by first author Dr. [inaudible 00:02:40] and corresponding authors, Dr. [Gerstein 00:02:43] from the Beth Israel Deaconess Medical Center and Dr. [Carr 00:02:47] from the Broad Institute of Harvard and MIT, who look at aptamer-based proteomic profiling. Now DNA aptamers are [alu 00:02:57] nucleotides of approximately 50 base pairs in length selected for their ability to bind proteins with high specificity and affinity. They therefore holds considerable promise for biomarker and pathway discovery in cardiovascular diseases.

These authors applied a novel technology that uses single-stranded DNA aptamers to measure over 1,100 proteins in a single blood sample. They applied this to a model of planned myocardial injury and that is patients undergoing septal ablation for hypertrophic cardiomyopathy, and they found that 217 proteins were significantly changed in the peripheral vein blood after planned myocardial injury in this derivation cohort. They validated 79 of these proteins in an independent cohort. Furthermore, among 40 validated proteins that increase within one hour after myocardial injury, 23 were also elevated in patients with spontaneous myocardial infarction.

Finally, the authors applied this to archive samples from the Framingham heart study and showed 156 significant protein associations with the Framingham risk score. This study is so exciting because it highlights any merging proteomics tool that captures a large number of low abundance analytes with high sensitivity and precision, thus providing important proof of principle for future clinical applications and this is discussed in an excellent editorial that accompanies this paper by doctors Graham [Malini 00:04:37], [Lau Enleui 00:04:39] from the University of Ottawa Heart Institute.

The next paper is by Dr. [Anter 00:04:51] and colleagues from the Beth Israel Deaconess Medical Center in Boston, Massachusetts, who looked at post infarction, reentrant ventricular tachycardia and addressed the problem that in vivo descriptions of ventricular tachycardia circuits are currently limited by insufficient spatiotemporal resolution. The authors therefore utilize a novel, high resolution mapping technology to characterize the electrophysiological properties of these reentrant circuits in 15 swine.

The main finding was that the zones of slow conduction within the reentrant circuits with the inward and outward curvatures while conduction velocity in the comment channel isthmus itself was nearly normal. The authors further demonstrated that entrainment mapping over estimated the true size of the isthmus. Thus, the conclusion was that high resolution activation mapping of ventricular tachycardia may better guide ablation therapy and ablation at zones of high curvature may be an attractive target for ablation.

The final papers from first author, Dr. [Tang 00:06:08] and corresponding author Dr. [Fitzgerald 00:06:10] from the University of Pennsylvania Perlman School of Medicine in Philadelphia. These authors studied the cardiovascular consequences of prostanoid I-receptor deletion in microsomal prostaglandin E synthase-1 deficient hyperlipidemic mice. The clinical background to this research question is that inhibitors of cyclooxygenase-2 or Cox-2 are well-known to relieve pain, fever and inflammation by suppressing biosynthesis of prostacyclin and prostaglandin E2.

However, suppression of these prostaglandins particularly prostacyclin by Cox-2 inhibitors or deletion of the I-prostanoid receptor for prostacyclin is known to accelerate atherogenesis and enhance thrombogenesis in mice. In contrast, deletion of the microsomal prostaglandin E synthase1 has been shown to suppress PGE2 but increase biosynthesis of prostacyclin. It therefore confers analgesia while attenuating atherogenesis and does not predispose mice to thrombogenesis. Therefore, possibly contributing to cardiovascular efficacy.

In this particular study, therefore, the authors sought to determine the relative contribution of suppressing PGE2 versus augmenting prostacyclin to the impact of depletion of microsomal prostaglandin E synthase-1 in hyperlipidemic mice. The main findings were that augmentation of prostacyclin is the dominant contributor to the favorable thrombogenic profile of microsomal prostaglandin E synthase-1 depletion in these atherosclerotic mice while suppression of PGE2 accounted for the protective effects in atherosclerosis and the exciting clinical take-home message is that inhibitors of the microsomal prostaglandin E synthase-1 may be less likely to cause cardiovascular adverse effects than NSAIDS or specific inhibition of Cox-2. Those were the highlights of this week. Now for our feature paper.

Our feature paper today is entitled "The frequency, [type 00:08:41] and volume of leisure time physical activity and risk of coronary heart disease in young women" and I am so excited to be joined by two lovely ladies today to discuss this paper. First, the first and corresponding author Dr. Andrea [Comastick 00:08:58] from the School of Public Health of Indiana University Bloomington and Dr. Wendy Post, associate editor from the Johns Hopkins University. Welcome Andrea and Wendy.

Hi. Thanks.

Thank you so much for having us.

I am just so excited that we are talking about a paper about women being discussed by women. What more could you ask for? I have to say this is a first for Circulation on the Run, which is why I’m just so excited, so let’s get straight into it.

Andrea, maybe I could just ask you to start by sharing the story of how you and your team came up with some new questions and new data because I’m sure a lot of listeners are thinking there’s a lot of data on exercise and how good it is for cardiovascular health in women already.

Yeah, that's a great question. When we started talking about conceptualizing this paper, the first thing was to focus on younger women. Most of the previous work on physical activity and heart disease has been in older adults and that's primarily because it's older adults that have heart attacks. It’s hard to get a large enough study of young women that has enough coronary heart disease events to be able to study this. We were fortunate where we had a large cohort in the nurses health study too of women and because it’s been followed for over 20 years, we had enough events to be able to examine this association.

We did want to think about, "Okay, what can we add?" because there’s a lot of information about just overall physical activity and health, so what can we do differently? I’m pretty familiar with the physical activity guidelines and really tried to look at what in the guidelines currently and then what could we add? What could be of interest when they start revising the guidelines which is actually going to happen very soon.

That was when we started focusing on, "Okay, instead of looking at just overall activity, look at intensity, comparing moderate and vigorous." We also wanted to look at frequency of physical activity and looking at frequency but also adjusted for a total time or total amount of physical activity that somebody does. Then we are also, the third thing was that we thought was important was looking at adolescent physical activity.

We know that kids, unfortunately as they get older and get into their teenage years, their activity declines quite a bit. Looking at how this physical activity during adolescence earlier life impact coronary heart disease risk in adulthood. Those were the three main things that we were focusing on when we first conceptualized the paper.

Nice. Tell us, what did you find?

We did find that exercise is just as beneficial in younger woman as it is in older adults, which is great. We also found that moderate intensity exercise is just as beneficial as vigorous intensity exercise, which I think is a really important message to get out there. I think a lot of people, especially those that are really inactive to begin with are completely intimidated about the fact of trying to think about going to a gym or trying to jog or run a marathon or something like that.

I think really emphasizing that moderate intensity activity is beneficial and we found that walking was actually the most beneficial activity that we looked at in our study, that brisk walking was really really good for everybody and really lowered risk of coronary heart disease.


Yeah, and the other thing we found which might be of interest for those that are also extremely busy, especially this target population where a lot of people are moms and working was that frequency didn't seem to matter, that as long as people were exercising for a couple hours a week that they should be that they could accumulate it in a couple times a week or they could do it more frequently, four or five times a week. It didn't seem to matter.

That’s cool. You know what? I think a lot of these things we'll also discuss at the Editorial Board when we're looking at this paper. Wendy, we promised that we would give a backstage pass to the Editorial Board and The Journal, so could you share a little bit about what we talked about there?

Well, the Editorial Board was really excited about this paper. We loved the emphasis on young women and the important public health message about how we need to get out there and move and exercise to reduce our risk for cardiovascular disease. As was mentioned, there have been previous studies that also show the benefit of exercise but the Editorial Board especially liked the large sample size, the long duration of follow-up, the number of events that had been accrued that allowed for sophisticated analyses, adjustment for confounders and the very rigorous study design and excellent statistical methods that have been used in this study and so many other studies from the nurses health study, but I think we particularly just loved the message. The message was great.

We need to get out there and move. We need to tell our patients, especially young women, that now we have data that if you start exercising now, it will help in the future but also the study showed that if you hadn't exercised much in early life that’s starting to exercise more proximal to the event was also important as well.

Thank you Wendy. I also remember that we talked about the lack of interaction with body mass index, and I thought that was a great message. Andrea, could you maybe share a little bit about that?

Yeah, this is something that previous investigators have looked at the interaction between body mass index and exercise. Unfortunately, we’ve all found the same thing so it doesn’t seem to matter whether women are normal weight or overweight or obese that they still get benefit when they exercise, and I think that’s really encouraging. I know a lot of people might start to exercise because they really want to drop some weight but just trying to emphasize even if the numbers on the scale aren't changing, that exercise still has all these really great benefits for heart disease and also for many other diseases.

Exactly. Can I just ask both of you and maybe I’ll start with Andrea, what will you do different now both as a woman and as a clinician seeing women now that you know what you do from your data?

Well, I’m not a clinician. I’m an epidemiologist so unfortunately I don’t get to see patients and counsel them although I do try to talk to community members as a public health person and really get in the community on board with what we’re talking about. I just try to tell people, I actually talked to a group of people last week, and just trying to say, "Anything is better than nothing and just trying to even start with some short walks." Again, just emphasizing you don’t have to go to a gym or you don’t have to be doing anything that's super strenuous but just do stuff that feels good and just try to get your heart rate up a little bit like going out for a brisk walk. I think that's my main message that I try to tell everybody is at least start with something and get moving a little bit.

I love that. Wendy?

I like to emphasize the data about brisk walking. I thought that was great because many of our patients don’t want to join a gym, don’t have the time to join a gym so just getting out and walking is fabulous exercise and now we have the data here that in young women that after 20 years of follow-up, brisk walking was associated with I think it was a 35% reduction in risk for cardiovascular disease during follow-up.

In addition, I liked the message about the total amount of time that you spend exercising in a week is what’s important. It doesn’t matter whether you divide that into seven days a week to get to that same amount of time or whether you do it in bursts of three days a week, and I think that’s particularly important for the many women who have so many different responsibilities and may not have time every day to go out and exercise. The days that you do have time, just exercise a little bit more those days, so lots of really important messages for our patients and for ourselves.

I really couldn’t agree more and just from my point of view, because I see a lot of patients in Asia and I do acknowledge just like you did, Andrea, in your paper that your data are predominantly in white populations. Still one of the messages I like to get out to the women I see is we have very skinny women and when I see younger women, and I really like emphasizing that, "Hey, just because you’re not struggling with an obesity issue or just because you’re young, it doesn’t mean you don’t need to exercise and that we all should just get moving." Thank you very, very much for that Andrea.

Oh, no. It's my pleasure and thank you for having me come on today and talk about this.

Thank you too, Wendy. Do you have any other comments?

No, but congratulations on your publication, Andrea.

Oh, thank you so much, Wendy. I was really happy to get the message that guys were excited about it. Thank you so much.

You’ve been listening to Circulation on the Run. Thank you for joining us this week and please tune in next week.


Jul 18, 2016


Speaker 1:
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. Joining me in just a moment are Dr. James Gammie and Dr. Timothy Gardner to discuss our feature paper this week describing the first-in-human clinical experience with a novel transapical beating heart mitral valve repair.

First, here are the highlights of this week's journal. The first paper is from co-primary authors doctors Yoon, [Tsue 00:00:49], and [Cha 00:00:50] as well as corresponding authors Dr. [Che 00:00:55]  and Dr. Kim from the Seoul National University College of Medicine. These authors examine mechanisms underlying diabetes-induced microvasculopathy, testing the hypothesis that Notch signaling in endothelial cells may play an important role in this condition.

The authors tested this hypothesis by inducing diabetes in eight-week-old adult mice using intravenous streptozotocin. They then modulated endothelial Notch signaling using chemical inhibitors in both wild type and transgenic mice. Results showed that the Notch ligand called Jagged-1 was markedly increased in endothelial cells of diabetic mice. Using endothelial specific Jagged-1 knocked down mice, they found that blocking Jagged-1 prevented diabetic microvaculopathy. Furthermore, using the induceable endothelium-specific Jagged-1 knocked down mice, blocking Jagged-1 even at four weeks after the establishment of diabetic microvaculopathy could reverse the condition.

In summary, these findings show that diabetes induces Jagged-1 over expression and suppresses Notch signalling in endothelial cells leading to diabetic microvaculopathy in adult mice. The clinical implications are that dysregulated intercellular Notch signalling may therefore represent a novel molecular target in the treatment of diabetic retinopathy.

The next study by Dr. Smith and colleagues at the Leiden University Medical Center in the Netherlands evaluated the association between LDL cholesterol variability and four cognitive domains at 30 months in the 4428 participants of the prosper study.

Results showed that a higher LDL cholesterol variability was associated with lower cognitive test performance for intermediate and delayed memory-related tasks, selective attention, and processing speed. Higher LDL cholesterol variability was also associated with lower cerebral blood flow and greater white matter hyperintensity load in an MRI substudy of 535 patients.

In addition to being independent of the mean LDL cholesterol levels and of clinically overt cardiovascular diseases, these associations were present both in the placebo and pravastatin treatment [inaudible 00:03:43] of the prosper trial suggesting that the findings did not mearly reflect pleiotropic effects of statins or of nonadherence.

The study importantly provides the first observational evidence that lipid variability, not just absolute or mean values, but the variability, maybe of importance to neurocognitive function and thus contributes while understanding potential pathways of neurocogniticve decline.

The next study is by first author, Dr. [Huh 00:04:19], and corresponding author, Dr. Ralph, from the Menzies School of Health Research Charles Darwin University in Australia. These authors aimed to investigate the long term outcomes from acute rheumatic fever and rheumatic heart disease.

They achieved this aim by using linked data between the rheumatic heart disease register, hospital data, and death register for residents of the northern territory of Australia, and examined 1248 patients with rheumatic heart disease as well as 572 patients with acute rheumatic fever in the period 1997 to 2013.

The main findings were that in the first year after an acute rheumatic fever episode, the incidents of progression to rheumatic heart disease was 10 times higher than acute rheumatic fever recurrence; 10% of rheumatic heart disease patients had severe disease at diagnosis. The presence of comorbidities was associated with higher incidence of rheumatic heart disease complications and mortality. In particular, comorbid renal failure and hazardous alcohol use accounted for 28% of the access indigenous mortality.

These findings have global relevance for settings with high acute rheumatic fever, rheumatic heart disease rates and really emphasized the need for integrated chronic disease management strategies for these patients.

The final paper is by first author Dr Bettencourt, corresponding author Dr. Blankstein, and colleagues from Brigman and Women's Hospital in Boston, Massachusetts. These authors sought to answer the question what is the most appropriate score for evaluating the pretest probability of obstructive coronary artery disease?

To answer the question, the authors compared the Diamond-Forrester score with the two CAD consortium scores recently recommended by the European Society of Cardiology, and they did this in 2274 consecutive patients without prior CAD referred for coronary CT angiography. CT angiography findings were used to determine the presence or absence of obstructive CAD defined as 50% or more stenosis.

Here's a refresher of the different probability scores. The Diamond-Forrester score is calculated based on chest pain type such as non-anginal, atypical or typical angina, gender, and age. The first CAD consortium model score called CAD consortium basic is also based on these factors, but was developed using more advanced statistical modeling strategies which were not available when the Diamond-Forrester model was derived. Additionally, the population had a lower prevalence of disease than the original Diamond-Forrester derivation cohort.

The second CAD consortium score called CAD consortium clinical included the same characteristics as CAD basic, but also included the following clinical risk factors; diabetes, smoking status, hypertension, and dyslipidemia. Moreover, the presence of typical chest pain was weighted less in diabetics compared to nondiabetics in the CAD clinical score.  Results showed that among symptomatic individuals referred for coronary CT angiography, the CAD consortium clinical pretest probability score demonstrated improved calibration and discrimination for the prediction of obstructive CAD compared to the Diamond-Forrester classification.

Driving home the clinical implications of this, the authors applied these observed differences in pretest probability of obstructive CAD to guidelines-based patient management algorithms and projected that the use of the newest score could decrease the proportion of individuals in whom testing would be recommended and increase the yield of diagnosing obstructive CAD.

Those were the highlights of these weeks issue. Now, for our feature paper. Our feature paper today is about the first-in-human clinical experience with the transapical beating heart mitral valve repair using a expanded polytetrafluoroethylene chordal insertion device. We're really lucky today to have the first and corresponding author, Dr. James Gammie from the University of Maryland Medical Center as well as Dr. Timothy Gardner, associate editor from Christiana Care Health System to discuss this exciting paper. Welcome, both of you.

Thank you.

Thank you.

Speaker 1:
James, may I start with you? What an exciting title, a first-in-human experience, and this is really sounding very reminiscent of our experience with TAVR and aortic stenosis valves. Could I ask you, with so many exciting things, what is it about the results that excited you most?

This is an exciting project in that we believe it affords a new treatment option for patients with degenerative mitral regurgitation. We believe that this is a less invasive way of achieving surgical grade reduction of mitral regurgitation. This is a project which has involved a great number of people on our team both within the university and then within Harpoon Medical, as well as our colleagues in Europe to bring this device from an idea which was asked more than a decade ago into a clinical experience.

It really rose out of our recognition in particularly my own practice that virtually, every patient with degenerative mitral regurgitation could be fixed with ePTFE or Gore-Tex neo-chords, and the question became how can we place neo chords on a prolapsed mitral leaflets without doing open heart surgery?

We begin working on that in the laboratory a number of years ago and went through a variety of prototypes, and ultimately, came up with this idea where we could use a 3 millimeter shafted instrument with a specially designed wrap of Gore-Tex on a 21-gauge needle such that we could land on the underside of the mitral leaflet, deploy device, and create a specially designed knot on the atrial surface of the leaflet, and that would anchor the ePTFE on the leaflet. We could repeat that a few times transapically and then adjust the length of those chords in real time using transesophageal echo guidance.

We got this to work in the laboratory and we had hoped that we would have some modest success in humans, but we've been quite pleasantly surprised that it has just worked and we've outlines this initial clinical experience in the manuscript.

Speaker 1:
First of all, I'd just like to pick up on the point that this is degenerative mitral regurgitation, so this is limited to the primary mitral regurgitation, not secondary?

That's correct and we know that right now, at least in North America, that two-thirds of mitral valve operations are done for degenerative disease. That's correct.

Speaker 1:
I think a lot of the audience out there is going to be wondering how this new technique compares to the MitraClip. Could you tell us a little bit more about that?

I do MitraClip as well, so I think I'm well positioned to comment on the differences. The Harpoon device right now is still in operation. It does require a small one or two-inch incision. We anticipate it's going to be a thoracoscopic approach in the very near future and then, beyond that, we would hope to extend it to a transcatheter approach. That's one difference.

The MitraClip now is certainly across the world. It's used predominantly for functional mitral regurgitation. In our own experience, it seems to work best for functional mitral regurgitation and as you know, there are anatomic limitations for MitraClip in degenerative disease. The MiraClip replicates the LCRA surgical approach and I think what we've learned from all the less invasive approaches to treat mitral valve disease is that we have to respect what we've learned from our surgical experience, and we know that the LCRA approach works best when it's combined with an annuplasty ring, and certainly, the MitraClip, again, is mostly this perfunctional MR.

Another point I'd bring up is that the experience with MitraClip has been that when you place a MitraClip, you get a fairly strong fibrous reaction and in most of the series, it's not been possible to then go back and surgical repair the valve, but you have to do a replacement because you've compromised the leaflets. Our own approach were simply putting Gore-Tex sutures in the leaflets and we believe that one advantage is that we're not burning any bridges, and that you can go back and do an open repair of you had to.

In our experience, you asked about our results, we had great results in 10 out of 11 of our patients. One patient did require a reoperation. Actually, one of the chords had come untied on the surface in that patient. We were able to go ahead and do a repair and we saw as we had anticipated it based on our animal experience, there was not much compromised to the leaflets.

One of the advantages of our approach is that we can titrate the length to the Gore-Tex chords to optimize the amount of coaptation and maximize the quality of the repair, and that's something that we can't do an open cardiac surgery, and one of the challenges of mitral valve repair is that you have to figure out how long to make those chords while the heart is arrested and placid, and that's one of the challenges in why mitral valve repair is certainly some degree of an art to doing that.

What we've found is that the imager is incredibly important, and so we've teamed up with our echocardiography colleagues, and they really provide essential input into the procedure, and it's done not looking directly at the valve, but looking up at the screens. I think as surgeons, with this procedure, we're moving more into almost becoming interventionalists.

Speaker 1:
Thank you, James. That was so exciting. Tim, I have to bring you into this now. Now that James has said they're becoming like the interventionalist. Back to my original comment of TAVR and aortic stenosis, are we witnessing history in the making now? You invited an editorial by Dr. Michael Mack and his title was very provocative, Transcatheter Treatment of Mitral Valve Disease. Is it deja vu all over again? What are your thoughts?

I think this is an exciting report and I think that this is the wave of the future. I agree completely with Michael Mack that we are beginning to see interventions for mitral valve disease that are effective, less invasive, in some instances catheter based, but this is just the beginning. In fact, mitral valve disease is somewhat more complex even than aortic stenosis, but this type of experience and the ingenuity and the technical prowess, and the ability to do this minimally, invasively, and so on really portend a whole new era.

I agree with Jim. This is sort of the common ground between the interventional structural cardiologist and the surgeon, and we're becoming even more entwined, more collaborative, and more mutually supportive. We are in a new era and I think over those next decade or so, we're going to see this and similar, and even different procedures tried and proven to be useful for the variety of mitral valve disorders that we encounter. Perhaps the era of the full sternotomy for fairly straightforward, single, focused operations will become something of a thing of the past.

Speaker 1:
That's beautifully put. James, with that comment, what are the next steps?

As we said in the manuscript, this isn't barely experience and we're continuing to learn as we move [inaudible 00:17:07] to the clinical arena. We are currently in the midst of a CE Mark trial in Europe. We rolled it out to eight separate centers. As we approve clinical experience, we will learn more about precisely which patients work best with this approach and we will accrue longer term data. We now have a number of patient out to a year with stable results and so, as the numbers go up, we'll do that, and then we anticipate a randomized trial in the United States in the early to mid portion of 2017 where we'll compare this approach to conventional open cardiac surgery.

Speaker 1:
That's fantastic. Thank you so much to both of you, gentlemen, for joining me on our podcast today.

Thank you.

Thank you.

Speaker 1:
You've been listening to Circulation on the Run. Thank you for joining us this week and don't forget to tune in next week.


Jul 14, 2016



Dr. 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. Sanjay Kaul and Darren McGuire will be joining me in just a moment to share their perspectives on the EMPA-REG OUTCOME trials. Are the results with empagliflozin in diabetic patients at high risk, are they too good to be true. First, here are the highlights from five original papers in this week's issue.

The first paper is from Dr. Gilboa, from the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention in Atlanta, Georgia, and Dr. Marelli from the McGill Adult Unit for congenital heart diseases in Montreal, Quebec, and colleagues. These authors recognize that because of advancements in care there has been a decline in mortality from congenital heart defects over the last several decades. However, there are still no current empirical data documenting the number of people living with congenital heart defects in the United States.

These authors address this gap in knowledge by using prevalence data from Quebec, Canada, in the year 2010, as a foundation for a mathematical model, and estimated that in the United States in the year 2010, approximately 2.4 million people, including 1.4 million adults, and 1 million children were living with congenital heart defects. This estimate is significant, because it corresponds to a 63% increase in the estimated size of the adult population with congenital heart defects in the United States since the year 2000. This has significant implications for resource allocation for health services delivery that will need to account for this growing population of adults with congenital heart defects.

The second paper is from first author Dr. Tabot, and corresponding author Dr. Liao, from the University of Chicago, and colleagues who aim to understand better the common complication of angiodysplasia leading to nonsurgical bleeding in patients with left ventricular assist devices. The authors studied 101 patients with heart failure, left ventricular assist devices, or orthotopic heart transplants. They found that compared to patients with heart failure, or transplant patients, patients with left ventricular assist devices had elevated serum levels, and endothelial expression of angiopoietin-2, which is a potent angiogenic mediator.

Elevated levels of angiopoietin-2 in these patients increase angiogenesis in vitro, and were associated with bleeding events. Furthermore, they found that increased thrombin levels in left ventricular assist device patients were associated with elevated angiopoietin-2 levels. In aggregate, therefore, the results indicate that high levels of thrombin induced endothelial angiopoietin-2 expression, which may then contribute to angiodysplasia and non-surgical bleeding in patients with left ventricular assist devices. The clinical implications are that clinical studies angiopoietin-2, and factor 12 inhibitors may therefore be indicated to prevent nonsurgical bleeding in patients with left ventricular assist devices.

The third paper is Dr. Gordon from Hasbro Children's Hospital in Rhode Island, and Dr. Kieran from the Dana Farber Cancer Institute in Boston, Massachusetts, and colleagues who addressed the Hutchinson Gilford Progeria Syndrome. An extremely rare, fatal segmental premature aging syndrome, where without specific treatment, death usually occurs at an average age of 14 1/2 years from an accelerated atherosclerosis.

A PRIA single arm clinical trial has demonstrated that the protein farnesyltransferase inhibitor, Lonafarnib, ameliorates some aspects of cardiovascular and bone disease in this syndrome. The current trial sought to further disease outcomes by additionally inhibiting progerin prenylation using pravastatin and zoledronic acid on top of Lonafarnib in 37 participants with the Progeria syndrome. Results showed that the composite primary study outcome of increased rate weight gain and decreased carotid artery echodensity was achieved. Overall, participants experienced increased bone density, size, and structural properties. However, unlike the PRIA single arm Lonafarnib monotherapy trial, mean carotid-femoral pulse wave velocity and mean carotid artery adventitial echodensity were not improved. In addition, rates of carotid and femoral artery plaques and extraskeletal calcifications all increased.

In summary, compared PRIA Lonafarnib monotherapy treatment, additional bone mineral density benefit, but likely no additional additional cardiovascular benefit was obtained with the addition of pravastatin and zoledronic acid. The authors concluded that since increased bone fracture is not a disease feature, the addition of a combination of statin and biphosphonate to Lonafarnib therapy is not recommended for clinical treatment of Progeria syndrome. However, it is reasonable to consider statins if concurrent lipid abnormalities need to be treated.

This paper is accompanied by an excellent editorial by Dr. Francis Collins, who describes our journey in seeking a cure for this rare disease of Progeria.
The fourth paper is by first author, Dr. Grisenti and corresponding author Dr. Tilley from Lewis Katz School of Medicine, Temple University in Philadelphia, and colleagues who aimed to better understand the role of leukocyte expressed beta-2 adrenergic receptors in regulating immune cell responses to acute cardiac injury. The authors achieved this aim by studying wild type mice who were irradiated, and then transplanted either with isoform specific beta adrenergic receptor knock out bone marrow, or wild type bone marrow. These chimeric mice, after full reconstitution then underwent myocardial infarction surgery.

Results showed that immune cell specific beta-2 adrenergic receptor expression was essential to the repair process following myocardial infarction. In the absence of beta-2 adrenergic receptors, vascular cell adhesion molecule-1 expression was increased in leukocytes, inducing their splenic retention following injury, and leading to impaired scar formation, followed by rupture and death. Splenectomy partially restored the beta-2 adrenergic receptor deficient leukocyte infiltration into the heart, but gene therapy to rescue the leukocyte beta-2 adrenergic receptor expression completely restored all injury responses back to normality.

This study is clinically important because it highlights a bit of a tension that we're facing. On the one had, beta adrenergic receptors are known to regulate cardiac function and remodeling following myocardial injury, by their effects through cardiomyocytes. That's why we use beta blockers to prevent, at first, cardiac remodeling. However, the current studies now indicate that inhibition or deletion of the immune cell expressed beta-2 adrenergic receptor causes leukocyte dysfunction, and impaired immunomodulatory responses to myocardial injury.
These results may, therefore, have implications on the use of beta blockers around the time of acute myocardial injury, such as myocardial infarction, or perioperatively. This is really an area that needs further research and understanding.

The fifth paper is by Dr. Herman, from the hospital of the University of Pennsylvania, and colleagues who report on the one year clinical outcomes of SAPIEN 3 transcatheter aortic valve replacement in high risk and inoperable patients with severe aortic stenosis. Now, as a refresher, in the initial partner trial of transcatheter aortic valve replacement for high risk and inoperable patients with severe symptomatic aortic stenosis, there was a demonstration of marked survival advantage compared to medical management ... But a high one year mortality of 24% in the high risk, and 31% in inoperable patients.

More recently, the lower profile SAPIEN 3 prosthesis system has become available. Which has a balloon expandable cobalt chromium frame, with bovine pericardial leaflets, and an external fabric seal. The early 30 day outcomes of this system have been reported, and show a very low rate of adverse events.

The current study now reports the one year survival, and showed that all cause survival was more than 85% for all patients, above 87% in the high risk, and above 82% in the inoperable subgroups. Furthermore, there was a high rate of transfemoral access at 84%, and a high all cause and cardiovascular one year survival in the high risk transfemoral subgroup of 89% and 93%, respectively. Between 30 and 365 days, the incidence of moderate perivalvular aortic regurgitation did not increase. There was no association between mild perivalvular leak and one year mortality. Although, a small increase in disabling stroke occurred.

These results, which likely reflect device iteration and procedural evolution, support the use of Taver as a therapy to consider in high risk and inoperable patients with aortic stenosis.

Those were the highlights from this week's issues, and now for our feature paper. We will be discussing the perspective paper entitled "Is the Mortality Benefit With Empagliflozin in Type 2 Diabetes Too Good to be True?". To discuss this, we have two very special guests. First, Dr. Sanjay Kaul, writer of this paper, and from Cedars-Sinai Medical Center. Second, Dr. Darren McGuire, deputy editor of circulation from UT Southwestern. Welcome, Sanjay and Darren.

Dr. McGuire: Thanks, Carolyn.

Dr. Kaul: Thank you, Carolyn.

Dr. Lam: To start us off, I'd really love if Darren could please introduce this new content category of circulation. Frame of reference section, of which this is one of the papers, a perspective article.

Dr. McGuire: Sure, so we envisioned, as we're evolving circulation to our new editorship, an opportunity for authors, luminaries in the field, to give us in a very encapsulated form, a laser focus perspective on a specific topic. These come in two flavors, the perspectives piece, which this is, is a little more evidence and scientific quantitatively based. Then we'll also have a section called on my mind, which is more of a free-flowing opinion editorial targeting possibly a contentious or controversial issue. These are going to be very short, and hopefully very entertaining, and kind of teasers for the readership of the Journal.

Dr. Lam: Sanjay, you made it very personal, and I like that, too. Share with us how this idea came about.

Dr. Kaul: Well, I was very impressed at the reception that the results of the EMPA-REG outcome trial received at the EAST meeting at Starcom last year. While I was witnessing the applause, I had polar reactions. On one hand, I thought that after nearly five decades of trials with checkered history, with regards to cardiovascular outcomes, here we have for the first time a trial demonstrating not only cardiovascular benefit, but a mortality benefit. I thought maybe it's time to take the trumpets out and sort of herald this holy grail, which we had failed to achieve. On the other hand, realizing that we had been fooled before many times by trials, yielding implausibly large treatments actually, that were never replicated at subsequent trials.

I had a skeptical response to it, and sort of asked this question rather tongue-in-cheek, or maybe used as a rhetorical tool to address whether this mortality benefit was too good to be true.

Dr. Lam: You know, you didn't just question it. You examined the data, and provided even more evidence. That's what I was impressed with in your paper. That table where you provided base factor, as well as a Bayesian analysis. Could you break that down for us, and explain what you found?

Dr. Kaul: Yes, I was trying to sort of examine the strength of the evidence, in terms of the quantitative aspect. Yes, the effect size for the cardiovascular benefit was quite impressive. For the primary endpoint, which was a compositive cardiovascular, death, non-fatal MI, and non-fatal stroke, the p-value was not very robust. It was .04. The p-value tends to overestimate the strength of evidence. I utilized base factor, which basically is a metric that allows the two competing hypotheses to predict the data. Using the base factor, I was able to demonstrate that the alternative hypothesis was stronger than the null hypothesis by eight-fold. The p-value of .04 translated into a base factor of .13. Which is not strong evidence against the null hypothesis. It requires independent confirmation and subsequent trials.

A p-value of .04, while meeting the superiority criteria, would not be sufficient enough to meet the FDA's requirement of substantial effectiveness. Substantial effectiveness just basically means that the FDA requires two trials, each with a p-value less than .05. In 1998, they modified their regulatory requirement, and accepted that one single trial would be sufficient, provided that there would be a persuasive p-value. Persuasive basically is defined as a p-value less than .001.
The base factor allows us to sort of interpret the strength of the evidence, with respect to the primary composite endpoint was not strong enough to meet this requirement. With respect to cardiovascular mortality, as well as all cause mortality, which trumps all other endpoints, it was persuasive enough.

Dr. Lam: What's your conclusion on that?

Dr. Kaul: What is controversial about that was that in the three specified statistical plan, the so-called hierarchical testing strategy, the non-inferiority for three point MACE, followed by non-inferiority for four point MACE, and followed by superiority of three point MACE, and lastly, superiority of four point MACE. Because the p-value of four point MACE superiority was .08, one can argue purely from a statistical perspective that you stop your testing strategy, and any analysis beyond that would be deemed exploratory. Even though cardiovascular mortality and all cause mortality was prespecified, the purist would argue that since you failed superiority for four point MACE, you really can't proceed further. You can analyze, but it will be considered an exploratory analysis.

I sort of wept and said that because Christopher Columbus had prespecified that he will be discovering the route to India, the fact that he stumbled upon America does not mean it doesn't exist because he had not prespecified it. I think all cause mortality is the most meaningful endpoint, and the least subjective measurement error. It meets the key attributes of regulatory decision making. Which it's prespecified, it's highly persuasive, therefore, it meets the replication criteria, and the p-value is so robust that even if you adjust for nearly 100 multiple comparisons, the p-value would still hold. It meets all the regulatory criteria for approval.

Dr. McGuire: Sanjay, let me just chime in here. I think it's also important, not only were these prespecified, but it's important, I think, for readers of these diabetes programs to realize that hospitalization for heart failure ... Although it's not part of the primary outcome ... In virtually every one of these trials, it is prospectively collected, chartered to find, and essentially adjudicated by blind endpoint adjudicators. You know, death is death. Cardiovascular death in these programs are all adjudicated, as well. I think the prospective collection and central adjudication also adds legitimacy to the hospitalization for heart failure are above and beyond the analytic issues.

Dr. Lam: Darren and Sanjay, I hear both of you kind of saying it does look like, even looking at it from different angles, the data do look strong. At the end of the day, Sanjay, you concluded that it does need another trial. Results do need to be replicated. That was your conclusion. I'd love to hear Darren's take on this.

Dr. McGuire: I think what Sanjay is saying there, and I think what we all believe, was we would really love to see this observation with another member or members of the class. We're learning a lot in hindsight based on these observations, and people are exploring potential mechanistic underpinnings. We're learning a lot about the mechanisms of these medications, above and beyond their glucose uric effects. There's a lot of implication about renal physiology and hemodynamics, and altered myocardial metabolism. I think as Sanjay points out in the paper, some of this looks like a possible arrhythmic effect. We have a lot to learn about this mechanism of action, and whether or not this will be unique to impact gliflozin.
It has been publicly announced, Boehringer Ingelheim is planning, they're in the planning phases for heart failure trials with empagliflozin to further explore this signal. I think they will address Sanjay's desire to have some replication in a different patient population. Still, we would love to see these extended into other patient populations. To both extend the use of the medications if they're found, but also provide further confirmation of the observations from EMPA-REG outcome.

Dr. Kaul: Carolyn, let me also add, I used the title as a rhetorical tool, as I stated earlier. I do conclude that the mortality data is not likely to be spurious. In the back of my mind, I still have that 1% skepticism that I would like to eliminate, because the findings were totally unexpected, and unprecedented, as we discussed earlier. If all the pathways, including the mechanistic pathways are aligned, I would have substantial reassurance, beyond any reasonable doubt that the findings are true. That's why I'm asking for replication. Not necessarily by empagliflozin in other trials, but by another molecule within the same class. I think that would be sufficient.

Dr. McGuire: Yeah, and I think it's really interesting to note there, is that I was involved in the early days of some of these drugs as they're being developed. When the other two members of this class went to the FDA, dapagliflozin and canagliflozin, they provided FDA's requirement and meta analysis from all of the phase 2B and 3 trials that had been completed to date. The meta analysis of the cardiovascular outcomes. Both dapagliflozin and canagliflozin had point estimates of cardiovascular death reduction of 30%, and 35%, respectively. When we saw those data, they were based on 25 to 40 total events. We chuckled, thinking this is spurious, from small events being analyzed. That there's no way they would prevent cardiovascular death. Sure enough, you know, you could almost superimpose those point estimate plots from the phase 2B-3 meta analysis, with the ultimate outcomes from EMPA-REG. There's some promising, although again, very statistically imprecise estimates that this may well be a class effect. As many of the listeners will know, there are ongoing cardiovascular outcomes trials for all of these medications. That will come some time in the next year or two.

Dr. Lam: That's fantastic. Thank you both for sharing those perspectives. I mean, I learned so much. I really think, Sanjay, your paper achieved exactly what you had meant for it to achieve, and exactly what circulation was hoping to create the discussion, as well.

Dr. McGuire: Thank you, Carolyn.

Dr. Kaul: Thank you very much.

Dr. Lam: You've been listening to Circulation on the Run. Thank you for listening. Don't forget to join us next week for more highlights and discussions.