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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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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.

 

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