Circulation September 22, 2020 Issue

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

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

Dr Carolyn Lam: Greg, our feature paper today talks about the risks of sudden cardiac death, something that we still grapple with, and do you know what, really highlights the important emerging role of biomarkers of myocardial stress, myocardial injury, or even subclinical inflammation in predicting this risk. A really important discussion coming right up.

But before we do that, let me tell you about a paper in today's issue that really provides novel mechanistic insights into atrial fibrillation pathogenesis. In fact, this is the first paper to demonstrate that decreased expression of a striated muscle preferentially expressed protein kinase, or SPEG in atria, is causally linked to altered diastolic calcium handling and human paroxysmal atrial fibrillation.

This is from corresponding author, Dr Wehrens and colleagues from Baylor College of Medicine. And they used phosphoproteomic studies to identify S2367 on ryanodine receptor type-2 as a novel kinase substrate of SPEG. Through the study of novel ryanodine receptor type-2 phospho-mutant mouse models, they revealed that in contrast to previously characterized phosphorylation sites on this receptor, S2367 phosphorylation inhibited diastolic calcium release from the receptor, while loss of phosphorylation of the site increased atrial fibrillation susceptibility.

Dr Greg Hundley: Wow, Carolyn. So the clinical implication is that normalizing S2367 phosphorylation in SPEG activity may provide novel therapeutic opportunities for the treatment of atrial fibrillation, right?

Dr Carolyn Lam: You bet, Greg. Too smart. And this is discussed in an accompanying editorial by Drs Knollmann and Blackwell from Vanderbilt University Medical Center.

Dr Greg Hundley: Very nice, Carolyn. Well, I've got a paper pertaining to COVID-19, and it comes to us from Dr Leo Nicolai from the Klinik der Universität München in Germany. Carolyn, I really enjoyed this article about COVID-19. I found it very intriguing, and the study addresses the mechanisms by which the SARS-CoV-2 infection, associated pneumonia or COVID-19, leads to subsequent respiratory failure, complicating renal and myocardial involvement, and the prothrombotic phenotype found in some patients with COVID-19.

62 subjects were included in the study, 38 patients with RT-PCR confirmed COVID-19 and 24 non-COVID-19 controls. The investigative team performed histopathological assessments of autopsy cases, surface marker-based phenotyping of neutrophils and platelets, and functional assays for platelet-neutrophil functions and coagulation tests.

Dr Carolyn Lam: Wow, that sounds like really sort of in-depth testing. And what did they find?

Dr Greg Hundley: Several things, Carolyn. First, the authors found evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. They found that in COVID-19 patients, inflammatory microvascular thrombi are present in the lung, kidney and heart, containing neutrophil extracellular traps associated with platelets and fibrin.

Second, they observed that COVID-19 patients also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood which changes with disease severity, whereas cases of intermediate severity show an exhausted platelet and hyperreactive neutrophil phenotype. This finding differs for severely affected individuals. Among severely affected COVID-19 patients, there is excessive platelet and neutrophil activation compared to healthy controls and non-COVID-19 pneumonia.

Finally, dysregulated immunothrombosis in SARS-CoV-2 pneumonia is linked to both ARDS and systemic hypercoagulability. So in conclusion, taken together, this team's data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19, and further work is suggested to identify methods to disrupt immunothrombosis in patients with COVID-19.

Dr Carolyn Lam: Wow. That makes a lot of sense and is important information. Thanks, Greg. Well, this next study really aimed to assess the current trends in US mortality related to congenital heart disease from infancy to adulthood over the last 19 years, and to determine if there were differences by sex and ethnicity.

This is from Dr Lopez from Texas Children's Hospital and Baylor College of Medicine and colleagues who conducted an analysis of death certificates from 1999 to 2017, and also used data from the National Center for Health Statistics' live birth data and US Census Bureau bridged-race estimates as denominators for these population estimates.

Dr Greg Hundley: Wow, Carolyn. Really interesting article. So what did they find here?

Dr Carolyn Lam: So overall, US mortality due to congenital heart disease throughout the lifespan has decreased over the last 19 years, with the greatest mortality rate in infants. Disparities in mortality due to congenital heart disease persists for males compared to females, with men having higher mortality than women, and for non-Hispanic blacks compared to non-Hispanic whites.

For those less than 50 years old with congenital heart disease as a contributing cause of death, associated genetic abnormalities are the leading underlying cause of death, whereas myocardial infarction was the leading cause of death in those 50 years and older.

And so, the authors also concluded that determining factors that contribute to these disparities, such as access to quality care, timely diagnosis and maintenance of insurance, will be very important moving into the next decade.

Dr Greg Hundley: Boy, that is such a timely topic. Beautiful presentation.

Dr Carolyn Lam: Thanks, Greg. And now for my last paper. We've heard a lot recently about angiotensin-converting enzyme 2, or ACE2, that's that membrane protein that enables COVID-19 infectivity and which also converts angiotensin II, which is a potent vasoconstrictor, to angiotensin 1-7.

Now, today we've got a paper that provides novel insights into the contribution of ACE2 to the development of pulmonary arterial hypertension. And this is from Dr Shyy and Yuan as co-corresponding authors from the University of California, San Diego, as well as Dr Yuan 00:08:06 from First Affiliated Hospital of Xi'an Jiaotong University in China.

The authors used cultured endothelial cells, mouse models, and specimens from patients with idiopathic pulmonary arterial hypertension to investigate the post-translational modification of ACE2 in terms of, firstly, phosphorylation by AMP-activated protein kinase, which enhances ACE2's stability, and two, ubiquitination of oncoprotein murine double minute 2, or MDM2, which is involved in ACE2 degradation.

Dr Greg Hundley: So what did they find here?

Dr Carolyn Lam: MDM2 expression was increased in lung tissues from patients with idiopathic pulmonary arterial hypertension and animals with experimental pulmonary hypertension.

On the other hand, N-kinase phosphorylates ACE2 at S680 and inhibits MDM2- mediated ubiquitination of ACE2 at K788. Functionally, ACE2 phosphorylation and deubiquitylation increases eNOS-mediated nitric oxide bioavailability in the endothelial cells.

Dr Greg Hundley: Okay, Carolyn. What are the clinical implications here?

Dr Carolyn Lam: So post-translational modification of ACE2 is a novel strategy to develop new therapies for pulmonary arterial hypertension. On the other hand, inhibition of MDM2 has great potential for pulmonary arterial hypertension by stabilizing ACE2.

Dr Greg Hundley: Wow, beautiful summary there. Let me describe some of the other articles in the issue. First, Dr Jawad Butt has a research letter regarding the impact of COVID-19 on first-time acute stroke and transient ischemic attack admission rates and prognosis in Denmark. It's from a nationwide cohort study.

Next, there's an exchange of letters regarding the article, preventive or deferred ablation of ventricular tachycardia in patients with ischemic cardiomyopathy and an implantable defibrillator, the Berlin VT multicenter randomized trial. And that comes to us from Drs Krisai and Kuck.

Next, there's a very nice ECG challenge from Dr Arrey-Mbi wide complex QRS rhythm in a 52-year-old male with an altered mental status.

And then finally, a nice case series from Dr Oscar Cingolani, entitled, ECMO therapy for cardiac lymphoma.

Dr Carolyn Lam: Well, I've also got a research letter by Dr Verdonschot on distinct cardiac transcriptomic clustering in titin and lamin-associated dilated cardiomyopathy patients.

There's also a white paper by Dr Butler on glucagon-like peptide-1 receptor agonists and heart failure, highlighting the need for further evidence generation and practice guidelines optimization.

And finally, an On My Mind piece by myself and Dr Butler entitled, "Victims of Success and Failure," where we really describe how, with so many effective therapies for HFrEF these days, have we become victims of our own success?

Dr Greg Hundley: Very nice, Carolyn. Well, how about we get on to that feature and hear a little bit more about myocardial stress injury and the association with sudden death?

Dr Carolyn Lam: Yes. Let's go, Greg. Sudden cardiac death is the most common cause of death in the United States but identifying individuals at risk before they suffer a fatal event remains really challenging. In fact, it's the sad truth that the majority of sudden cardiac deaths occur in low-risk populations, often as the first manifestation of cardiovascular disease.

Now, can biomarkers help us identify those at risk of sudden cardiac death? Well, you have to listen to our discussion of today's feature paper, a beautiful paper that I'm so pleased to be welcoming the first and corresponding author, who's also our associate editor, Dr Brendan Everett from Brigham and Women's Hospital, who will talk about it, as well as our guest editor, Professor Harvey White, who is director of research at the Green Lane Cardiovascular Service in Auckland, New Zealand.

So welcome, gentlemen. And Brendan, could I get you to start by telling us what you did in this study and what you found?

Dr Brendan Everett: We were interested in exploring this problem. Dr Albert, Christine Albert, who is the senior author on the paper, has years of experience looking at sudden cardiac death as an important outcome amongst patients who may not have yet been diagnosed with cardiovascular disease.

And of course, as you mentioned in your introduction, it can be the first manifestation of cardiovascular disease. And because we, as physicians, don't get a chance to then help patients recover and treat them for their cardiovascular disease, we often feel like we've missed the opportunity to help people live longer and more productive lives.

The problem, of course, with this is that there's a huge population of people who are at risk, but actually identifying tests that will work well enough and can be used in a broad population, who, in aggregate, are actually at low individual absolute risk, is very challenging.

The markers that we selected to study for this paper included measures of lipids, in this case, total cholesterol, the HDL cholesterol, NT-proBNP, a marker of myocardial stress, which is, I'm sure, familiar to many people on the podcast, high-sensitivity cardiac troponin I, which again, is increasingly used throughout the world, including here in the United States, and hsCRP, a marker of subclinical inflammation.

I think the advantage that we had is that, over the years, Dr Albert has compiled a number of cases of sudden cardiac deaths in cohorts that have been followed prospectively for a long period of time. These are NIH-funded cohorts and include studies that may be familiar to your listeners, like the Nurses' Health Study, the Physician's Health Study I and II, the Women's Health Study.

These are cohorts that have been following patients for, in some cases, decades, and of course, when you have a lot of patients or participants and you follow them over many years, some of them die suddenly. Not very many, fortunately, but enough so that if you aggregate all six cohorts together, you can have a total of, in our case, 565 cases, which is more, I think, as far as I know, anyways, than other cohorts that are out there that have studied this question.

We were able to match those two-to-one with 1090 controls, and then measure the biomarkers I mentioned earlier in all of those patients, and then look at the association between those common, relatively accessible biomarkers and the risk of sudden death.

Dr Carolyn Lam: Congratulations. I do think this is the largest collection of sudden cardiac death cases, as well as with prospectively collected blood samples. And I do believe yours is the first to really have a multi-marker approach. So now, could you tell us what you found?

Dr Brendan Everett: We first assessed each of these four markers individually and found that their risk of sudden cardiac death was relatively strong and was independent of other traditional cardiovascular risk factors, such as cigarette smoking or body mass index and those sorts of things. It appeared, at least in our analysis, that NT-proBNP and cardiac troponin might have been slightly more powerful correlates of the risk of sudden cardiac death in total to HDL cholesterol ratio in hsCRP.

But nonetheless, when we put them all together in a comprehensive model, we found that the risk estimates for each individual marker were maintained. In other words, they were independent of one another and they all remained statistically significant. So this tells me, as a cardiologist and an epidemiologist, that we're getting a sense of somebody's risk from multiple different perspectives. We're integrating that information, and then potentially, when we combine those markers together, have the opportunity to have an improved ability to identify individuals at risk.

And so, that's actually what we did, and I think this is what you're asking about. We decided to create a very simple biomarker score where we gave each participant one point if their concentration of a given biomarker was in the top core tile of that biomarker's range, so the top 25%. So just by way of example, if somebody had all normal biomarkers except for a high total cholesterol, the HDL ratio, they would get one point.

The total number of points, of course, could range from zero to four, and then we looked at what the risk of sudden cardiac death was across that scale. And what we found is that it went up in a relatively linear fashion. The odds ratio increased by about 1.6 per individual point of score increase, such that, for example, compared to those individuals with a score of zero, who of course, had normal concentrations of these four biomarkers, if you had all four be elevated, your odds ratio of sudden cardiac death was actually seven. If you just had three out of the four being abnormal, it was approximately four. So those participants with at least three or four abnormal concentrations of these biomarkers seemed to be at a high relative risk or odds ratio for sudden cardiac deaths.

Dr Carolyn Lam: Ah. Love it, Brendan. And for all of you who are listening, you have to pick up the paper and look at the figures. The story is all there, the individual biomarkers and that score. I love the simplicity and the clarity of the message.

Harvey, could you summarize for us and perhaps give us a sneak peek of the discussions that occurred behind the scenes when this paper landed on your desk?

Dr Harvey White: When I saw this paper, it was terrific. And I had to decide whether to get reviewers who are experts in sudden death, or are experts in cholesterol, or troponin, or each of the four biomarkers, and I chose to get people who are interested in sudden death. And I had three reviewers, and they all said it was absolutely terrific, elegant study, robust data.

They focused on the cut points, for example, NT-proBNP. Initially, Brendan, you looked at the median for your study, and the reviewers said, "Well, can we look at clinically relevant?" So they requested that you consider that, and I must say, your responses were just terrific. And so, you went to a cut point of 125, which is clinically relevant. I think this is extraordinarily important. The reviewers stressed that you should be careful with your conclusions. And you carefully said, "This represents only the first step in testing whether these biomarkers may serve as valuable clinical tools."

I would go further than that. I think these four tests are inexpensive, they're clinically available. I don't do them on all patients, but I do them on some. I always do lipids, and I do NT-BNP in somebody with heart failure or decreased ejection fraction. And I always do troponin, which I think is extremely important. Even in the normal range, it trebles its risk.

So a question to Brendan. I think if I found a high troponin, I want to look at CRP, look at NT-proBNP, and I'd have the cholesterol HDL ratio. So what would you think about cascade screening and the implications of that on cost effectiveness?

Dr Brendan Everett: I think that's a really excellent suggestion. We hadn't thought of that, as you know, and it doesn't come up as an idea in the discussion. I think, at least here in the United States, the standard test would be a total cholesterol to HDL ratio, and of course, with that, oftentimes in LDL cholesterol, because that's where we focus our preventative efforts with statins, as you mentioned. And we typically would not do a troponin in otherwise healthy and ambulatory patients.

I think that's a creative suggestion, the idea that if you had an abnormal cholesterol, and then an abnormal NT-proBNP, and then would you move to a CRP and a troponin as well? I think in the type of patient that we're talking about, a primary prevention patient who may have occult cardiovascular disease, CRP is probably the best validated, epidemiologically, as a marker of risk and to guide therapy.

But I think one thing that we struggled with, and I'd be interested in your view on this because you're such an expert on cardiac troponin, is, what are the therapeutic interventions that you would use for somebody with an elevated biomarkers for... And we addressed this a little bit in the discussion, and I think it's just common sense preventive therapy, but I don't know if that struck you as the right thing to do, or if you had other ideas about how to address somebody who might have, theoretically, an elevated risk of sudden cardiac death.

Dr Harvey White: I think it's challenging common sense. Do people use them? So I think the stress should be that preventive therapy should be used in these patients. So blood pressure and history of hypertension is related to sudden death. In your study, sudden death was more common in individuals who didn't exercise. Obviously, they're higher cholesterol, so you got to promote weight loss, blood pressure, nonpharmacological means diabetes is associated with, and a higher HbA1c, so you really want to get the HbA1c down.

Whenever you find an abnormal troponin, you need to go back to the patient and get an echocardiogram. Have they got left ventricular hypertrophy? Have they got underlying LV dysfunction, and so forth? And to get the patient on board, one of the things that you would challenge with doing is the drug use during follow up. And I was particularly interested in beta blockers, which of course, may reduce sudden death.

But I'm also interested in, about 30% of patients with sudden death have taken cocaine or alcohol. And so, addressing drug use is important, addressing alcohol is important. And just as an add-on in this age of COVID, don't take hydroxychloroquine, because that might cause sudden death.

Dr Carolyn Lam: Harvey and Brendan, those were just really excellent points. In fact, I was sort of thinking along the same lines of, what are the therapeutic implications of this? And I think one of the management implications addresses one of the limitations, perhaps though, because this study did not include electrocardiographic or imaging information, like left ventricular ejection fraction. I just wanted to double-check if that's the case, Brendan. And if you could, how has this impacted your own practice, or what's the next steps, you think?

Dr Brendan Everett: You are absolutely correct, that as a routine, none of the studies that we included in this research work actually had baseline electrocardiograms or echocardiograms. I think when you take the perspective of wanting to screen or thinking about screening a broad population for the risk of sudden cardiac death, an echocardiogram is probably not a feasible study. Although, to Harvey's earlier point and to your own point, using that as a subsequent test, along the lines of the cascade screening approach, when you have an abnormal cardiac troponin or an abnormal NT-proBNP, perhaps an echocardiogram is a very good study to order at that point.

The lack of electrocardiograms, I think, is another limitation of our work. Those are more commonly used, at least I think, as a screening tool, at least in the United States, when somebody has a history of hypertension, for example.

I think, with respect to your last question, "How has it changed my own practice?", I think the key thing that I wanted to emphasize, which is an important limitation of the study, is that this is a case control study. So what we're able to do is, we're able to estimate relative risks. And relative risks of seven are high. They're impressive, right?

The problem is that we can't actually estimate what the absolute population risk is of sudden death based on the patients or the participants in these studies. So it's hard to take the group of participants that we were able to look at and watch carefully prospectively, and then back-calculate what the absolute risk of sudden cardiac death would be in a broader population.

So in order to take a research finding like this, where there's a high relative risk, and start to think about population-wide screening, you have to know how that will implicate or affect the absolute risk. If your absolute risk is tremendously low, seven times tremendously low is still tremendously low.

However, if you can find a population where a relative increase of seven in your absolute risk actually becomes clinically important, then you begin to have an argument about population screening and whether or not it's worthwhile and effective, or potentially how it can reduce the occurrence of sudden death, which is our goal, after all, with a study like this.

Dr Carolyn Lam: What a balanced discussion. So thank you, Brendan. That was a very important point. Finally, are you planning next studies, or what's the next step then, you think?

Dr Brendan Everett: Well, I think the next step would be to try and figure out how to translate the data that we have here into a real sense of how this would affect absolute risk. This would then have implications for cascade screening, as Harvey mentioned earlier, potentially broader use of these biomarkers as screening tools in otherwise healthy populations, and of course, implications, both about the testing characteristics and false positives and those sorts of important issues, and then the cost and the cost effectiveness, how much it would cost to screen such and such a population to prevent one sudden cardiac death. Those would all be the next steps, I think, in terms of determining whether or not this approach could be implemented more broadly.

Dr Carolyn Lam: Thanks, Brendan, and thank you so much for this paper. It's just so beautifully and elegantly put. It's something I'm going to remember and already taken my clinical practice to recognize persons at risk and whom I want to do further work of.

Thank you so much for joining us today, Brendan. Thank you so much, Harvey. And thank you, audience, for listening today. Please tune in again next week.

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