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Circulation on the Run

Jun 1, 2020

In today’s episode, Dr Carolyn Lam discusses the prevalence of familial hypercholesterolemia among the general population and patients with atherosclerotic cardiovascular disease with Dr Kausik Ray (KOSH) and Dr Amit Khera.

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

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

Dr Carolyn Lam: Greg, ever wondered what's the prevalence of familial hypercholesterolemia in the general population? It's an important question, but we're going to wait to discuss that with our feature discussion coming right up.

First, I want to tell you all about valvular heart disease. In a preclinical model, would you believe, but first let me just remind us all that primary valvular heart disease is a really prevalent cause of morbidity and mortality. And although the primary consequence of valvular heart disease is myocardial dysfunction, treatment of valvular heart disease has always centered around valve repair or replacement, rather than the prevention or reversal of myocardial dysfunction.

In fact, have you thought about this? We know very little about the mechanisms, the actual preclinical underlying mechanisms of left ventricular dysfunction and primary severe mitral regurgitation. Well, in the first paper I want to talk about today, Dr Li from First Affiliated Hospital, Sun Yat-sen, University Guangzhou, and Dr Sadek, from UT Southwestern Medical Center and their colleagues develop the first mouse model of severe mitral regurgitation. And they did this by severing the mitral valve leaflets and chords using iridectomy scissors.

Similar to the human condition, induction of mitral regurgitation was followed by gradual left ventricular dilatation and dysfunction resulting in severe systolic dysfunction. Further analysis revealed that severe mitral regurgitation resulted in a marked increase in cardiac mass, increased cardiomyocyte length, but not with, and electron microscopy evidence of sarcomere disarray and the development of sarcomere disruption. From a mechanistic standpoint, severe mitral regurgitation resulted in activation of multiple components of both the mTOR and Kelson urine pathways. Now intriguingly, inhibition of mTOR signaling even preserved sarcomeric structure and prevented left ventricular remodeling and systolic dysfunction.

Finally, immunohistochemical analysis uncovered a differential pattern of expression of the cell polarity regulator CRB2, along the longitudinal axis of cardiomyocytes and close to the intercalated discs, with a similar pattern of polysome localization. And all of this suggests a potential new mechanism of longitudinal cardiomyocyte growth.

Dr Greg Hundley: Well, Carolyn, there is a lot of basic science and a lot going on both histopathologically, but also mechanically with this model. What's our take home message?

Dr Carolyn Lam: Well, Greg, this mitral regurgitation mouse models suggest that cardiomyocyte hypertrophy in response to mitral regurgitation is a maladaptive process that may be pharmacologically targeted by mTOR inhibitors.

Dr Greg Hundley: Oh my, very nice Carolyn. Well, I'm going to bring you another kind of basic science paper as well. And it's from Dr Jin Li from the Institute of Biochemistry and Molecular Medicine at the University of Bern. And it really involves auto antibody signatures in cardiac arrests. So Carolyn, a quiz of what percentage of individuals sustaining out of hospital cardiac arrest have no known cause?

Dr Carolyn Lam: You said, “Oh oh!” I’m on the spot here, Greg. Okay. What about if I start with what I do know? Coronary artery disease is the most common cause. I think that may be, I don't know, large majority, 80% of it. And then we get inherited cardiomyopathy, channelopathies. So I'm going to guess less than 10%.

Dr Greg Hundley: Wow. That is why you're just the stellar extraordinaire. So it's exactly about 5% to 10%. So Carolyn this study sought to address the etiology for this out of hospital arrests in this 5% to 10% of individuals, using a peptide micro-ray designed to screen for IgG targeting epitopes from all known cardiac ion channels with extracellular domains.

So plasma samples from 23 patients with unexplained cardiac arrest were compared to 22 cardiac arrest cases of ischemic origin and a group of 29 age, sex, and BMI matched healthy subjects.

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

Dr Greg Hundley: The auto antibody against the poor domain of the L tight voltage gated calcium channel or Cav 1.2 was consistently identified as a biomarker of idiopathic cardiac arrest and functional studies on human induced pluripotent STEM cell derived cardiomyocytes demonstrated that the anti Cav 1.2 IgG purified from patients with idiopathic cardiac arrest is pro-arrhythmogenic by reducing the action potential duration through calcium channel inhibition.

Dr Carolyn Lam: Wow, that seems huge. Clinical implications?

Dr Greg Hundley: I thought you'd asked me that. So the present report addresses the concept of autoimmunity and cardiac arrest and hitherto unknown auto antibodies targeting extra cellular sequences of cardiac ion channels were detected. And so moreover, this study identifies an auto antibody signature to specific patients with cardiac arrest, thereby explaining perhaps a potential etiology for this 5% to 10% of individuals that here to for, we were uncertain of that particular ideology.

Dr Carolyn Lam: Wow. That clearly needs follow-up, but you know what? What also needs follow-up is a quiz question for you. What do you say to a young adult with stage one hypertension about his or her future health risks?

Dr Greg Hundley: Well, how about A, see a physician, B, listen to that physician and follow their recommendations?

Dr Carolyn Lam: Oh, you are brilliant. Well, guess what? I'm going to tell you a little bit more about this in the next paper from Dr Kim from Yonsei University College of Medicine and Colleagues who looked at almost six and a half million participants aged 20 to 39 years. So young, and without taking any antihypertensive medication in 2003 to 2007 in a nationwide health screening database.

Now participants were categorized according to the 2017 ACCAHA guidelines as having a normal blood pressure. That is an untreated systolic blood pressure, less than 120 and diastolic blood pressure less than 80. Or stage one, isolated diastolic hypertension. So that's when systolic is less than 130 and diastolic between 80 and 89. Or stage one isolated systolic hypertension. So that's when systolic blood pressure is between 130-139 and diastolic is less than 80. Or finally, stage one systolic and diastolic hypertension. So that's when systolic is between 130-139 and diastolic is between 80 and 89. And these were followed up for the primary outcome of composite cardiovascular disease events, including myocardial infarction, stroke, heart failure, and cardiovascular related death.

Dr Greg Hundley: Caroline, I am dying to hear what did they find?

Dr Carolyn Lam: So over a median follow-up of 13.2 years, more than 44,000 new cardiovascular disease events occurred. Among these young adults who had a median age of only 30 years stage one, isolated systolic hypertension, isolated diastolic hypertension, and systolic and diastolic hypertension were each associated with higher cardiovascular risks compared to normal blood pressure.

Cardiovascular risk of stage one systolic and diastolic hypertension was higher than the risks of stage one isolated systolic and isolated diastolic hypertension.


Dr Greg Hundley: Very good. That was an outstanding presentation and very pertinent to our younger listeners as well as young patients with hypertension. In the rest of this journal, we are jammed packed with more articles. Let me tell you about a few. First, I've got a research letter by Professor G. Kees Hovingh from Amsterdam UMC discussing Inclisiran and how that durably lowers LDLC and PCSK-9 expression in homozygous familial hypercholesterolemia. Next there's an ECG challenge from Dr Miguel Arías from Complejo Hospitalario Universitario de Toledo involving syncope and alternating QRS morphologies.

Next Professor Qing Yang from Tianjin Medical University General Hospital has a perspective piece regarding anti-platelet therapy following percutaneous coronary interventions in patients complicated by COVID-19.

One of our own associate editors, Dr Nicholas Mills, has a very nice on my mind piece related to the use of serum troponin and biomarkers, as well as their utility in managing patients with COVID-19. Next, Dr Courtney Campbell from Ohio State University and Wexner Medical Center has a perspective piece regarding will compliment inhibition be the new target in treating COVID-19 related systemic thrombosis.

And then finally, Carolyn, there's a nice exchange of research letters regarding Orai 1 channel inhibition, preserving left ventricular systolic function, and normal calcium handling after pressure overload. And the contributing authors that provided these letters are Dr Muddassir Mehmood from University of Tennessee Medical Center and Dr Jessica Sabourin from INSERM UMR S1180.

Dr Carolyn Lam: And that's not all, Greg. There's also an in-depth article on the implications of altered ketone metabolism and therapeutic ketosis in heart failure by Dr Salvaraj, Kelly, and Margulies. Now this review is a must read. It summarizes the current evidence supporting a role for ketones in heart failure and covers normal myocardial ketone utilization, alterations, and ketone metabolism in a failing heart and effects of therapeutic ketosis in both animals and humans with heart failure. There's also a research letter by Dr Susanna Larson who used the UK Biobank Cohort to perform a Mendalian Randomization investigation into the causal effects of circulating LPA levels on atherosclerotic, cerebral vascular thrombotic, and valvular disease.

There's another research letter by Dr Eliseo Guallar and that's on mitochondrial DNA copy number, which is an indirect biomarker of mitochondrial dysfunction and its association with incident heart failure in the Eric study.

Wow, such a full issue, but now let's go on to our feature discussion. Shall we, Greg?

Dr Greg Hundley: You bet.

Dr Carolyn Lam: Today's feature discussion is all about familial hypercholesterolemia. Now, recent study suggests it is more frequent than previously reported. And in fact, increasingly recognized as affecting individuals of all ethnicities and across many regions of the world. Well, today's feature paper really represents one of the most comprehensive assessments of the prevalence of familial hypercholesterolemia.

More than 7.3 million individuals from 62 studies. So pleased to have with us the corresponding author of this beautiful paper, Dr Ray Kosh from Imperial College London, as well as our editor of digital strategies, Dr Amit Khera from UT Southwestern. Kosh, if I may call you that, congratulations again on another just really important paper. This systematic review and meta-analysis is really revealing. So could you tell us a little bit more of the details of what you did and just really tell us the take home messages.

Dr Kausik Ray: We've been getting signals that familial hypercholesterolemia... So this is where essentially individuals inherited an abnormality that results in lifelong elevations of LDL cholesterol birth, increases risk of cardiovascular disease. The previous prevalence was believed to be about one in 500 and suggestions... It's actually not just a suggestion, there's a lot of data suggesting that it's a lot more prevalent than that. And one of the queries that we often have, if you think about global health is does it affect all regions of the world? And if we don't go out looking for it, you're not going to find it. So this is really why this was done. And we basically synthesize the global data and there was basically over 7 million people approximately from general population primary care settings, if you will. And the global prevalence for FH is one in 311. Confidence interval is between about one and 250 to one in 397.

If you look at WHO regions of the world, it's equally prevalent across all regions of the world. And we know there are many regions of the world where they're not going out looking for this. So if you don't look for it, you won't find it. And we think that that should inform public health policies. The other key things about this or that because this is a condition that results in premature cardiovascular disease, there's been emerging data that actually in people with early myocardial infarction, for example, the possibility of FH may be higher.

So in proportion of studies where we had participants with established cardiovascular disease, the possibility of this being present is about one in 17. Now they're not all going to be FH, but it means that actually the coronary care unit where the vast majority of these patients arose from, that's a great starting place. If you see somebody with premature MI before the age of 55, high LDL cholesterol above 190, start thinking about it. If you find one, you can think about cascade testing and finding family members because each effected individual potentially the likelihood in a first degree relative is 50%, 1 in 2. So that becomes really important. And I think those are probably where I'd stop now and maybe take a few more questions, but I think that's the take home message.

Dr Carolyn Lam: Very, very important and practical take home messages. So thanks for that, Kosh. But could I just go back with one basic question? For those of us who don't think of it every day, what is the definition of familial hypercholesterolemia? There are so many definitions out there. Could you simplify it for us?

Dr Kausik Ray: Yeah, so basically all the definitions, the common ones that have been used in making an early diagnosis. So met that criteria, looking at family history, looking at elevated cholesterol levels. There's the Simon-Broome criteria with some clinical signs, as well as family history and genetic mutations. And then there's the Dutch lipid criteria. That's probably the most used in the world, looking at the physical signs, LDL cholesterol levels, and also family history.

And they give you essentially a score of the likelihood of this. And if you like, the gold standard really is probably genetic testing. That's not available in all regions of the world. There may be cost and other issues with that, but essentially that is giving you a diagnosis of a known variant of monogenic disorder and there's over 1,800 or so variants identified. So those are the ways that you can essentially do this.

Dr Carolyn Lam: Thanks, Kosh. Amit, I have to bring you in here. Thank you so much for managing this beautiful paper and recognizing how important it is. You invited an editorial as well. Could you share some of your thoughts?

Dr Amit Khera: Sure. The one thing, Kosh, as we look at this, which is so important to understand the prevalence worldwide and really glad that your group took on this project. But if you look at your figure, what's striking is how many areas are essentially white where there's no data. I mean, huge proportions of countries around the world. Why do you think that is? And how do we close that gap?

Dr Kausik Ray: That becomes really important. So what I would say is this was looking at prevalence and those are areas of the world where prevalence has not been reported. So if I were to overlap that with countries, for example, where we are starting to get definitive diagnosis through gene mutations, for example, there would be fewer gaps. We don't yet have enough data in terms of prevalence in those areas. But if you look, there's a huge gap, for example, in Africa. You've got a few countries that we know that haven't reported prevalent but have published on FH. So we do know it's there. And then you've got South Africa at the bottom and you've got Nigeria now also collecting data.

But part of it is, I guess, one important thing is misclassification. So if somebody dies in those regions of the world, often it's attributed to other causes. And because there is little public health information, because there hasn't been investments on thinking about cholesterol, for example, is it common in our population? If you were in sub Saharan Africa, maybe you think about infectious disease or other things, right? So it's not on the agenda. So there hasn't been that investment and therefore data is then lacking. We starting to see shifts in that, and hopefully this will move the needle a little bit more. And I think once that is done, what will then happen is we will get more reliable estimates from that part of the world. I think we've all got patients from that part of the world. And when I think about my clinical practice, I have patients from the middle of Africa, West, East, Sri Lanka, none of which is represented on that map.

Dr Amit Khera: I think that's a great point. And you know, there's no reason to think that the prevalence is much different. We just have a gap in knowledge there. And I guess the next part comes to implications. As you rightfully discussed many times in your paper, less than 1% of people are diagnosed. And even if someone publishes prevalence data, a diagnosis could involve genetic testing, it could involve broad limpid screening, a combination of both. What do you think is the next step?

Dr Kausik Ray: That's incredibly important. And I think you have to think about two different approaches. They're are the populations already out there living with this condition. So how do we picture those? It's going to be very difficult to think about universal screening in everybody 40-60, for example. So one way is to look at those people, the index case who comes in premature myocardial infarction in particular and use that as a source for cascade testing.

We know that that is cost-effective. There've been formal evaluations of that approach. I do think with the cost of genetic testing, for example, that will make life a lot easier. And I think that that point in CCU, the elevated LDL premature MI should be the start of that thought process. What we tend to do is we have a whole list of medications. We start people on that and it's an afterthought, depending upon the post-treatment cholesterol levels. It shouldn't be.

The other thing I think that you could do, there are lots of opportunities for screening. If you think about those people now, who are under the age of 10, 11, and you think about vaccination programs, you think about pre-college, pre-university health assessments that are often done in many parts of the world. Those offer opportunities to get a blood sample. David Wall did a lovely piece several years ago, looking at child parents screening, reverse cascade, if you will. And that showed that it could be cost effective. You don't need a small sample of blood. You can use DNA. And each of those interactions gives you an opportunity for screening.

What I'd love to see is we all think that there will be or there could be an update of the WHO recommendations for cholesterol management. And that might advocate, for example, universal screening for cholesterol before the age of 29. If that is done, then if you think of low middle-income countries, a lot of those white gap, we will start to see those things being or this condition being picked up and potentially huge numbers of lives being saved. And because this is a genetic condition which is ultimately dominant, you find one, you can either exclude or find other people early and early diagnosis changes prognosis as you well know.

Dr Amit Khera: Thank you for that, the implications and the potential profound if one could implement that broad screening. And as you pointed out early treatment, and I have one last question for you and it has to do with other part of the coin, which you touched on, which is the ASCBD. You know, your estimates of one and 17 were really helpful. I think many people aren't appreciative of how relatively common FH is in patients with coronary artery disease. And you talked about the implications being cascade screening of family members, but I know you work in therapeutics as well. There've been some data about maybe even earlier intervention or more aggressive intervention once someone's diagnosed with FH and after cardiovascular disease. What are your thoughts on that part of the investigation?

Dr Kausik Ray: Yeah, no, that's a really important question. So most of the studies that have actually looked at ACVD, they didn't utilize, for example, a genetic diagnosis. So it's largely the clinical phenotype. And remember, you have an A priority bias in terms of scoring on the Dutch Lipid Network Criteria, by virtue of the fact that you've had premature disease. Some of these people will probably have elevations in LP(a) and others it could be polygenic hypercholesterolemia, which does carry an increased risk, but not as much as FA.

If you could separate those three out the implications really are if you think about the ACVD patient population with true FA, you basically missed 40 years of unexposed exposure. And so in these people, I think those are people that we should be thinking about mainly more aggressive intervention with either lower LDL targets, because the absolute benefit is likely to be much, much greater. So I think that's the key implication I think of these findings.

Dr Carolyn Lam: Thanks so much, Amit. Thanks so much, Kosh. As someone living in an area where there is... It's white on that map as well, but no available data in Southeast Asia, I've learned a lot.

Thank you, listeners, for joining us this week. You've been listening to Circulation On the Run. Please tune in again next week.

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