Circulation June 2, 2020 Issue

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.