Circulation November 19, 2019 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 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.