Circulation September 9, 2020 Issue

This week’s episode includes author Charlotte Andersson and
Associate Editor Naveed Sattar as they discuss familial
clustering of aortic size, aneurysms, and dissections in the
community.


TRANSCRIPT:


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, director of the Pauley
Heart Center at VCU health in Richmond, Virginia. Well, Carolyn,
our feature this week has to do with aortic size, aneurysms, and
predilection to dissection. But before we get to that, how about
if we grab a cup of coffee and go through some of the other
articles in the issue?


Dr Carolyn Lam: I got my coffee, Greg, and you know what? I'm
going to start with quiz for you.


Dr Greg Hundley: All right.


Dr Carolyn Lam:  True or false, in the setting of obesity
and/or diabetes, cardiac substrate metabolism shifts towards
increased fatty acid oxidation, while lipid accumulates in the
heart? True or false? Of course, you're right. Oh, but there's a
part two. Can you guess, by increasing fatty acid oxidation, will
we induce or prevent obesity-induced lipotoxic cardiomyopathy?


Dr Greg Hundley: I'm going to say, because you asked it in the
way you asked it, prevent.


Dr Carolyn Lam: Wow. All right. Well, the truth is we didn't
really know before today's paper. The specific link between
cardiac metabolism and lipotoxic cardiomyopathy was elusive and
there was no specific therapy available for this condition. And
these authors, Dr Rong Tian from University of Washington and
colleagues, hypothesized that cardiac pathology-associated
obesity would be attributable to the imbalance of fatty acid
supply and oxidation. So using a diet-induced obesity model in
the current study, they demonstrated that enhancing fatty acid
oxidation through deletion of acetyl-CoA carboxylase 2, was
sufficient to prevent obesity-induced cardiomyopathy.


So, increasing cardiac fatty acid oxidation alone does not cause
cardiac dysfunction, but instead protects against cardiomyopathy
in chronically obese mice. The cardiac-protective effect of
increasing fatty acid oxidation and obese mice is through
maintenance of Parkin-mediated mitophagy, and thus preventing
mitochondrial dysfunction. These findings indicate that impaired
mitophagy contributes to mitochondrial dysfunction in obese mice,
and that targeting the Parkin-dependent pathway is a viable
therapeutic intervention for obesity-induced cardiomyopathy.


Dr Greg Hundley: Very nice. Carolyn.


Dr Carolyn Lam: I'm going to be greedy and go on to my next
paper. So Greg, do you think cardiac regeneration is possible?


Dr Greg Hundley: Well, Carolyn, I would have said, several years
ago, no, but that trip that we took to China with Joe Hill and
Hesham Sadek, our Associate Editor and our Chief Editor,
convinced me otherwise. So I'm going to definitely answer yes on
this one.


Dr Carolyn Lam: Oh, Greg, you're just too smart. And speaking of
China, this next paper is from there, from co-corresponding
authors, Dr Nie and Hu, from Fuwai Hospital National Center for
Cardiovascular Disease and Chinese Academy of Medical Sciences
and Peking Union Medical College. So, using seven genetic mouse
lines, they identify that Oncostatin M is the top upregulated
cytokine during neonatal heart regeneration. Oncostatin M is a
pleiotropic secretory protein that belongs to the interleukin 6
family, and associates with the pathological process of dilated
cardiomyopathy.


And these authors found that macrophages promote heart
regeneration by secreting Oncostatin M, which promotes
cardiomyocyte proliferation via a co-receptor, gp130. Employing
RNA-seq and functional screening, they further found that
Src-mediated gp130 triggered cardiomyocyte proliferation by
activating the downstream signaling pathway involving Yap, with
Y357 phosphorylation independent of the Hippo pathway. So the
last thing that they did was show that gene therapy with
adenovirus-associated virus and coding this activated gp130
improved heart regeneration and pumping function, thus serving as
a potential therapeutic target. An amazing paper.


Dr Greg Hundley: Very nice, Carolyn. What a great summary and so
much detail. Well, Carolyn, I'm going to turn our attention to
catecholaminergic polymorphic ventricular tachycardia. And this
article comes to us from Dr Jason Roberts, from the Western
University. Carolyn, genetic variants in calsequestrin 2 can
cause an autosomal recessive form of catecholaminergic
polymorphic ventricular tachycardia, though isolated reports have
identified arrhythmogenic phenotypes among heterozygotes. So in
this study, a total of 112 individuals, including 36
catecholaminergic polymorphic ventricular tachycardia probands,
24 were homozygotes for compound heterozygotes, and 12 were pure
heterozygotes, against 76 family members possessing at least one
presumed pathogenic calsequestrin 2 variant. These were all
identified.


Dr Carolyn Lam: Wow, a very precious cohort. So what did they
find, Greg?


Dr Greg Hundley: This international multicenter study of
calsequestrin 2 catecholaminergic polymorphic ventricular
tachycardia really redefined its heritability and confirmed that
pathogenic heterozygous calsequestrin 2 variants may manifest
with a catecholaminergic polymorphic ventricular tachycardia
phenotype, indicating a need to clinically screen these
individuals. Among individuals heterozygous for a pathogenic
calsequestrin 2 rare variant, medical therapy and exercise
restriction are likely not necessary in the absence of the
catecholaminergic polymorphic ventricular tachycardia phenotype.
Though, you have to be certain over time, an intermittent
clinical screening to ensure they remain phenotype-negative
should be obtained.


Dr Carolyn Lam: Wow, Greg, clinically important study there.
Well, I'm going to go back to the basic science world and talk
about calcineurin. Now, calcineurin has long been implicated in
the induction of pathological cardiac remodeling but has not been
therapeutically targetable for the prevention of heart failure
because of its pleiotropy and our lack of understanding of its
specific protein-protein interactions and compartmentation within
the cardiomyocyte.


Dr Greg Hundley: Okay. Carolyn, do you want me to give background
on calcineurin?


Dr Carolyn Lam: No, Greg, you're off the hook. I'm going to give
you some background on calcineurin. So, calcineurin is the
calcium-calmodulin-dependent phosphatase that exists as a
heterodimer, consisting of a catalytic subunit and a regulatory
subunit. Now, of the three catalytic subunit isoforms, alpha,
beta, gamma, it's the beta isoform that appears to be the most
important for the development of cardiac hypertrophy. Binding of
calcium to the calcineurin regulatory subunit enables binding of
the calcium-calmodulin complex, thereby releasing auto-inhibition
and freeing the enzyme to dephosphorylate downstream substrates.
That's the background.


Now, in today's issue, we have this great paper from
co-corresponding authors, Dr Kapiloff from Stanford University,
and Dr Nikolaev from University Medical Center Hamburg. And, with
their colleagues, they described the discovery of a calcineurin
catalytic subunit beta binding protein Cdc42-interacting proteins
4, and I'm going to call that CIP4, which functions as a scaffold
to sequester the pool of calcineurin near the sarcolemma of
cardiomyocytes, where it regulates pro-hypertrophic signaling.


These findings have really important implications for
understanding how cardiac calcineurin is selectively activated by
stress signals, as opposed to the pleiotropic second messenger,
calcium, that really floods the cardiomyocytes during each
contractile cycle. Furthermore, the data provide proof of concept
for an innovative therapeutic approach, whereby CIP4-anchoring
activity is selectively inhibited to block the action of a small
pathogenic pool of calcineurin as a means of treating heart
failure. How about that? This is really discussed in an elegant
editorial by doctors, Woulfe, Travers, and McKinsey.


Dr Greg Hundley: Very interesting, Carolyn. Sounds like another
possibility for treating and managing heart failure. Well, let me
share with you some of the other findings in our mailbag this
week. First, I've got, from Professor Lang Li and Stephen
Wiviott, they swap research correspondence regarding the prior
publication entitled, Effect of Dapagliflozin on Atrial
Fibrillation in Patients with Type 2 Diabetes Mellitus, Insights
from the DECLARE-TIMI 58 Trial. And then Professor Laszlo
Littmann has a nice ECG challenge for us related to a high-risk
ECG that exposed some downstream worrisome vital signs.


Dr Carolyn Lam: In addition, there's a perspective piece by Dr
Nambi discussing the fact that a zero-calcium score is desirable,
but isn't enough to defer therapy, given that up to one-third of
events will occur in this group. There's also an In Depth paper
by Dr Borlaug, entitled, “Altered Hemodynamics and End Organ
Damage in Heart Failure, The Impact on the Lung and Kidney,” and
oh boy, this one is so beautifully illustrated. Just a must read
for the understanding of the hemodynamics in the lung and kidney
and heart failure. Next is a research letter by Dr Loeys on
enrichment of rare variants in the Loeys-Dietz syndrome genes in
spontaneous coronary artery dissection, and not in severe
fibromuscular dysplasia. And finally, another research letter by
Dr Arora on racial differences in serial NT-proBNP levels in
heart failure management with insights from the GUIDE-IT Trial.
What a rich issue, but let's move on to our future discussion,
shall we?


Dr Greg Hundley: You bet, Carolyn.


Well, listeners, we're now getting to our feature discussion and
it's very interesting this week where we're going to evaluate
aortic aneurysms. And we have with us one of the lead authors of
this paper, Dr Charlotte Andersson from Boston Medical Center,
and our own Associate Editor, Naveed Sattar from Glasgow,
Scotland. Charlotte, welcome to our feature discussion. Could you
tell us a little bit about the background and the hypothesis that
you put forward with this study?


Dr Charlotte Andersson: The background for this study was based
on clinical work and what we observed in clinic. We had a few
patients where we had been stricken by the fact that they came in
with an acute aortic syndrome and they had a first-degree
relative themself with the condition, but they did not look
syndromic at all. And we started to wonder, what is the actual
risk in the community, in people without obvious syndromic
features of suffering from an aortic event itself. And although
there are quite a few studies out there that have, to some
degree, focused on the familial clustering of aortopathies, there
is not a lot of information based on communities and whole entire
populations. So we wanted to, frankly, estimate what is the
incidence rates of aortic dissections and aortic aneurism in the
community if you have a first-degree relative that has suffered
from the disease themselves.


Dr Greg Hundley: How you organize your study and what was your
population and what was your design?


Dr Charlotte Andersson: This study was actually based on two
independent samples. First, we used the Framingham Heart study
population that is very densely phenotypes over many years of
spanning three generations of participants, where we looked at
people who had at least one parent who had an aortic size in the
upper quartile index to body-surface area and adjusted for age
and sex. And we saw what's the risk of you, as a child, having an
aortic size in the same upper quartile.


And second, we looked in the general Danish population, the
Danish healthcare system is, as you probably know, governmental
funded and we have very good registries of all hospitalizations,
all outpatient visits, and so we were able to link more hard
clinical events in people with and without a first-degree
relative. What we did was we started time when people had an
aortic dissection, we identified all the first-degree relatives
in these people, and we matched them with up to 10 sex and age
match controls from the general population without a first-degree
relative with the disease.


Dr Greg Hundley: What did you find?


Dr Charlotte Andersson: We found that in the Framingham sample,
if you had at least one parent who belongs into the upper
quartile of aortic size, you had an odds ratio of two to three,
adjusted for various clinical risk factors, such as hypertension
and smoking yourself. And in Danish population, we found that if
you had a first-degree relative with an aortopathy, the hazard
rates for you developing the disease yourself was almost a
tenfold-increase compared to age and sex match controls. And
importantly, seemed like hazard ratios use were, more or less,
unchanged when we start adjusting various known risk factors,
such as bicuspid aortic valve, Marfan syndrome, and Ehlers-Danlos
syndrome, normally those kinds of things. And we also found that
the younger your proband were at the time of an acute event, the
higher was your relative risk yourself. So among people who were
below the age of 50 when they suffered an event, the hazard
ratios were up to a 50-fold increase.


Dr Greg Hundley: Very nice. Naveed, what attracted you to this
article as it was coming through the editorial process? And then
second, how do we take the information that Charlotte's just
conveyed and will be published here today, how do we take this in
the context of what we already know about aortic aneurysms?


Dr Naveed Sattar: I think it's a beautiful study, so well done,
Charlotte. I think it's a beautiful fusion. As Charlotte said, an
in-depth cohort study, which has got very well-measured
parameters of systematic points and a fantastic population-based
data set from Denmark, which Sweden shares and Scotland shares
and relatively small countries like us share. So small countries
like Denmark punch above their weight in these kinds of studies,
which is fantastic. But there's a rich seam of research that
comes from these, and this is one of them. So I think that fusion
of two data sets with different strengths and limitations
combined giving off same signals is good.


I think, as Charlotte said, this is the first major population
study to look at this question. So there's been people around the
world who have got this sense that the aortic aneurism may well
be familial, this provides, probably, some of the best data to
suggest, yes, it definitely is.


Now the questions going forward is, okay, at what point do you
screen everybody's got a family history with a proband, or do you
screen those who've got a family history of younger probands? And
I think what Charlotte and the team and other people around the
world thar are going to look at this say,


"Okay, we now think, in addition to screening, for example, in
the UK and the US we probably screen just men above 65, where
most of the disease is, do we also then implement screening in
younger people with family histories? And who do we screen, and
when and how? And do we need to develop some kind of risk score?"
And then when we do that screening, what do we do about it? Is
going to be the questions and I'm sure Charlotte and her
colleagues have thought about these things and it'd be
interesting to see what her view is on those things. But I think
it was a beautiful study in every sense.


Dr Greg Hundley: So Charlotte, he's really set you up nicely,
what study do we need to perform next in this area? What are you
and your group thinking about?


Dr Charlotte Andersson: Yeah, I think there are two implications
of this study. First, clinical, as Naveed says. They already had
a sense that aortic diseases were heritable, and I think these
data definitely support that we should probably screen
first-degree relatives. And I think, at some extent, this is what
the guidelines already encourage us to do. So I'm not sure it
would be feasible to randomize people or do a clinical trial
where we screen some but not others. I'm not sure that would be
ethical. I think the evidence is too strong for familial
clustering and that we should probably screen these people.


But I think also, our estimates, they are so strong that I
suspect that there are likely more genetic variants associated
with non-syndromic aortopathies that we are not aware of just
yet. So I think the next step would be to try to disentangle the
genetics a little bit more. I have seen some preliminary analysis
based on the UK Biobank, for instance, and I think there are more
genetic variants to come up with also, more common genetic
variants, at least, that we are not aware of just yet. So that
would be the next step as I see it.


Dr Naveed Sattar: And that might particularity in younger
probands.


Dr Charlotte Andersson: Right.


Dr Naveed Sattar: Those with the younger probands, because it
looks like, as you said, the hazard ratio, the risks, are so
high, it could also potentially be monogenic, but anyway.


Dr Charlotte Andersson: I agree.


Dr Greg Hundley: Well, Charlotte, Naveed, we really appreciate
your time and taking this opportunity to discuss these really
interesting findings and helping us understand that, truly, there
may be a familial component to understanding this disease
process, particularly in patients with aortic aneurysms that may
go on to develop aortic dissections.


Well listeners, we hope you have a great week and on behalf of
Carolyn and myself, catch you on The Run next week. This program
is copyright, the American Heart Association, 2020.