Circulation December 14, 2021 Issue

Please join Guest Host Mercedes Carnethon, author Jason
Roberts, and Associate Editor Vlad Zaha as they discuss the
article "Epigenetic Age and the Risk of Incident Atrial
Fibrillation."


Dr. Carolyn Lam:


Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and its editors. We're your
co-host, I'm Dr. Carolyn Lam, Associate Editor from the National
Heart Center in 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. Well, Carolyn,
this week's feature we're going to learn more about the risk of
incident atrial fibrillation, but as that pertains to
epigenetics. But before we get to that feature, how about we grab
a cup of coffee and get started on some of the other articles in
the issue. Would you like to go first?


Dr. Carolyn Lam:


I would love to. And the first paper I want to highlight asks the
question, are social economic variables associated with 30 day
survival after out of hospital cardiac arrest. And this comes
from Dr. Jonsson from Karolinska Institute in Stockholm, Sweden,
and colleagues. They linked data from the Swedish Registry of
Cardiopulmonary Resuscitation with individual level data on
social economic factors. In other words, educational level and
disposable income, all from statistics, Sweden. And what they
found was that both higher disposable income and higher
educational level independently associated with better 30 day
survival following out of hospital cardiac arrest. The
relationship between disposable income and 30 day survival was
more robust for mediating factors compared to educational level.


Dr. Greg Hundley:


Oh, wow Carolyn. Really interesting in a very, what I would call
hot topic these days. So what are the clinical implications of
this particular study?


Dr. Carolyn Lam:


Well, the results really highlight the importance of preventive
efforts aimed at patients with lower social economic status. And
these preventive actions could include both early recognition and
warning signs and for example, CPR and AED training. So very
lovely paper there.


Dr. Greg Hundley:


Absolutely. Very nice Carolyn. Well, my first paper comes to us
from Dr. Nan Wang from Columbia University Medical Center. And
Carolyn this paper focuses on a common genetic variant called
link RS 3184504, and it is associated with increased platelet and
neutrophil counts, coronary artery disease, thrombotic stroke,
and autoimmune diseases. And so this research group previously
has shown that hematopoietic link deficiency synergizes with
hyperlipidemia to promote platelet production and activation,
neutrophilia, platelet neutrophil aggregates, atherosclerosis and
arterial thrombosis, all of those things. So platelet activation
and platelet neutrophil interactions have been shown to promote
neutrophil extracellular traps or net formations. So nets are
formed when neutrophils release their contents leading to the
formation web-like structures made of DNA, myeloperoxidase,
citrullinated histone and proteases that entrap and kill
bacteria. Now, while nets may help to suppress infection, the
formation of nets called NETosis in blood vessels can promote
atherosclerosis and thrombosis. And so this study was undertaken
to investigate the hypothesis that linked deficiency might
promote NETosis leading to formation of unstable atherosclerotic
plaques, and arterial thrombosis.


Dr. Carolyn Lam:


Wow. What a really neat hypothesis and NETosis. I learn new
things all the time. So what do they find?


Dr. Greg Hundley:


Right Carolyn. First of all, hypercholesterolemic mice with
hematopoietic link deficiency displayed accelerated arterial
thrombosis with nets in thrombi and these changes were reversed
by PAD4 deficiency or OxPL antibodies. Second, linked deficient
platelet from hyperlipidemic mice expose and release increased
OxPL when activated promoting NETosis, when incubated with link
deficient neutrophils. Third, an AntiOxPL antibody reduced OxPL
levels, NETosis and arterial thrombosis specifically in link
deficient mice, and finally Carolyn targeting atherothrombotic
risk using OxPL antibodies might be particularly effective in
genetically defined populations with reduced link function or
increased JAK-STAT signaling.


Dr. Carolyn Lam:


Wow. Okay. So they proved their hypothesis. Could you sum it up
for us, Greg?


Dr. Greg Hundley:


You bet Carolyn. So this foundational work suggests that perhaps
future studies targeting NETosis and OxPL in patients carrying
the common link loss of function variant, could reduce
atherothrombotic risk.


Dr. Carolyn Lam:


Wow. Thanks, Greg. My next paper is super interesting in its
approach. Listen up. Now the assessment of the relationship
between myocardial ATP production and cardiac workload. We know
is important for better understand disease development and choice
of nutritional or pharmacological treatment strategies. So what
Dr. Berndt from Charity University and colleagues did, was they
developed a comprehensive physiology based mathematical model of
cardiac energy metabolism. And this model is called cardiokine
one. And what it does is it recapitulates numerous experimental
findings on cardiac metabolism obtained with isolated
cardiomyocytes, perfused animal hearts and in vivo studies with
humans. The model encompassed all pathways along, which the
possible energy delivering substrates like glucose, long chain
fatty acids, keto bodies, acetate, branch chain, amino acids are
utilized.


Dr. Carolyn Lam:


They use the proteomic space, the abundance of metabolic enzymes
and cardiac tissue to generate individualized metabolic models of
cardiac energy metabolism. And so to prove their case, they
further applied this approach to the left ventricles of controls
in patients with mitral insufficiency and aortic stenosis, and
showed that despite overall preserved systolic function, the ATP
producing capacity of these left ventricles of patients with
valvular dysfunction was generally diminished and correlated
positively with mechanical energy demand and cardiac output.


Dr. Greg Hundley:


So Carolyn really interesting findings. Sort of linking
metabolism them with ventricular dysfunction in those with
valvular heart disease. So what were the clinical implications
here? What's the take home?


Dr. Carolyn Lam:


Well, this methodology is just awesome, but what they also found
I think is a very important physiological principle. And that is,
while metabolic capacity have a significant correlation with
biomechanical properties like myocardial power and cardiac
output, they can also vary considerably between individual
patients and therefore help us to understand in future perhaps
why some patients develop heart failure over time while others
with similar hemodynamic conditions do not. So just interesting.
I think it just opens the space to a lot more.


Dr. Greg Hundley:


Absolutely beautiful summary there Carolyn. Well, in the rest of
the mailbag for this issue, we have an exchange of letters
between Professors Hu and Trifon on the previously published
paper, entitled “Short Term Treatment with Aspirin plus
Clopidogrel Compared to Monotherapy of Aspirin May Not
Significantly Decrease the Risk of Stroke Recurrence.” Also,
there's a Research Letter from Professor Catalucci entitled,
“Nano miR-133A Replacement Therapy, Blunts Pressure Overloaded
Induced Heart Failure.” And then finally Carolyn, there's an
In-Depth article from Professor Aengevaeren entitled,
“Exercise-Induced Cardiac Troponin Elevations From Underlying
Mechanisms to Clinical Science.” Well Carolyn, how about we get
onto that feature discussion and learn more about incident atrial
fibrillation and the age of epigenetics.


Dr. Carolyn Lam:


Let's go.


Dr. Mercedes Carnethon:


Welcome to this episode of Circulation on the Run, where we're
going to have a very exciting discussion about a paper on
epigenetic age and the risk of incident atrial fibrillation.
We're extremely excited to have the lead author here with us, Dr.
Jason Roberts from the Population Health Research Institute,
McMaster University and Hamilton Health Sciences in Ontario
Canada. And I am really excited to host this episode alongside
the handling editor. My name is Mercedes Carnethon and I'm the
professor and vice chair of Preventive Medicine at the
Northwestern University School of Medicine. And I'm pleased to be
hosting this with Dr. Vlad Zaha from UT Southwestern Medical
School, who was the associate editor who handled the piece. So
I'm really excited to jump right into this because I think
there's a lot that we can all learn from this. So welcome Jason,
and thank you so much, Vlad.


Dr. Jason Roberts:


Thank you so much for having me, it's a delight to be here.


Dr. Mercedes Carnethon:


So Jason, tell us a little bit about the rationale for this
study, what you found and what it means.


Dr. Jason Roberts:


Absolutely. So as a cardiac arrhythmia specialist, I see a lot of
patients with atrial fibrillation. And in 2021, our understanding
of its underlying pathophysiology still remains modest. Our
treatment strategies for the condition are also somewhat modest,
although catheter ablation and antiarrhythmic drugs can
potentially be very effective. In the context of these
limitations, they're also exacerbated to some extent by the
prevalence of atrial fibrillation, increasing dramatically in
developed countries. Part of this is related to the obesity
epidemic. Things like hypertension increasing becoming more
common, but because atrial fibrillation is age dependent and
because of our aging populations in developed countries, this is
felt to have a major contribution to the growing prevalence of
atrial fibrillation. Unlike obesity and hypertension and other
risk factors, which are potentially modifiable, chronological
aging is viewed as non-modifiable. It's not something that we can
tackle. That said, we know within the population and just from
personal experience that people age at different rates. There are
some people that are 65 who behave more like they're 50, other
people that are 50 who behave more like they're 65.


Dr. Jason Roberts:


And in that context, biological aging, we wondered whether or
not, does biological aging independent of chronological aging
potentially impacts the risk of atrial fibrillation. If that was
the case, because there are gradually accumulating to suggest
that biological aging is potentially modifiable, that could
potentially open up the possibility of tackling aging as a
respective for atrial fibrillation. So that drove us to ask this
question. In terms of what we found in the approach that we used.
So we used our biological marker of aging, was something called
an epigenetic clock. So it's been found that modifications to
DNA, specifically methylation at CpG at dinucleotides, they
correlate with aging. This has been appreciated for a few
decades. It was initially felt that with aging, methylation
levels gradually reduced over time. But with more careful
interrogation, it's shown that there's patterns. Some methylation
areas increase, other methylation areas there's decreases.


Dr. Jason Roberts:


And Steve Horvath, who is a scientist at UCLA has found that
using mathematical algorithms, you're able to very accurately
ascertain chronological age based on the patterns of DNA
methylation, he's called these things epigenetic o'clock. That
said, even though they very accurately ascertain chronological
age, they aren't perfect in each individual in terms of matching
up to their chronological age, but that's actually turned out to
be a good thing. So when people, their epigenetic age is older
than their chronological age, they're said to have positive
epigenetic age acceleration. They may be biologically older than
their actual chronological age. And then the reverse also holds.
So using this concept of epigenetic age acceleration, we ask
whether or not do people that are older biologically on the basis
of their epigenetic age, do they have an increased risk of atrial
fibrillation? And then we tackle that using a few different core
works that I'm certainly happy to elaborate on in terms of what
we found.


Dr. Jason Roberts:


So we used three population based cohorts from the United States,
the well known Framingham Heart Study, the Cardiovascular Health
Study and Eric as well. There were approximately just under 6,000
people from those studies that had undergone genome wide
methylation analysis that in the enabled us to calculate their
epigenetic ages. The follow period for these people was just
under 13 years. And then we look to see whether or not these
epigenetic clocks associated with instant atrial fibrillation. In
these cohorts, we look at five different clocks. So there's the
Horvath Clock and the Hannum clock that were designed to predict
chronological aging. The more recent clocks, things like DNAm
PhenoAge and DNAm GrimAge are more designed to predict aspects of
clinical phenotype and also mortality. We found that in
unadjusted analyses, all of these clocks were associated with
atrial fibrillation. When we then adjusted for multiple different
clinical variables, we found that the DNAm PhenoAge clock and the
DNAm GrimAge clock continued to exhibit statistically significant
associations with atrial fibrillation.


Dr. Jason Roberts:


Interestingly, the multi-variable adjustment, one concern is, do
these clinical factors, are they confounders where we should be
adjusting, or are they potentially mediators. If we adjust for
mediators that potentially masks the effect of the clock. But
regardless of how we treat them both DNAm PhenoAge and DNAm
GrimAge, we're associated with increased risks of incident atrial
fibrillation. Alluding to the possibility that biological aging
independent of chronological aging is important in terms of
determining risk for atrial fibrillation. And it may be that if
we're able to modify biological aging, we could potentially
reduce the risk of atrial fibrillation. So that's the study in a
nutshell.


Dr. Mercedes Carnethon:


No, that is really exciting. You said something early on about
chronological age being immutable. And I would have to say, both
Vlad and I are not aging. And in fact, we are going in the
opposite direction. If only this were not just an audio podcast,
you would see that I steadily gotten younger and younger and I'm
suddenly about 25 now. But no, these are really important
findings. I really like the innovation of using multiple
different strategies to characterize epigenetic age and genetic
aging. So tell me Vlad, I want to turn to you. When this came
across your desk, what excited you about this particular piece
and why did you think that it would be of great interest to our
readership?


Dr. Vlad Zaha:


Good morning Merci and Jason. This is a great question. And as in
associate editor at Circulation for the bridging discipline
section, it was fascinating to see this topic coming on my desk,
thinking about all the genome wide association studies in nature
of fibrillation and predisposition to atrial fibrillation, that
in that case would not be changed by interventions because of
different loci that would be determined. This was coming as a
completely new perspective that was opening some new potentials.
And it was very interesting to see some of the findings.


Dr. Mercedes Carnethon:


Certainly. So Jason, I have a question. So what surprised you
about the findings of this particular study?


Jason Roberts:


Yeah, that's a great question. So we had hoped that biological
aging would be associated with atrial fibrillation. I think the
concept of being able to tackle biological aging is exciting. In
terms of what surprised us, I guess we were hoping for these
results, I guess.


Dr. Mercedes Carnethon:


Yeah.


Dr. Jason Roberts:


But we were…Yeah. So I guess we were pleasantly surprised that
our hypothesis was born out. It's important to note that the
epigenetic clocks don't tell the full story with chronological
aging. So after we insert the clock into the model, chronological
age continues to remain associated with instant atrial
fibrillation. So this measure biological aging is just part of
the story. So I think that's very important. I had wondered
whether or not inserting the epigenetic clocks would that
potentially eliminate the subsequent association of chronological
aging. So that finding suggests it's part of the story.


Dr. Jason Roberts:


I think that in terms of the overall concept, the idea of this
being reversible really excites me. In terms of the approach of
how to reverse biological aging. Right now healthy lifestyle
seems to be very important. I think it provides more evidence to
suggest to patients with atrial fibrillation, living healthy from
a diet perspective, from exercise, keeping your weight under
control, all of these things that seem to impact epigenetic aging
and biological aging can be helpful for preventing atrial
fibrillation. So I think that can help reinforce this message to
our patients.


Dr. Jason Roberts:


I think ultimately in terms of where we'll be at in 15 to 20
years, it's possible that new therapies in the future are
developed that are able to more powerfully address biological
aging. As you alluded to, will it be possible to reverse
biological aging as you and Vlad are experiencing that?


Dr. Mercedes Carnethon:


Most definitely. Yes.


Dr. Jason Roberts:


I think it may be possible. This is an intense area of
investigation that's being pursued and it's still in its relative
infancy. But I think that could it be small molecules? Could it
be potentially gene editing that can help adjust biological aging
and not only increase lifespan, but also health span? I think
those concepts are really exciting.


Dr. Mercedes Carnethon:


I completely agree. There's a lot of richness in this paper and I
think our readership is going to really enjoy digging in. Part of
the richness is the use of three different cohorts and the use of
multiple measures of epigenetic age. And I think you provided a
really nice description of the unique information that each of
these markers of epigenetic age provide. One thing I note are
differences in the strength of association across the different
measures of epigenetic age, which I think makes sense, because
you said they characterize different aspects of the phenomenon,
but I also see what looks like some variability across the
cohorts with Framingham in particular seeming to stand out. And
that being the only cohort that is 100% one race. It's white.
Versus both the cardiovascular health study and the Eric study,
which have more diverse study populations. I'm wondering what
your hypothesis is about the differential strength of association
that it seems Framingham is demonstrating and what you think is
possibly the source of those differences.


Dr. Jason Roberts:


Yeah. I think those are great questions for all of genetics. The
question is, does it apply to all races? For example, polygenic
risk scores. It seems like when a polygenic risk scores develop
for one race, it may not perfectly translate over to other races.
So how relevant is that for epigenetic age acceleration. In this
study, I think it's difficult to make definitive conclusions
about it. We needed the three cohorts to have adequate
statistical power in terms of being able to determine a
differential effect of race. I think it would really be primarily
hypothesis generating. We weren't really powered to look at the
different races. So it's difficult for me to comment.


Dr. Jason Roberts:


I think ultimately and I want to believe anyways, that epigenetic
age acceleration is relevant to all races, but in terms of, was
it race that drove the differential impacts that we saw to some
extent in terms of the magnitude of the hazard ratios, it's
difficult to know in terms of tests for interaction and were
these actually truly statistically different. We weren't
adequately powered to address that hypothesis. So it's difficult
for me to comment in a definitive matter I'd say. And sorry to
cop out on…


Dr. Mercedes Carnethon:


No, not at all. I mean, I think there are a lot of things where
there is no firm answer and that was just one of my hypotheses
when I saw what was going on differently across the cohorts. I
think that's a perfectly reasonable answer that sets us on a
course for thinking about how we set up future studies. So I
wanted to turn to you Vlad for the closing frame around this. As
the editor, how do you hope that our readership will use these
findings?


Dr. Vlad Zaha:


That is an excellent question. I was going to follow on this
excellent unpacking of the core messages of the manuscript by
Jason here to get his perspective as an electrophysiologist into
what these type of work may represent for the everyday life of an
electrophysiologist in the connecting with the patients and how
would this type of approach influence, and maybe now, maybe later
when our treatment for atrial fibrillation.


Dr. Jason Roberts:


Yeah. So that's a great question. I think, as I alluded to some
extent before, as far as reinforcing healthy lifestyle, I think
this provides more evidence in that respect. So we know that
things like excessive alcohol consumption, being excessively
obese, poor diets, not engaging in enough exercise, all of those
things seem to accelerate your epigenetic age. And those are all
things that we think or feel that are important with atrial
fibrillation in terms of driving the path of physiology and
people progressing. So I think this gives more data to us to
reinforce the patients that in addition to the treatments that
we're offering in terms of catheter ablation and antiarrhythmic
drugs, the concern is that the substrate can continue you to
progress. And that's likely driven by to some extent these
modifiable risk factors. So keeping all of these under best
control as possible, and hence trying to slow your biological
aging as much as possible.


Dr. Jason Roberts:


I think that this will provide us more motivation to push these
messages to our patients. A lot of patients can sometimes be
like, "Let's just get on with a catheter ablation and I want to
get on with my life…" but it really I think, provides more data
to suggest that modifying these very important risk factors that
can lead to accelerated biological agents, is very important. And
in terms of the future as mentioned, so chronological aging, as
people get older, people view it as, "Well, there's nothing I can
do, and I'm just going to get gradually more and more unhealthy."
I think, and this is somewhat futuristic, but to what extent can
we slow biological aging? Can we potentially reverse it in the
future? There's certainly lots of very compelling and interesting
animal work and people are starting to delve into this in a big
way.


Dr. Jason Roberts:


And not only to increase lifespan, will we some day live until
we're 200. Who knows? But the concept of prolonging your health
span as well. So the number of healthy years that you have before
your body starts to gradually give way, I guess to some extent.
Hopefully in the future will have therapies that will help keep
us healthy. And if we do that increased health span, I think this
data suggests that atrial fibrillation will be one thing that
benefits from this. So hopefully in the future, maybe in terms of
curbing the AFib pandemic, being able to address biological aging
will help push things in the right direction.


Dr. Mercedes Carnethon:


Well, thank you so much Jason. And thank you so much Vlad for
your thoughtful questions. I really like that the final bottom
line leans towards my area as an epidemiologist, which is
maintaining and promoting healthy lifestyles as a way to
hopefully help prevent some of the difficulties of atrial
fibrillation and its long-term outcomes. Really pleased to have
you on this episode of Circulation on the Run, Jason, and thank
you again Vlad, and I hope everyone enjoys this episode of the
journal and has an opportunity to really dig into this piece.
This is Mercedes Carnethon from Northwestern University Feinberg
School of Medicine, saying thanks for listening today.


Dr. Greg Hundley:


This program is copyright of the American Heart Association 2021.
The opinions expressed by speakers in this podcast are their own
and not necessarily those of the editors or of the American heart
association for more visit ahajournals.org.