Circulation September 01, 2020 Issue

This week’s episode includes author Allan Sniderman and Associate
Editor Anand Rohatgi as they discuss the expected 30-year
benefits of early versus delayed primary prevention of
cardiovascular disease by lipid lowering and management.


TRANSCRIPT:


Dr Greg Hundley: Welcome everyone to this September 1 issue, as
we start into the fall in North America, and I guess we're
getting into spring-ish in the Southern hemisphere. Today, it's
just myself, Dr Greg Hundley, Associate Editor and Director of
the Pauley Heart Center at VCU Health in Richmond, Virginia.


And, I'm so sad because my good friend, Carolyn, cannot be with
us today. However, we have a great feature for the latter half of
this recording and discussing some of the benefits of primary
prevention using lipid lowering therapy to help prevent
cardiovascular disease. But, before we get to that, let's grab a
cup of coffee and let's go through some of the other articles in
this issue.


So, the first one is from the world of basic science and it's
from Professor Eldad Tzahor, from the Weizmann Institute of
Science. And, it's focusing on Agrin. So, this team previously
reported that a fragment of the extracellular matrix protein,
Agrin, promoted cardiac regeneration following myocardial
infarction in adult mice. And, in this study the investigators
propose to test the therapeutic potential of Agrin in a
preclinical porcine model.


They performed ischemia reperfusion injuries using balloon
occlusion for 60 minutes, followed by either a 3, 7, or 28-day
reperfusion period. They demonstrated that local antegrade
delivery of recombinant human Agrin, or RH Agrin, to the
infarcted pig heart can target the effected regions in an
efficient and clinically relevant manner. In fact, a single dose
of recombinant human Agrin improved heart function, reduced
infarct size, reduced fibrosis and reduced adverse remodeling
parameters, 28 days post myocardial infarction.


Short-term myocardial infarction experiments, along with
complementary mirroring studies, revealed myocardial protection,
improved angiogenesis, inflammatory suppression, and cell cycle
reentry as aggregation mechanisms of action. So in summary, this
team demonstrated that a single dose of Agrin was capable of
reducing ischemia reperfusion injury and improving heart
function. Demonstrating that Agrin could serve as a therapy for
patients with acute MI and potentially heart failure. So, this
set the stage for future studies in human subjects.


Okay. Well, our next paper is clinical and evaluates exposure to
air pollution and particle radioactivity with a risk of
ventricular arrhythmias. And, it comes to us from Ms. Ajani
Peralta from Harvard University. Now, individuals are exposed to
air pollution and ionizing radiation from natural sources through
inhalation of particles. So, in this study, the team investigated
the association between cardiac arrhythmias and short-term
exposures to find particulate matter, PM 2.5, and particle
radioactivity.


So, ventricular arrhythmogenic events were identified among 176
patients with dual chamber implanted cardio defibrillators in
Boston, Massachusetts, between the period of time of September
2006 and June 2010. And, patients were assigned exposures based
on their residential addresses. So, what did they find? Well, in
this high-risk population, those with these defibrillators,
intermediate, 21-day parts per million, 2.5 exposure was
associated with higher odds of a ventricular arrhythmia event
onset among those with known cardiac disease and indication for
ICD implantation. But this was independent of particle
radioactivity. So, important information coming to us relating to
air pollution and ionizing radiation in relation to ventricular
events.


Next, let's get back to another informative study from the world
of basic science. And, this one involves genomic binding patterns
of forkhead box protein 01 and how that is implicated in the
development of cardiac hypertrophy. The study comes to us from
Walter Koch from Temple University and their co-investigators.


So, cardiac hypertrophic growth is mediated by changes in gene
expression, as well as changes that underlie the increase in
cardiomyocyte size. The former is regulated by ischemia
reperfusion or loss, while the latter involves incremental
increases in the transcriptional elongation activity of Pol II,
that is preassembled at the transcription start site, or TSS.


The differential regulation of these two distinct processes, by
transcription factors, really hasn't been explored. So, this
group sought to investigate the forkhead box protein, and we're
going to call it FOX01, which is an insulin sensitive
transcription factor that is regulated by hypertrophic stimuli in
the heart. To date, however, the scope of its gene regulation is
also somewhat uncertain.


So, to address this, the investigators performed FOX01 chromatin
immunoprecipitation deep sequencing, or ChIP-sequencing, in mouse
hearts following seven-day isoproterenol injections, transverse
aortic constriction, or vehicle injection by sham surgeries. The
investigators found that FOX01 may mediate cardiac hypertrophic
growth via regulation of Pol II de novo recruitment and pause
release. As the latter represents the majority, or almost 59% of
FOX01 bound Pol II regulated genes following pressure overload.


So, in conclusion, these findings demonstrate the breadth of
transcriptional regulation by FOX01 during cardiac hypertrophy,
which is important information that should be valuable for future
therapeutic targeting.


Moving on from basic science and coming back into the world of
clinical science. And, this next paper is from Professor Sripal
Bangalore from New York University School of Medicine. And, it
involves routine revascularization versus initial medical therapy
in those with stable ischemic heart disease.


So, coronary arterial revascularization is often performed, as we
know, in patients with stable ischemic heart disease. And, these
authors conducted a PubMed Embase central search for randomized
trials, comparing routine revascularization versus an initial
conservative strategy in patients with stable ischemic heart
disease. The primary outcome was death, and secondary outcomes
included cardiovascular death, myocardial infarction, heart
failure, stroke, unstable angina, and freedom from angina. And,
the trials were stratified by percent stent use, and by percent
statin use, to evaluate the outcomes across all of these trials.


So, 14 randomized clinical trials that enrolled 14,877 patients
followed up for a weighted mean of 4.5 years with a total of
64,678 patient years of follow-up, were used for the study. Most
of the trials enrolled patients with preserved left ventricular
systolic function, low symptom burden, and they excluded patients
with left main coronary artery disease.


So, here are the results, revascularization compared with medical
therapy alone, was not associated with a reduced risk of death.
The trial sequential analysis showed that the cumulative Z curve
crossed the futility boundary indicating firm evidence for lack
of a 10% or greater reduction in death. Now, revascularization
was associated with a reduced non-procedural MI rate, but also
with an increased procedural MI rate with, therefore, no overall
difference in myocardial infarction incidents.


So, another point in this study is that there was a significant
reduction in unstable angina and increase in freedom from angina
was observed in those that underwent revascularization. Finally,
there were no treatment related differences in the risk of heart
failure or stroke. So in conclusion, in patients with stable
ischemic heart disease, routine revascularization was not
associated with improved survival, but was associated with a
lower risk of non-procedural myocardial infarction, and unstable
angina with greater freedom from angina at the expense of higher
rates of peri procedural myocardial infarction. Now, longer term
follow-up of trials is needed to assess whether the reduction in
these non-fatal spontaneous events actually improves long-term
survival.


Well, listeners what else is in the issue? Now, we refer to this
as what's in the mailbox? So, we have a research letter from
Jianyi Zhang regarding the apical resection prolongs the cell
cycle activity and promotes myocardial regeneration, after left
ventricular injury, in the neonatal pit. We have another research
letter from Roger Foo, assigning distal genomic enhancers to
cardiac disease-causing genes. What else is in the issue? There's
a nice, On My Mind piece, from Anthony Wierzbicki on phenomics,
not genomics, for cardiovascular risk assessment. And, there's a
Perspective piece from Dr Dana Gal, regarding considerations for
triaging elective cases in children with cardiac disease in a
time of crisis.


Finally, we have an exchange of letters from Dr Daxin Wang and Dr
Prabhakara Nagareddy regarding the previously published article,
“Neutrophil Derived S100A8/A9 Amplification of Granulopoieses
After Myocardial Infarction.” There's a very nice case series
regarding an unusual reversible cause of acute high output heart
failure complicated by refractory shock from Dr Matthew
Durstenfeld. And then, finally, we have an ECG challenge from Mr.
Alejandro Cruz-Utrilla, regarding giant T-wave inversion and
dyspnea in the time of this coronavirus pandemic.


Well, listeners, what a great issue. And now, we get to look
forward to that feature discussion from Dr Allan Sniderman,
regarding the benefits of early versus delayed primary prevention
by lipid lowering therapy.


Well, listeners, now we get to move to our feature discussion
today and understand a little bit more about lipid management.
And, with us, we have Dr Allan Sniderman from McGill University,
and our own associate editor, Dr Anand Rohatgi from University of
Texas Southwestern in Dallas. Allan, we're going to start with
you. Can you give us a little bit of information pertaining to
the background, or the hypothesis? Why did you want to perform
this particular study?


Dr Allan Sniderman: Let us start from where we are in
cardiovascular prevention now, which is the risk model. All of
the major guidelines, throughout the world, select candidates for
statin prevention based on their risk of a cardiovascular event
over the next 10 years. Well, that's been a very positive
development, but we need to appreciate what the limitations are.
Because, tenure risk is so heavily based on age, what it boils
down to is that if you're 60 and over, and a male you're going to
be eligible. An increasing proportion of women will be eligible
as they're older. But, if you're younger, regardless of your
other causal factors, you may well not be eligible. And, the net
result of that is, almost 50% of all cardiovascular events occur
before 60, 65. So, half of the events are occurring before
prevention even kicks in.


The second point is that you can't get be at risk until you have
disease within your arterial tree. So, what we've done is, we're
trying to prevent the disease that's already present. So,
although it's been a wonderful step forward, we think it's time
to start moving beyond that model, and trying to prevent disease
itself, rather than preventing people who've already had disease.


So, what we decided to do, which we're shifting focus here from
risk to causes. Risk, after all, is a consequence of causes. And,
when you look at the pathology of atherosclerosis, with a few
exceptions such as FH, up until the age of 30, 35, you don't have
the complex lesions that can actually cause clinical events. So,
we said, "Okay, we'll start at that time point. And, we'll try
and quantitate the benefit of earlier intervention, versus later
intervention, at different starting points." So, we based our
analysis on NHANES, and we identified the people within the
NHANES cohort, who would not have been eligible for prevention,
based on the current American guidelines.


So, we had three age starting categories, 30 to 39, 40 to 49, and
50 to 59. And, we followed them out for 30 years. Our analysis
has the same duration of the follow up, but the same final date.
That has to be kept in mind because it limits the total benefit
on the early starters. And, we further sub divided the groups
based on non-HDL cholesterol, into those who had a level above
160, those who had an intermediate level, and those who had a low
level because we'd previously shown that non-HDL identifies a
high-risk group over 20 to 30 years.


We decided we'd look at two different models of the likelihood of
the drug preventing events. One is the standard estimates that
you would get from the statin clinical trials. But, if you reduce
LDL cholesterol by a milli mol of 40 milligrams percent of your
language, you reduce risk by about 22%. And, that's our
conservative model. Then we took a model that's more biological
and based on Mendelian randomization because, as you know, the
Mendelian randomization analysis, the benefit, the reduction and
event rate per milligram, per deciliter, lower LDL cholesterol is
two or three fold greater than in the statin clinical trials.


So, Brian Friends had produced a formula in which you blend those
two together, the statin estimate and the Mendelian randomization
and it varies depending on how early you start. And, that was a
more optimistic model, obviously. But the major point I emphasize
is that both models showed that if you start early, you do
better. Now, how surprising is that?


But the benefit depended on the level of non-HDL cholesterol. So
starting at age 30, 35 in somebody who has a normal or low
non-HDL cholesterol, doesn't really gain you all that much.
Starting with somebody who has a high level, different story. In
each of the categories, the conservative model, if you did the
full 30-year prevention, you get a third to a half reduction in
events. And, with the more optimistic model, you get half to two
thirds reduction.


The closer you get to where you'd start with the guidelines,
you're losing that benefit. Then you say, "Okay, well, how
optimistic is the optimistic model?" And, all the optimistic
model is saying, "Let's remember how we get disease." If we stop
the formation of a new lesion, well, that's perfect prevention.
Well, we're doing it, present is trying to stabilize existing
lesions. The older we get, the more disease we have, the less new
lesion we have, the less potential for the big game in
prevention. So stopping new lesion formation, it seems to me is
from clinical reasoning, a pretty biologically and clinically
coherent way to formulate what your prevention strategy should
be.


What we think we contributed, what we hope we've contributed with
this analysis is saying, "Let's take a real step back, let's look
at what we're doing and let's see how can we make a Magnus step
forward in prevention?" And, the way we think you can do it is to
start moving away from exclusively a risk paradigm, because that
made sense. You want to treat people who were at risk. We get
away from this 10-year duration and start focusing more on the
causes, because when we look at an individual, we can measure the
causes. Well, we talked about risks, that's a much slipperier
concept, because it's a group. Is everybody in the group the same
risk? They're clearly not. So, to try and get this to a much more
concrete level, that's what we tried to do.


Dr Greg Hundley: Very nice, Allen. And so, Anand, why did you
select pushing this paper forward? And, what do you think this
means for patients with high cholesterols? They're in their 40s
and 50s. Help expand on some of what Allan has, so elegantly,
described for us.


Anand Rohatgi: First of all, Allan, thank you so much for doing
this work and sending this to circulation. We were really excited
to see this come across our desks, because at the end of the day,
this manuscript, this study by Allan Sniderman and others, has
very important public health consequences. And, that's why we
were really interested in what they found and what they had to
say about this topic.


And, really what it comes down to is, like Allan mentioned, the
trials for statin just really never addressed what to do about
risk in younger individuals and over a longer period of time. And
so, it was really these genetic studies, the Mendelian
randomization studies, that really strongly showed the cumulative
exposure effect of higher cholesterol levels, over time, and the
benefits of maintaining really low levels. And so, what I think
this paper does is it translates those scientific studies, those
genetic studies, into a public health concept that's easily
digestible for physicians, for clinicians, for people, for
patients and stakeholders about what does this all mean? How can
we benefit and when?


And, I think it's very clear, the earlier you start, the more
benefit you get over the life course. And, honestly, the take
home message to me, it seems like for most of adulthood, the
being able to maintain low risk and low cholesterol levels is the
best path forward and not waiting until you find something wrong.
And so, we were very, very excited about seeing that message
translated in such an easy manner and compelling manner by
Allan's work.


Dr Greg Hundley: Very nice, 40 to 49-year old with non-HDL
cholesterols greater than 160 milligrams per deciliter, would be
expected to reduce their average predicted 30-year risk by 17%.
That's just amazing.


Allan, very quickly, in a minute, what do you think is the next
study that needs to be performed in this area?


Dr Allan Sniderman: I don't think we're ever going to get the
primary prevention trial that we want, because it's too many
people, too early, and we already know too much. I think the
thing that we really need to do is figure out how we're going to
most accurately measure the cause within the individual. I'll put
in a plug for FOV, because I think it is a more effective
measure, even the non-HDL cholesterol. And, I think that when we
commit people or when we invite people to take medications early
in life, we ought to be doing it on the strongest ground
possible.


I want to say thank you to be review process at Circulation,
because the final paper that came out is not the paper that went
in. The reviewers made superb, tough criticisms of this paper and
not of the calculations, but of the way we were expressing it.
And, they forced us to rethink and reimagine the context, in
which the final form of this paper appears. So, we have a big
thank you to our reviewers. We have a thank you to the patients
of the editorial staff at Circulation. And, I have a big thank
you to my collaborators, because they're really the strength of
the paper.


Dr Greg Hundley: Very nice, well listeners, it's been another
great week here at Circulation and another very important piece
of information in this feature discussion regarding monitoring
and evaluating non-HDL cholesterol in the earlier years, and
really considering initiation of statin therapy, to prevent the
atherosclerotic lesions from forming, not just stabilize them
later in life afterwards.


Thanks to Anand Rohatgi and also Allan Sniderman for bringing us
this wonderful article. We hope you have a great week. This
program is copyright the American Heart Association 2020.