Circulation February 25, 2020 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 Dr Greg Hundley, director of the Pauley
Heart Center at BCU Health in    
               
                               
Richmond, Virginia.


Dr Carolyn Lam: So Greg, guess what? We are going to be
discussing predicting the benefit of evolocumab therapy in
patients with atherosclerotic disease using a genetic risk score.
That's our featured paper this week coming from the results of
the FOURIER trial. I bet you can't wait to discuss it, but I'm
not going to let us until we talk about some of the papers in
today's issue. Do you have one?


Dr Greg Hundley: Yes, Carolyn, but first I'm going to get a cup
of coffee because there's a lot of data in this one. This study
is from the ODYSSEY trial and it involves alirocumab and it's
from Dr Charles Paulding. Remember Carolyn, the ODYSSEY trial was
a randomized double-blind placebo-controlled trial comparing
alirocumab, a PCSK9 inhibitor or placebo in 18,924 patients with
acute coronary syndrome and elevated atherogenic lipoproteins
despite optimized statin treatment. And the primary endpoint of
this trial comprise death from coronary artery disease, non-fatal
MI, ischemic stroke, or unstable angina requiring
hospitalization. Now Carolyn, this is a sub-study and it was
performed an A genome wide polygenic risk score for coronary
artery disease comprising 6,579,025 genetic variants. And they
were evaluated in 11,953 patients with available DNA samples.
Analysis of the MACE risks, all those outcomes together, was
performed in placebo treated patients while treatment benefit
analysis was performed across all the patients.


Dr Carolyn Lam: Ooh, so what did they find?


Dr Greg Hundley: Well, Carolyn, both the absolute and relative
reduction of MACE by alirocumab compared to placebo was greater
in high versus low PRS patients. Those genetic, polygenetic risk
scores combined in the patients. There was an absolute reduction
by alirocumab in high versus low PRS groups of 6% and 1.5%
respectively, and relative risk reduction in the alirocumab of
37% in the high PRS group versus 13% in the low PRS group. And so
Carolyn, these results suggest the possibility of an independent
tool for risk stratification using sort of precision medicine by
selecting those using these genetic constructs, who may be more
likely to benefit from this form of therapy.


Dr Carolyn Lam: Wow Greg, that is really interesting. I genuinely
think that our world is moving towards precision medicine and
this really, really speaks to remember that feature paper also
talking about genetic risk scores, but from the FOURIER trial.
But before we get to that, I've got a basic science paper. Now
this one provides insights into the mechanisms underlying age
related hypertension. And it's from Dr Ying Yu and colleagues
from Tianjin Medical University who hypothesize that since
proinflammatory cytokines increase in T lymphocytes with aging
and prostaglandin D2 suppresses T helper 1 cytokines through the
D-prostanoid receptor 1, that this axis in T cells may play a
role in age related hypertension.


Dr Greg Hundley: Ah, Carolyn. What did they find in this study?


Dr Carolyn Lam: Prostaglandin D2 biosynthesis and D-prostanoid
receptor 1 expression, were both markedly decline in CD4 positive
T cells from older humans and aged mice. D-prostanoid receptor 1
depletion in these CD4 positive T cells, exaggerated age
dependent blood pressure elevation in mice by increasing tumor
necrosis factor alpha and interferon gamma secretion. Whereas its
over expression showed the opposite effect and its activation
suppressed TH1 cytokines. These results really indicate that
D-prostanoid receptor 1 and its downstream pathway may serve as
an attractive immuno-therapeutic target for age dependent
hypertension.


Dr Greg Hundley: Oh wow. Very insightful Carolyn. Well, I've got
a basic science paper to go over and it's from professor Kinya
Otsu from Kings College London. This study addresses the
mechanism of ongoing inflammation within the hearts of patients
with cardiomyopathy. The study involves the assessment of
Regnase-1 and RNAs involved in the degradation of a set of pro
inflammatory cytokine messenger RNAs in immune cells. And the
study involves the role of Regnase-1 in non-immune cells such as
cardiomyocytes.


Dr Carolyn Lam: Wow.


Dr Greg Hundley: The degradation of cytokine messenger RNA by
Regnase-1 and cardiomyocytes plays an important role in
restraining sterile information in failing heart. Once the
inflammatory cascade gets going, this is that constant
inflammation that's ongoing. In addition, the Regnase-1 mediated
pathway might be a therapeutic target to treat patients with
heart failure as adeno-associated virus 9 mediated cardiomyocyte
targeted gene delivery of Regnase-1 or administration of
anti-IL-6 receptor antibody, attenuated the development
cardiomyopathy induced by severe pressure overload in wild type
mice.


Dr Carolyn Lam: Wow, that's really interesting. I find this whole
field of inflammation in heart failure of course, of key
interest, but I'm going to next tell you about the results of the
FUEL trial, which is the Fontan Udenafil Exercise Longitudinal
trial.


Dr Greg Hundley: Tell us about the Fontan operation.


Dr Carolyn Lam: Aha, I thought you may ask, Greg. Well, the
Fontan operation to remind us all, really creates a total
cavopulmonary connection and a circulation in which the
importance of pulmonary vascular resistance is therefore
magnified. Over time, the circulation needs to deterioration of
cardiovascular efficiency associated with a decline in exercise
performance. This FUEL trial and reported this time by David
Goldberg and colleagues from the Children's Hospital of
Philadelphia was a phase 3 clinical trial, which randomized 400
patients with Fontan physiology from 30 sites in North America
and the Republic of Korea. The participants were randomly
assigned to Udenafil at 87.5 milligrams twice daily or placebo.
And the primary outcome was the between group difference in
change in oxygen consumption with peak exercise.


Dr Greg Hundley: Hmmm, very large important trial it seems like
Carolyn. What did they find?


Dr Carolyn Lam: Treatment with Udenafil did not result in a
significant increase in peak oxygen consumption, which was the
primary outcome, but did result in improvements in measures of
exercise performance at the anaerobic threshold, which was a
secondary outcome. Udenafil was well tolerated with side effects
limited to those previously known to be associated with
phosphodiesterase type 5 inhibitors.


These results and future perspectives are discussed an editorial
called FUELing the Search for Medical Therapies in Late Fontan
Failure, by Doctors Gewillig and De Bruaene.


Dr Greg Hundley: Very nice, Carolyn. Now how about the rest of
the journal?


Dr Carolyn Lam: Oh well I want to tell you about this in-depth
review by Dr Rosenkranz and it's entitled, Systemic Consequences
of Pulmonary Hypertension and Right-Sided Heart Failure. Very
intriguingly, talking about non-cardiac features, as well as
cardiac, of right heart failure, a real, real must read with
beautiful figures.


In the cardiovascular case series we discuss a case of left
ventricular non-compaction and cardiogenic shock by Dr Shenoy.
There are also two research letters I want to tell you about one
by Dr Gillinov on the accuracy of the Apple watch for detection
of atrial fibrillation. And this time looking at the Apple watch
series 4, which interestingly employs electrodes to generate a
single lead ECG and provides two mechanisms for rhythm
assessment. Won't tell you more. You got to pick up this
beautiful letter.


The next is by Dr Mazer on the effect of empagliflozin on
erythropoietin levels IN stores and red blood cell morphology in
patients with type II diabetes and coronary artery disease. And
this really provides evidence to suggest that SGLT 2 inhibition
with empagliflozin may stimulate erythropoiesis via an early
increase in erythropoietin production in people with diabetes.


Dr Greg Hundley: You know Carolyn, we just keep hearing more
about EMPA and DAPA and they are just going to really pave the
way I think for a whole new class of agents that we're going to
be using frequently.


I've got a couple letters in the mailbox and one is by Sugimoto
and Taniguchi regarding the article, Internal Versus External
Electrical Cardioversion of Atrial Arrhythmia in Patients with
Implantable Cardio Defibrillators, a randomized clinical trial.
And then also there's another research letter by Dr Hiroshi
Sugimoto from Kobe Red Cross Hospital with a response by Jakob
Lüker from University of Cologne.


What a great issue. How about we proceed to that feature article?


Dr Carolyn Lam: You bet.


Can a genetic risk score identify individuals who will derive
greater benefit from PC SK9 inhibition? Well guess what? We're
going to find out now in our feature discussion. So pleased to
have with us the first and the corresponding authors of our
feature paper, Dr Nicholas Marston and Dr Christian Ruff, both
from the TIMI study group in Brigham and Women's Hospital and
Harvard Medical School and also to have our lovely associate
editor, Dr Svati Shah from Duke University in Durham, North
Carolina. Welcome everyone.


Nick, could I get you started with telling us about this exciting
analysis that you did from the FOURIER trial?


Dr Nicholas Marston: The FOURIER trial was a 27,000 patient
cardiovascular outcomes trial that studied the PC SK9 inhibitor,
evolocumab and it demonstrated a significant reduction in major
adverse cardiovascular events in patients who had established
atherosclerotic disease. And in the study, there was a 15%
relative risk reduction and a 2% absolute risk reduction, which
earned it a class 2 recommendation for very high-risk patients
with atherosclerosis in the recent cholesterol management
guidelines. And what we've done in previous lipid trials is we
studied the interactions between genetic risk and treatment
benefit. For example, in 2015 we showed that patients with high
genetic risk, those in the top 20% of genetic risk, had the
greatest benefit from statin therapy in terms of both absolute
and relative risk reductions. And so now we have the opportunity
with evolocumab and data from the FOURIER trial to ask the same
question of PC SK9 inhibitor. That is, could a genetic risk score
identify patients who will drive a greater treatment benefit and
we hypothesize that like statins, there would in fact be a
significant interaction between genetic risk and therapeutic
benefit.


Dr Carolyn Lam: That's so cool Nick. But could I ask, the
question always comes, is it nature versus nurture? And so I
really love the way that you dealt with the clinical risk factors
as well. Could you maybe walk us through that and then tell us
the results?


Dr Nicholas Marston: Yes, absolutely. We for this study, kind of
had two objectives. One was to look at risk prediction and then
the other look at treatment benefit and using a genetic risk
score for both. However, we wanted to go further than just use
the genetic risk score. We wanted to incorporate clinical risk
factors since that's how we would do it as physicians in the
clinic. We would have not just genetic risk data in front of us
but also clinical data. And so when we were grading a patient's
risk using genetic risk, we also factored in if they had multiple
clinical risk factors. And what we found by combining both
genetic and clinical risk was that there was a significant
gradient of risk across these risk categories.


That is patients who were without high genetic risk and without
multiple clinical risk factors actually had no benefit from
evolocumab over the 2.2-year follow-up period. However, those
without high genetic risk, but who did have multiple clinical
risk factors, derived an intermediate benefit. About a 13%
relative risk reduction and 1.4% absolute risk reduction. And
then it was the high genetic risk group, independent of whether
or not they had multiple clinical risk factors that had the
largest benefit from evolocumab with a relative risk reduction of
31%, absolute risk reduction of 4% and the number needed to treat
of 25. And that's actually a twofold greater benefit than was
seen in the overall FOURIER trial population.


Dr Carolyn Lam: That's really stunning results. Now I know
Svati's going to have questions for us, so maybe I should invite
you Svati, just put these results into context and let the
audience know what we were thinking as editors when we saw this
brilliant paper.


Dr Svati Shah: Yeah, thanks Carolyn. And I think Nick has done a
fantastic job of describing the exciting results from this paper
and just kind of taking a step back to help the audience
understand what we're talking about when we're talking about
genetics. For decades, we've been trying to figure out the
genetics of heart disease and we're not talking about the
genetics of things that are really rare like long QT syndrome,
but the genetics of just common complex heart diseases. And
amongst the scientific community, we've tried all different ways
of sort of analyzing these data and so I want to make sure that
everybody who's listening understands the novelty of really
looking at these polygenic risk scores. Where we have now come to
understand that it's not a single gene, it's not even two genes,
that it's multiple variants and multiple genes and when they're
combined, that's when you really have the power to understand how
it might be useful in terms of how we take care of patients.


Really important with how Nick and Christian have laid out this
really nice paper as well as their prior work in statins, is that
not only did they show that these polygenic risk scores are
associated with cardiovascular outcomes or even different amongst
whether you get treated with the drug or whether you don't, but
really importantly they're getting it clinical utility, not only
with regards to showing that they compare it to a clinical risk
score, but really showing that if you use these polygenic risk
scores, you can identify patients who may derive the greatest
benefit from PC SK9 inhibitors. And importantly in their paper,
they show that if you have low polygenic risk score and low
clinical risk score, you may not derive benefit from PC SK9
inhibitors. With all the caveats that this is a secondary
prevention population, so I really applaud Christian and Nick and
his team for the nice work that was done.


Dr Carolyn Lam: Oh, couldn't agree more, Svati. You know what I
was very struck with too, because some people go, I may have a
genetic risk. Maybe I could undo it or somehow overcome it with
my clinical risk factors. And that's why I really appreciated
that they showed that it was additive, and genetics still matter
even if you have risk factors and vice versa. That was really
cool. Christian, could I ask you to maybe describe a bit, what
kind of genetic risk score this was and maybe perhaps point out
some of the limitations therefore of what you studied.


Dr Christian Ruff: As Svati mentioned, this is really a quickly
evolving field. We now have the ability to either genotype or
sequence all of the variation that makes us different from one
another. Our susceptibility to disease as well as our potential
benefit for treatment. We had for this study, looked at several
different risk scores. The one we focused on was a coronary
artery disease genetic risk score that had 27 different variants
that had been shown to predict having a cardiac event, both in
primary and secondary populations. And we have previously
identified patients who may have been at a higher risk who
received greater benefit from statin therapy. And in this study,
we actually compared this 27 variant genetic risk score with
actually a much larger score of over six million variants. And
interestingly, the two scores performed fairly similar with
respect for risk prediction. One of the big questions going
forward is, we have lots of ways to develop genetic risk scores,
how many different variants do we need? What more information do
we have with more complicated scores?


And I think Svati really hit on a really critical point is that
really this study is really layering in genetic risk on top of
clinical risk factors, which we can easily assess at the bedside.
And I think what's reassuring to patients is that not only is
genetic risk able to give us much more information for prognosis,
but that this risk is modifiable. People think that their genetic
risk, they're sort of born with it and there's nothing that they
can do about it. But in this study, as Nick pointed out, even
over a very short period of time with powerful lipid lowering
therapy with a PC SK9 inhibitor, we essentially reduced these
patients at high genetic risk to the risk of the very low risk
patients on placebo. I think this is a reassuring message that
genetics plays an important role for risk prediction and it
identifies patients who we might target for more intensive
therapy and that we can potentially reduce that risk even though
that risk is based on the DNA that they're born with.


Dr Carolyn Lam: Indeed. That's a great point. And Svati, I'm sure
you were thinking along those lines when you invited that
beautiful editorial by Doctors Daniel Raider and Michael Levin.
But Svati, would you like to comment on your thoughts on, is this
ready for prime time?


Dr Svati Shah: I think that's the key question. What Christian
and Nick and his team have done is take us a big step forward in
how we use these polygenic risk scores. I think there still are
many skeptics amongst the genetic scientific community about,
well great, you can look at 27 variants and some of these
polygenic risk scores, you're looking at a million things. How do
we actually use that to take care of patients?


I actually want to turn this back, that question back around
Carolyn, and I'd like to ask Christian next, what are the next
steps? There are a lot of cardiologists who if you're listening
to this podcast, should we all run out and get our patient's
genotype to order this genetic chip so that we can figure out
what their polygenic risk score is?


Dr Christian Ruff: Yeah, that's a great question and I could
start off and then hand off to Nick, but I think one of the key
questions is obviously there are a lot of genetic risk scores and
I don't think as a field that we've come up with which one we
really should implement in clinical practice. There's still a lot
of fine tuning and figuring out which score gives us the most
amount of useful information.


And then I think as something that you had mentioned that these
scores are generated in both a healthy cohort population and now,
we're looking at it in clinical trials and there's no sort of
reference. Like when we have a blood test and we say, "If your
hemoglobin A1C is above or below this number that means that you
have diabetes." And we haven't figured out, what are the actual
thresholds that you use for these genetic risk scores that you
can implement broadly across different patient populations.
There's still a lot of work that needs to be done to make these
scores ready for prime time. This is really setting the stage. Is
this something that we should be doing? And I think these studies
and others say that the data looks great that we should be doing
this, but we haven't yet figured out the logistics of which score
and how do we actually reference to population.


Dr Nicholas Marston: Yeah, I agree with Christian definitely that
we need to figure out what's the optimal genetic risk tool and
for which population and what the cut points are. And then I
think another piece that's going to be very important moving
forward is doing a lot of this work and studying in non-European
ancestry and cohorts and populations. Because most of the work
done so far in discovery has been in databases such as the UK
Biobank. And that limits us in our analyses to European ancestry
patients. And so, I think for this to go to prime time, we want
to be able to offer it to all of our patients. And so that means
making sure we have scores that fit all populations, not just
primary and secondary, but also all different types of ancestry.


Dr Carolyn Lam: Oh, I'm so glad you mentioned that, Nick. That
was exactly on my mind coming from Asia. And the other thing of
course, would be cost effectiveness of these approaches. Oh my
goodness. I wish we had all the time in the world to talk about
this more. The implications are enormous, but just let me thank
you on behalf of all of us for publishing this remarkable paper
in Circulation.


Audience, you've been listening to Circulation on the Run. Don't
forget to tune in again next week.


Dr Greg Hundley: This program is copyright, the American Heart
Association 2020.