Circulation June 22/29, 2021 Issue

First join author Marc Dweck and Associate Editor Victoria
Delgado as they discuss the article "Effect of Denosumab or
Alendronic Acid on the Progression of Aortic Stenosis: A
Double-Blind Randomized Controlled Trial." Then, join authors
Torbjørn Omland and Geeta Gulati as they discuss the article
"Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer
Therapy (PRADA) Extended Follow-Up of a 2×2 Factorial,
Randomized, Placebo-Controlled, Double-Blind Clinical Trial of
Candesartan and Metoprolol."


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-hosts. I'm Dr. Carolyn Lam Associate Editor from the National
Heart Center and Duke National University of Singapore.


Dr. Greg Hundley:


I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley
Heart Center, VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


Hooray, it's another double feature week! And guess what, these
two papers are two randomized control trials. One looking at
progression of aortic stenosis and the other, looking at a
prevention of cardiac dysfunction following adjuvant breast
cancer therapies.


Dr. Carolyn Lam:


So, very interesting two papers coming right up. But Greg, why
don't you start by highlighting some of your favorite papers from
today's issue.


Dr. Greg Hundley:


You bet Carolyn.


Dr. Greg Hundley:


So my first study was conducted by Dr. Gabriela Trifan and
colleagues from University of Illinois who performed a meta
analysis of major studies that compare the efficacy and safety of
dual anti-platelet therapy versus monotherapy for secondary
prevention of recurrent stroke or transient ischemic attack in
those previously experiencing minor non cardioembolic stroke. And
their primary outcomes were stroke and the composite of stroke,
TIA, acute coronary syndrome and death of all cause. And the
safety outcome was major hemorrhage.


Dr. Carolyn Lam:


Oh, okay. Very important study. What did they find?


Dr. Greg Hundley:


Right Carolyn. So the analysis included 27,358 patients. And
compared with monotherapy, dual anti-platelet therapy reduced the
risk of recurrent stroke and the composite outcome, but increased
the risk of major bleeding. And in subgroup analysis at less than
or equal to 30 days, dual anti-platelet therapy increased the
risk of hemorrhage relative to monotherapy. In sensitivity
analyses, the risk for hemorrhage with less than or equal to 30
days of dual anti-platelet therapy, after excluding the
combination of aspirin plus Ticagrelor, was comparable to
monotherapy. However, the risk of stroke recurrence and composite
outcomes in the subgroup and sensitivity analyses remained
decreased compared to monotherapy.


Dr. Greg Hundley:


And so Carolyn, the take-home message from this paper is that
dual anti-platelet therapy decreases the risk of recurrent stroke
and composite events compared with monotherapy. But, dual
anti-platelet therapy increases the risk of major hemorrhage,
except if the treatment is limited to 30 days and does not
include the combination of aspirin plus Ticagrelor.


Dr. Carolyn Lam:


Ah, thanks for that last take home message. Thank you.


Dr. Carolyn Lam:


Well, the paper I'm going to tell you about is the first to
examine the role of epicardial fat derived extracellular vesicles
in the pathogenesis of atrial fibrillation. And this comes from
Dr. Leor from Sheba Medical Center, Tel Aviv University in Israel
and his colleagues who collected epicardial fat specimens from
patients with and without atrial fibrillation during elective
heart surgery.


Dr. Carolyn Lam:


Epicardial fat samples were grown as organ cultures and the
culture medium was collected every two days. And the authors then
isolated and purify these epicardial fat extracellular vesicles
from the culture medium.


Dr. Carolyn Lam:


They found that epicardial fat extracellular vesicles of patients
with atrial fibrillation had unique pro-inflammatory, profibrotic
and proarrhythmic properties. Epicardial fat extracellular
vesicles could in fact induce cellular, molecular and
electrophysiological remodeling that could result in atrial
fibrosis, myopathy and the development of atrial fibrillation.


Dr. Greg Hundley:


Wow Carolyn, so what are the clinical implications of epicardial
fat extracellular vesicles?


Dr. Carolyn Lam:


Hmm, good question. Well, understanding their role in the
pathogenesis of atrial fibrillation may for one lead to the
discovery of new diagnostic markers or new targets for the
prevention and treatment of atrial fibrillation. And that
combined pro-inflammatory profibrotic and proarrhythmic effects
of these epicardial fat and extracellular vesicles may in fact be
relevant to the pathogenesis of other cardiovascular diseases
associated with obesity and abnormal adipose tissue deposition.


Dr. Greg Hundley:


Very nice Carolyn.


Dr. Greg Hundley:


My next paper comes again to us from the world of preclinical
science and these authors led by Dr. Masanori Aikawa from Harvard
Medical School applied a systems approach in mouse experiments to
discovering therapeutic targets for vein graft failure. They use
global proteomics and high dimensional clustering on multiple
vein graft tissues to identify potential pathogenic mechanisms.
And experiments were conducted in both in vivo mouse models and
in vitro human macrophages.


Dr. Carolyn Lam:


Oh wow. So what did they find?


Dr. Greg Hundley:


So Carolyn, peroxisomes proliferator activated receptors or PPAR
alpha agonism by pemafibrate retarded the development and
inflammation of vein graft lesions in mice, while gene silencing
worsened plaque formation. Pemafibrate also suppressed
arteriovenous fistula lesion development.


Dr. Greg Hundley:


Now, metabolomics, lipidomics, functional metabolic assays and
single cell analysis of cultured human macrophages revealed that
PPAR alpha modulates macrophage glycolosis, citrate metabolism,
mitochondrial membrane sphingolipid metabolism and heterogeneity.


Dr. Carolyn Lam:


Okay. So what is the take home message Greg?


Dr. Greg Hundley:


Right Carolyn, thought you would ask me that.


Dr. Greg Hundley:


So PPAR alpha activation suppresses the development of vein graft
and arterial venous fistula lesions. And PPAR alpha reduces
macrophage activation by influencing macrophage heterogeneity,
mitochondrial integrity, and the metabolome. So Carolyn, given
that peripheral arterial disease and chronic kidney disease
prevalences are increasing, warranting needs for more vein grafts
and arterial venous fistulas, this target discovery platform is
applicable to investigating therapies for these diseases.


Dr. Greg Hundley:


And a really nice accompanying editorial is provided by doctors
Reilly and Bornfeldt.


Dr. Greg Hundley:


Well Carolyn, how about we turn to look at what is in the mailbag
this week?


Dr. Carolyn Lam:


Well let me tell you about it Greg. We've got a cardiovascular
case series by Dr. Borlaug on things are not always as they seem,
multimodality exercise assessment and evaluation of dyspnea. In
cardiology news by Kuhn there's a discussion of Evinecumab
approval adds a new option for homozygous familial
hypercholesterolemia with a hefty price tag. A perspective piece
by Dr. Watkins on time to think differently about sarcomere
negative hypertrophic cardiomyopathy. And finally a research
letter by Dr. Ahn on reduction in Kawasaki disease after
non-pharmaceutical interventions in the COVID-19 era, a
nationwide observational study in Korea.


Dr. Carolyn Lam:


Wow. That wraps it up for the summaries. Let's go on to the
feature discussions shall we, Greg?


Dr. Greg Hundley:


You bet.


Dr. Carolyn Lam:


We are about to talk about the extended follow-up results of the
PRADA trial. Oh, so interesting. So happy to have with us today,
doctors Geeta Gulati and Dr. Torbjørn Omland, both from the
Akershus University hospital in Norway, and you would probably
recognize that Dr. Torbjørn Omland is also one of our associate
editors, but both here are the co-corresponding authors of this
beautiful paper.


Dr. Carolyn Lam:


Thank you so much for coming here today. Torbjørn, maybe you
could start with what is the PRADA trial? Why did you decide to
do an extended follow-up?


Dr. Torbjørn Omland:


Yeah so PRADA was a two times two factorial randomized double
blind clinical trial that sought to evaluate the effects of
intervention with receptor blocker Candesartan. And a beta
blocker Metoprolol in patients with early breast cancer who
received anthracycline therapy as part of their chemotherapy. And
then we wanted to assess the effect of this sort of preventative
therapy, left ventricular function and injury.


Dr. Torbjørn Omland:


So we reported the primary results of the trial a few years ago
and showed that intervention with Candesartan most associated
with a significant elevation of the reduction in left ventricular
ejection fraction that these patients may experience, and also
that treatment with the beta blocker Metoprolol was associated
with an intimation of the increase in cardio proponents
suggesting a beneficial effect on myocardial injury. However,
whether these results were or these effects were sustained after
termination of the study drugs was unknown. And that was what we
really wanted to address with extended follow-up study.


Dr. Carolyn Lam:


Yeah, makes a lot of sense, especially because these injuries I
suppose could still continue. And just to be very clear, the
medications though were only taken during the adjuvant
chemotherapy and therefore could be a variable duration from what
I understand. Right? Great.


Dr. Carolyn Lam:


So Geeta then, could you tell us what did the extended analysis
show?


Dr. Geeta Gulati:


The extended follow-up was interesting and it was something we
really wanted to figure out because there are not many studies
who have been done on the extended follow-up and you're not
giving these study medications afterwards.


Dr. Geeta Gulati:


So very interestingly we saw that the decline in the ejection
fraction was still there in the whole group. But this time there
was no difference in the group who received Candesartan do those
who didn't. And we show that there was a different in the primary
results, but now in the extended follow-up there was no
difference. And then also in the Metoprolol group that had
previously shown that there was lesser rise in the troponins.
Again, there was no difference in the groups now on the extended
follow-up.


Dr. Geeta Gulati:


So this is very interesting because this shows that there is a
small, modest decline in a left ventricular ejection fraction
during and after the breast cancer therapy. But what does this
really mean? It's a small decline and it's within the normal
range and the cardioprotection is not working. So, are we perhaps
looking at the wrong group? Perhaps we should look at patients
who have the higher cardiovascular risk factors. Perhaps even we
should look at more novel heart failure or cardiac drugs that may
have a stronger effect on the ejection fraction.


Dr. Carolyn Lam:


Right. So Geeta though, can we unpack that a little bit? You see,
the patients were not on the medication anymore at the time of
follow-up. So you're saying that even though they were given
adjuvant chemotherapy and covered with the drug, that even not
having any more chemotherapy, their ejection fraction still fell.
And if I'm not wrong, this was an MRI analysis. And so it was
only by an ejection fraction of two percent on mean fall, right?
How do we think about that clinically?


Dr. Geeta Gulati:


And that's the important question, isn't it? Because a decline in
the ejection fraction of less than two percent within the normal
range, what does it really mean? Well initially we thought that
if there was a different in those who had cardioprotective
medication compared to those that didn't, it may prevent
development of further decline in the cardiac function and then
heart failure in the future. But now, there is really no
difference between the groups. So perhaps the clinical
implication of giving cardio protection to all cancer patients is
not really that useful. Perhaps they should look at those who are
at higher risk because they would have a greater fall in ejection
fraction and then more cardioprotective effect of these drugs.


Dr. Carolyn Lam:


Yeah, totally. And perhaps the metrics that we're used to seeing
in the past with greater falls of ejection fraction, maybe it
just doesn't apply currently or perhaps with the specific
chemotherapeutic regimens perhaps that you're using now. Because
with a very small fall, and I believe you only had one heart
failure event, right? If I'm not wrong in this extended
follow-up. So, just to let the audience know, it was very small
fall, little number of events. It's hard to really tease apart
what that clinically means. Now, could I ask though, does it mean
we need actually a more sensitive marker? Because there was some
interesting stuff about global longitudinal strain. Could you-


Dr. Geeta Gulati:


I would throw that question back to Torbjørn I think.


Dr. Torbjørn Omland:


Yes. So that's a very interesting question Carolyn. So we did
observe what seemed to be a beneficial, but a sort of minor
effect on global longitudinal strain. So we know that that is the
more sensitive index of systolic function than left ventricular
ejection fraction, that was the pre defined primary outcome. So
that's raises of course questions whether a future trial should
more focus on these more sensitive indices of cardiac function.


Dr. Carolyn Lam:


Yeah. Geeta, could I then really put it back to you? And the
tough question I always get, how do we apply these results
clinically then? I mean, you see these patients right? Now what?
Do you give or do you don't give? And which one do you give? And
how do you identify high risk patients? I don't know.


Dr. Geeta Gulati:


Again, I think all the patients are unique aren't they? So that's
where we have to start. So in my clinic, if I have a high risk
patient with hypertension, diabetes, hypercholesterolemia, yeah
perhaps they even have had a cardiovascular disease before
something like this. Then I will take more care of these patients
and be more careful with the echo measurements I'm doing and if I
find that they have a decline in their cardiac function, I may be
more eager to start them on cardioprotective medication.


Dr. Geeta Gulati:


But then in R-Regen we follow all the HER two positive breast
cancers with echo. If I don't have echoparamaties that clearly
tells me that they have a decline in the cardiac function, then I
may wait to start cardio protection because none of the studies
has really so far show that all patients should have these
cardioprotective medication or prevention.


Dr. Carolyn Lam:


Nice. Thank you. That was a tough one to get at. And I suppose
Torbjørn I have to give you another tough one then. Because how
to address the remaining unanswered questions, right? Because one
of them on my mind too, is how to identify the high risk, do
biomarkers play a role? And then the other is if we then start
the preventive therapies like ERBs and beta blockers, should we
actually continue it forever? And so on. But anyway Torbjørn
please, please, what does the future hold?


Dr. Torbjørn Omland:


I think it's worthy of a recap or underscoring that these are
really good news for many breast cancer patients that actually
the risk of an important decline in ventricular function is lower
than we thought. So that may be because of several things. I
think in general, those whose used these cardiotoxic drugs are
lower. And we also, I think that there's increased collaboration
between oncologists and cardiologists. Also meaning that we are
better to pick up the high-risk patients at an early stage.


Dr. Torbjørn Omland:


But of course, it's very important questions that you asked
regarding how to identify the high risk patients. And I think
that's where really future research should focus. So there we
know that traditional risk factors are important. We are looking
into whether biomarkers can be used, if there's more sensitive
imaging in this can be used. But so far we haven't really
succeeded in getting the risk model that really identifies it on
the patient level. So that's work that remains to be done.


Dr. Torbjørn Omland:


And then we are also looking for new types of intervention, good
exercise, good other drugs. We are doing now a PRADA two study
where we look at the effects of Sacubitril Valsartan in this
setting. And those are also very exciting, I think, and we look
very much forward to present that in the future.


Dr. Carolyn Lam:


Oh wow thank you so much Torbjørn and Geeta. The PRADA two trial.
I've got to ask you, why do you then call it the Chanel trial?
But I think I'll save that for another day. So thank you. Thank
you once again, this is fabulous and congratulations to you both.


Dr. Torbjørn Omland:


Thank you.


Dr. Geeta Gulati:


Thank you.


Dr. Greg Hundley:


Well listeners, welcome to our second feature discussion today.
And we have with us Dr. Marc Dweck from University of Edinburgh
in Scotland and our own associate editor, Victoria Delgado from
Leiden in the Netherlands. Welcome to both of you.


Dr. Greg Hundley:


Marc, we're going to get started with you. Could you tell us a
little bit about the background for your study and what was the
hypothesis that you wanted to test?


Dr. Marc Dweck:


Thanks very much Greg for the invitation. So I guess aortic
stenosis is perhaps the last major cardiovascular condition where
we don't have a medical therapy. We're unable to treat these
patients. We're unable to prevent progression. We're only left
with a valve replacement. And so we, like a lot of groups around
the world, want to develop a treatment for aortic stenosis. Our
group did the first SALTIRE trial, where we looked at statins
seeing if we could slow aortic stenosis progression. And that,
like similar trials, was neutral. No effect on the valve
progression.


Dr. Marc Dweck:


And so actually I've spent the last 10 years looking at some of
the factors associated with aortic stenosis progression in
particular. The answers that we've had from those trials have
kind of come back telling us that really it's a process of
calcification. If you look at what triggers progressive valve
narrowness is this calcific process, that seems to be a self
perpetuating disease.


Dr. Marc Dweck:


So the question is, how do you target this calcification process?
How can you interrupt it? And how can you do that without
compromising bone health in these elderly patients? So in trying
to come up with a solution to that we thought about using
osteopetrosis agents, which we hypothesized would maintain both
bone health and reduce vascular calcification on the basis of
observational data and also animal data suggesting that. And that
was really where we came from in the design of the SALTIRE two
trial.


Dr. Marc Dweck:


And doing a big trial with clinical endpoints wasn't felt to be
feasible and instead we decided to look at imaging end points and
see whether we could slow disease progression using these agents.


Dr. Greg Hundley:


Very nice Marc. And so you're really leading us into, tell us a
little bit more about your study population and your study
design.


Dr. Marc Dweck:


Yeah so we wanted to take patients from our outpatient clinic
with mild, moderate and even early severe disease, asymptomatic
patients crucially, patients that aren't scheduled for aortic
valve replacement and see the effects of these drugs on disease
progression.


Dr. Marc Dweck:


So we did a randomized control trial. There was three arms.
Patients were randomized to Alendronate, Denosumab, these are the
two osteopetrosis agents, or placebo. We then did a series of
baseline imaging tests. So the primary end point was based on CT
calcium scoring. So they had a baseline CT calcium score. They
also had a baseline echocardiogram and they had a baseline
fluoride PET scan. So this measures calcification activity in the
valve. And then we essentially repeated those tests after a
period of time on the drugs, or on placebo. We repeated the
calcium score and the echo after two years and repeated the PET
scan after one year.


Dr. Greg Hundley:


Very nice, and so before you tell us your results, a little bit,
how many patients? And maybe their average age and the rough
distribution of men versus women.


Dr. Marc Dweck:


Yeah so study recruited roughly 50 patients in each arm. The
average age was 72 and there was 21% females in the study. So,
like a lot of studies in aortic stenosis, a low female
prevalence. Despite our best efforts, that's something we need to
attend to in the future, but otherwise, a representative age
group and patients with this disease.


Dr. Greg Hundley:


And what did you find?


Dr. Marc Dweck:


Well we found that the drugs didn't have an effect on any of
these imaging assessments. So, there was no effect on the
progression for CT calcium score at two years, no effects on any
of the echocardiographic assessments of hemodynamic severity, and
no effect on calcification activity as measured with the
fluoride.


Dr. Marc Dweck:


So a very consistent result using multiple different imaging
modalities, which I think gives us confidence that there isn't at
least a dramatic effect of these drugs on disease activity or
disease progression, in aortic stenosis.


Dr. Greg Hundley:


Very good. Well listeners, we're now going to turn to one of our
associate editors, Dr. Victoria Delgado, and she is really a
valvular heart disease expert member of our team.


Dr. Greg Hundley:


Victoria, I know you see a lot of papers that kind of come across
your desk. What attracted you to this manuscript? And then how do
you put the results in the context of other research that's going
on to halt the progression of aortic stenosis.


Dr. Victoria Delgado:


Thank you Greg. So first the first thing that attracted my
attention for this article is the question. We know that we don't
have any medical therapy for halting the progression of aortic
stenosis. And even if the previous studies have been negative or
neutral, still there is the interest of trying to find a less
invasive therapy for these patients, or even prevent that they
arrive to surgical or transcatheter aortic valve replacement.


Dr. Victoria Delgado:


And the second is that these are very strong analysis because
it's a randomized clinical trial and using as end points imaging.
So that trial also in a way answers the question of which imaging
technique we need to use in order to see the effects of specific
therapies. Previous studies have used mainly echocardiography,
but that only gave us information on the modynamic effects of the
aortic stenosis. While in this study, we have the combination of
CT and a combination of a PET that he give us also information on
how the calcification is happening. So that makes the study very
comprehensive and give us more insights into this
pathophysiology, to this pathology particularly.


Dr. Greg Hundley:


Very nice. So it sounds like looking at aortic stenosis from
multiple different angles, whether it be echocardiography or
perhaps imaging processes that look at the progression of
calcification.


Dr. Greg Hundley:


Well, Marc, I want to come back to you. What do you think is the
next, sounds like you've been working in this area for an
extended period of time. What do you see as the next research
study that you and your group may undertake in this area?


Dr. Marc Dweck:


I Think we've got the study design about right. I think if in the
future studies we want to do, I think we would adopt a similar
design using these imaging end points.


Dr. Marc Dweck:


I have to say I'm very influenced by the recovery trial that has
been conducted in the UK with COVID. I mean, here's a disease
where we wanted to get a treatment as quickly as we can. And in
doing that, developing a platform type trial where you
potentially test multiple different promising agents
simultaneously across multiple centers across the world or the
UK, I think that would be the quickest way to developing a
treatment. And so I'm encouraged that there are five or six very
good targets where we could, for a new therapy in aortic
stenosis. And I think a platform type design where we engage
multiple groups using imaging as that initial end point. And
then, the drugs that appear to have an effect on these imaging
end points we can start to recruit more patients at those sites,
into those centers, looking for clinical end points.


Dr. Marc Dweck:


I think that kind of discussion is happening around the world now
between groups that are interested because we want to crack this
problem quickly. We don't want to wait and do these different
studies sequentially. We want to try and do them simultaneously.
And I'm excited about that. I think if we do that, we've got a
real shot at developing a treatment over the next five to 10
years say.


Dr. Greg Hundley:


Fantastic.


Dr. Greg Hundley:


And Victoria, I know you have interest in this particular area.
Do you have anything you'd like to add?


Dr. Victoria Delgado:


Yeah. I think that those studies that Mark said are really
welcome and I hope that they are positive. And give us a little
bit of more to treat these patients. My main fear is that these
patients are not as frequent, for example, as heart failure
patients. Where we have several therapies where we have
possibility to enroll patients in trials for new drugs, that we
know that probably are going to be effective. But for valvular
heart disease it has been always the end point to reach surgery
or to reach an aortic valve replacement or indication of the
mitral valve and mitral valve repair. So in early phase of the
disease, my main concern is that maybe the patient is not going
to be well-trained to understand what are the consequences. I
want to always wait until maybe when is needed for the surgical
or transcatheter procedure.


Dr. Victoria Delgado:


But I think that increasing the awareness of the prevalence of
valvular heart disease and the consequences may help people to
understand, to put more attention for an early diagnosis and
develop new drugs that can help, like in this case, aortic
stenosis one of the most frequent valvular heart disease, to
prevent the proliferation and to prevent the replacement of the
valve.


Dr. Greg Hundley:


Very nice. Well listeners, this has been a wonderful discussion
and we greatly appreciate the input that we've been able to
gather today from Dr. Marc Dweck from Edinburgh in Scotland and
our own associate editor, Dr. Victoria Delgado. Bringing this
information from a randomized trial, evaluating osteoporosis
drugs, and really indicating they did not disrupt the progression
of calcification in patients with aortic stenosis.


Dr. Greg Hundley:


Well, on behalf of Carolyn and myself, we want to wish you a
great rest of your week and we will catch you next week on The
Run.


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.