Circulation April 27, 2021 Issue

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


Dr Carolyn Lam:


Greg, we got double features today. Now, the first one's all
about fruit and vegetables. Now, before you switch off, this is a
very important one, okay? So, listen on. And the second is on the
EMBRACE heart failure trial. Now, this was a late breaker, very
important, more data on empagliflozin, that SGLT2 inhibitor. So
really, really fun discussions coming right up. But first, can I
dig into one of the papers that I'm really dying to tell you
about?


Dr. Greg Hundley:


Absolutely.


Dr Carolyn Lam:


Okay. This is all about the diagnostic performance of
high-sensitivity cardiac troponin T strategies, that super hot
topic. We know that European data support the use of low high
sensitivity troponin measurements or a 0/1 hour algorithm for
myocardial infarction or to exclude MACE among emergency
department patients with possible acute coronary syndrome.
However, there's really very modest U.S. data to validate these
strategies. This study today from Dr. Allen and colleagues from
University of Florida, really evaluated the diagnostic
performance of an initial high sensitivity cardiac troponin T
measure below the limit of quantification. And that is six
nanograms per liter, a 0/1 hour algorithm, and their combination
with heart scores for excluding MACE in a multi-site U.S. cohort.
And this is the largest prospective multi-site U.S. study of high
sensitivity troponin T strategies to date.


Dr. Greg Hundley:


Wow, Carolyn you've really piqued my interest. So what did they
find?


Dr Carolyn Lam:


Okay. And initial high sensitivity, cardiac troponin T below that
level of quantification of six nanograms per liter was associated
with a negative predictive value of 98.3% for 30-day MACE. Okay.
That was that value itself. Now the 0/1 hour algorithm rolled out
57.8% of patients with a negative predictive value of 97.2% for
30-day MACE. The addition of a low-risk heart score to that
initial high sensitivity troponin T level below that six nanogram
per liter and the 0/1 hour algorithm improved the negative
predictive value for 30-day MACE to 99% and 98.4% respectively.


Dr. Greg Hundley:


Wow. Carolyn, it looks like a really comprehensive analysis of
the high sensitivity troponin. So tell us what are the clinical
implications of this study?


Dr Carolyn Lam:


So these data seem to imply that when used without a risk score
and initial high sensitivity troponin T below six nanograms per
liter, or a 0/1 one hour algorithm, may not have sufficient
sensitivity or negative predictive value to exclude 30-day MACE
in the U.S emergency department patients. But the addition of
that low-risk heart score to those measures improves the negative
predictive value, but rolls out fewer patients. And so in
totality, these results suggest that in the U.S. Emergency
departments, adding a risk score to either of these strategies
really increases their safety.


Dr. Greg Hundley:


Boy, great new information in our journal. Well, Carolyn, I'm
going to switch to the world of basic science and start to
evaluate in this next paper, the regulation of cellular
signatures in children with dilated cardiomyopathy, and the work
comes to us from Dr. Stephanie Dimmeler from Goethe University in
Frankfurt. So Carolyn, Stephanie's team performed single nuclei
RNA sequencing with heart tissues from six children with dilated
cardiomyopathy. One was age 0.5, 1.75 and another at 5, 6, 12,
and then 13 years of age. And they did this to gain insight into
age and disease-related pathophysiology, pathology, and molecular
fingerprints. And the goal was to gain further insight into
dilated cardiomyopathy, which is a leading cause of death in
children with heart failure.


Dr Carolyn Lam:


Cool. So what did they find Greg?


Dr. Greg Hundley:


Right, Carolyn. So, the number of nuclei in fibroblast clusters
increased with age in dilated cardiomyopathy patients, a finding
that was consistent with an age-related increase in cardiac
fibrosis quantified by cardiovascular magnetic resonance imaging.


Dr. Greg Hundley:


Now Carolyn, fibroblast of the dilated cardiomyopathy patients
over six years of age showed a profoundly altered gene expression
pattern with enrichment of genes encoding fibrillary collagens,
modulation of proteoglycans and a switch in thrombospondin
isoforms and signatures for fibroblast activation. Additionally,
Carolyn, a population of cardiomyocytes with a high
pro-regenerative profile was identified in infant dilated
cardiomyopathy patients, but was absent in those children that
were greater than six years old. And this cluster in these
infants showed high expression of cell cycle activators, such
cyclin D family members increased glycolytic metabolism and any
oxidative genes and alterations in beta adrenergic signaling
genes.


Dr Carolyn Lam:


Wow. That sounds like a magnificent and elegant study. Could you
boil it down to the take home messages?


Dr. Greg Hundley:


You bet. Carolyn. Great question. So two points first, infants
with a predominantly regenerative cardiomyocyte profile, may
preferentially receive treatment strategies to support cardiac
regeneration while patients with a pattern associable with
cardiac fibrosis may benefit from an early anti-fibrotic therapy
to avoid diastolic dysfunction. And second, despite the
impracticality of performing these large cohort studies in
children with dilated cardiomyopathies, tailored pharmacological
treatment is possibly realistic. For example, based on the
expression of beta adrenergic signaling genes.


Dr Carolyn Lam:


Oh wow. That is super cool. That's Circulation for you,
publishing these amazing basic science papers with very big
clinical implications. Well, I've got another basic science paper
for you and this time I've learned a new word actually. It's
called O-GlcNAcylation. I should get you to say it after me. I
had to get our editor-in-chief Joe Hill to teach me to say that,
O-GlcNAcylation. So, cardiomyopathy from diverse causes is marked
by increased O-GlcNAcylation. Now, in this paper,
co-corresponding authors, Dr. Anderson and Umapathi from Johns
Hopkins University provide a new genetic mouse model to control
myocardial O-GlcNAcylation independent of pathological stress.
Their data actually provided evidence that excessive
O-GlcNAcylation caused cardiomyopathy, at least in part due to
defective energetics. Enhanced O-GlcNAcase activity was
well-tolerated. And conversely, attenuation of O-GlcNAcylation
was beneficial against pressure overload induced pathological
remodeling in heart failure.


Dr. Greg Hundley:


Interesting, Carolyn. So what are the clinical implications of
these findings?


Dr Carolyn Lam:


Well, the data really provide new proof of concept that excessive
O-GlcNAcylation is sufficient to cause cardiomyopathy, and they
also suggest that attenuation of this excessive O-GlcNAcylation
may represent a novel therapeutic approach for cardiomyopathy.


Dr Carolyn Lam:


Shall we go on and sort of wrap up on what else is in this issue?
Because I'd like to talk about highlights from the Circulation
family of journals that Sarah O’Brien really beautifully
summarizes, talking about everything from Circulation: Arrhythmia
& Electrophysiology, to [Circulation:] Cardiovascular Quality
& Outcomes. It's just a beautiful piece where we get all the
highlights. Must read. There's also a Perspective piece by Dr.
Gillis on Rhythm Control in Atrial Fibrillation: Is Earlier the
Better?, and that discusses the EAST-AFNET 4 and early AF trials.


Dr. Greg Hundley:


Very good, Carolyn. Well, from the mailbox, professors Pan and
Liu exchange letters regarding a prior response to a letter
regarding the article Genetic Architecture of Abdominal Aortic
Aneurysm in the Million Veteran Program. Also, Dr. Arbus-Redondo
has an EKG challenge entitled, Dual Chamber Pacemaker after Sinus
Node Dysfunction and an Enlarged Right Atrium. Is it what it
seems?


Dr. Greg Hundley:


And then finally, Dr. Corrado has a very nice Research Letter,
entitled, Serial versus Single Cardiovascular Screening of
Adolescent Athletes.


Dr. Greg Hundley:


Well, Carolyn, I'm dying to hear about fruits and vegetables. How
about we get onto those featured discussions?


Dr Carolyn Lam:


Cheeky, cheeky, Greg. Here we go.


Dr Carolyn Lam:


Oh, I'm so excited about today's featured discussion because it's
about my favorite thing, fruits and vegetables. Okay, wait a
minute, everybody. Before you start rolling your eyes, this is a
really important one. Have you ever asked yourself, what is the
optimal intake levels of fruit and vegetables for maintaining
long-term health? Well, guess what? We're about to find out and
I'm so pleased to have the first author of today's feature paper,
Dr. Wang Dong, and he's from Harvard medical school and Brigham
Women's Hospital. We also have our Associate Editor, Dr. Mercedes
Carnethon from Northwestern University and our Associate Editor
who is also the editorialist to this paper, Dr. Naveed Sattar
from University of Glasgow. So welcome, everyone. Dr. Wang,
please tell us what you did in this study and what were your main
results?


Dr. Wang Dong:


Thank you, Carolyn. So, basically, in this study, we analyzed the
data from two long running cohort study. That is the Nurses'
Health Study and Health Professional Follow-Up Study. So these
two study includes more than 100,000 participants who had been
followed for up to 30 years. And we also include a meta-analysis
that includes in total 26 studies and about two million
participant from 29 countries, and had countries around the
world. So, basically, the major finding from this study is, of
course, the intake of fruits, vegetable is inversely associated
with the risk of death from all cause and the different kinds of
cause-specific mortality. And we have a very interesting finding
that is intake of about five servings per day, that can be
translated into two serving of fruits and three servings of
vegetables per day, was associated with the lowest risk of total
mortality. So that's an optimal intake level for fruits and
vegetable.


Dr. Wang Dong:


And another important finding from this study is, not all foods
that some people consider to be fruits and vegetables can offer
the same health benefits. For example, in this study, we found
that starch vegetables such as peas and corn, and some fruits
juice and potatoes are actually not associated with any benefit
in terms of longevity. On the other hand, if you look at green
living vegetables such as spinach, kale, and fruits that's orange
color fruits and vegetables, that's rich in beta-carotene and
vitamin C such as citrus fruits and berries, carrots they're
associated with a substantial reduction in the risk of total
mortality. That's a major finding from this paper.


Dr Carolyn Lam:


Oh, I just love it. I mean, just like such wholesome, beautiful
findings from a wonderful study. Now, if I could ask you, cause I
think the first thing everyone's going to say is, okay, these are
associations. I mean, what'd you do about the residual risks?
Could you maybe describe how you try to address some of these
things like, is taking in fruits and vegetables just a surrogate
for people who, I don't know, exercise more, for example?


Dr. Wang Dong:


Yeah. So in original data analysis, we actually have extensive
data collection of all kinds of foods, lifestyle, risk factors,
medication use, any health-related variables. So we carefully
adjust for a large number of confounding factors. So actually
another thing I want to point out, most all of these
health-related lifestyle factors actually are inverse confounding
factors in this kind of analysis. So when you adjust for other
confounding factors, it's tend to attenuated your inverse
association. So the review from confounding actually wouldn't be
a major explanation for this association.


Dr Carolyn Lam:


Oh, that's great. And by the way, I think I misspoke. I'm not
sure if I said residual confounding or residual risk just now,
but you absolutely read me right, that I meant residual
confounding. So thanks. Now that we've got that out of the way,
if I could ask Mercedes, please. I mean, ah, another fruits and
vegetables paper, I mean, what made this one different that we
said we have to have it at Circulation.


Dr Mercedes Carnethon:


Well, thanks so much, Carolyn. And thank you Dong, for your
team's outstanding work. I know what excited me about it was the
demonstration of something that we have adopted into our lexicon,
that one needs five fruits and vegetables. So I was excited to
see you quantify it. In particular, the question I have for you
is, did you see that these patterns of association of fresh fruit
and vegetable intake were consistent across the age range and in
both sexes?


Dr. Wang Dong:


Yes, of course. In total, this acts as a stratification variable.
So basically, in our original data analysis, we did the analysis
in the Nurses' Health Study, which all the participants are
women, and in the Health Professional Follow-Up study, in which
all the participants are men, would be analyzed separately and we
found very consistent results in both cohorts. Then will be the
meta-analysis to meta-analyze the results from these two cohorts.
It comes out age, actually if you look at the paper, I think in
one of the supplemental table, with the age stratified analysis,
to look at the a better association if it still holds in
different age group. And we did found that the results is pretty
consistent in different age groups. And also, I would point out
this meta-analysis provides further support to show that this
results is generalizable in different people with different
social economic status, demographics status also from different
background.


Dr Mercedes Carnethon:


Thank you so much, Dong. it brings me to what Naveed wrote about
in his editorial, that food is medicine and I just really loved
that and loved the implications of that. So, I don't know,
Naveed, if you've got some comments to make? Questions?


Dr Naveed Sattar:


Yeah, thanks Mercedes. No, I really love this as well because
clearly the cardiovascular community, we do lots of trials. Lots
of us are nihilists and just look at trials, but actually it's
hard to do trials in the food and the dietary area, but these
data are very consistent. I think there are multiple potential
mechanisms that may explain this. We all have to eat every day,
so it's a big part of our lives. Increase fiber intake, increase
potassium, micronutrients, food displacement, the more fruit and
veggies you eat, the less you'll eat of other things that perhaps
are not as protective. And actually, part of the motivation to
write an editorial was to put all that into context in terms of
mechanisms. And particularly fiber, I think we underestimate the
importance of fiber, but then it was also to discuss, well, if
this is true, how do we help people make the changes?


Dr Naveed Sattar:


And at the level of policy, at the level of high risk groups, and
my own particular favorite is really communicating dietary change
in the clinic. And one of the things I often try, and we put this
in a kind of headline figure in the editorial, was actually
getting people to try to undergo the palate test or the
retraining their palates. I have lots of patients, who, would you
believe, in the west of Scotland, never really eat fruit and veg,
and I really pushed them to say, "Look, would you please try? And
it might take a few weeks for you to retrain your palate". And
lots of people come back saying, "Ah, you're correct. And my God,
now I like banana and I now like salad."


Dr Naveed Sattar:


So actually, there's lots of tips that we can do to help people
increase from their average of two to three intake, which is the
vast majority of population, to four to five, but it's a gradual
process and it requires good communication with our patients and
to compel them that these changes might take time, but that if
they make these changes, they can get to a point where they
really enjoy eating fruit and veg and all the multiple health
benefits that come, which this paper has now showed, Mercedes.


Dr Naveed Sattar:


I think for me, that was the real nub of this.


Dr Carolyn Lam:


Naveed, I just love the way you express it. And indeed, everyone
take up that editorial and look at that beautiful figure. I love
the colorful fruits and vegetables on top because it also reminds
us, and this paper shows, we are not talking about potato chips,
and was it those, corn and peas. But, you know, we're talking
about nutrition and fiber and the good stuff. Oh, this is just
amazing. I wish we could go on forever, but we have a double
feature this issue. And I just want to end by saying, thank you,
thank you all of you, for being on the show today. It was such an
important topic and I really loved the discussion as I'm sure the
audience did. Thank you.


Dr Mercedes Carnethon:


Thank You.


Dr Naveed Sattar:


Thanks very much.


Dr. Wang Dong:


Thank you so much.


Dr Carolyn Lam:


I am so pleased to have with us today, a friend, a deeply admired
colleague and the corresponding author of today's feature
discussion, Dr. Mikhail Kosiborod from Saint Luke's Mid America
Heart Institute.


Dr Carolyn Lam:


Welcome, Mikhail. And thank you for publishing this beautiful
paper on EMBRACE heart failure with us. I know that this was
presented as a late-breaking trial at the Heart Failure Society
of America meeting, and it's a very much anticipated paper, but
maybe I could start with it's all about SGLT2 inhibitors these
days. So please tell us how does EMBRACE add to this accumulating
knowledge that we have on SGLT2 inhibitors and heart failure?


Dr. Mikhail Kosiborod:


Well, first of all, Carolyn, thanks so much for publishing our
trial in Circulation. And you're right, SGLT2 inhibitors have
been taking the world of cardiometabolic medicine and heart
failure by storm over the past few years. EMBRACE is a very
unique trial because it really, took this world of rapidly
developing technology in heart failure and heart failure
monitoring, and coupled it with one of the hottest topics in
heart failure today in terms of drug management, which is the
advent of SGLT2 inhibitors and the emergence SGLT2 inhibitors as
a efficacious therapy, not just for prevention of heart failure,
but also treatment of heart failure. Because as you know,
pulmonary artery pressure and hemodynamic status are one of the
strongest predictors of patient outcomes, both in terms of
symptoms, hospitalizations, and deaths in heart failure. And we
know actually that monitoring and intervening on elevated
pulmonary pressure in this patient population may lead to
hospitalizations and possibly even death.


Dr. Mikhail Kosiborod:


But up until recently, it's been very difficult to monitor
pulmonary pressures and to use them as an outcome in heart
failure trials, because you will have to use invasive monitoring,
essentially a right heart catheterization to get that data. Well,
now we can actually have this implanted sensors like CardioMEMS,
which are the sensors that we use in EMBRACE-HF trial. So, the
question we wanted to ask is, we know SGLT2 inhibitors in DAPA-HF
and EMPEROR-Reduced trials, clearly reduce the risk of
cardiovascular death and hospitalization for heart failure,
worsening heart failure, but the mechanisms have been hotly
debated. Is there a possibility these agents can actually have an
impact on hemodynamic status and pulmonary pressures? And that's
the key central question that we tried to address and EMBRACE-HF
trial by using this novel technology at the time, now it's been
around for a few years, to noninvasively measure pulmonary
pressures and use it as a primary outcome in our trial.


Dr Carolyn Lam:


Mikhail, first of all, hats off, it was a very, very clever idea
to look at these patient populations who already have CardioMEMS
right, and then perform this randomized trial. I mean, when I saw
this, I was like, "Aw, man, how come I didn't think of that?
That's just like so clever, but it's just so Mikhail to be ahead
of the curve." But I'd like to remind the audience, this was a
prospective randomized trial, the pre-specified outcomes, right?
So maybe you could describe that in a greater detail and then the
results. Yeah.


Dr. Mikhail Kosiborod:


Absolutely. Well, Carolyn, first of all, once again, thank you
very much. You're being very kind. We do think it was a very
novel clever idea and that you're absolutely correct, as this was
very rigorously designed, randomized, double blind placebo
controlled investigating trial within this study and 10 sites in
United States. And the patients had to have heart failure, either
with reduced or preserved ejection fraction, about half-and-half
actually, as it turned out to be once it's all said and done with
the trial. Because they had to have implanted CardioMEMS for
clinical indication previously, they were quite advanced in terms
of their heart failure. So more than half of the patients were in
NYHA class III or IV, they had elevated brain natriuretic peptide
levels, they had hybrid symptoms as you would expect. And
essentially the patients were screened, and if they were
eligible, randomized to use a empagliflozin-placebo in a
double-blind fashion.


Dr. Mikhail Kosiborod:


And they were monitored actually for a couple of weeks prior to
randomization to get a baseline pulmonary artery diastolic
pressure. They were then treated for 12 weeks with empagliflozin,
10 milligrams a day, or a matching placebo. And we were measuring
pulmonary pressure twice a day, every day for the 12 week
treatment period, and then at the end of the treatment period,
the treatment was stopped, but we actually continued to measure
pulmonary pressure for one additional week again, twice a day,
every day. So we actually saw what happened for one week after
the treatment was stopped. And, as I mentioned before, the
patient population was quite advanced from a heart failure
standpoint. These were patients that were adequately managed with
guideline-directed medical therapy for heart failure. Of course,
about half of those patients have, have HFpEF. Did I mention
before was the standard of care is not a thoroughly defined?


Dr. Mikhail Kosiborod:


And essentially what we observed was quite remarkable, which is
average pulmonary artery diastolic pressure at baseline was about
22 millimeters of mercury across the patient population, and in
patients treated with empagliflozin, there was quite a rapid
reduction in pulmonary artery diastolic pressure that we saw
almost immediately within one week as compared with placebo. And
that divergence of curves in terms of pulmonary artery diastolic
pressure continued over the entire 12-week treatment period. And
by the end of the treatment period, there was nearly two
millimeter of mercury difference in favor of empagliflozin, with
lower pulmonary artery diastolic pressure in patients with
empagliflozin compared with placebo. And also interestingly, even
after the treatment was stopped for an additional week, those
curves continued to diverge, with even greater lowering of
pulmonary artery diastolic pressure in patients that received
empagliflozin. So, I think to our knowledge, this is the first
evidence from a randomized clinical trial, randomized double
blind placebo controlled clinical trial, that SGLT2 inhibitors,
in this case, empagliflozin, have essentially direct the
congestion effect towards a lower pulmonary artery pressure
rapidly and with effect amplified over time.


Dr Carolyn Lam:


Yes. Congratulations and beautifully present it there. Now, if I
could ask a few more questions now, because the things will come
up there. What happened to the diuretic dose? Is this depend on
diuretic dose? Are there any subgroups that appeared to benefit
more?


Dr. Mikhail Kosiborod:


No, excellent question, Carolyn. So first of all, we monitored
average daily furosemide equivalent dose continuously throughout
the trial, and what we observed was that there was no difference
in diuretic dose, essentially, between the two groups from a loop
diuretic management standpoint. Now, remember this patients are
getting frequent pulmonary pressures with diuretics being
adjusted all the time. But if you look at what happens over time,
that's one of the figures in the paper you see essentially the
flat lines in both groups. And coupling that with the fact that
pulmonary pressures continue to diverge for another week after
the treatment was stopped, at least in my mind, suggests that
this hemodynamic benefits as we observed with empagliflozin as
compared with placebo was lowering of pulmonary pressures is
likely not simply due to diuretic effect. It just cannot be
explained only by diuretic effect. I think these findings are
very much in line with the analysis that we had in DAPA-HF trial
with the analysis that recently were published from
EMPEROR-Reduced, showing that you just can't explain what you see
with heart failure benefits with SGLT2 inhibitors simply by
diuresis.


Dr Carolyn Lam:


Fascinating. Well, how about the question of diabetes?


Dr. Mikhail Kosiborod:


Yes. So in terms of subgroups, that you mentioned, we did do
subgroup analysis. Now I will say that the subgroup analysis have
to be interpreted with a great deal of caution in this trial,
because the entire trial had about 65 patients, so it's a small
trial. It was really powered to look at the entire patient
population and look at the primary end point of the diastolic
pressure. Nevertheless, as I mentioned before, we had
half-and-half reduced and preserved EF and we did not see a
statistically significant heterogeneity in the treatment effect
when we look at patients with reduced to preserved EF, so that
hopefully both for outcome trials in preserved EF heart failure,
we'll see, of course, what happens with that. And in terms of
diabetes we saw a bit greater effect in patients with diabetes as
compared to patients without diabetes, in terms of pulmonary
artery pressure reduction.


Dr. Mikhail Kosiborod:


But again, I would just strongly caution interpretation of those
subgroups because certainly when we look at clinical outcomes in
those DAPA-HF and EMPEROR-Reduced, we see no such difference. We
see that the benefits, right, the hard clinical outcomes,
benefits, are quite consistent regardless of diabetes status. I
will say one other thing, which I think is really important. If
you look at the pulmonary artery pressure trajectory in patients
treated with placebo in EMBRACE-HF, you see that they actually go
up over time. And this is in patients that have frequent
monitoring of blood pressures, our own guideline-directed medical
therapy are closely watched by predominantly heart failure
cardiologists and their teams to make sure that they're
well-managed. And despite that, you see this increase in
pulmonary pressure over time, and that's just another reminder to
us that heart failure is a progressive disease despite best
available therapy.


Dr. Mikhail Kosiborod:


These patients deteriorate over time, which is why treatment,
novel advancements, treatments like SGLT2 inhibitors and their
effective implementation is just so important because we know the
benefits occur very early. We saw one week here, when we start
seeing separation of curves, certainly see a significant
difference by 12 weeks with pulmonary pressure. But of course we
know with clinical outcomes, we see within a few weeks of
randomization, already a significant benefit in reducing CV death
and hospitalization for heart failure, both in DAPA-HF and
EMPEROR-Reduced trials. So I think that's a critical point for
clinicians to keep in mind at the time of the death.


Dr Carolyn Lam:


Mikhail, those are just such important and practical take-home
messages. Thank you again. In the last minute though, I just
really, really have to go back to that very clever method. Could
I just pick your brain? I mean, it's like a very clever
population. This CardioMEMS population that maybe what's in the
future plans? Give us a sneak peek!


Dr. Mikhail Kosiborod:


Well, Carolyn, very insightful as always. I really think of it as
a novel platform for drug development and heart failure. I think
this is the proof of concept. This is really the first time we
did something in the heart failure space was with monitoring of
pulmonary pressures that shows that drugs that work for hard
clinical outcomes actually do something meaningful on
hemodynamics. We've struggled for such a long time in heart
failure to have a good surrogate endpoints that would be
reflective of clinical outcomes. This may be it. It may be one of
them. And I think EMBRACE-HF is a good concept proving study that
can say, if you have a compound and you think that compound may
be effective for heart failure. So of course the congestion is so
important that we know correlates so well with clinical outcomes


Dr. Mikhail Kosiborod:


When we started to trial all the way back to late 2015, very few
patients had this device. It's not lots of patients have this
device. And testing novel treatments to try to understand will
there promise in heart failure, and even making go-no-go
decisions, in terms of drug development, I think is starting to
become a potential future development, which we should at least
seriously consider in the heart failure space.


Dr Carolyn Lam:


Wow, Bravo. And Mikhail, I mean. Okay, audience, listen, you
heard it right here. This is amazing. Thank you once again for
publishing with us and congratulations on the beautiful paper.


Dr Carolyn Lam:


And from Greg and I, thank you audience for joining us again
today, you've been listening to Circulation on the run. Tune in
again next week.


Dr. Greg Hundley:


This program is copyright of the American Heart Association 2021.