Circulation November 24, 2020 Issue

This week’s episode features author Emma Birks and Associate
Editor Hesham Sadek as they discuss the article " Prospective
Multicentre Study of Myocardial Recovery Using Left Ventricular
Assist Devices (REmission from Stage D Heart Failure:
RESTAGE-HF): Medium Term and Primary Endpoint Results."


TRANSCRIPT BELOW:


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, associate editor, director of the
Pauley Heart Center of VCU Health in Richmond, Virginia. Carolyn,
our feature article this week, we're going to examine myocardial
recovery using left ventricular assist devices, getting some
early results from the RESTAGE-HF study. But before we jump to
the feature discussion, how about we discuss some of the papers
in the issue? Would you like to go first?


Dr. Carolyn Lam:


Yes I would. Have you thought about what's the benefit of
emergent coronary angiography after resuscitation from out of
hospital cardiac arrest for patients without ST elevation? It's
an important question. Well, the portal study was reported by Dr.
Kern from University of Arizona and colleagues, and this was
designed to evaluate the efficacy and safety of early coronary
angiography and to determine the prevalence of acute coronary
occlusion in resuscitated out of hospital cardiac arrest in
patients without ST elevation. So adult comatose survivors
without ST elevation after resuscitation, were prospectively
randomized to early coronary angiography versus no early coronary
angiography, where early was defined as less than 120 minutes
from arrival at the PCI capable facility. The primary endpoint
was a composite of efficacy and safety measures, including
efficacy parameters of survival to discharge favorable
neurological status at discharge echo measures of left
ventricular ejection fraction, more than 50% and a normal
regional wall motion score within 24 hours of admission.


Dr. Greg Hundley:


So, lots of data here. What did they find?


Dr. Carolyn Lam:


So, unfortunately the study was prematurely terminated before
enrolling the target numbers of patients. A total of 99 patients
were enrolled from 2015 to 2018 and 49 were randomized to early
coronary angiography. The primary endpoint of efficacy and safety
was not different between the two groups. Early coronary
angiography was not associated with any significant increase in
survival or adverse events. And early coronary angiography
revealed a culprit vessel in 47% with a total of 14% of patients
undergoing early coronary angiography, having an acutely occluded
culprit coronary artery. So while this was an underpowered study,
when considered together with previous clinical trials, it does
not support early coronary angiography, comatose survivors of
cardiac arrest without ST elevation, whether early detection of
occluded potential culprit arteries leads to interventions that
improve outcomes does require additional study. And this is
discussed in an editorial by Dr. Lemkes from Amsterdam university
medical center.


Dr. Greg Hundley:


Very nice Carolyn. So at least the study that points us toward
the next study that has to be performed and also does with other
studies provide a little more clarity. Well, my next paper is
from Professor Sanjiv Shah and--oh, wait a minute! And also from
you as a co-author. Well, Carolyn, how about we have a little
mini feature discussion where I can ask you some questions and
then you can tell us all about your paper.


Dr. Carolyn Lam:


Happy to.


Dr. Greg Hundley:


Great. So Carolyn, what hypotheses were you testing and what was
your study design and who was included in your study population?


Dr. Carolyn Lam:


Okay. So the question was we wanted to answer was thus a systemic
pro-inflammatory state as indicated by proteomic profiling. Does
that mediate the association between comorbidities and normal
cardiac structure and function in HFpEF. To answer that we
studied 228 patients with HFpEF from our multicenter promis HFpEF
study. And these patients had 248 unique circulating proteins
quantified using the old link multiplex immunoassay. Now I'm
going to describe a complex analysis, but we basically had to
first perform principal component analysis. And we did this to
summarize 47 proteins known a priori to be involved in
inflammation, and then used unbiased network analysis of all the
248 proteins to identify clusters of proteins that
over-represented inflammatory pathways. We then used a mediation
analysis to determine whether and to what extent inflammation
mediates the association of comorbidity burdens with abnormal
cardiac structure and function. And finally, we externally
validated our findings in an independent cohort of 117 HFpEF
cases and 30 comorbidity controls without HFpEF.


Dr. Greg Hundley:


Wow Carolyn, such a great design and an app machine learning
mediation analyses, and then validation in an independent cohort.
So tell us, what did you find?


Dr. Carolyn Lam:


So first, comorbidity burden was associated with abnormal cardiac
function and structure and with these principle components of
clusters of inflammation proteins. Second, systemic inflammation
was associated with echo indicators of worse hemodynamics, like
higher EDE' ratio and worse, right ventricular function. And
third, inflammation indeed mediated the association between
comorbidity burden and many of these echo parameters with, and
I'm going to name a couple of routines. So TNF-R1, uPAR, IGFBP-7
and GDF-15 being the top individual mediating proteins. In the
validation cohort inflammation was up-regulated in HFpEF compared
to controls and the most prominent inflammation protein cluster
identified was also the same one as in PROMIS-HFpEF.


Dr. Greg Hundley:


Beautiful Carolyn. So with these new proteins identified, what's
the take home message here?


Dr. Carolyn Lam:


Here it is. Proteins involved in inflammation form a conserved
network in HFpEF. And this was found across two independent
cohorts. This may mediate the association between comorbidity
burden and echo indicators of worst hemodynamics and right
ventricular dysfunction. In totality, these findings support the
comorbidity inflammation paradigm in HFpEF.


Dr. Greg Hundley:


Great job Carolyn, I liked the mini feature. That was so nice
having one of the authors of the study here to explain kind of a
two for one here, because we're going to get a feature and a mini
feature. Have you got another paper you want to tell us about?


Dr. Carolyn Lam:


Thanks Greg and that works both ways. This next paper provides
insights into the identity origin and function of many cells that
make up late stage atherosclerotic lesions. It also identifies
the mechanisms by which these control plucks stability. So
corresponding author, Dr. Owens from Virginia School of Medicine
and colleagues conducted a comprehensive single cell RNA
sequencing of advanced human carotid endarterectomy samples, and
compared these with murine micro dissected advanced
atherosclerotic lesions with smooth muscle cell and endothelial
lineage tracing to survey all plaque cell types and to rigorously
determine their origins.


Dr. Greg Hundley:


Carolyn you know, this is another great study where we have both
human subjects research and small animals. What were their
results?


Dr. Carolyn Lam:


They provided evidence that smooth muscle cell specific knockout
of transcription factors, KLF4 versus Oct-4 showed virtually
opposite genomic signatures and their putative target genes
played an important role, regulating smooth muscle cells
phenotypic changes. They also provided evidence that smooth
muscle cell derived cells within advanced mouse and human
atherosclerotic lesions exhibited far greater phenotypic
plasticity than generally believed, with KLF4 regulating the
transition to multiple phenotypes, including LGALS 3 plus
osteogenic cells likely to be detrimental for late stage
atherosclerosis plaque pathogenesis. So in summary, smooth cell
phenotypic switching produces cells that can be beneficial or
detrimental to lesion stability and may be an important mechanism
controlling the risk of unstable atherosclerotic plaque and
myocardial infarction or stroke.


Dr. Greg Hundley:


Oh, great job, Carolyn. Well, the next paper I have is from
Professor Muredach Reilly from Columbia University. And Carolyn
smooth muscle cells play significant roles in atherosclerosis via
phenotypic switching, a pathological process and with smooth
muscle cell D differentiation, migration and trans
differentiation into other cell types yet how smooth muscle cells
contribute completely to the pathophysiology of atherosclerosis
remain somewhat illicit. So the authors sought to reveal the
trajectories of smooth muscle cell trans differentiation during
atherosclerosis, and to identify molecular targets for disease
therapy by combining smooth muscle cell fate mapping and single
cell RNA sequencing of both mouse and human atherosclerotic
plaques.


Dr. Carolyn Lam:


Echoing what you said earlier, Greg, both animal and human data.
Terrific. So what were the results?


Dr. Greg Hundley:


The authors found that smooth muscle cells transitioned to an
intermediate cell state during atherosclerosis, which was also
found in human atherosclerotic plaques of carotid and coronary
arteries. Smooth muscle cell derived intermediate cells termed
stem cells were multiphoton and could differentiate into
macrophage like and fibro chondrocyte like cells as well as
returned towards the smooth muscle cell phenotype. Retinoic acid
signaling was identified as a regulator of the transition of
smooth muscle cells to stem cells and RA signaling was
dysregulated in symptomatic human atherosclerosis. Finally
Carolyn, human genomics revealed enrichment of genome-wide
association study signals for coronary artery disease in RA
signaling target gene low PSI and correlated between coronary
artery disease risk levels and repressed expression of these
genes. Now, activation of RA signaling by all trans retinoic acid
and the anticancer drug for acute promyelocytic leukemia blocked
the smooth muscle cell transition to stem cells, and that also
reduced atherosclerotic burden and then promoted fibrous cap
stability. So a lot of clarification of the role of smooth muscle
cells, trans differentiation and the development of
atherosclerotic disease


Dr. Carolyn Lam:


Indeed and translational implications. Interesting. Now let's
review some of the other papers in this issue. Shall we? First as
an, on my mind paper by Dr. Kullo on familial
hypercholesterolemia, a reportable disorder. There's an exchange
of letters between doctors Lazzerini and Li regarding the article
autoantibody signature in cardiac arrest.


Dr. Greg Hundley:


Thanks Carolyn. Well, I've got a couple other papers to tell you
about really a series of research letters from the mailbag. So
first Daniel Modin has a Research Letter entitled “Acute COVID-19
and the Incidents of Ischemic Stroke and Acute Myocardial
Infarction.” Dr. Christian Mueller has a Research Letter entitled
“Effect of a Proposed Modification of the Type 1 and Type 2
Myocardial Infarction Definitions on Incidents and Prognosis.”
And finally Carolyn a Research letter from Dr. Jizheng Wang
involving an East Asian-specific common variant in TNNI3 that
appears to predispose to hypertrophic cardiomyopathy. Well,
Carolyn, what a great issue and thank you for that many feature,
but how about we proceed on next to our feature discussion?


Dr. Carolyn Lam:


Let's go, Greg.


Today's feature paper is one of those that I think is going to
change clinical practice. So please listen up. It's about the
RESTAGE-HF study. So pleased to have with us the first and
corresponding author, Dr. Emma Birks from University of Kentucky
Gill Heart and Vascular Institute, as well as our associate
editor, Dr. Hesham Sadek from UT Southwestern to discuss this
very important paper. Emma, could you please describe the RESTAGE
heart failure study?


Dr. Emma Birks:


Let's say prospective study of patients getting left ventricular
assist devices. So patients with very advanced heart failure are
receiving left ventricular assist devices as either a bridge to
transplant or as destination therapy. And they're seeing them for
chronic heart failure because really all other medical therapy
has failed and we use the pump to try and recover their own
heart. So when the pump's implanted, we optimize the LVAD
unloading, the maximum loading, and we give them a very
aggressive medical therapy regime, unless they may not have
tolerated these medications before because of poor blood pressure
and renal dysfunction, we find they do tolerate them. So we give
them in very aggressive doses and then we monitor their
underlying function at regular intervals and try and promote
recovery. So with that, we had done this in England in the past,
in a single center study, but it had not yet been reproduced,
which was obviously essential to have a bigger impact.


Dr. Emma Birks:


So we did a prospective study of six big US centers. We found
that we've created a primary endpoint that was statistically
powered in advance. And the primary endpoint was the number of
patients that recovered within an 18 month period, that were
explanted and remained off the pump and alive without transplant
over for one year. So overall we found that of the 40 patients we
recruited in the centers with chronic heart failure, we were able
to explore 19. Of those that satisfied the primary endpoint, that
was actually 40% of patients, with 52.3% being explanted overall.
And importantly, patients were explanted in all six centers, so
we found that the protocol was reproducible under the how much
higher rate of recovery that you would otherwise see. Normally
there is a database in the US that tracks outcomes from bad
patients. And generally only 1-2% seemed to recover enough to be
explanted generally. So this was a much bigger percentage.


Dr. Carolyn Lam:


Emma, first of all, congratulations, what an important trial and
what stunning results. More than half of patients receiving that
protocol were explanted. That's just remarkable. Now, could I
just ask, what is it that you did that was different? I noticed
you spent a lot of time saying this was an aggressive
pharmacological protocol that was along with the LVAD unloading.
Could you maybe elaborate on that a little bit more?


Dr. Emma Birks:


Yeah, I think that was a very important part of it. So generally
I think when the LVAD goes in most centers, the patients are very
sick, so most of those patients wouldn't then try and recover
them or look at underlying functions. I think that was the first
thing that was different was to try very hard. And then we had
centers, the experience, I had done this before, it was also very
helpful, all agreeing to do the same thing. We use a very
aggressive regime of ACE inhibitors, Beta blockers, auto
serotonin antagonists and ARBs. And that was also an unusual
thing. We use the fact that they're supported with the pump to
use both an ACE and an ARB together, but the idea that they have
better blood flow in the cranial is way more tolerant and we give
very high doses. So we use Lisinopril with the target dose of 40
milligrams, Coreg with a target dose of 50 BID, Aldactone 25
milligrams daily.


Dr. Emma Birks:


And then we add in losartan if they tolerate it and actually aim
for 150 milligrams daily, so those doses are very high. And I
think not normally given to people on LVADs. So you must've had
the LVAD that don't tolerate the medical therapy and stop it.
They might just have blood pressure control, etc. There is now
also another INTERMACS trial, a sort of big study that's come out
that actually shows benefit of neurohormonal antagonists in
general. So that goes together with our study to show that they
should already be given and then the regular testing. So we had
quite thorough testing. So first of all, we do echos on the pump
and then we do echos with the LVAD turned down to a speed at
which is not contributing. So we do that and we do an echo at
five minutes with it down 15 minutes, and then we walk the
patient, distress them. Once we show that the hearts come down in
size and improved function, then we do an exercise test, right
heart cath on an off pump to look at the hemodynamics.


Dr. Carolyn Lam:


Wow. So tremendous effort and really the protocol is unique in
and of itself, not just the pharmacological therapy, also the way
this is monitored and decisions are made really, really amazing.
Just one last question for me, because it's a humbling reminder
of the importance of neurohormonal blockade in these patients. Do
you continue that after they're explanted?


Dr. Emma Birks:


Yes, we do. And we continue aggressively and that's slightly
different as well in that normally you wouldn't give a patient a
nascent an up of course, but given that they've already tolerated
it on the pump in that same patient. So we restart the same drug
regime afterwards, and we actually like to get them to quite
along that dosage before we discharge them from the XPLAN, we
don't want to do that slowly. We get them back on it quite
quickly. And then we follow them very carefully because we don't
really know the long-term durability.


Dr. Carolyn Lam:


Wow, thank you. Hesham. I would love your thoughts on this paper.
I mean, it really, really is remarkable results.


Dr. Hesham Sadek:


Yeah. I mean, I was very happy that we received this paper to
review, frankly I've been following that work for a long time
since the first new England paper that came out and I'd like to
congratulate you for an amazing work. I think this will change
the field. First, how was this trial different from the first
trial, other than the fact that it's multicenter, what would you
say are the major changes that you made to the protocol and what
you've learned since the first trial?


Dr. Emma Birks:


Yes, you're absolutely right. We did make some changes. So first
of all, it was six sites instead of one site. I think it was very
important to reproduce it in the US but we changed the protocol
itself as well. The first trial had optimization of the LVAD
speed, really just by echo looking at the reduction in the
ventricle size. It had the aggressive medical regime was very
similar except this time we increased the Losartan dose from 100
to 150 after the Hill's trial came out. The testing was very
frequent in the original English Sheffield study, probably a
little bit too frequent to be able to be adopted on a wide scale.
So we tried to reduce it down a little bit. So we decrease the
frequency of the low-speed echos. I think we had them at six
weeks, four months, six months, nine months in a year.


Dr. Emma Birks:


And after that, we saw if they were already improving and started
and only did them at a year to 18 months, if they were improving.
And then we also cut down the number of exercise tests. So we
didn't do the exercise test until the echo was already showing
significant improvement. For two reasons, one, we didn't find it
very reliable and two, it was just too much testing for the
patient. So it was more of a confirmatory test. In fact, it
wasn't a requisite for a pump explantation. We didn't do a left
heart catheter, which we did before. Previously we tried to
measure LVEDP, this time we decided which was enough. So we just
did a right heart cath on and off pump. And we did that once the
echo was improved as well. So we rationalized that a little bit.
And then the other important thing was before in hayfield study,
once we saw the ventricular size come down and injection fraction
start to improve, we actually added in Clenbuterol, which was a
Beta-2 agonist.


Dr. Emma Birks:


And the idea with that was to cause a kind of physiological
hypertrophy so that when you took the pump out, the heart didn't
just dilate. We were worried about atrophy at the heart on the
pump long-term. So we did that to try and improve the durability
of recovery. So the reason we left off this time was really the
previous protocol was very good, but was very complicated. So we
wanted to see what rate of recovery we could get just with the
aggressive reverse remodeling, neurohormonal drugs, plus the
aggressive testing and the optimum loading with the idea that
later on, we could add on either Clenbuterol or something later
to improve the durability of recovery, if the ability of recovery
is not good enough, but actually so far it's proven to be pretty
good because the study itself takes quite a long time. It was
sort of to recruit them. We had an 18 month period than the
follow-ups. It was already a multi-year study. So we wanted to
establish a regime that many centers could use to try and promote
recovery.


Dr. Hesham Sadek:


I want to follow up on that last point, because as you know, I've
looked at some of these Heights as well in our center, and we
looked at the results with you and Stavros and others. So the
myocytes size is expected to change, decrease with unloading,
right with sufficient unloading. So how would you prepare the
Myocardium to take on the normal afterload if you are not going
to induce by a beta agonist, for example,


Dr. Emma Birks:


What I would like to do in the future is try using the pump
itself actually. Sometimes there's heart recovers, the heart
shrinks and actually start opening their own valve and working in
the heart. Of course, when you have the HeartMate one, actually,
sometimes wasn't synchronous with the heart. So sometimes the
heart will beat against the pump anyway. Once you go to the
continuous flow pumps, you've got continuous unloading. So I
think it'd be very interesting to intermittently turn down the
pump speed and load the heart to work it before you take the pump
out. So I would really like to do that. I think that might be the
next interesting phase of the study to improve your ability to..
So I guess once you've got maximum reverse remodeling and
improvement in function, you could just turn the pump speed down
to let the valve open.


Dr. Hesham Sadek:


Do you think perhaps if you do that, you will increase the
percentage of patients that can be explanted? Do you think that
could be a factor in the percentage of patient that can be
explained?


Dr. Emma Birks:


I think it might be, it might more improve the, to your ability
to make sure we have for a long, good echo function afterwards.


Dr. Hesham Sadek:


That's great. So another question this was limited to not
ischemic cardiomyopathy patients. Can you elaborate a bit on why
not include, for example, revascularized ischemic cardiomyopathy
patients.


Dr. Emma Birks:


Yeah, so we did that really just because we didn't want to change
too much from the original protocol. We also stuck with one
device because we thought if you have multiple pumps, multiple
diagnosis, it does get hard to analyze in a multicenter trial. So
we did that on purpose and we were always trying to simulate the
bridge to transplant population in the age group too. But
actually interestingly, most of the patients recruited in the
trial were destination therapy patients in the end.


Dr. Emma Birks:


I think this could be done with ischemic cardiomyopathy. I think
we don't have enough data on ischemic cardiomyopathy to know
whether it does or it doesn't recover. So I don't think our
results say that it's only known as ischemics. I think it just
means we haven't studied ischemics sufficiently. Logically they
might have more scarred. It might be harder to get such a good
percentage to recover. I think all of us in our individual
centers have seen a few and we've sort of seen the on pump echo
improved, and we've tested them and then taken some out. But most
of these cases are anecdotal. So I think that is another
important study that needs to be done, obviously a large group of
patients.


Dr. Hesham Sadek:


I agree. So given that they're not ischemic cardiomyopathy, do
you know how many of them had genetic testing or what is the
percentage of monogenic cardiomyopathys or how do you think these
patients would respond to this protocol?


Dr. Emma Birks:


But if you had a familiar history and actually found it didn't
make any difference, whether they recovered or not. I think some
of us have personally seen actually those were the familial
cardiomyopathy tend to recover more actually again, anecdotally.
We published a people before looking at the Titin gene saying
that that did recover. I think actually only five of these
patients, 12% of them had a family history, but some of them
recovered


Dr. Hesham Sadek:


One final question, as you know, I'm a basic scientist. So
ultimately the question I'm going to ask, what do you think the
mechanism is? Is it that these hearts are just in a vicious cycle
of remodeling and validation, increased pressure, and you were
sort of giving it a chance for actual structural reverse
remodeling where you changed the geometry of the myocardium and
perhaps rest of myocardium, allow for improvement of calcium
cycling dynamics, or do you think, is something more exciting?
Like three-generation for example.


Dr. Emma Birks:


Yeah, that's very interesting because I think the LVAD doesn't
unload, so it shrinks the ventricles. I think it does improve the
geometry and the dynamics. And then you use the drugs where they
may have felt before you almost put them from class four, heart
failure into class three with the bad to give that chance to work
again. And then I think various cellular and fibrotic factors
have been looked at and it's hard because there was so many
factors have been looked at that. You were going to find some
that go up and some that go down and what's important. But the
impression I get overall is that you do get improvement, the
matrix limits, the recovery on the fibrosis and the matrix.
Whereas you do get improvements of myocardial function and
cellular function. The cells will tend to reverse the dysfunction
and it's really whether that happens or not. It's probably
limited a lot by the matrix


Dr. Carolyn Lam:


That is amazing here. Hesham, I'm going to put you on the spot.
Do you have your own hypothesis about this


Dr. Hesham Sadek:


Based on the work that they did initially in the new England
paper, we did actually a small pathology study looking at cell
cycle of cardiomyocytes from the core samples and from the
explanted hearts post-transplant and we saw evidence of increased
cardiomyocytes cell cycle in these patients along with decreased
DNA damage and some metabolic remodeling as well with
mitochondria. So, you can't really tell much from tissue whether
you regenerated it or not, but as you know myocytes don't divide
and this is the basis for the lack of spontaneous regeneration of
the myocardium. So if this in fact removes the block to
cardiomyocyte cell cycle, then this might be a regenerative
therapy mechanism.


Dr. Carolyn Lam:


Well, this is amazing. I wish we had all day to discuss this
more. I mean, this is the only place you can get a discussion
that goes from clinical to basic signs and back to clinical.
Thank you so much, Emma and Hesham for sharing today. Thank you
audience for joining us today. You've been listening to
circulation on the run on behalf of Greg as well. Don't forget to
tune in again next week.


Speaker 1:


Program is copyright the American heart association, 2020.