Circulation May 23, 2017 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. In just a moment we'll
take a deep dive into hemo-compatibility-related outcomes in the
MOMENTUM 3 trial of a fully magnetically levitated pump in
advanced heart failure. But first, here's your summary of this
week's journal.


                                               
The first paper sheds light on the biological mechanisms
underlying cardioprotective effects of the Mediterranean diet.
First author, Dr. Wang, corresponding author Dr. Hu and
colleagues of Harvard, TH Chan, School of Public Health in
Boston, Massachusetts studied 980 participants from the PREDIMED
Trial including 230 incident cases of cardiovascular disease and
787 randomly selected participants at baseline followed up for
7.4 years.


                                               
Participants were randomized to a Mediterranean diet supplemented
with extra virgin olive oil, a Mediterranean diet supplemented
with nuts, or a controlled diet. Plasma ceramide concentrations
were measured and the primary outcome was a composition of
non-fatal acute myocardial infarction, non-fatal stroke or
cardiovascular death.


                                               
The authors found a novel positive association between baseline
plasma ceramide levels and incident cardiovascular disease. In
addition, the association between baseline ceramides and incident
cardiovascular disease varied significantly by treatment groups
where a Mediterranean dietary intervention appeared to mitigate
the potential deleterious effects of elevated plasma ceramide
concentrations on cardiovascular disease.


                                               
These findings, therefore, strengthen the evidence base for
recommending the Mediterranean diet for cardiovascular disease
prevention and suggest that plasma ceramides have the potential
to serve as markers of future cardiovascular disease risk.


                                               
The next paper describes a novel therapeutic approach against
hypertensive cardiac remodeling and provides the first evidence
of the cardio protective effect of cardiofibroblast-specific
activating transcription factor 3 or ATF3. In this study from
first author Dr. Li, co-corresponding authors, Dr. Du from
Beijing Anzhen Hospital in China, and Dr. Ma from Thomas
Jefferson University in Philadelphia and colleagues, the authors
used a discovery-driven unbiased approach to identify increased
ATF3 expression in mirroring hypertensive hearts and the human
hypertrophic heart, expressed primarily by cardiac fibroblast
cells. ATF3 knockout markedly exaggerated the hypertensive
ventricular remodeling, a state rescued by lentivirus mediated
microRNA aided cardiac fibroblast selective ATF3 over-expression.


                                               
Conversely, cardiac fibroblast specific ATF3 over-expression
significantly ameliorated ventricular remodeling and heart
failure. The authors further identified MAP2K3 as a novel ATF3
target, and that p38 was the downstream molecule of MAP2K3,
mediating the profibrotic hypertrophic effects in ATF3 knockout
animals.


                                               
In summary, this study provides the first evidence that ATF3
up-regulation in cardiac fibroblasts in response to hypertensive
stimuli, protects the heart by suppressing MAP2K3 expression, and
subsequently p38 TGF-beta signaling. Thus, identifying molecules
mimicking endogenous ligands or inhibiting microRNA that
down-regulate ATF3 expression, may represent novel therapeutic
approaches against hypertensive cardiac remodeling. These, and
other issues, are discussed in an accompanying editorial by Dr.
Jennifer Davis of University of Washington.


                                               
The next paper tells us that clinical frailty score may need to
be part of the pre-operative assessment of patients undergoing
transcatheter aortic valve replacement, or TAVR. First author,
Dr. Shimura, corresponding author, Dr. Yamamoto and colleagues of
Toyohashi Heart Center in Japan, utilized the optimized catheter
valvular intervention or OCEAN Japanese Multicenter Registry of
1215 patients undergoing TAVR and found that clinical frailty
score correlated with other markers of frailty, such as body mass
index, albumin, gait speed and grip strength. Furthermore, the
clinical frailty score was an independent predictive factor of
increased late-cumulative mortality risk. Thus, in addition to
reflecting the degree of frailty, the clinical implications of
these findings are discussed in an accompanying editorial by Dr.
Jonathan Afilalo from McGill University in Montreal.


                                               
In the final study, we learned that long-term anabolic androgenic
steroid use may be associated with myocardial dysfunction and
accelerated coronary atherosclerosis. Dr. Baggish and colleagues
from Massachusetts General Hospital in Boston, used a
cross-sectional cohort design of 140 experienced male weight
lifters, age 34-54 years, comprising 86 men reporting at least
two years of cumulative lifetime anabolic androgenic steroid use,
and 54 non-using men. Compared to non-users, steroid users
demonstrated relatively reduced left ventricular systolic
function and diastolic function on transthoracic
echocardiography. Furthermore, steroid users demonstrated higher
coronary artery plaque volume on coronary CT angiography compared
to non-users. In summary, this is the first large controlled
study of its type to demonstrate that long-term anabolic
androgenic steroid use is associated with both systolic and
diastolic myocardial dysfunction, as well as coronary
atherosclerosis. Thus, when clinicians encounter young or
middle-aged men who exhibit evidence of unexplained left
ventricular dysfunction or premature coronary artery disease, the
possibility of cardiotoxicity due to long-term anabolic
androgenic steroid use should be considered in the differential
diagnosis.


                                               
Well, those were your summaries. Now, let's move on to our
featured discussion.


                                               
For our featured discussion today, we are actually reviewing a
secondary analysis of the MOMENTUM 3 Trial, which is a
multicenter study of the mag lev technology in patients
undergoing mechanical circulatory support, with the HeartMate 3.
And to discuss today's findings I'm so pleased to have the
corresponding author, Dr. Mandeep Mehra from Brigham and Women's
Hospital in Boston, Massachusetts, as well as Dr. Biykem Bozkurt,
Associate Editor from Houston, Texas.


                                               
Welcome Mandeep and Biykem.


Dr. Mandeep Mehra:     Thank you. It's a
pleasure to be with you all.


Dr. Biykem Bozkurt:       
Thank you.


Dr. Carolyn
Lam:              
Let's start by getting a few definitions right, shall we, just
for our audience. This specific article, and congratulations
Mandeep, it's just so great, it speaks of
hemo-compatibility-related outcomes. Could you start by telling
us what that is, and maybe reminding us what the original
MOMENTUM 3 short-term results showed.


Dr. Mandeep Mehra:     Sure. As our listeners
are aware, left ventricular assist devices have really
transformed the management of refractory advanced heart failure,
by the introduction of a form of flow, called continuous flow, in
the devices, which tend to render patients, relatively low
pulsatiles to non-pulsatile. Now what we've seen is that the
interface between this very unnatural physiology from continuous
flow in concert with the patient's biology tends to create a
constellation of problems that we sort of refer to as
hemo-compatibility-related adverse events.


                                               
For example, we have seen a very curious development of recurrent
gastrointestinal bleeds that tend to occur in a manner similar to
what was observed with critical aortic stenosis, the so-called
Heyde's Syndrome. Similarly we see stroke-related problems and we
also see evidence of thrombosis that can sometimes develop within
the pump. So we refer to the conglomeration of these unique
complications that arise from the abnormal interface between the
device and the patient as hemo-compatibility-related adverse
events.


Dr. Carolyn
Lam:              
And this is a secondary analysis, a six-month secondary analysis,
right? So could you give a little bit of background of why you
would hypothesize that these events might be different with the
HeartMate 3 versus 2? I mean, it's quite unique that we're going
back to creating a pulse.


Dr. Mandeep Mehra:     Yes. Let me fist
define for our audience what the MOMENTUM 3 Trial was designed to
initially do, and is still doing. MOMENTUM 3 is a randomized
controlled trial of two devices: one, a conventionally available
continuous flow device called the HeartMate 2, and the second
device, the novel pump called the HeartMate 3. The HeartMate 3 is
a pump that took two decades to engineer. And it took that long
because it is very unique, based on the following principles.


                                               
First, it's a small profile, so the entire pump can be placed
intrathoracically. Second is that the way in which it moves
blood, its rotor, is fully magnetically levitated, which means
that it has no friction when it rotates. The third is that
despite its small profile, this device has wide blood flow gaps,
meaning that as blood is moving in this centrifugal flow pump, it
does not expose the blood elements to as much of sheer stress as
one sees with other conventionally available devices. And then
finally, what this device has uniquely is a intrinsic pulse, and
what that means is that we program this device in a fixed program
to actually ramp its speed up and ramp it down so that it creates
an intrinsic pulse of about 30 beats per minute, which is
engineering-wise designed to improve pump wash out; that's the
intention.


                                               
So the MOMENTUM 3 Trial was constructed to really compare these
two devices and we recently reported, on the primary end point of
the six-month outcomes of this trial. And the trial primary end
point was set at survival free of a disabling stroke, or the need
for re-operation because of pump malfunction. And what we found
was that this pump, the HeartMate 3, clearly met its
non-inferiority end point, versus the HeartMate 2, but also
demonstrated superiority on the primary end point at six months.
We were certainly not expecting to see superiority at this early
time point, but we were very fortunate to see that.


                                               
Now what is unique about this is that for the first time ever, we
saw no cases of suspected or manifest established pump
thrombosis, as a result of de novo pump thrombosis requiring
re-operations with the HeartMate 3 device. And this is a
frequency of about 10% that we normally observe with pumps. That
is one in 10 pumps will clot off within about six months, and
require re-operation. So we were very gratified to see this
observation in the short-term data of the primary MOMENTUM 3
database.


                                               
Now as a result of that observation, Carolyn, we thought that the
hard end points, as are typically adjudicated for the primary
basis of these clinical trials, missed the entire constellation
of hemo-compatibility-related outcomes because these are patients
who develop both bleeding and clotting complications. And the net
burden of hemo-compatibility is not entirely available for
review, which is the basis of this important secondary analysis
that was published in Circulation.


Dr. Carolyn
Lam:              
What striking findings. So tell us the bottom line.


Dr. Mandeep Mehra:     What we found in the
secondary analysis was evidence that the burden of
hemo-compatibility-related adverse events is lower in patients
with the HeartMate 3, compared to the HeartMate 2 device. And
that was the basis of the bottom line that we found.


                                               
In particular, we knew that there were no episodes of de novo
pump thrombosis with the HeartMate 3, but we also found that
there was evidence of a reduction in non-disabling strokes with
the HeartMate 3 device. So we now have evidence that thrombotic
complications, minor strokes, as well as pump thrombosis, seem to
be abrogated by this new pump.


                                               
What we should keep in mind, however, is that this is still early
data from the ongoing MOMENTUM 3 Trial, and the trial is actually
designed to enroll and observe over a thousand patients, over two
years. And we are basically showing in this a very early look at
six months of about 300 of these patients. And so that needs to
be kept in mind. But we are extremely encouraged by these early
trends suggesting that we may have started to break the issues
related to the barriers of implementation of such therapy in the
hemo-compatibility domain.


Dr. Carolyn
Lam:              
Yeah, and as a heart failure doc, I can tell you that I share
that excitement and I know that Biykem does too, as did the
editors.


                                               
Biykem, tell us a little bit about what we talked about as
editors about this paper.


Dr. Biykem Bozkurt:       
Indeed. Mandeep, the hemo-compatibility concept which is being
addressed in this new publication is quite novel and is exciting,
and addresses the continual spectrum of the pathology, ranging
from the GI bleed, to the stroke spectrum. The question I have,
in this study, the overall scores were not different in the
absolute number that we saw as a score from the
hemo-compatibility ranking.


                                               
Do you think we would continue to use this approach as a
quantitative score, given the fact that there may be
bidirectional impact from different devices on the different
spectrum, especially with the recognition that HeartMate 3 seemed
to be protective against the thrombotic, perhaps events, or
should we use it more of a qualitative score card looking at
which perhaps spectrum the device tends to be a little bit more
risky or beneficial. So shall we color code this score and try to
perhaps focus on the spectrum of thrombosis versus bleeding and
then try to strategize?


Dr. Mandeep Mehra:     Thank you for that
very erudite question, Biykem. You hit right at the heart of the
matter. So let me make a few comments about that. The first issue
is that so far, the field has not had a clear definition of
hemo-compatibility. Hemo-compatibility has been more of a
engineering term. When someone said hemo-compatibility, they
thought of biomaterials, rather than a clinical definition of
hemo-compatibility. So for the first time, we have actually
introduced the term hemo-compatibility into the lexicon of
definition, managing patients with LVAD, so that's one important
point.


                                               
The second important point is that we, until this day, until this
analysis, have not had the ability to really provide people with
a full picture of the entire burden of experience of
hemo-compatibility-related complications that an individual
patient experiences as they are on this device, because you know
that patient's going to have a GI bleed, and then they may have a
stroke, because we may change, dynamically we may change
anticoagulation for instance if someone has one event then the
other, and the traditional way in which studies are done, hey do
not give you a clear picture into the burden of
hemo-compatibility. So the most innovative thing about this
clinical hemo-compatibility definition, is that we've not
introduced a score that reflects the burden of disease, and we
have also created tiers of severity of the burden of disease
experience into three quantitative tiers that include various
subsets which are hierarchal.


                                               
So for example, is one gastrointestinal bleeding the same as
non-disabling stroke? Well, no. One gastrointestinal bleeding may
be a milder form a hemo-compatibility-related problem. So our
early look at this clearly shows that survival free of a
hemo-compatibility-related event is clearly lower in the patients
with a HeartMate 3. However, as you astutely pointed out, when
you examine purely the burden of hemo-compatibility-related
complications experienced by the survivors, one actually sees a
trend in favor of the HeartMate 3, but not a statistically
significant difference, largely because we have not yet abrogated
problems related to bleeding complications on the side of the
hemo-compatibility.


                                               
Why is that? Well, it's because we still treat all patients in
both groups with the HeartMate 2 or the HeartMate 3 with the same
intensity of anticoagulation. What this sort of data points out
to us in the future, first of all, is that it allows us to
compare apples to apples, as we are looking at different device
platforms, that's number one. Second is it gives a much more
robust look into the total patient experience. And third, it
actually gives us insight into whether altering one component of
the equation, so let's say there's a bleeder, if you actually
react to that clinically, will you start to see problems on the
clotting side.


Dr. Biykem Bozkurt:       
This is a very, very important study that addresses the whole
spectrum of hemo-compatibility in a more comprehensive fashion,
and also points out perhaps the differences that we see in
overall others, centrifugal flow, left ventricular assists,
support systems such as the Heartware HVAD study that showed
increase in hemorrhagic stroke, especially hemorrhagic stroke in
the first six months in the ENDURANCE Trial, whereas the
HeartMate 3 has shown in the MOMENTUM 3 publication, as well as
the Circulation secondary end point study demonstrates a
reduction in disabling strokes and absence of any pump
thrombosis.


                                               
So there are differences, despite both of the pumps are
centrifugal, there are differences in the profile, and the
spectrum of the risk and hemo-compatibility. And one other
interesting finding from this study is that the predictors for
hemo-compatibility outcomes are complementary to what has been
known in the sense that lower antiplatelet and anticoagulation
management strategies are associated with increased risk of
hemo-compatibility adverse events.


                                               
And surprisingly, the control of blood pressure did not appear to
correlate with the hemo-compatibility outcomes. So from that
perspective, it differs from the ENDURANCE Trial where the
uncontrolled blood pressure or hypertension was associated with
hemorrhagic strokes, in the ENDURANCE Trial, whereas in the
MOMENTUM 3, the blood pressure did not appear to correlate with
the hemo-compatibility outcomes or pump thrombosis.


                                               
So these are very interesting findings and I think are
complementary to the evolving field of the risk benefit ratios in
patients with LVAD support. And from that perspective, we in
Circulation felt that this will be a very valuable publication
for our readership as well as for the whole heart failure and
transplant community.


Dr. Carolyn
Lam:              
Thank you, so much for joining us today, don't forget to tune in
next week.