Circulation August 06, 2019 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
cohosts, I'm Dr Carolyn Lam, associate editor from National Heart
Center and Duke National University of Singapore


Dr Gregory Hundley:       And I'm
Greg Hundley, associate editor from the Pauley Heart Center in
Richmond, Virginia at VCU Health. Our feature article today
really invokes thought regarding LVAD bridging to heart
transplantation. I really look forward to the conversation with
Dr Veli Topkara from Columbia University, the corresponding
author and our associate editor, Dr Mark Drazner from UT
Southwestern. And it's regarding the outcomes from their study,
evaluating patients waiting for transplant that are bridged with
an LVAD versus not. But before we get to that, let's dive into
some of our other original articles with our little coffee chat.
Do you have an article that you'd like to discuss?


Dr Carolyn
Lam:               
You bet I do Greg and I have my coffee here. Have you ever
wondered, does microvascular disease, in any location in the
body, increase the risk of lower limb amputation? Well, this was
looked at in the paper that I chose first today. It's from Dr
Beckman from Vanderbilt University Medical Center in Tennessee
and his colleagues, and they basically examined 125,674
participants in the Veterans Aging Cohort Study from 2003 to 2014
and analyzed the effect of prevalent microvascular disease
defined as retinopathy, neuropathy and nephropathy and peripheral
artery disease status on the risk of incident amputation events,
of which there were 1,185 amputations over a median of 9.3 years.


Dr Gregory Hundley:       Wow,
Carolyn. What did this study find? What did Josh and his
colleagues find?


Dr Carolyn
Lam:               
They found that the presence of microvascular disease increases
the risk of amputation significantly in the absence of peripheral
artery disease. As many as one in six below knee amputations may
result from microvascular disease, even without peripheral artery
disease. Microvascular disease also potentiates the amputation
risk in persons with peripheral artery disease to more than
20-fold, compared to persons with neither peripheral artery
disease nor microvascular disease. Further research is really
needed to understand the mechanisms by which this occurs. And in
the meantime, clinicians should bear this increased risk in mind
when screening for and managing lower extremity disease.


Dr Gregory Hundley:       Ah. Well
Carolyn, my first paper is somewhat related because we're going
to talk about triglycerides. And this paper is from Zahid Ahmad
from UT Southwestern Medical Center. He's the corresponding
author. And can you imagine Carolyn an antibody that could
correct elevations in serum triglycerides?


Dr Carolyn
Lam:               
Tell us about it, Greg.


Dr Gregory Hundley:       Well, I'm
going to give you a little background first. Low levels of
triglycerides and other lipids are observed in individuals with
loss of function mutations in angiopoietin-like protein 3 which
inhibits lipoprotein lipase activity, increasing triglycerides
and other lipids, and providing a rationale for development of a
monoclonal antibody therapy.


Dr Carolyn
Lam:               
Interesting. What did this study do Greg?


Dr Gregory Hundley:       It
evaluated evinacumab. They looked at the safety of this. This is
a fully human angiopoietin-like protein 3 antibody, and it was
compared with placebo, with no serious treatment emergent adverse
events, no events related to death or treatment discontinuation
was reported. They did two phase one studies evaluating single
and multiple ascending doses. In addition, substantial and
sustained percent reductions from baseline versus placebo were
observed and triglycerides with absolute levels reaching about 50
milligrams per deciliter for several of the evinacumab doses at
specific time points in both studies. And therefore, the data
from these two phase one studies in this one paper support
further clinical evaluation of this new antibody in larger
studies of hypertriglyceridemic individuals.


Dr Carolyn
Lam:               
Definitely a space to look out for. Well Greg, my next paper is a
basic paper. Genome wide association studies have identified
chromosome 14 Q32 as a locus for coronary artery disease. The
disease associated variants fall in a hitherto uncharacterized
gene called Hedgehog Interacting Protein Like 1, or HHIPL1. the
function of this gene and its role in atherosclerosis has
previously been unknown, well, until today's paper. But Greg,
here's your quiz. What do you know about the hedgehog proteins?


Dr Gregory Hundley:       Well, I
know hedgehogs are friendly little animals and I know they must
have great proteins because they're so friendly.


Dr Carolyn
Lam:               
Why did I expect that? Oh, let me tell you a little bit about
them. The mammalian hedgehog proteins like sonic hedgehog, desert
hedgehog, and Indian hedgehog are secreted molecules that exert a
concentration and time dependent effect on target cells following
binding and complex signal transduction pathways. They induce the
transcription of target genes, primarily involved in cell
proliferation, survival, and fate specification.


                                               
Now in adults, the hedgehog signaling is involved in the
maintenance of adult vasculature and ischemia induced
neovascularization, including after myocardial infarction.
Today's authors, however, including Tom Webb from University of
Leicester and colleagues, report the first experimental
investigation of HHIPL1 and the present evidence that it is a
secreted proatherogenic protein that regulates smooth muscle cell
proliferation and migration. So, that's novel.


                                               
Through a series of experiments involving coronary artery
disease, relevant human cells and mouse models, they showed that
HHIPL1 is a secreted protein that interacts with sonic hedgehog
and is a positive regulator of hedgehog signaling. In murine
models, HHIPL1 deficiency attenuates the development of
atherosclerosis by reducing smooth muscle cell proliferation and
migration. The clinical implications are two-fold. First, this
study supports HHIPL1 as the causal gene at that 14 Q32 coronary
artery disease locus that we did not really understand
previously. And secondly, HHIPL1 is a promising therapeutic
target that affects a pathogenic mechanism not addressed by
current mechanisms for coronary artery disease. Room for novel
development.


Dr Gregory Hundley:       Very
interesting Carolyn. Well, I've got another basic science paper,
and this is from Dr Kenneth Walsh at University of Virginia and
it's going to look at the role of neutrophils, not necessarily
macrophages but neutrophils and their role in pressure overload
induced cardiac dysfunction. While the complex roles of
macrophages in myocardial injury is widely appreciated, the
function of neutrophils in nonischemic cardiac pathology has
received relatively little attention. This study examined the
regulation and function of neutrophils in pressure overload
induced cardiac hypertrophy as mice underwent treatment with Ly6G
antibody to deplete neutrophils and then subjected them to
transverse aortic constriction or TAC.


Dr Carolyn
Lam:               
Huh? What did they find?


Dr Gregory Hundley       
Caroline, the study revealed that neutrophils played a critical
role in the hypertrophy of the left ventricle that results from
pressure overload in this murine model of heart failure and
identified that a non-canonical Wnt protein is essential for the
recruitment of neutrophils to the injured myocardium.


Dr Carolyn
Lam:               
Hmm. What do you think are the clinical implications of this?


Dr Gregory Hundley        This
study demonstrates how neutrophils contribute to the hypertrophy
of the left ventricle under conditions that do not involve
ischemia or myocardial necrosis. Also, since cardiac hypertrophy
is a risk factor for the development of heart failure, this study
implicates WnT5a mediated neutrophil infiltration as an early
step in the progression of this disease.


Dr Carolyn
Lam:               
Wow, thanks Greg. That was so cool. But let's hurry on to our
feature discussion, shall we?


Dr Gregory Hundley        You
Bet.


Dr Carolyn
Lam:               
Bridge to transplant with left ventricular assist devices is a
mainstay of therapy for heart failure in patients awaiting heart
transplantation. The criteria for heart transplantation listing
does not differ between patients medically managed versus
mechanically bridged to heart transplant. However, are there
differences in post-transplant outcomes between medically managed
and mechanically bridged patients? Well, today's paper provides
important data to address this question. So pleased to have with
us the corresponding author, Dr Veli Topkara from Columbia
University Medical Center, New York Presbyterian as well as Dr
Mark Drazner, associate editor from UT Southwestern. Welcome
gentleman. Veli, this is an important question. Could you please
tell us how you addressed it and what you found?


Dr Veli
Topkara:               
We decided to visit an old question of whether bridging with LVAD
confers at risk for post-transplant mortality. Because the field
and pump technology has been rapidly changing. There has been a
significant increase in utilization of devices nationwide to the
extent that more than 50% of patients already have an LVAD in
place by the time they receive a heart transplant. And patients
also wait much longer on these pumps before they could get a
heart.


                                               
Currently, available devices provide continuous flow and patients
essentially live without a pulse for many months to years waiting
for a heart. And with this unique physiology, they also have
unique complications such as RV failure and there has also been
pre-survey reports including one from our center suggesting an
increase in the primary graft failure rates after heart
transplant. And mostly seen in patients who were bridge to
transplant with an LVAD.


                                               
To address some of these questions, we took advantage of the UNOS
database, which is the largest prospective transplant data
registry in the United States. We were able to identify more than
14,000 patients who are either medically or mechanically bridged
to transplant. We then derived a cohort from patients who were
LVAD baseline by propensity score and we looked at their
outcomes.


                                               
And what we found was that patients who were mechanically bridged
to transplant with an LVAD, had 9.5% mortality at one year,
compared to 7.2% in patients who were medically bridged. And this
is more than 30% increase in relative risk of death for LVAD
patients. When we looked at the specific cause of death at one
year, LVAD patients had a higher number of cardiovascular death
secondary to primary graft failure, confirming findings of the
recent studies at a larger scale.


                                               
Next, we looked at whether mortality risk factors were similar in
the mechanical versus medical bridged patients. And this is a
very important question clinically because the criteria for
transplant listing do not distinguish between the two patient
cohorts. For example, at my center age cutoff transplant listing
is less than 72 years of age and that is whether or not patients
are on VAD support. And same applies for example, GFR cutoff for
renal function or PVR cutoff for pulmonary hypertension. And all
the cutoffs that are utilized are essentially identical for
transplant candidates irrespective of the bridging strategy.


                                               
But what we found in this paper, however, what's quite different
that if we apply the same thresholds for mechanical versus
medical bridged patients, for some of these risk factors, you end
up having outcomes that are remarkably different. For example,
for patients with a normal renal function, the mortality risk is
similar going into transplant with or without an LVAD, but for
patients with borderline renal function observed mortality has
more than doubled for those going into transplant with an LVAD,
as opposed to medical therapy.


                                               
And we also observed similar trends for recipient age, BMI and
PVR, in which numerical increase in these factors would translate
to high risk of mortality in LVAD patients going into heart
transplant. Despite the limitations of this large registry
analysis, I think these findings suggest that we may need to
think of it differently when it comes to listing or transplanting
patients who are on LVAD. And there seems to be a group of
patients who are perhaps maybe better served by staying on an
LVAD as opposed to moving on to heart transplant and we need to
better identify who these patients are.


Dr Carolyn
Lam:               
Oh Wow. Veli, thank you. First, congratulations on a very
important paper and also how you beautifully summarized.
Mechanically bridging patients associated with a higher risk of
early post-transplant mortality and even providing data on the
cause and risk factors associated with that mortality. Mark,
could I bring you in here? Not just as AE (associate editor), but
as a doc[tor] who manages many of these patients. What were your
perspectives?


Dr Mark
Drazner:            
As I step back and as Veli said, there's an increasing number of
patients who are being bridged with a VAD, so the question
clearly is important, and we don't really have any randomized
data available to us in terms of how the bridging strategy may
impact outcomes. When you look at the groups of patients who are
supported with VADs or not, they're very different and so you
need to do some statistical manipulation which here they did
propensity matching, to try to come up with equal groups as you
look at their outcomes. That was nicely done.


                                               
And then theoretically I think you could argue there may be
reasons why patients bridged with VADs may do better or they may
do worse. They may do better because you may restore their
functionality, you may improve renal function and, but they may
do worse because they have coagulopathies, the VAD itself may
lead to complications and so it's a question you can't really
answer just logically. You really need some data which is I think
the best study that's been brought forward so far as the one
we're discussing today. Veli, let me ask you because the obvious
question then is why do you think the outcomes are worse among
the patients who are bridged?


Dr Veli
Topkara:               
I think they are doing worse for multiple different reasons.
Having an LVAD is clearly an additional surgery which technically
makes the second transplant surgery more complicated. But when we
looked at the risk factors for primary graft failure at our
institutions, the predictors of primary graft failure in LVAD
patients were also very similar to factors we identified in this
nationwide analysis which included renal failure, RV dysfunction,
as well as trans-transplant and increased time on device support.
I think it's clear that some subset of LVAD patients who have
these risk factors are at higher risk for increased
post-transplant mortality for some of the mechanistic reasons are
unclear at this point.


Dr Mark
Drazner:            
Do you think their continuous flow exposure is part of it?


Dr Veli
Topkara:               
That's clearly one of the hypotheses that we have been talking
about because as we discussed, these patients are exposed to
continuous flow for a long time and one of the concerns is
whether they lose their peripheral arterial venous-reactivity
over time. And this could potentially also be the reason why
patients who are on pump support for longer times are at higher
risk for PGF. That's a possible underlying mechanism. But in this
data set, we didn't have fair data with regards to pulse pressure
and pulsatility, which could have helped answering this question.


Dr Mark
Drazner:            
And just for clarification for the listeners, this was
pre-HeartMate 3 data, is that correct?


Dr Veli
Topkara:               
Yes. This analysis doesn't include any HeartMate 3 patients.


Dr Carolyn
Lam:               
And Mark, if you don't mind, could you also clarify for the
listeners why you specifically pointed out HeartMate 3 in the
setting of the pulsatility?


Dr Mark
Drazner:            
There is some degree of pulsatility reintroduced with the
HeartMate 3, whether that has any physiological consequences is
not yet known. Certainly, in terms of the impact of transplants.
But as Veli said, the dataset available didn't yet include the
HeartMate 3 so that's, remains an unanswered question for us
currently, but certainly an important one.


Dr Veli
Topkara:               
We would probably be able to do this analysis now that we have
accumulated more patients with HeartMate 3. At the time of the
study we didn't have any HeartMate 3 patients in the registry. In
terms of primary graft failure, we have implanted over 160
patients with HeartMate 3 at my center, but we still see primary
graft failure in HeartMate 3 patients going into heart
transplant, but that would clearly be an interesting follow up
project.


Dr Mark
Drazner:            
Yeah, for sure. Another point that people, as they looked at your
paper and asked me, is in terms of the impact of the VAD
complications, whether the patients who are doing worse or those
who, because they are patients who had VAD who have had
complications and then went on a transplant and the impact of
that, in terms of your findings. I know you did some analyses on
that. Could you just clarify that for our listeners as well?


Dr Veli
Topkara:               
Sure, so we wanted to look at for the LVAD patients, if there
were any VAD related factors that would impact the posttransplant
mortality and one of the things that we looked at was, their
specific complications on LVAD support and were able to pull that
data by looking at their reason for 1A upgrade status which
clarifies the complication pipe. And when we looked at, based on
complication type, we didn't see any impact of complication on
the post LVAD mortality. In other words, the other patients who
are transplanted with an infection or they were transplanted
because of device thrombosis, they did not have any difference in
terms of their posttransplant mortality.


                                               
We also compared patients who were supported by axial flow
devices versus centrifugal flow devices and again, there was no
significant difference in terms of posttransplant mortality. One
factor that we found that was significant was the duration of the
LVAD support and patients who stayed on the LVAD for longer times
clearly had increased higher risk of posttransplant mortality.
And this is also something that we had found in our institutional
data.


Dr Mark
Drazner:            
And Veli that would potentially speak to the impact of the
continuous flow if duration of VAD is a risk factor.


Dr Veli
Topkara:               
That's our hypothesis Mark. And I think we all tend to think that
continuous flow is not natural, and we have pulse style flow for
a reason. Now it's possible that if our bodies and end organs and
vessels are exposed to continuous flow for a long time, that may
be potentially a reason for, increased risk of PGF or raise of
PGF after heart transplant. But I don't think we have enough data
yet.


Dr Mark
Drazner:            
Veli, one of the other interesting findings was the lack of
impact on long-term outcomes. I'd be interested in your thoughts
about that, why there was an impact on the first year but not
long term.


Dr Veli
Topkara:               
Absolutely. And that was a critical part of the findings and when
we looked at our survival, when we visually looked at the curve,
it seemed like the curves really separated early on and they sort
of remain parallel to each other after one year. And for that
reason, we did a conditional survival analysis starting from one
year and then we compared starting for one year. There was
actually no difference between the LVAD versus medical group.
Again, confirming that the adverse impact of survival was really
early, within the first year after transplant and I think that
really has to do with primary graft failure as well as vasoplegia
which are, typically seen early posttransplant. And I think the
reason the VAD support is increasing mortality is most likely
through increasing risk of PGF as well as vasoplegia. Now that's
my read on the early risk rather than the late impact.


Dr Mark
Drazner:            
Do you think that speaks to maybe not as big an impact on the
immunological milieu of VADs as one might anticipate?


Dr Veli
Topkara:               
Certainly, I mean the immunology, one thing we know is that LVAD
patients have higher HLA sensitization going into transplant.
However, primary graft failure is typically very early after
transplant. And in general, we don't find, obviously we don't see
any rejection in these patients. The mechanism is not related to
HLA mediated rejection.


Dr Mark
Drazner:            
That's interesting.


Dr Carolyn
Lam:               
Well Mark and Veli, thanks so much. This is such an important and
interesting discussion. Could I wrap it up now by asking each of
you, you've already covered possibly the important areas for
future research including the pulsatile devices, but what should
clinicians take home right now? Veli, if I could start with you,
because you had already said earlier that perhaps these patients
need to be more carefully considered. What do you mean by that?
What's the take home for now?


Dr Veli
Topkara:               
I think the question is whether we should be listing or
transplanting LVAD patients who are high-risk, and I think the
research should focus on developing tools to better identify LVAD
patients who are too high-risk for transplant. In this project,
we only worked with a limited number of variables that were
available in the UNOS registry, but there may be more specific
clinical risk factors or even biomarkers predicting outcome in
this unique cohort of LVAD patients potentially transitioning
into transplant. I think that's an important question to figure
out.


                                               
And another important question is whether we should be using
identical cutoffs for listing patients with or without LVAD and
if not, what would be the ideal cutoff for each one of these risk
factors? Because what I read from this paper is that, a
creatinine level of 1.8 may signal a different risk in an LVAD
patient versus another patient on a minor trump. That's another
important question.


                                               
And also, since October of last year, the new heart allocation
policy has been in place, which now defines LVAD patients to
appear status three or four based on their complication profile.
And it will be interesting to see how the new allocation system
would impact patients are on LVAD support waiting for an organ.
And it's possible that these patients may end up waiting longer
compared to patients who are with cardiogenic shock and are
assigned to higher tier status. And if LVAD patients wait longer
as we see from this data, they will have worse posttransplant
outcomes. It's going to be very interesting to see how the new
allocation policy impacts.


                                               
Another point I want to make is that with the recent MOMENTUM-3
trial patients receiving HeartMate 3 LVADs, had a 13.4% mortality
risk at one year and this is actually lower than 17.6% mortality
at one year in high risk LVAD patients in our study. Again,
questioning transitioning from LVAD to transplant in high risk
patients.


Dr Mark
Drazner:            
I might take a step back even further. It's an important, it
touches on a critical question in my mind, which is if you have a
patient who needs to go into transplant and they're not crashing
and burning. I'm assuming if they're crashing and burning, you
need to go onto an LVAD, the following comments won't apply to
that group. If you're a patient who's relatively stable, is it a
better strategy to try and get them to transplant directly? Or is
it better to go through and VAD and then transplant them? And
ultimately that strategy question I think would require
randomization to really answer that. But the data that we have
discussed today, I think are opening that question and touch upon
that in terms of the strategy of the impact of bridging people
with VADs itself, which is why I think this is such an important
question.


Dr Carolyn
Lam:               
Thanks again, Mark and Veli. That was an amazing discussion.


                                               
Thank you, audience, for joining us. You've been listening to
Circulation On The Run. Don't forget to tune in again next week.


                                               
This program is copyright American Heart Association 2019.