Circulation June 12, 2018 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. Today's feature discussion
revolves around important hemodynamic and echo data from the
reprise three trial, comparing the lotus and core valve
transcatheter aortic valves in patients with high surgical risk.
Can't wait? Well it's coming right up after these summaries.


                                               
The first original paper this week provide experimental data
showing that the endothelium controls cardiomyocyte metabolism
and function via notch signaling. Corresponding author, Dr.
Fischer, from German Cancer Research Center in Heidelberg,
Germany, and colleagues, studied fatty acid transport in cultured
endothelial cells and transgenic mice with endothelial specific
notch inhibition, or wild type mice treated with neutralizing
antibodies against the Notch ligand. They showed that notch
signaling in the endothelium controlled blood vessel formation
and fatty acid transport in the adult mouse heart. Inhibition of
Notch signaling in the vasculature led to expansion of the
cardiac vasculature and impairment of fatty acid transport to
cardiomyocytes. This resulted in metabolic reprogramming and
heart failure.


                                               
Together, these data provide compelling evidence for a central
role of Notch signaling at the coordination of nutrient transport
processes in the heart. These findings help to explain how
pharmacological inhibition of Notch signaling, for example, in
oncology could lead to heart failure. The findings also help to
identify the signals and molecules involved in endothelial
transport capacity and show how these could offer new targets for
the treatment of heart failure.


                                               
The next paper raises the prospect of new treatment options to
combat ischemic heart disease and its progression to heart
failure. Ischemic injury to the myocardium is known to trigger a
robust, inflammatory response, which is an integral part of the
healing process, although much effort has been directed at
tempering the inflammatory response in hopes of achieving
clinical gain. Major efforts have focused on individual
cytokines, the complement cascade, and antibodies to adhesion
molecules preventing leukocyte invasion.


                                               
In contrast, relatively little effort has focused on macrophages.
Although macrophage transformation is known to be crucial to
myocardial repair, the events governing this transformation are
poorly understood. In today's paper, co-corresponding authors of
the trial in Hill, from UT Southwestern Medical Center, performed
an elegant series of experiments and showed that release of DNA
from necrotic tissue during myocardial infarction, triggered in
macrophages a recently described innate immune response known as
the GMP-AMP synthase-stimulator of interferon genes pathway or
cGAS-STING pathway.


                                               
This response in turn promoted an inflammatory macrophage
phenotype. Suppression of the pathway promoted emergence of
reparative macrophages, thereby mitigating pathological
ventricular remodeling. These results therefore reveal for the
first time, that the cytosolic DNA receptor, GMP-AMP synthase,
functions during cardio ischemia as a pattern recognition
receptor in the sterile immune response.


                                               
Furthermore, this pathway governs macrophage transformation,
thereby regulating post injury cardiac repair. As modulators of
this pathway are currently in clinical use, these findings raise
the prospect of new treatment options to combat ischemic heart
disease and its progression to heart failure.


                                               
Cigarette smoking is a well-known risk factor for atherosclerotic
cardiovascular disease. However, less is known about the risk for
heart failure. First author, Dr. Kamimura, corresponding author,
Dr. Hall, from University of Mississippi Medical Center, and
their colleagues investigated 4129 black participants without a
history of heart failure or coronary heart disease at baseline in
the Jackson Heart Study.


                                               
They examined the relationship between cigarette smoking and left
ventricular strength and function by using cardiac magnetic
resonance imaging. They found that current cigarette smoking
status, smoking intensity in terms of cigarettes per day, and
smoking burden in pack-years, were independently associated with
higher left ventricular mass, lower left ventricular strain,
higher brain natriuretic peptides, higher BNP levels and higher
risk of incident heart failure hospitalization in blacks.


                                               
These relationships were significant after adjustment for
coronary heart disease, suggesting mechanisms beyond
atherosclerosis may contribute myocardial dysfunction and
increased risk of heart failure in smokers. In summary, these
findings suggest that smoking is associated with structural and
functional left ventricular abnormalities that lead to heart
failure in blacks and that smoking cessation should be encouraged
in those with risk factors for heart failure.


                                               
What happens to the risk modifying effects of exercise in
individuals with increased genetic risk of cardiovascular
disease. Drs. Tikkanen, Gustafsson, and Ingelsson from Stanford
University School of Medicine performed the study in about
500,000 individuals from the UK Biobank and reported and compared
the association's objective and subjective measures of fitness
and physical activity with prospective cardiovascular disease
events and all-cause death.


                                               
They found consistent and robust inverse association,
particularly between objective measures of fitness and physical
activity and six cardiovascular outcomes and total mortality.
Using genetic risk scores for coronary heart disease and atrial
fibrillation, they showed that these inverse associations were
present in each genetic risk category, suggesting that elevated
genetic risk for these diseases can be compensated for by
exercise.


                                               
The knowledge that lifestyle choices have substantial effects on
disease risk could encourage individuals to initiate a healthier
lifestyle to reduce their overall risk. In the longer term,
identifying subgroup space on genetic risk that benefit most from
lifestyle interventions, could help personalize preventive
strategies for chronic diseases.


                                               
Well, that wraps it up for our summaries, now for our feature
discussion.


                                               
Today's featured paper deals with transcatheter aortic valve
replacement, which we are all going to recognize has rapidly
emerged as a treatment of choice in inoperable patients and, it's
a reasonable alternative to surgical aortic valve replacement in
high- and intermediate-surgical-risk patients. However, the
success of this technology is in large part due to the rigor with
which quantitative echocardiography by core laboratories has been
used to assess the native and prosthetic aortic valve function.


                                               
Today's feature paper gives us such important data from the
REPRISE III trial, which compares the Lotus and the CoreValve
transcatheter aortic valve in patients with high and extreme
surgical risk. I'm so pleased to have the corresponding author,
Dr. Federico Asch, from MedStar Washington Hospital Center, as
well as our associate editor, Dr. Dharam Kumbhani from UT
Southwestern. All right Federico, please help me here, so as a
noninterventionist and a person who doesn't deal with all these
different types of valves every day, please tell us what was the
motivation of looking so closely at the echocardiographic data
from REPRISE, because the REPRISE III trial results were already
published?


Dr Federico
Asch:            
The most interesting aspect of this analysis is really that there
is a very methodic, blinded comparison of two different valves.
The valve that is being tested and that the reason why Boston
Scientific has sponsored the study, is the Lotus valve, the Lotus
System is, if you want, a new valve that is not clinically
approved in the United States yet, that basically, it's a
completely repositionable bovine pericardial valve that comes in
different sizes.


                                               
The three sizes that were tested in here are what we would call
the small, or 23 millimeters, the medium, 25 millimeters, and the
large, 27 millimeters. Each patient, at the moment of
randomization, or at the moment of inclusion, were randomized to
the small, medium, or large Lotus valve vs the clinically
approved CoreValve, which is a Medtronic product. Obviously, this
is taken as the control group because this is one of the valves
that is widely clinically available nowadays in the United States
and worldwide.


                                               
This is exactly the motivation here. On one side, to prove
whether this valve was as good as CoreValve or not and whether it
was as safe as the CoreValve as well, and that, the study was
about. Every three patients that were randomized, two were
randomized to the new valve, the Lotus, and one was randomized to
the CoreValve.


                                               
An important note to make here is because the control arm
included clinically available valves at the beginning of the
study, the previous generation of CoreValve was used and then
about halfway through the trial, the Evolut valve was the one
being used, so there's two different valves on the CoreValve
system that were tested in this trial while Lotus was a single
earlier generation valve.


We focus here on the hemodynamic implications, that meaning, the
gradients and the degree, if you want, of obstruction that these
valves could have over time, and the amount of regurgitation that
these two valves and how they compare to each other.


Dr Carolyn
Lam:               
That's great. Could I ask if you had any hypothesis going in,
because as I recall, the Lotus valve actually met the
non-inferiority comparison, but it did have significantly higher
rates of new pacemaker implantation and valve thrombosis, right?
So, was that perhaps a hypothesis going in and what did you find?


Dr Federico
Asch:            
So, the initial hypothesis of the trial overall was that this new
valve was one that was designed to have less paravalvular
regurgitation, which is something as you probably know, has been
of significant concern in the cardiology world ever since the
initial clinical trials for Tyler with Partner and CoreValves.


                                               
Patients with more significant paravalvular leak did have worse
outcome over time, so, one of the main goals of this valve
itself, was to prevent that paravalvular regurgitation. So, that
was the initial idea behind this product I would say, not just
the clinical trial and obviously, this clinical trial tried to
prove that, indeed, as I mentioned before, the primary
effectiveness end point was mortality, disabling stroke, and
paravalvular leak, the main driver on the difference between the
two valves there was indeed a much lower paravalvular
regurgitation on the Lotus valve compared to CoreValve.


                                               
There was also lower stroke rate, but the most important
difference was on the paravalvular aortic regurgitation. Of
course, when you think of any of these devices, for them to be
able to prevent paravalvular leak, they have to have some kind of
skirt or cushioning around the valve, an adaptive seal, which in
the case of the Lotus valve, that would prevent any flow around
the stent, but one of the risks of that of course is that by
trying to seal the valve, you're actually, you may be decreasing
a little bit the effective orifice area, so it was actually very
important to understand whether gradients with this valve were
higher and whether the potential differences in the gradients did
turn into any difference in clinical outcomes.


Dr Carolyn
Lam:               
That is super clear now. What did you find?


Dr Federico
Asch:            
I would say, the findings from a hemodynamic standpoint, we can
briefly summarize them in two aspects of it. No surprise, the
paravalvular leak was significantly lower for Lotus compared to
CoreValve, and that was true for any of the three sizes, for the
small, medium, and large size in all of them, the rate was
significantly lower for Lotus. It was actually under 1% of the
patients with moderate or higher paravalvular leak, as opposed to
an average of 6.7% on the CoreValve, but on the other side of the
spectrum, the gradients and the effective orifice area, and the
dimensional index were all significantly better on the CoreValve
compared to the Lotus.


                                               
The bottom line is, we have two valves that each of them has a
specific strength. On one side, Lotus has less paravalvular leak.
On the other hand, CoreValve has a better gradient profile than
Lotus. I would say in two lines, that's the findings of this
study. We did take these findings further and compared among
different valve sizes and we saw that these differences were
consistent at each of the valve size, so if we would compare the
small Lotus with the small CoreValve or the large Lotus with
CoreValve, the findings were very similar.


                                               
They were always significant, and what is important is that while
there was a difference, both for paravalvular leak and for
gradients and other hemodynamic parameters, the reality is that
when it came to clinical outcomes, there was no significant
difference among the two.


Dr Carolyn
Lam:               
Dharam, you have to weigh in now as an interventional
cardiologist, what does this mean to you.


Dr Dharam Kumbhani:   First of all, Federico, congrats
to you and Ted and the rest of the group. I think this is
obviously a very important trial and I think this hemodynamics
paper, I think definitely moves, helps understand the differences
a little bit better, so I think this is a very valuable
contribution. I think you said it exactly right. I think what is
really interesting is that you have a significant introduction
into the paravalvular leak, but yet you have, because of
difference in valve design, one being annular vs the other being
super annular, you have higher gradients with the Lotus valve
compared with the CoreValve, so you wonder if the two differences
can cancel themselves out in some way, because you don't see any
difference in clinical end points at one year, and also, I guess,
what we've learned from the Partner data and other CoreValve data
is it would be really helpful to see how this evolves over time,
whether there will be any late separation of the curves or just a
long-term follow-up, whether that will still be important.


                                               
I think that is the really interesting insight that we glean from
this analysis. I want to make two other points. I think the other
interesting thing about the design of the Lotus valve, and
probably having such a great seal for the paravalvular leak
reduction and having higher radial strength, I would think, at
the annulus, I suspect that that's probably also the reason why
the pacemaker rate is higher with this, compared with CoreValve,
so it's almost 30% in this trial. About 20%, 18% already had an
existing pacemaker, so particularly I guess, as we move to
lower-risk population, I think that will certainly, balancing the
two and deciding probably one valve doesn't fit everybody and we
may have to have strategies to figure out which may be the best
valve for a given patient based on this.


                                               
The other point I'd like to make is the question about stents or
valve thrombosis and I know that your group has been heavily
invested in that research, because I know in the JAMA paper,
there was a report of few valve thrombosis events and you also
bring that home here in this hemodynamics paper. Is there
anything you want to elaborate on that or any insights that you
feel would be helpful for the next set of trials and next
generation of the Lotus valve?


Dr Federico
Asch:            
Yeah, you're bringing two very, very important points. Let me
address the thrombosis one first. As you very well described, we
have been working a lot on multiple different valves and
understanding why this is happening. It's clearly something of
concern. In this study in particular, we did not have data
collected to detect subclinical thrombosis, which is what most of
us have been talking mostly about over the last few years. The
diagnosis of thrombosis here was not so clinical. These were
patients that mostly, because gradients were going up, were
detected. They were image ... there was one or two cases with TE
and the other ones with CTs and then they were given
anticoagulation and those results, and based on that is that the
diagnosis of thrombosis was made. All those cases, nine cases,
indeed, happen on the Lotus group. The CoreValve is one in that
overall has shown to have lower rates of thrombosis in general
and I'm not just talking about our own report. Our report was
consistent with that.


                                               
That may be something related to the fact that it's a super
annular valve and the flow through the valve may be better, if
you want, but we don't know that. The rate of thrombosis, again,
clinical thrombosis, in this case, for the Lotus valve was 1.5%,
which is still low, but it's impossible to compare to all those
new reports that are coming out because those are mostly
subclinical, which is not the case here.


                                               
One could argue that if would have done CTs on every patient here
at 30, 45 days, we would have found much higher rates in both
valves, but we don't know that. We don't have the data to address
that.


Dr Dharam Kumbhani:   As I remember, almost all of
them, I think seven out of eight of those reported, were in the
23 valve, right? They were not ... I think the larger valves ...


Dr Federico
Asch:            
Exactly. There were nine cases overall, eight of them were on the
small valve, on the 23 millimeters, and one was in the middle
size, on the 25 millimeters. You are completely right.


Dr Dharam Kumbhani:   I don't know what to make of
that, but that was an interesting observation as well.


Dr Federico
Asch:            
Yeah. It's interesting because when you look at reports of
subclinical thrombosis, actually some of the reports suggest that
this is more common in bigger valves than in smaller valves.
Registries, I'm talking about, but that didn't seem to be the
case here, but again, we need to understand the limitations. This
was not a study geared towards detecting sub clinical thrombosis
or thrombosis overall. These are just clinically reported cases
that were analyzed thoroughly but they were triggered by some
kind of clinical event, what's mostly an increase in the
gradient.


                                               
That's all that I would make out of the thrombosis. I think there
is definitely more that we need to learn about it. We know that
both CoreValve and Lotus have been reported to have cases of
thrombosis, but in general, CoreValve seems to be of all the type
of devices, the one with the lowest incidents.


Dr Dharam Kumbhani:   Maybe your studies will help in
understanding the influence of hemodynamic profile,
patient-prosthesis mismatch, to the risk of thrombosis. I think
the interactions are not well understood. I think that will be
very interesting going forward.


Dr Federico
Asch:            
Exactly. And the other comment that I wanted to make, Dharam,
regarding your first impression about the pacemakers and the
gradients, a couple of observations that I want to make out of
that, one is that the difference in gradients between Lotus and
CoreValve seem to be the highest early and then over months, that
difference seemed to get smaller and smaller, still significant
though, even at one year, but one could argue that if, as we
continue following up these patients, maybe the difference starts
getting smaller and smaller to the point that to become
irrelevant, but we don't know that. That is just the impression
that we get at looking at the curves over time.


                                               
The pacemaker, obviously, as you can imagine, this is something
that is of concern for everybody. It's a high rate, the newer
Lotus generations are geared towards having lower paravalvular
leak, like the head Lotus Edge and so we would expect that in the
future that would be the case, but we don't know. The same way
that it is important to mention that CoreValve has been
addressing their initial concern, which was paravalvular leak.


                                               
I mentioned before that the control arm in this clinical trial
included CoreValve classic, earlier generations from roughly half
of the patients, and the paravalvular leak in that group was a
little bit over 10%, while the second group, which was the Evolut
R had already a much lower rate of paravalvular leak, but was
still significantly higher than Lotus, but was definitely better.


                                               
I think what this points out to, is that all these devices are so
early in their life, in their history, that all the efforts that
each of these companies are making into fixing the specific
problems that each of them have, really turn into a next
generation that addresses more aggressively all these things. In
the case of CoreValve, definitely the paravalvular leak is one
and they are making very good progress in the care of Lotus, the
permanent pacemaker is one and we expect in subsequent
generations to improve as well.


Dr Carolyn
Lam:               
It's been very enlightening for me and I'm sure for all our
listeners. Thank you for joining us today listeners. Don't forget
to tune in again next week.