Circulation December 8, 2020 Issue

Dr. Carolyn Lam :


Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the Journal and its editors. We're your
co-hosts, I'm Dr. Carolyn Lam, associate editor from the National
Heart Center and Duke National University of Singapore.


Dr. Greg Hundley :


And I'm Greg Hundley, director of the Pauley Heart Center at VCU
Health in Richmond, Virginia.


Dr. Carolyn Lam :


Greg, today's feature paper is a research letter, but, oh my
gosh, it is so interesting. It's about surgical explantation of
transcatheter aortic bioprosthesis. TAVRs we know is on the rise
and so is the rise of surgical explantation cases and we really
need to understand it better. Hang on, we're coming to that, but
maybe, let's start with some other papers in the issue first,
shall we? Let me go first, you go grab your coffee and listen
because we're going to talk about the efficacy of ertugliflozin
on heart failure related events in patients with type II diabetes
and established atherosclerotic cardiovascular disease in the
results of the VERTIS CV trial.


Dr. Greg Hundley :


Carolyn, tell us a little bit about the VERTIS CV trial.


Dr. Carolyn Lam :


Sure. The primary results of the VERTIS CV trial have already
been published. This cardiovascular safety trial was actually
performed to satisfy the 2008 guidance from regulatory agencies
for new antihyperglycemic agents. It found that patients with
type II diabetes and atherosclerotic cardiovascular disease
randomized to ertugliflozin achieved the primary objective of
non-inferiority to placebo in time to first major adverse
cardiovascular event or MACE, a composite endpoint of
cardiovascular death, non-fatal MI, or non-fatal stroke. The
first secondary outcome in the hierarchal testing sequence was
superiority for the time to composite of cardiovascular death or
heart failure hospitalization, which was not met and therefore
formal hypothesis testing ended with this endpoint. Now in
today's paper, the authors led by Dr. Cosentino from Karolinska
Institute and Karolinska University Hospital in Stockholm,
Sweden, present the results from pre-specified analyses of the
effect of ertugliflozin versus placebo on a series of heart
failure related outcomes from this VERTIS CV trial.


Dr. Greg Hundley :


Ah, Carolyn. Tell us what were the results of this new study.


Dr. Carolyn Lam :


Of more than 8,200 randomized patients, almost 24% had a history
of heart failure and almost 61% had a pre-trial ejection fraction
available, including 959 patients with an injection fraction less
than or equal to 45%. While ertugliflozin did not significantly
reduce first heart failure hospitalization or cardiovascular
death, it did reduce first and total hospitalization for heart
failure events with a relative risk for first heart failure
events being similarly beneficial number one, in those with
versus without a history of heart failure and number two, in
those with a history of heart failure with reduced ejection
fraction or preserved ejection fraction. However, the risk
reduction tended to be greater for those with an ejection
fraction less than or equal to 45%. Although, the test for
interaction by injection fraction was not significant. The effect
of ertugliflozin on risk for first heart failure hospitalization
was consistent across most baseline subgroups with a greater
effect in three populations, including those with impaired kidney
function and those taking diuretics. Now, this is discussed an
editorial by Doctors Faiez Zannad and Martin Cowie. You must pick
it up and read it.


Dr. Greg Hundley :


That's great, Carolyn. What a fantastic another piece of
information on the SGLT2 inhibitors.


Dr. Greg Hundley :


Well, my first paper comes to us from Dr. Peter Liu from the
University of Ottawa Heart Institute and his colleagues. Carolyn,
this article focuses on cardiac hypertrophy, which as you know,
is a key biological response to injurious stresses such as
pressure overload. Also as you know, when cardiac hypertrophy is
excessive, it can lead to heart failure. Innate immune activation
by danger signals through intracellular pattern recognition
receptors such as nucleotide-binding oligomerization
domain-containing protein 1, or NOD1 and its adaptor receptor
interacting protein, RIP2, may play a major role in cardiac
remodeling and progression to heart failure. These authors
hypothesized that NOD1 and RIP2 are major contributors to cardiac
hypertrophy, but may not be sufficient to fully express the
phenotype alone.


Dr. Carolyn Lam :


I like that, NOD1 and RIP2. What did they find?


Dr. Greg Hundley :


These authors found that innate immune NOD1/RIP2 signaling was a
major contributor to cardiac remodeling following stress. This
process was critically joined by and regulated through the
mitochondrial danger signal protein adapter MAVS. The authors
found that this novel complex coordinates remodeling,
inflammatory response and mitochondrial energy metabolism in
stressed cardiomyocytes, thus NOD1/RIP2 MAVS signaling complex
may represent an attractive new therapeutic approach toward
modulating LV hypertrophy mediated heart failure.


Dr. Carolyn Lam :


Very nice, Greg. Now in the next paper, do you remember the
VOYAGER PAD trial? Well, it was the trial that demonstrated
superiority of rivaroxaban plus aspirin versus aspirin alone to
reduce major cardiac and ischemic limb events following lower
extremity revascularization. Now clopidogrel is commonly used as
a short term adjunct to aspirin after endovascular
revascularization. However, does clopidogrel modify the efficacy
and safety of rivaroxaban in this setting? Well, that's the
question that today's paper is addressing and it is led by
corresponding author, Dr. Hiatt from University of Colorado
School of Medicine.


Dr. Greg Hundley :


What did they find, Carolyn?


Dr. Carolyn Lam :


Well in the VOYAGER PAD trial, rivaroxaban plus aspirin reduced
the risk of adverse cardiovascular and limb events with an early
benefit for acute limb ischemia, regardless of clopidogrel use.
The safety of rivaroxaban was consistent regardless of
clopidogrel use as well, but with a trend for more ISTH major
bleeding with clopidogrel use more than 30 days than a shorter
duration. These data support the addition of rivaroxaban to
aspirin after lower extremity revascularization, regardless of
concomitant clopidogrel with a short course of less than 30 days
associated with less bleeding.


Dr. Greg Hundley :


Very nice, Carolyn. Well, my next paper comes to us from Dr.
Hinson from the Jackson Laboratory for Genomic Medicine. Carolyn
this paper focuses on a particularly challenging heart failure
associated sarcomere gene, cardiac troponin T, that is encoded by
TNNT2. Remember Carolyn, this is a thin filament protein that
functions in the tripartite troponin complex, where calcium binds
and triggers twitch force. Relative to other sarcomere genes,
pathogenic TNNT2 variants are associated with poor prognosis as
they carry an increased risk of sudden cardiac death that is
disproportional to myocardial remodeling. The investigators used
human pluripotent stem cell derived cardiomyocytes in cardiac
microtissue and single cell assays and functionally interrogated
51 TNNT2 variants, including 30 pathogenic likely pathogenic
variants and 21 variants of unknown significance called VUSs.
They utilized RNA sequencing to determine the transcriptomic
consequences of pathogenic TNNT2 variants.


Dr. Carolyn Lam :


Wow. And so what were those consequences, Greg?


Dr. Greg Hundley :


They found that hypertrophic cardiomyopathy associated TNNT2
variants increased cardiac microtissue contraction while dilated
cardiomyopathy associated variants caused decreased contraction.
Both of which parallel changes in myofilament calcium affinity.
Transcriptomic changes, including NPPB levels, directly
correlated with sarcomere function and could be utilized to
predict TNNT2 variant pathogenicity. In summary Carolyn, this
research found that number one, inheritance of pathogenic TNNT2
variance is a leading cause of cardiomyopathy and number two, the
majority of TNNT2 variants identified in the human population are
classified as those VUSs or variants of unknown significance,
which limits their clinical utility in genetic testing. As such,
reclassification of TNNT2 variants would improve cardiomyopathy
risk determination and treatment responses for individuals
harboring these variants.


Dr. Carolyn Lam :


Nice. Thank you, Greg. Well, in this next paper, I think the
title summarizes it all: “Is There a Sex Gap in Surviving an
Acute Coronary Syndrome or Subsequent Development of Heart
Failure?” Well, Dr. Justin Ezekowitz from Vigor Center,
University of Alberta in Canada and his colleagues used a large
population based cohort of more than 45,000 patients with MI
between April 2002 and March 2016, to examine the incidence and
geographic findings, treatment and clinical outcomes of patients
with a first time and MI. To elucidate the difference between
sexes, a series of multi-variable models were created to explore
all MI and non-ST elevation MI versus ST elevation MI over time.


Dr. Greg Hundley :


What did they find Carolyn?


Dr. Carolyn Lam :


Well, some attenuation of differences in clinical outcomes over
time had occurred. Women maintained a higher risk than men of
dying or developing heart failure in the subsequent five years
post both STEMI or non-STEMI, even after accounting for
differences in angiographic findings, revascularization and other
confounders.


Dr. Greg Hundley :


Well, Carolyn, how about we get to some of the other articles in
the issue. And I've got a really nice Research Letter from
Professor Damien Bonnet entitled, “Addition of Corticosteroids to
Immune Globulins is Associated with Recovery of Cardiac Function
in Multi-inflammatory Syndrome in Children.” There's also a
Research Letter from Professor Peter van der Meer entitled,
“Human Pluripotent Stem Cell Derived Cardiomyocytes of Peripartum
Cardiomyopathy Patients Reveal at Aberrant Regulation in Lipid
Metabolism.” And Carolyn, finally I have an ECG Challenge
entitled, “Wide QRS Complex Tachycardia in a Young Pregnant
Woman, is it SVT or VT?” The age old question from Dr.
Gunaseelan.


Dr. Carolyn Lam :


Nice. Well, there's also an exchange of letters between Drs. Ross
and Loupy regarding the article, “Identification and
Characterization of Trajectories of Cardiac Allograft
Vasculopathy after Heart Transplantation: a Population Based
Study,” and a beautiful Perspective piece by Dr. Verma entitled,
“Two Tales, One Story and that is talking about the
EMPEROR-reduced and DAPA-HF trials.” A beautiful summary there.
Let's get on now though to that feature discussion. Shall we,
Greg?


Dr. Greg Hundley :


You bet looking forward to it.


Dr. Carolyn Lam :


Transcatheter aortic valve replacement or TAVR has indeed become
an established alternative to surgical aortic valve replacement
for patients with severe aortic stenosis. Now, while the TAVR
usage has increased, so has surgical TAVR valve explantation.
However, that's not been really well described its clinical
impact or outcomes well until today's research letter in
Circulation, which represents the largest series of TAVR explants
from a national database. And I'm so pleased to have with us the
first and corresponding author, Dr. Shinichi Fukuhara from
University of Michigan to describe the study as well as our
associate editor, Dr. Tim Gardner from University of
Pennsylvania. Welcome, gentlemen. Shinichi, if you don't mind for
non-interventionists and non-surgeons like myself, why would you
need to explant TAVR in the first place? Maybe you could start
with that and then tell us about your study.


Dr. Shinichi Fukuhara:


First of all, thank you so much for the kind invitation. It's a
great honor to be with you and Dr. Gardener. That's a very good
question and a very timely question actually. When we started
implanting TAVR valves probably about nine years ago or so, that
was when the TAVR valve was FDA approved, we were not thinking
about second TAVR procedure after the initial TAVR valve fails.
And then as time goes on, we started to recognizing, some
patients' TAVR valves started failing and these failure patterns
can be paravalvular leak, can be structural valve degeneration,
can be endocarditis. Not all patients with a failing TAVR valve
can be treated with a second TAVR valve procedure and the most
common driving factor at least in my program at the University of
Michigan is unsuitable anatomy for a second TAVR valve and the
most common anatomy pattern is a risk of a coronary artery
obstruction by the second TAVR valve. These are the common
scenarios where patients need TAVR valve explantation scenarios.


Dr. Carolyn Lam :


Thank you so much for that as a background. And as you nicely set
up in your paper, as we do more TAVR, obviously there are going
to be more situations like this. Please tell us what you found.


Dr. Shinichi Fukuhara:


First of all, what we found from this project, first, surgical
TAVR valve explant procedure is not as simple as people thought
it would be. I remember back in 2014, 2015 when I was still a
trainee, people were talking about, which is better TAVR SAVR
TAVR or SAVR TAVR SAVR? However, based on what we are just
starting to see, TAVR SAVR sequence may not be a good option for
younger people based on the present study data. The fact that
more than 50% of patients who require the major simultaneous
procedures such as aortic repair and the mitral procedures is a
something TAVR implanters in our community should be more aware.


Tim Gardner:


I think it's very important for Shinichi to tell us to emphasize
the mortality rate that you saw with the SAVRs following TAVR
because that's really, I think the sobering information here.
This is not comparable to doing a redo aortic valve or redo SAVR.
Just tell us about that, Shinichi.


Dr. Shinichi Fukuhara:


First of all, these STS database. We have a STS predicted risk of
a mortality, which is available for patients undergoing isolated
SAVR procedure. And then based on the even isolated the SAVR
procedure, the OE ratio of observed to expected mortality ratio
was actually higher than 1.5 for isolated SAVR procedure in
patients requiring TAVR explant. More importantly, patients who
are requiring TAVR explanted SAVR, as well as a concomitant
cardiac procedure are demonstrating almost close to 20% mortality
rate, which is to me very striking after we analyze that data
set. And this is something our community, the TAVR implanters in
our community should keep in mind.


Dr. Timothy Gardner:


Yeah. Obviously not only is the surgery, the removal of the TAVR
device and replacement with a surgical valve, not only is that
complex anatomically and technically, but the associated
mortality seen in this series of patients that they reported is
higher than expected and actually quite high in terms of absolute
operative or hospital mortality. I take this important research
letter as a sort of a warning message to all of us, in
particular, the cardiology community, to realize that once a TAVR
valve is placed, it is more difficult and riskier to remove that
and replace it with a surgical aortic valve replacement, if for
some reasons such as endocarditis or valve failure or whatever
comes to play.


Dr. Timothy Gardner:


And obviously as Shinichi has already said, when you're looking
at a younger patient, patient under 60 for example, who needs an
aortic valve procedure, you need to keep in mind whether as he
said earlier, it's might be safer to do a SAVR first. And then if
there's another procedure required, that could be because of
valve failure, a TAVR could be done rather than just assuming
that the TAVR is going to be there and that it can be easily
replaced or taken care of. At any rate, I think that's the very
important point of this paper. And I think this is really the
first report and not only by the way, does it show that this is
happening, but in the most recent year of your report, Shinichi,
how many SAVRs after TAVR were reported, number of cases?


Dr. Shinichi Fukuhara:


The 2018, the last year of this study period was actually the
highest obviously and it was a close to 300 cases reported. And
then the number of case is a steeply increasing as I demonstrated
in the figure one in the paper.


Dr. Timothy Gardner:


That really emphasizes obviously TAVR volume is increasing. TAVR
is now being placed in younger patients who have perhaps a
greater chance of requiring a second procedure. And if it has to
be explantation of the TAVR because of the complexity and the
inability to use another TAVR to fix the valve, the technical
challenges and the operative risks are much higher.


Dr. Timothy Gardner:


Well, I just think that this is a warning call that we have to be
realistic about the secondary requirements for patients that have
TAVR and we don't yet even have a much more than a 10 year
experience with TAVRs and we're seeing an increasing number of
patients just in the STS database who are having to come back for
TAVR explant and it's a difficult, challenging procedure. One
point that Shinichi made in his article is that this technical
challenge of TAVR explant may be something patients requiring
this procedure may need to be referred to surgeons and hospitals
with high aortic surgery volume. This is not necessarily a
procedure that a surgeon can get experienced with and comfortable
with doing two or three a year. That's another bit of the message
here.


Dr. Carolyn Lam :


Thanks, Tim. And Shinichi, what would be your take home message
to the clinical community listening in?


Dr. Shinichi Fukuhara:


Thank you so much. Yeah, this is a little bit redundant
statement, but I think that another important message from this
paper is that these low risk younger patients choosing to have a
TAVR procedure as the initial valve therapy should be informed of
the future procedure risks of a TAVR explant which frequently
requires more of device explanating and the possible unplanned
concurrent procedures and for these reasons careful assessment of
aortic root anatomy and the feasibility of a repeat TAVR
procedure should be part of with the initial TAVR workup. If we
decide to proceed with TAVR for younger patients and then
therefore heart team approach remains extremely important in the
TAVR practice, that's my take home message.


Dr. Timothy Gardner:


And I'd like to reinforce that. This is, as we know, the heart
team concept has been so important in providing optimal care for
patients with aortic valve disease and this is a reminder of part
of the discussion that should be happening at the heart team
level.


Dr. Carolyn Lam :


Thank you so much. Clear take home messages that you've got right
here on Circulation on the Run.


Dr. Greg Hundley :


This program is copyright the American Heart Association, 2020.