Circulation May 4, 2021 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 Dr. Greg Hundley, associate editor, director of the
Pauley Heart Center at VCU Health in Richmond, Virginia. Well
Carolyn, it's another double feature Tuesday and today we get to
discuss two articles. One, some insights from the CREDENCE trial.
And second, another article about left atrial appendage closure
devices, some results from the PINNACLE FLX trial. But before we
get to those, how about we grab a cup of coffee and dive into
some of the other really interesting articles in this issue?
Would you like to go first?


Dr. Carolyn Lam:


I would, because this next paper, right up your alley and I'm
sure you'll like it. But first, we talk about mitral valve
prolapse. Now, we know that's a frequent disease that can be
complicated by mitral regurgitation, heart failure, arterial
embolism, rhythm disorders, and death. Left ventricular
replacement myocardial fibrosis is a marker of maladaptive
remodeling and has been described in patients with mitral valve
prolapse. However, the implications of this finding remain
scarcely explored. So these authors, led by Dr. [Le] Tourneau
from Hôpital Laennec in France, aimed at assessing the
prevalence, pathophysiological and prognostic significance of
left ventricular replacement myocardial fibrosis through late
gadolinium enhancement by cardiac magnetic resonance in 400
patients with mitral valve products. I bet you like that, right
Greg?


Dr. Greg Hundley:


Oh my gosh Carolyn, not only a favorite topic of cardiovascular
magnetic resonance, but this is a really large patient population
with mitral valve prolapse that underwent CMR. So tell us, what
did they find?


Dr. Carolyn Lam:


So replacement myocardial fibrosis was observed in 110 patients,
so that's 28% of the patients. It was associated with mitral
valve apparatus alterations, left ventricular remodeling, and
ventricular arrhythmia. The ventricular arrhythmias were more
frequent in patients with replacement fibrosis, but were not
associated with the grade of mitral regurgitation. In patients
with trace or mild mitral regurgitation, the presence of
replacement myocardial fibrosis was nonetheless associated with
specific mitral valve apparatus alteration at normal left
ventricular dilatation, not explained by volume overload and
ventricular arrhythmias, suggesting the presence of a mitral
valve prolapse-associated cardiomyopathy.


Dr. Greg Hundley:


Wow Carolyn, really interesting. So the late gadolinium
enhancement and the evidence therefore of replacement myocardial
fibrosis that was identified by CMR, maybe this particular study
is suggesting that we might want to integrate that into the
clinical workup of patients with mitral valve prolapse. Very
interesting work, and great job on that fantastic CMR
presentation. I must say, got to recruit you into the club.


Dr. Greg Hundley:


Well, my next paper is another wonderful paper from the world of
basic science and it comes from Dr. Douglas Lewandowski at the
Ohio State University College of Medicine. So Carolyn, the
failing heart is energy starved with impaired oxidation of long
chain fatty acids at the level of reduced carnitine
palmitoyltransferase-1, or CPT-1, activity at the outer
mitochondrial membrane. Recent work shows that elevated ketone
oxidation and failing hearts as an alternate carbon source for
oxidative ATP generation. So Carolyn, these authors hypothesized
that another short chain carbon source, short chain fatty acids
that bypass CPT-1, could similarly support energy production in
failing hearts.


Dr. Carolyn Lam:


Wow. Okay, so what did they find?


Dr. Greg Hundley:


So Carolyn, the failing heart oxidizes short-chain fatty acids
more readily than ketones, with short-chain fatty acids also
displacing long-chain fatty acid oxidation to somewhat of a
greater extent. So in particular, the short-chain fatty acid
butyrate has a higher affinity for entry into mitochondrial
oxidation at the enzyme, short-chain Acyl-CoA dehydrogenase than
does the ketone 3-hydroxybutyrate at the hydroxy butyrate
dehydrogenase and then also through the respective downstream
metabolic pathways for each substrate. So Carolyn, failing hearts
of rats and humans have increased levels of Acyl coenzyme A
synthetase medium chain three enzyme, which can also oxidize
short-chain fatty acids to enhance butyrate oxidation.


Dr. Carolyn Lam:


Wow, that really is interesting. I can't say that I would have
predicted that result. So could you give us a clinical
implication?


Dr. Greg Hundley:


You bet, Carolyn. A lot of basic science here. So here's I think
what we can take home, and what we learned. So while ketones have
been sought as a potential supplemental fuel to remedy the
impaired oxidative metabolism of the failing heart, this study
shows that failing hearts preferentially oxidize short-chain
fatty acids over ketones and short-chain fatty acids may prove to
be a more efficient energy source during pathological stress.


Dr. Greg Hundley:


Next, novel alterations in metabolic pathways, favoring
short-chain fatty acid oxidation in the failing heart occur in
patients with non-ischemic cardiomyopathy. Then finally,
circulating ketones are not a unique, super fuel beyond the
ability to bypass the inhibition of long-chain fatty oxidation in
the failing heart, as do the short chain fatty acids.


Dr. Carolyn Lam:


Thanks, I like the way you broke down the clinical implications.
Well, Greg, I've got a question for you. Have you ever thought
that statins may do more than lower cholesterol, but depending on
what you eat?


Dr. Greg Hundley:


Oh wow, Carolyn. We always hear about the pleiotropic effects of
statins, but I never really thought that could depend on what you
eat. Tell me, so what did these authors investigate?


Dr. Carolyn Lam:


Yeah, so this next paper is so interesting. It's from Dr. Hu from
Huazhong University of Science and Technology in Wuhan, China and
colleagues, who present a novel perspective on the story of the
pleiotropic effects of statins, exactly like you said, Greg. They
started with the premise that statins exert pleiotropic or
cholesterol-independent effects by reducing geranylgeranyl
pyrophosphate production. I'm not going to keep saying that, so
geranylgeranyl pyrophosphate or GGPP, is how I'm going to refer
to it.


Dr. Carolyn Lam:


So they developed a sensitive technique to quantify dietary GGPP,
and conducted proteomics, RT-PCR screening, and western blot, to
determine signaling cascades, gene expression, protein-protein
interaction, and protein-membrane trafficking in wild-type and
transgenic rats, focusing on models of pulmonary hypertension,
given their interest in the potential therapeutic efficacy of
statins in pulmonary arterial hypertension.


Dr. Greg Hundley:


Interesting, Carolyn. Really complex and sophisticated. So what
did they find?


Dr. Carolyn Lam:


Okay, listen up. Red meat and soybean have a high content of GGPP
and their ingestion increases GGPP plasma levels, but reduces the
effects of statins in rat models of pulmonary hypertension.
Ingestion of garlic extracts, rich in methyl-L-phenyl sulfonate,
which is a natural inhibitor of GGPP production, decreases GGPP
bioavailability, and rescues statin effects in pulmonary arterial
hypertension models. So consequently, first of all, diet may
influence the cholesterol-independent effects of statins and the
data really raise a provocative question of whether populations
in which the typical diet contains high amounts of soybeans of
beef may benefit less from statins. All this is discussed in an
elegant editorial by Dr. Thomas Eschenhagen from Germany, who
really ends with saying the present study should be considered
hypothesis-generating and stimulate retrospective analysis of
clinical registries and existing large interventional trials to
either validate or refute this hypothesis. Whatever the outcome,
the study is a nice example of thorough scientific underpinning
of the widely held maxim that we are what we eat.


Dr. Greg Hundley:


Oh, absolutely Carolyn. I think next time with my spaghetti, I'll
have the-


Dr. Carolyn Lam:


Garlic.


Dr. Greg Hundley:


... sauce with the garlic, but I won't add the red meats.
Especially if I'm taking a statin.


Dr. Carolyn Lam:


Oh, that's what I was afraid you might say. Oh well, let me tell
you about other papers in this issue. There's an ECG challenge by
Dr. Del-Carpio Munoz and entitled A Carousel ECG Confusion.
There's an on my mind paper by Dr. Hammond, on the importance of
shared decision making for return to play after COVID-19.


Dr. Greg Hundley:


Great, Carolyn. So, in the mailbag, there's a really nice
research letter from Dr. Robert-Ebadi evaluating the impact of
the age-adjusted D-dimer cutoff to exclude pulmonary embolism.
It's from a multinational prospective real-life study or the
RELAX-PE study. Well Carolyn, it's another double feature
Tuesday. How about we get off to understand a little bit more
about those insights from the CREDENCE trial, and then also left
atrial appendage closure devices?


Dr. Carolyn Lam:


All right, come on with your garlic breath.


Dr. Greg Hundley:


Well listeners, we are onto our feature discussions and we are
very fortunate, we're going to have two feature discussions. Our
first feature really addresses high blood pressure. And we have
with us today, Dr. Brendan Neuen from the George Institute of
Global Health in Sydney, New South Wales, Australia. And our own
associate editor, Dr. Wanpen Vongpatanasin from UT Southwestern
in Dallas, Texas. Welcome to you both. Brendan, we're going to
start with you. Could you describe the hypothesis that you wanted
to test and what was your study population and your study design?


Dr. Brendan Neuen:


Well, thanks Greg. In this study, what we wanted to assess was
the blood pressure lowering effects of the SGLT-2 inhibitor
canagliflozin in people with type two diabetes and chronic kidney
disease. The reason we thought that this is important is because
what we know about the blood pressure lowering effects of these
drugs is largely based on people with normal kidney function,
with relatively less data in people with chronic kidney disease.
So we aim to assess both the blood pressure lowering effects of
SGLT-2 inhibition in chronic kidney disease, as well as treatment
effects by baseline blood pressure and other blood pressure
defined variables. This was conducted in the CREDENCE trial,
which was a large primary renal outcome trial of the SGLT-2
inhibitor, canagliflozin, which enrolled about 4,400 people with
type two diabetes and chronic kidney disease with a urine albumin
to creatinine ratio greater than 300 milligrams per gram and a
GFR greater than 30 at enrollment. This was a high risk
hypertension population, about 30% of patients had apparent
treatment resistant hypertension, about 60% of people had a GFR
less than 60 and about 20% of people were on four or more blood
pressure lowering agents. So really high burden of hypertension
in the CREDENCE trial.


Dr. Greg Hundley:


Very good. Tell us a little bit about that design. So is this a
randomized trial?


Dr. Brendan Neuen:


So CREDENCE was an event-driven randomized, double blind, placebo
controlled, international trial. It was the first primary renal
outcome trial of an SGLT-2 inhibitor, the primary results of
which were reported in the New England journal in 2019. What this
trial did, was it randomized participants, as I mentioned, with a
GFR of greater than 30 and significant albuminuria and type two
diabetes to either canagliflozin 100 milligrams or matching
placebo in a one-to-one ratio with primary outcome overall of
doubling of serum creatinine, kidney failure, cardiovascular or
renal death. The trial was conducted in several, I think, 20 or
30 countries overall and enrolled at approximately 4,400 people,
with participants followed for a median of about two and a half
years.


Dr. Greg Hundley:


Excellent. So Brendan, tell us, what did you find?


Dr. Brendan Neuen:


So we found a couple of important findings with regards to blood
pressure. Firstly, what we found was that canagliflozin reduced
systolic blood pressure by about three and a half millimeters of
mercury in the overall trial population. But most importantly,
this blood pressure lowering effect was consistent across the
number of blood pressure defined subgroups, including in people
on multiple numbers of blood pressure lowering agents. So
irrespective of the number of blood pressure lowering agents at
baseline, and also irrespective of a history of apparent
treatment-resistant hypertension at baseline, that was important.
We also, secondly, found that the blood pressure lowering
effective SGLT-2 inhibition was present very early at the first
trial visit at three weeks. This effect was sustained over the
duration of the trial.


Dr. Brendan Neuen:


Thirdly, we also found that canagliflozin reduced the risk of
kidney failure and cardiovascular events, regardless of the
number of blood pressure lowering agents at baseline and
regardless of blood pressure, history of resistant hypertension.
Finally, there is this often important question of how do these
drugs reduce the risk of kidney failure and heart failure. So we
did a mediation analysis, looking at to what extent the blood
pressure lowering effect of this drug explains the treatment
effect on these important outcomes. We found that only about less
than 10% of the treatment effect on kidney failure and
cardiovascular events was explained by blood pressure lowering.


Dr. Greg Hundley:


Very interesting and strong, powerful results. Well, now we're
going to turn listeners to our associate editor, Dr. Wanpen
Vongpatanasin. Wanpen, I know you see a lot of papers come across
your desk at circulation, really focused on blood pressure and
its lowering. What struck you about this paper, and then how do
you put into context the results that Brendan just describe for
us with all the other results that you see in new blood pressure
lowering strategies?


Dr. Wanpen Vongpatanasin:


Yes, so I think this is very important study and add to a body of
literature showing that the canagliflozin, like many SGLT-2
inhibitors, inducing significant lowering of blood pressure. If
anything, because CREDENCE is not designed to be hypertension
study the effects of blood pressure lowering my even be
underestimated because the backup ground therapy allowed to be
changed throughout the trial, depending on physician judgment.
Also, I think the effects of many studies start to look at
effects of SGLT-2 inhibitor on out of office blood pressure, like
home blood pressure, or 24 blood pressure. Some even that we have
published over the years, show more pronounced blood pressure
lowering effects when measure outside the office. So I think that
it is very interesting study but it could be not just only the
drug that we use cardiovascular and renal outcome, but maybe a
new class of antihypertensive medication that we could use for
that purpose, although it has to be tested.


Dr. Greg Hundley:


Very nice. Well, Brendan, I want to turn back to you and then
we'll come to Wanpen. Brendan, what do you think as a followup
study to yours, what do you think is the next study that needs to
be performed in this space?


Dr. Brendan Neuen:


Thanks, Greg. I think there's so much we still need to know about
the blood pressure lowering effects of these drugs in people with
advanced CKD. It would be very interesting to look at the
DAPA-CKD trial, to look at the blood pressure lowering effects in
people with advanced CKD not due to diabetes, so nondiabetic
kidney disease. These patients also have a high burden of
hypertension and whether or not these effects are also present in
this population would also be important to know, and study
patients with even more advanced kidney disease. That is being
done in the EMPA-KIDNEY study with empagliflozin. Those results
should be known in the next 12 to 24 months.


Dr. Brendan Neuen:


So, I'm studying this further in people with kidney disease. And
also as Wanpen mentioned, looking at effects on blood pressure
phenotype, you know, 24 hour blood pressure dipping status would
also be important though, blood pressure variability, all those
things can add to our understanding of the effect of these agents
on blood pressure.


Dr. Greg Hundley:


Excellent. And Wanpen, do you have anything to add?


Dr. Wanpen Vongpatanasin:


Yes. I think one also very important study that helps someone
with carrying in the future is in the CREDENCE, the people who
are already treated with a mineralocorticoid receptor antagonist
were excluded. So whether among resistant hypertension group,
adding canagliflozin will be beneficial in those groups already
treated MRA and lower cardiovascular outcome in already treated
with MRA will be very interesting to see.


Dr. Brendan Neuen:


Yeah, I think that's a really important point to point out about
the design of the CREDENCE trial, that patients who were on MRAs
were excluded from the trial initially. This was due to early
concerns that canagliflozin might increase the risk of
hyperkalemia. I think that risk has now been put to bed in the
other SGLT-2 inhibitor trials. We've got more data looking at the
effects on serine potassium coming out soon, hopefully, but the
other trials in which enroll more patients on MRAs, it will be
very important to look at the blood pressure lowering effects in
these populations.


Dr. Greg Hundley:


Excellent. Well, listeners, we've heard a great discussion today
and we want to thank Brendan Neuen for bringing this wonderful
science to us through circulation at the American Heart
Association. We also want to thank our associate editor, Wanpen
Vongpatanasin for being present today and helping us discuss how,
in patients with type two diabetes and chronic kidney disease,
describing that the blood pressure lowering effect of
canagliflozin occurs early and appears sustained over the long
term and therefore perhaps canagliflozin and can be used or
considered as an adjunct blood pressure lowering medicine in
addition to perhaps its protective effects on the kidney and
other cardiovascular-related issues. Well now listeners, we've
got another feature to get onto. So we're going to get to that
second feature discussion right now.


Dr. Greg Hundley:


Well listeners, we are now turning to our second feature
discussion and we're so fortunate today to have with us Dr.
Saibal Kar from the Los Robles Regional Medical Center in Los
Angeles, California, and our own associate editor, Dr. Mark Link
from UT Southwestern in Dallas, Texas. Welcome gentlemen. Saibal,
let's start with you. Could you describe for us the hypothesis
that you wanted to test and what was your study population and
your study design?


Dr. Saibal Kar:


Dr. Hundley, or if I could allow to call you Greg, thank you very
much for asking me this question. The hypothesis was that we do
know that the WATCHMAN device does prevent ischemic strokes. We
do know that the first generation device has a few limitations.
So there were some modifications made to the new WATCHMAN device,
which is now called the WATCHMAN FLX. We thought that these
changes should translate into better safety and better efficacy.
So, that was the hypothesis of the study. The study population
was patients with nonvalvular atrial fibrillation with a
CHADS-VASc score of three or more, who had high risk of bleeding
or patients who cannot take long-term anticoagulants. The study
design was a single arm, prospective multicenter study with
endpoints, which were based on performance goals from previous
clinical trials.


Dr. Greg Hundley:


Excellent. Before we get to your results, Saibal how many
patients and how many centers participated in your trial?


Dr. Saibal Kar:


So as the national principal investigator, I've never seen a
study which was enrolled so fast. So the intended population was
400 patients in 29 centers and before half those centers could be
activated, the study was over in four months.


Dr. Greg Hundley:


Congratulations. I think all of us that have ... especially in
this pandemic era for recruiting so well, and tell us, what did
you find?


Dr. Saibal Kar:


So what we found is that there were two endpoints, a safety
endpoint and the efficacy endpoint. So the first thing that we
found is that of the 400 patients, we could actually implant in
395 patients, device actually, which made the primary success
rate over 98%. regarding the safety endpoint, we had a safety
margin around 4% based on a performance score and set about 2.5,
but the actual safety event rate was 0.5%, which was only two
minor ischemic events, peri-procedural. There were no pericardial
effusions in the first seven days, and there was no device
embolizations at any time period, so that was the primary safety
endpoint. So we were actually clearly safer than the
first-generation device.


Dr. Saibal Kar:


When it comes to efficacy, it was an anatomical efficacy and we
set the primary goal for the previous generation to be 99%. We've
made a delta to make it about 97% effective, but we actually
achieved an effective closure in 100% of patients. When I say
effective closure, I mean that anyone with a peri device leak of
less than five millimeters. Going into a little bit of granular
detail, we actually found out that 90% of the patients actually
had no leak at all. So we did at least achieve both the
anatomical as well as the safety endpoints.


Dr. Greg Hundley:


Excellent. Well, listeners, we're now going to turn to our
associate editor, Dr. Mark Link and Mark, I know you have many
papers that pass through your hands. What attracted you to this
paper. Then, these results really sound significant. Can you
describe what impressed you also with the results of this study
and how do they relate to other studies pertinent to implantation
of devices in patients with atrial fibrillation?


Dr. Mark Link:


Yeah, we were interested in this paper at CERT because it's the
next generation of the WATCHMAN. The numbers of patients that are
being implanted with this device to prevent strokes is
dramatically going up, but it's not a perfect device. So we were,
as the EP community, very interested in the next generation
device. We're obviously also interested in other competitors'
device, but it's clear that the WATCHMAN is probably the world's
leader in this time. So we knew that many of our people reading
this magazine, reading the circulation, would want to see how the
next generation turned out, was it really safer. That was really
the primary goal of this study, it's really a safety study more
than an efficacy study because the efficacy was defined by echo
criteria, not by clinical criteria of stroke, which is the
ultimate criteria. It was a well done study and the results came
out more positive than I think even the investigators thought it
was going to come out. So we liked it and that's why we did our
best to get it published in circulation.


Dr. Greg Hundley:


Very good. So it sounds like great new innovation and very, very
safe, especially relative perhaps to the first-generation device.
So Saibal, can you tell us in just a few words, what do you think
is the next study to be performed in this space? After you
answer, Mark, we'll turn to you and basically ask the same
question.


Dr. Saibal Kar:


Thank you very much, Greg. Transcatheter left atrial appendage
closure has been approved by the FDA, specifically the WATCHMAN
device, for patients who are candidates for long anticoagulation,
but have limitations to long-term anticoagulation and therefore
not for all-comers and there's a reason for that. The time has
now come to actually evaluate this device for all-comers. That
means all patients with nonvalvular atrial fibrillations who are
suitable for anticoagulants. Therefore, the next best study is
the CHAMPION trial. This study is going to be a randomized trial
of the WATCHMAN FLX versus NOACs, or more correctly DOACs, in
all-comers, patients with nonvalvular atrial fibrillation who
require long-term anticoagulants. It's a 3,000 patients clinical
trial with a one-to-one randomization to WATCHMAN FLX or the
continuation of DOACs and the primary endpoints will be estimated
at three years with a follow-up up to five years. Our goal is to
show that we are non-inferior in comparison to stroke and death,
and superior respect to long-term bleeding.


Dr. Greg Hundley:


Very good, and Mark?


Dr. Mark Link:


Yeah, I agree. The CHAMPION trial is the obvious next trial that
everyone wants to see the results of, comparing this device to
DOACs. Another trial or data I'd like to see is the immediate
post-procedural anticoagulation. It's still an area that we don't
have enough data to know how to treat these patients.
Traditionally, they've been treated with warfarin and
anti-platelet agents, but many of the patients getting this
WATCHMAN have a relative contraindication to anticoagulation. So
I'd like to see some data on shorter term duration of
anticoagulation post-implant.


Dr. Greg Hundley:


Very good. Well listeners, we've had a wonderful discussion here
and we want to thank the lead author, Dr. Saibal Kar and also our
own associate editor, Dr. Mark Link, for really providing us with
new information that this left atrial appendage closure device
met the primary safety outcome in 99.5% of all of those implanted
within seven days, what a remarkable finding. So, on behalf of
Carolyn and myself, we want to wish you a great week and we will
catch you next week on the Run. This program is copyright of the
American Heart Association, 2021.