Circulation June 1, 2021 Issue

In this week’s podcast, articles “The Cardiac Late Sodium Channel
Current is a Molecular Target for the Sodium-Glucose
Co-Transporter 2 Inhibitor Empagliflozin” by Light et al
(www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.053350) and
“Metabolic effects of empagliflozin in heart failure: A
randomized, double-blind, and placebo-controlled trial (Empire HF
Metabolic) by Jensen et al
(www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.053463) are
discussed.


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,


Dr. Carolyn Lam:


Greg, it's double feature day. And guess what? Both papers that
we're going to talk about are regarding the SGLT2 inhibitors, and
really look at the mechanism of action of these amazing
compounds, from both a pre-clinical and clinic point of view.
That's all I want to say, because we've got to tune in, a very
interesting discussion coming right up.


Dr. Carolyn Lam:


But first I'd like to ask you a question. What do you think is
the association between health-related quality of life and
mortality in heart failure around the world?


Dr. Greg Hundley:


Well, Carolyn, I would think that, actually, they might be
linked.


Dr. Carolyn Lam:


That's a really clever answer. Thanks Greg. Well, the authors are
actually going to tell you with this next paper. It's from Dr.
Salim Yusuf from Population Health Research Institute and
McMaster University in Hamilton, Canada, and colleagues, who
looked at the global congestive heart failure, or GCHF study,
which is the largest study that has systematically examined
health-related quality of life, measured by the Kansas City
Cardiomyopathy Questionnaire, which is the largest study that has
systematically examined health-related quality of life and its
association with outcomes in heart failure, across eight major
geographic regions, spanning five continents.


Dr. Greg Hundley:


Wow, Carolyn. So what did they find here?


Dr. Carolyn Lam:


Health-related quality of life, as measured by the Kansas City
Cardiomyopathy Questionnaire, or KCCQ, really differs
considerably between geographic regions, with markedly lower
quality of life related to heart failure in Africa compared to
elsewhere. Health-related quality of life was also a strong
predictor of death and heart failure hospitalization in all
regions, irrespective of symptoms class, and with both preserved
and reduced ejection fraction.


Dr. Carolyn Lam:


Indeed, this paper really highlighted a great need to address
disparities that impact health-related quality of life in
patients with heart failure in different regions of the world.


Dr. Greg Hundley:


Fantastic, Carolyn. Well, I have two studies to discuss, Carolyn,
and they're kind of similar, so we're going to do them back to
back. The first study reports the results of the Sort Out X
Trial, a large scale randomized multi-center, single-blind,
two-arm, non-inferiority trial, with registry based follow-up
designed to evaluate the Dual Therapy Sirolimus-Eluting, and CD34
positive antibody coated combo stent or DTS versus the
Sirolimus-Eluting Orsiro Stent or SES.


Dr. Greg Hundley:


And the study comes to us from Dr. Lars Jakobson, from Arhus
University Hospital. The primary endpoint target lesion failure,
or TLF was a composite of cardiac death, myocardial infarction,
or target lesion revascularization within 12 months, all analyzed
using intention to treat.


Dr. Carolyn Lam:


All right, Greg. So the DTS compared to the SES, what did they
find?


Dr. Greg Hundley:


Thanks, Carolyn. So the DTS did not confirm non-inferiority to
the SES stent for target lesion failure at 12 months. The SES was
superior to the DTS, mainly because the DTS was associated with
an increased risk of target lesion revascularization. However,
rates of death, cardiac death, and myocardial infarction at 12
months did not differ significantly between the two stent groups.


Dr. Greg Hundley:


Now Carolyn, in this same issue, we have another study evaluating
endothelial function and implantation of intercoronary stents.
And this second study comes to us from Professor Alexandra
Lansky, from the Yale University School of Medicine and Yale
Cardiovascular Research Group. And Carolyn, the study evaluated
whether implantation of an intercoronary stent that facilitated
endothelialization after the four to six weeks smooth muscle
anti-proliferative effects post-stent implantation would be
non-inferior to traditional drug-eluting stents.


Dr. Carolyn Lam:


Okay, another interesting study. And so, how did they do that?
What did they find?


Dr. Greg Hundley:


Yeah, so Carolyn, a total of 1,629 patients were randomly
assigned in a two to one fashion to the supreme DES stent, so
1,086 patients, or the DPDES stent, which was 543 patients. And
there were no significant differences in rates of device success,
clinically driven, target lesion revascularization, or stent
thrombosis at 12 months.


Dr. Greg Hundley:


And the safety composite of cardiovascular death and target
vessel revascularization or myocardial infarction was 3.5 versus
4.6% with the supreme DES stent compared to the DPDES stent. But
target revascularization for this new stent was two and a half
fold higher.


Dr. Greg Hundley:


So Carolyn looking at these two papers, what have we learned? So
first, the Jakobsen, et al, tested whether the stainless steel
COMBO Sirolimus-Eluting Stent coated luminally with CD34 positive
antibody could theoretically capture endothelial progenitor cells
and regrow endothelium.


Dr. Greg Hundley:


And the investigators observed that this stent had higher, not
lower or equivalent, target lesion revascularization relative to
the current generation Cobalt-Chrome Stent that only eluted
sirolimus.


Dr. Greg Hundley:


In the second study, Lansky and associates examined an approach
which was touted as enhancing endothelial recovery, where the
early erosion of material and release of drug was thought to
allow earlier endothelial recovery enhancing vascular response.
Non-inferiority of the rapid release was demonstrated, but rather
than hints of superiority, there were signs of inferiority.
Hereto, target lesion revascularization was problematic and was
two and a half fold higher.


Dr. Greg Hundley:


And so, Carolyn, there's a wonderful editorial from Professor
Elazer Edelman from the Massachusetts Institute of Technology
entitled, “Karnovsky's Dictum that Endothelium is Good Looking
and Smart,” where Dr. Edelman emphasizes that while some
endothelial cells may have been present after deployment of these
devices, perhaps a fully constituted functioning endothelium may
not have been achieved.


Dr. Greg Hundley:


And as we know, it is a fully functioning endothelium with nitric
oxide release, buried platelet adhesion that is most protective.
It is a really provocative read that reflects on previous
thoughts from Morris Karnovsky, who suggests preservation of
endothelial function is optimized by minimizing injury to it. And
so, Carolyn, these combined articles really highlight the current
state of new developments within interventional cardiology to
thwart re-stenosis and highly recommend them to our readers.


Dr. Carolyn Lam:


Wow, thank you, Greg. That was amazing. But you know what, so's
this next paper, because it really provides novel insights into
that enigma of the role that the epicardium plays in the
pathogenesis of arrhythmogenic cardiomyopathy.


Dr. Carolyn Lam:


Now, to delineate the contributions of the epicardium to the
pathogenesis of arrhythmogenic cardiomyopathy, doctors Marian
from University of Texas Health Science Center at Houston, Texas
and colleagues performed a series of elegant mouse experiments
using conditional deletion of the gene encoding desmoplakin in
the epicardial cells of mice. Mutations in genes and coding
desmosome proteins, including desmoplakin are known to be major
causes of arrhythmogenic cardiomyopathy.


Dr. Greg Hundley:


Wow, Carolyn, very interesting. So what did they find here?


Dr. Carolyn Lam:


Epicardial derived cardiac fibroblasts and epithelial cells
expressed paracrine factors, including TGF-β1 and fibroblasts
growth factors, which mediated epithelial mesenchymal transition
and contributed to the pathogenesis of myocardial fibrosis,
apoptosis, arrhythmias, and cardiac dysfunction in a mouse model
of arrhythmogenic cardiomyopathy. These findings really uncover
contributions of the epicardial derived cells to the pathogenesis
of arrhythmogenic cardiomyopathy.


Dr. Carolyn Lam:


Greg, there's a whole lot of other interesting stuff in today's
series, as well. There's an exchange of letters among doctors
Mehmood, doctors Moayedi and Dr. Birks regarding the article
“Prospective Multicenter Study of Myocardial Recovery Using Left
Ventricular Assist Device.” There's an ECG challenge by Dr.
Ezekowitz on a silent arrhythmia. How would you treat this
patient? Go quiz yourself.


Dr. Carolyn Lam:


There is an AHA Update by Dr. Churchwell on how federal policy
changes can advance the AHAs mission to achieve health equity.
And finally, a Perspective by Dr. Talbert on rheumatic fever and
the American Heart Association, The Nearly 100 hundred-Year War.
Well, that wraps it up for the summaries. Let's go to the double
feature, shall we?


Dr. Greg Hundley:


You bet.


Dr. Carolyn Lam:


Wow, today's feature discussion is really all about SGLT2
inhibitors, and that question that we're still asking, how do
they work? And today, we are discussing two papers, very
interestingly, looking at it from different aspects, one from a
preclinical lens, finding a very novel target for SGLT2
inhibitors, and the other from a clinical lens, and really
looking at the metabolic effects of the SGLT2 inhibitors in a way
you've not seen before.


Dr. Carolyn Lam:


I'm very pleased to have with us the authors of these very
exciting papers. We have Dr. Jesper Jensen from Herlev and
Gentofte University Hospital in Denmark. We have Dr. Peter Light
from University of Alberta, in Canada, and we have our associate
editors, Dr. Thomas Eschenhagen from University Medical Center,
Hamburg, and Dr. Justin Ezekowitz from University Alberta.


Dr. Carolyn Lam:


So, welcome gentlemen, thank you so much for joining us today. I
suggest, let's start from the mice before we go to the men, and
Peter, if you don't mind by starting us in, please tell us about
this novel target you found, why you looked at it, how you found
it, what it means.


Dr. Peter Light:


Hi, Carolyn, yeah, happy to discuss that. So, we all know that
through numerous clinical trials, there's a very unexpected and
exciting cardioprotective effect against heart failure with the
SGLT2 inhibitors. And we decided to investigate some of the
molecular mechanisms, which may underlie that protection. And in
looking at the literature previously, and from my own lab's work,
we're very interested in control of electrical excitability and
ionic homeostasis in cells.


Dr. Peter Light:


So we investigated a known target or a known iron channel, which
is involved in the etiology of heart failure as well as cardiac
arrhythmias. And that would be the cardiac sodium channel. So, we
investigated the effects specifically on a component of the
cardiac sodium channel called the late sodium current, which is
only induced in disease states, and they could be that during
heart failure or ischemia, or can actually be in congenital
conditions such as Long QT Syndrome Three, which involves certain
mutations in this sodium channel.


Dr. Peter Light:


So we basically investigate the effects of empagliflozin,
dapagliflozin and canagliflozin, in several different models of a
sodium channel dysfunction, including mice with heart failure.
And really what we've found is that this class of drug, and this
is a class effect, it's not specific to just one of these SGLT2
inhibitors, what we found, they are very good inhibitors of this
late current of the sodium channel. And in fact, they don't even
affect the peak current at all.


Dr. Peter Light:


And when we did this and we analyzed the data, we found the IC
50s were in the low micromolar or even sub micromolar range for
these drugs, which is exciting. And we extended those studies
into cardiac myocytes and looked at calcium handling in those
cardiac myocytes and saw that we get a very nice reduction in
abnormal calcium handling in cardiac myocytes.


Dr. Peter Light:


We also used in silico molecular docking of these drugs to the
cryo-EM structure of the NaV1.5, which is the cardiac sodium
channel and identified that these drugs bind to a known region of
that channel, which also binds the local anesthetics or
anti-arrhythmic drug, Lidocaine, as well as the anti-anginal
drug, Ranolazine.


Dr. Peter Light:


And finally, we showed that these drugs also reduce inflammation
through the NLRP3 inflammasome in an isolated beating heart
model. So collectively, we provide evidence that the late
component of the sodium channel is a really important, or maybe a
really important target for the molecular actions of this drug,
and may underlie those observations received from the clinical
trials relating both to heart failure, as well as sudden cardiac
death.


Dr. Carolyn Lam:


Thomas, could you put this in context for us?


Dr. Thomas Eschenhagen:


Thanks, Carolyn. I mean, we immediately liked the story because
as you said, and Peter as well, these drugs have amazing effects
and every clinical paper and indeed some new ones, but it's
really unclear how they do that. And what is, besides the
established target, the SGL2 in the kidney, what could be the
reason for all of this or some of this?


 


Dr. Thomas Eschenhagen:


And then, of course, other examples proposed, like the sodium
hydrogen exchanger, but this story didn't go so far. So we saw
now this data from Peter showing that, and this is, of course,
for a pharmacologist, just like me, very important, it's very
potent binding. It's not a binding which happens in a millimolar
or high micromolar, but as Peter said in low micromolar range. So
that makes it a very realistic effect, for example, much more
potent than ranolazine.


Dr. Thomas Eschenhagen:


And, of course, now the question is, to which extent could this,
now I would say, establish the effect on the late sodium current,
explain some of the findings which came out of the clinical
studies, and actually, a question I would have to Peter, now that
I think most of you know, the late sodium current is a reason for
the increased sodium for LQT3 syndrome, very rare.


Dr. Thomas Eschenhagen:


But, of course it would be tempting to say, okay, maybe that
would be a very good drug, particularly for people with LQT3. Did
you think about that, Peter? Is it something on your list,
mexiletine has been tried.


Dr. Peter Light:


Yeah, so I think that it's a certainly intriguing possibility. In
fact, in our study, we did test out several different Long QT3
mutations and saw a reduction in the late component as also
sodium channel. It's tempting to speculate that, indeed, these
could actually be a rather effective anti-arrhythmic drug in
patients with these LQT3 mutations or specific ones. I would love
to be able to test that in at least some of the genetic mouse
models of Long QT3 and to see whether this concept holds water or
not.


Dr. Carolyn Lam:


Wow, this is incredible. SGLT2 inhibitors from anti-diabetic to
now anti failure, and now anti-arrhythmic drugs? That's just
amazing. Thank you, Peter. We should move on to this next paper,
and this one all the way on the other spectrum, a clinical paper
called Empire Heart Failure, Empire Heart Failure Metabolic,
actually. Jesper, could you tell us about your trial and what you
found?


Dr. Jesper Jensen:


Sure, thanks for the invitation to take part in the podcast,
first of all. I'll tell you a little bit, we designed this study
to try to get behind mechanisms, so the clinical benefits of the
SGLT2 inhibitors in order to try to make a clinical outcome
trial. But as you know, the DAPA-HF and the EMPEROR-Reduced were
competed very fast, demonstrating the clinical benefits in HFrEF
patients.


Dr. Jesper Jensen:


So, the data of our study provides some detailed mechanistic
insights to these findings. And from the literature, we know that
SGLT2 inhibitors improve glucose metabolism in patients with
diabetes, and these changes might not be surprising in the
diabetes population, but moreover, alterations in glucose
metabolism may not be the main mechanism for the early occurring
clinical benefits.


Dr. Jesper Jensen:


However, we know that many of our heart failure patients without
diabetes are insulin resistant as a metabolic feature of the
heart failure, and the insulin resistance is associated with an
increased risk of developing future diabetes, which in turn
reduces the long-term survival and quality of life. So, the
targeting insulin resistance in HFrEF patients is, therefore, of
clinical relevance to our patients.


Dr. Jesper Jensen:


So, the population of the Empire HF Metabolic consisted of
patients with chronic HFrEF, with or without type two diabetes,
who are on a stable guideline directed heart failure therapy, and
have also indicated on anti-diabetic therapy. And we randomized
patients to receive empagliflozin 10 milligrams once daily, or
matching placebo as an-add on for 12 weeks.


Dr. Jesper Jensen:


And this was a modest sized randomized control trial, including
120 patients. A very large proportion of patients received
guideline directed heart failure therapy, and they generally
consisted of the best one third of atypical HFrEF population, and
only 10% had concomitant history of type two diabetes.


Dr. Jesper Jensen:


We then, at baseline and after 12 weeks, we formed an oral
glucose tolerance test to assess the hepatic and a peripheral
insulin sensitivity and performed a whole body DXA scan to
investigate alterations in body composition. We know that
patients lose weight when they get an SGLT2 inhibitor with and
without diabetes, but we don't know what it consists of in a
HFrEF population.


Dr. Carolyn Lam:


Tell us what you found after 12 weeks.


Dr. Jesper Jensen:


Yeah, so a large proportion, actually half of the patients
without a history of diabetes, had a new onset diabetes, or
impact glucose tolerance at baseline. So even though few have no
diabetes, this population were at very high risk of developing
future diabetes. And the main finding was that empagliflozin
improved insulin sensitivity. So the hepatic insulin sensitivity
was improved by 13% and the peripheral insulin resistance was
improved by 20% compared to placebo.


Dr. Jesper Jensen:


And moreover, both fasting and postprandial glucose were
significantly reduced. And regarding the body composition,
patients in a mean lost at 1.2 kilos, or 2.6 pounds, which mainly
consisted of a loss in lean mass and no significant changes were
observed in fatness, and this is from the DXA scan.


Dr. Carolyn Lam:


Hmm. Justin, could you shed some light on what the editors
thought about this, and there's lots of questions still, huh?


Dr. Justin Ezekowitz:


Yeah, absolutely, Carolyn, and thanks Jesper for sharing this
paper with Circulation. Thanks for summarizing it so well. I
think the questions that come up and the reason why we liked it
so much was we're all trying to understand mechanism of how these
medications work so profoundly for our patients.


Dr. Justin Ezekowitz:


Now, in this predominantly non-diabetic population, the fact that
the liver and the peripheral insulin sensitivity improves, how
does that bear out for the fact that there is no fat loss in the
early stages, yet that's all been linked to later improved
exercise capacity and increased fat loss later on in life.


Dr. Justin Ezekowitz:


So, do you think those two are going to be linked if you went to
say from 12 weeks beyond the 52 or two years down the road?


Dr. Jesper Jensen:


Yes, that is what we've seen from diabetes populations, at least.
So you could imagine that the same would be the case also in the
HFrEF primarily non-diabetic population, but again, we don't
know. But early loss is the mass loss.


Dr. Justin Ezekowitz:


So Jesper, when you think about the peripheral insulin
sensitivity improvement, is that largely indicating mostly muscle
based insulin sensitivity improvement, and that would indicate
that the muscles, perhaps, are functioning better in the short
term with just a simple change in therapy.


Dr. Jesper Jensen:


Yeah, that could be a way to put it. I would agree upon that.


Dr. Justin Ezekowitz:


So thanks, Jesper, I think that may indicate the quality of life
improvement that we may be seeing in the functional status there,
Carolyn.


Dr. Carolyn Lam:


Yeah, but as you said, Justin, there just seems so many other
questions. To Jesper, I want to know, what further might you want
to do to find out what's happening with this? The loss of lean
mass surprised me, frankly. I thought it would have been fat
mass. So, what are you doing to look at that? And then to Peter,
I want to go the other direction. What are you planning next that
might bring this closer to humans and a clinical study? So maybe
I'll ask Jesper to go first.


Dr. Jesper Jensen:


So, I definitely agree with you, Carolyn. We would also have to
put our money on the fat from the beginning, before the study. So
with respect to the weight loss, then a loss in lean mass is not
preferable if it represents muscle. So however, the weight loss
works to mediate the observed change in insulin resistance. And
additionally, a significant loss in muscle would result in
reduced insulin sensitivity. And we observed the opposite.
Therefore, the observed loss in lean mass may be speculated to
represent water and pointing towards the early diuretic effect
SGLT2 inhibitors. So, the DXA scan is good at looking at body
composition, but it has difficulties in separating lean mass from
whether it's muscle or water, but combined with the findings on
the insulin resistance, we speculate that the lean mass loss is
more.


Dr. Carolyn Lam:


Thank you. And Peter, could you very quickly tell us what are
next steps, in your view?


Dr. Peter Light:


Yeah, obviously we were studying mouse model of heart failure.
We'd like to make a more of a translational step in the next
experiments we do by studying human tissues. So getting access to
ventricular tissue from ex-planted hearts, human hearts, too, and
then measure electrical activity as well as some calcium imaging.


Dr. Peter Light:


Looking at some of these Long QT3 animal models would be another
thing that we're going to do. And also start looking at to see
whether we can get access to any electrophysiological data from
electronic medical records to start looking for DCGs and
measuring QT interval, for example, would be another nice step to
that.


Dr. Peter Light:


And then, more of a drug development side of things, we are
actively synthesizing new derivatives of these drugs and seeing
whether we can enhance the cardio-protective effects on the late
sodium current, but actually remove the ability to inhibit SGLT2.
So we would no longer have a glucose-lowering drug, but we'd have
a cardioprotective drug. So, it's all very exciting work going on
right now.


Dr. Carolyn Lam:


You've been listening to Circulation on the Run. From Greg and I,
don't forget to tune in again next week.


Dr. Greg Hundley:


This program is copyright of the American Heart Association,
2021. The opinions expressed by speakers in this podcast are
their own and not necessarily those of the editors or of the
American Heart Association. For more, visit ahajournals.org.