Circulation September 15, 2020 Issue

This week’s episode includes author Jeffrey Testani and Associate
Editor Justin Grodin as they discuss empagliflozin heart failure,
including diuretic and cardio-renal effects.


TRANSCRIPT:


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 Centre and Duke National University of Singapore.


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


Dr Carolyn Lam: Greg, the SGLT-2 inhibitors have really
revolutionized heart failure treatment, but we still need to
understand a bit better how they work. And today's feature paper
is so important, talking about diuretic and cardio-renal effects
of Empagliflozin. That's all I'm going to tell you though,
because I want to talk about another paper in the issue very
related. And it's from John McMurray from the University of
Glasgow with insights from DAPA-HF. But maybe a question for you
first. Have you ever wondered what to do about loop diuretics
doses in patients with heart failure and whom you're thinking of
initiating an SGLT-2 inhibitor, Greg?


Dr Greg Hundley: Absolutely, Carolyn. That comes up all the time
and how do you make that transition.


Dr Carolyn Lam: Exactly. And so this paper is just so important,
and Dr McMurray and his colleagues showed that in the DAPA-HF
trial, the SGLT-2 inhibitor, dapagliflozin, first, just as a
reminder, reduce the risk of worsening heart failure and death in
patients with heart failure and reduced ejection fraction. And in
the current paper, they examined the efficacy and tolerability
that dapagliflozin falls in relation to background diuretic
treatment and change in diuretic therapy, following randomization
to dapagliflozin or placebo. They found that 84% of patients
randomized were treated with a conventional diuretic, such as the
loop or thiazides diuretic. The majority of patients did not
change their diuretic dose throughout follow-up. And the mean
diuretic dose did not differ between the dapagliflozin and
placebo group after randomization. Although a decrease in
diuretic dose was more frequent with dapagliflozin than with
placebo, the between-group differences were small. So treatment
with dapagliflozin is safe and effective regardless of diuretic
dose or diuretic use.


Dr Greg Hundley: Very nice, Carolyn. That's such a nice practical
article. I really enjoyed your presentation of that. My next
article comes from Professor Karlheinz Peter, and it's
investigating the reduction of shear stress and how that might
impact monocyte activation in patients that undergo TAVI. So this
group hypothesized that the large shear forces exerted on
circulating cells, particularly in the largest circulating cells,
monocytes, while passing through stenotic aortic valves results
in pro-inflammatory effects that could be resolved with TAVI. So
to address this, the investigative team implemented functional
essays, calcium imaging, RNA gene silencing and pharmacologic
agonist and antagonist to identify the key mechanical- receptor
mediating the shear stress sensitivity of the monocytes. In
addition, they stained for monocytes in explanted, stenotic,
aortic human valves.


Dr Carolyn Lam: Lots of work done in a very translational study.
So what did they find Greg?


Dr Greg Hundley: They found monocyte accumulation at the aortic
side of the leaflets in the explanted aortic valves. That was the
human subject study. In addition, they demonstrated that high
shear stress activates multiple monocyte functions and identify
PZ1 as the main responsible mechanoreceptors representing,
therefore, a potentially druggable target. So reducing the shear
stress from a stenotic valve promotes an anti-inflammatory effect
and, therefore, could serve as a novel therapeutic benefit of
those undergoing TAVI procedures.


Dr Carolyn Lam: Really nice, Greg. Thanks. We're going to switch
tracks a bit, Greg. What do you remember about Noonan's syndrome?


Dr Greg Hundley: Oh boy. Impactful, congenital disease for both
the probands, as well as the family.


Dr Carolyn Lam: That's truly beautifully put and you're right.
Noonan syndrome is a multisystemic developmental disorder
characterized by common clinically variable symptoms, such as
typical facial dysmorphism, short stature, developmental delay,
intellectual disability, as well as cardiac hypertrophy. Now the
underlying mechanism is a gain of function of the RAs MAPK
signaling pathway, kinase signaling pathway. However, our
understanding of the pathophysiological alterations and
mechanisms, especially of the associated cardiomyopathy, really
remains limited. So today's paper contributes significantly to
our understanding and is also notable for the methods that these
authors use to uncover this novel potential therapeutic
approaches. The paper is from Dr Cyganek and Wollnik as
co-corresponding authors from the University Medical Center
Göttingen in Germany. And they presented a family with two
siblings, displaying an autosomal recessive form of Noonan
syndrome with massive hypertrophic cardiomyopathy. As the
clinically most prevalent symptom caused by allelic mutations
within the leucine zipper like transcription regulator 1. They
generated induced pluripotent STEM cell derived cardiomyocytes of
the effected siblings and investigated the patient-specific
cardiomyocytes on the molecular and functional level.


Dr Greg Hundley: Carolyn, is such a thorough investigative
initiative. So what did they find?


Dr Carolyn Lam: They found that the patients induced, pluripotent
STEM cell cardiomyocytes recapitulated the hypertrophic phenotype
and uncovered, a so far not described, causal link between this
leucine zipper like transcription regulator 1 dysfunction and ras
map, kinase signaling hyperactivity, as well as, the hypertrophic
gene response and cellular hypertrophy. Calcium channel blockade
and MEK inhibition could prevent some of the disease
characteristics providing a molecular underpinning for the
clinical use of these drugs in patients with Noonan syndrome. In
a proof of concept approach, they further explored a clinically
translatable intronic CRISPR repair and demonstrated a rescue of
the hypertrophic phenotype. Massive amount of work in a beautiful
paper.


Dr Greg Hundley: You bet, Carolyn, and boy giving hope to address
some of that adverse phenotype in the heart. What an outstanding
job.


Dr Carolyn Lam: You're right, Greg. But now switching tracks a
yet again. What do you know about ischemic preconditioning?
Ischemic preconditioning refers to the process in which
non-lethal ischemic stress of the heart prevents subsequent
lethal ischemia reperfusion injury and provides important
intrinsic protection against ischemia reperfusion injury of the
heart, as well as other organs. So in this paper co-corresponding
authors, Doctors, Zhang, Xiao and Cao from Peking University and
colleagues provided multiple lines of evidence that a
multifunctional TRIM family protein, the Mitsugumin-53 or MG53 is
secreted from the heart in rodents in response to ischemic,
preconditioning or oxidative stress. Now this secreted MG53
protected the heart against ischemia reperfusion injury. In the
human heart, MG53 was expressed at a level about 1/10th of its
skeletal muscle counterpart. And MG53 secretion was triggered by
oxidative stress and human embryonic STEM cell derived
cardiomyocytes, while deficiency exacerbated oxidative injury in
these cells.


Dr Greg Hundley: Very nice, Caroline. Tell me the take home
message. How do I incorporate this information, maybe even
clinically?


Dr Carolyn Lam: Well, these results really defines secreted MG53
as an essential factor, conveying ischemic preconditioning
induced cardioprotection. Now, since systemic delivery of MG53
protein restored ischemic preconditioning mediated
cardioprotection in deficient mice, recombinant human MG53
protein could perhaps, or potentially be developed, into a novel
treatment for various diseases of the human heart in which
indigenous MG53 may be low.


Dr Greg Hundley: All right, Carolyn. I'm going to tell you about
a couple of letters in the mailbag. First, there's a research
letter from Richard Vander Heide regarding unexpected feathers in
cardiac pathology in COVID-19. And then, there's a large exchange
of letters between Dr Yuji MIura, Chuanli Ren and Laurent Azoulay
regarding a prior publication, entitled "Aromatase Inhibitors and
the Risk of Cardiovascular Outcomes in Women With Breast Cancer,
A Population-Based Cohort Study." And then finally, Carolyn,
there's another research letter from professor, Nilesh Samani,
entitled "Genetic Associations with Plasma ACE2 Concentration:
Potential Relevance to COVID-19 Risk."


Dr Carolyn Lam: Wow, interesting. There's also an "On My Mind"
paper by Dr Kimura on "contextual imaging, a requisite concept
for the emergence of point-of-care ultrasound." There's an ECG
challenge, by Dr Dewland, with a case of an intermittent -wide
QRS complexes. There's a cardiovascular case series presentation
by Dr Nijjar on "a solitary left ventricular septal mass and
amaurosis fugax."


Dr Greg Hundley: That's great, Carolyn. How about we move on to
the feature discussion.


Dr Carolyn Lam: Let's do that.


Dr Greg Hundley: Well listeners, we are here to discuss again,
another important paper related to SGLT-2 inhibition. And we have
with us, Dr Jeff Testani from Yale New Haven and our own
associate editor, Dr Justin Grodin from University of Texas
Southwestern Medical Center. Welcome gentlemen. Jeff let's start
with you. Can you describe for us some of the background behind
this study, and then also the hypothesis that you wanted to
address?


Dr Jeffrey Testani: Our lab is very interested in understanding
volume overload and heart failure, why does the kidney retain
sodium and why it stops responding to loop diuretics. Several
years ago, when the SGLT-2 first came out, we saw them as a
diuretic with the side effect of glucosuria. Back when they were
still being thought of as primarily diabetes medications. But as
the story unfolded and we saw that the SGLT-2 seemed to be doing
something much more than just control blood glucose in diabetics
and was demonstrating, particularly, a pronounced effect on heart
failure outcomes, we got very interested in, better understanding
this.


We know that loop diuretics, they're really a double-edged sword.
Loop diuretics are our mainstay of therapy to relieve congestion
and heart failure patients, but they do so at the expense of
quite a bit of toxicity. And we know that the loop diuretics
directly cause neuronal activation, elaboration of rennin,
norepinephrine, etc. through their effects directly on the
kidney. In addition to causing normal moral activation through
the volume depletion they cause. And as we all know, blocking the
neurohormonal activation is one of the primary therapies we use
in heart failure. So even though it helps our patients keep the
fluid off, it does that at an expense of potentially some very
negative effects.


The interesting thing with the SGLT-2 inhibitors is, we've seen
that in the diabetic populations, that they seem to actually
improve volume status in diabetics, more so than one would really
expect by the week diuretics that they are. And by and large,
they were doing that without a pronounced activation of the
neurohormonal system. So this led us to the conclusion that we
really need to rigorously study this in heart theory and see what
exactly are these effects of diuretics volume status and how much
negative impact will any of those effects bring towards normal
activation, kidney dysfunction, etc.


Dr Greg Hundley: Very clever, Jeff. How did you go about
addressing this question? What was your study design and what was
your study population? Who did you enroll?


Dr Jeffrey Testani: We wanted to have a pretty clean mechanistic
study here. We weren't looking at ethnicity. We were really
trying to understand a mechanism here and what are these agents
doing to sodium handling in the kidney, etc.


We enrolled diabetic patients that were stable. Per their
advanced heart failure position, they were at added at a stable
volume status. They hadn't had recent changes in medications
diuretics, and we use the crossover design where we brought the
patient in for about an eight-hour rigorous GCRT type study where
we administered empagliflozin in 10 milligrams and then did some
pretty rigorous characterization of them. As far as body fluids
spaces, renal function, normal activation, your sodium excretion.
Then they would continue that therapy for two weeks, come in for
a terminal visit, that was a very similar protocol. Then we'd
wash them out for two weeks and cross them over to the
alternative therapy. And they were randomized whether they had
placebo or epilobium first in order.


Dr Greg Hundley: Very good. So a crossover design. And what were
your study results, Jeff?


Dr Jeffrey Testani: We were quite interested in the overall
effects and it was actually quite surprising. We know the loop
diuretic resistance is common and when physicians and patients
are not responding well enough, oftentimes we add thiazides. And
thiazides waste potassium. They waste magnesium. They increase
uric acid. They usually cause renal dysfunction and significant
normal activation. That was the default hypothesis that we would
see that. And to the contrary, we pretty much saw the opposite of
what a thiazide did. We saw a modest, but clinically significant
natriuresis. So as a monotherapy, these drugs are quite weak.
Although we saw a doubling of a baseline level of sodium
excretion, that's sort of a clinically irrelevant amount as an
acute diarrheic. However, when we added the eplerenone to a loop
diuretic, we got a 30, 40% increase in sodium excretion. And just
to benchmark that, if you look at the dose trial where they
compared low dose to high dose Lasix, which were one X versus two
and a half X, their home loop diuretic, they got a similar
increase in sodium excretion.


So even though 30, 40% increase in sodium excretion doesn't sound
like a lot, it's all of our normal interventions. It's actually a
pretty significant increase. We found that happened acutely. And
to our surprise, that natriuretic effect had not completely gone
away by two weeks. So the patient was still in a negative sodium
balance at the two-week time point. And they actually had a
reduction in their blood volume, in their total body water, in
their weight, as a result of that kind of slow persistent,
natriuresis that had happened over those two weeks.


We were unable to detect any signs of normal MAL activation with
this. There was actually a statistically significant better
change in norepinephrine during the dapagliflozin period versus
placebo. And there's some evidence that, that might be an actual
finding of saccharolytic effect of these drugs. As in many of the
other trials we've seen no, despite a reduction of blood pressure
and probably volume status, heart rate stays the same or even
goes down. And we saw an improvement in uric acid. We saw no
additional potassium wasting. We saw an improvement in serum
magnesium levels. So really kind of like I started this way is
the opposite, in many ways of what we see, side effect wise, with
the diuretic is what we saw with addition of an SGLT-2 inhibitor.


Dr Greg Hundley: Listeners, we're going to turn now to Dr Justin
Grodin, who's one of our associate editors and is also an
editorialist for this paper. And Justin, we've heard some really
exciting results here. The addition of a dapagliflozin to a loop
diuretic enhancing the neurohormonal access and receiving some
unexpected benefits on the electrolyte portfolio. Can you tell us
a little bit about how you put this work in the context of
everything else that we have been reading about this exciting new
class of drug therapy?


Dr Justin Grodin: This certainly is exciting because with the
release of the DAPA-HF clinical trial, just about a year ago,
we've really come to recognize that there really are substantial,
long-term beneficial effects with SGLT-2 inhibition in patients
with heart failure, and as Jeff alluded to, a lot of these
effects, we saw that they were beneficial in individuals that are
high risk or who already had heart disease and diabetes. And we
weren't sure if that was going to translate to individuals with
heart failure. We really saw beneficial effects in both,
individuals with heart failure, with or without diabetes. So this
is an interesting paradigm because, although we saw dramatic
effects in long-term survival quality of life, the mechanism was
actually somewhat murky. And a lot of this was transitive based
on prior works. We obviously had a strong hypothesis that they
would work through reducing incident heart failure and diabetics,
but then we were left questioning what is the mechanism? And I
think Jeff highlighted it quite well.


There was the early thought that this was perhaps just a weak
diuretic and that it was additive, and these patients were just
getting long-term natiurer recess. And then others thought that
there might've been, perhaps, some positive influence by some
very low level, blood pressure reduction with these therapies.


So in that sense, I think Jeff's paper really is put in context
and when we reviewed it, we thought it was quite fascinating
because I think as Jeff showed in his paper quite elegantly and
actually in a very, very careful study, which the reviewers and
your editorial staff appreciated, we really saw that there was a
probably more robust response to natriuresis than we had
anticipated. And importantly, this was independent of glycosuria,
which is a very important observation. And if I might take a
10,000-foot view of at least this therapy and how we might think
about it as an incremental therapy in heart failure, it's really
doing something else. So we thought that with SGLT-2 inhibition,
you get a little sodium and a little natriuresis, maybe perhaps a
little bit extra, as it complexes with glucose.


I think if you look at what the potential physiology would be
with this therapy is that it's doing far more than that. And I
think Jeff's study at least supports some of the speculation. And
again, I'm going to perhaps look beyond SGLP-2 inhibitor, and
then more so focus on the physiology of the proximal convoluted
tubule. And given the location of the blockade, this is really
priming the kidney, or at least Jeff's manuscript, and Jeff's
analysis, supports the hypothesis that SGLT-2 inhibitors
influence the proximal tubule environment, such that the kidney
is ready to reset in natriuresis. And I think Jeff's data it at.
least supports that because if we look at the proximal tubule
physiology, there's really a lot more going on, then SGLT-2
inhibition.


There are other receptors that it can influence that might also
promote natriuresis. It can also promote increased distal sodium
delivery to other areas of the nephron. And in essence, this
almost, and in Jeff has put it this way before, which I totally
agree. This gives the opportunity for the kidney to taste the
salt, as opposed to the more common state that we have in
somebody with heart failure and congestion, where, and I talk
about this on rounds all the time, the kidney's response to a
failing heart is to retain salt and water. So this kidney is in
this perpetual state of dehydration. And I think the idea that
Jeff's analysis is at least supporting, is that somehow, we were
influencing the physiology in the proximal convoluted tubule, we
are actually priming the kidney and readying it. We're almost
hitting reset, where the kidneys may lose this physiology,
thinking that the body is dehydrated and in essence, really
readying it to assist with decongestion.


Dr Greg Hundley: I love the way you explained that. It's almost
as if I'm on ward rounds with you that just knocks home a lot of
the message here, and the importance of Jeff's work.
Understanding the physiology of the proximal tubule and then
readying the kidney, instead of moving into a mode of retaining
salt and water, actually allowing that to flow and facilitating a
diaresis. I'll start with you, Jeff, and then come back to
Justin. You might have unlocked a really special key here. What
do you see as the next steps in research in this particular
field?


Dr Jeffrey Testani: I think Justin really, really captured the
essence of what excites us so much about this is, most diuretics
are a brute force sort of approach to getting salt out of the
body. They are a stick, not a carrot and SGLT-2 inhibitors, when
you look at them as how they would work as a brute force
diarrheic, they are really wimpy and there is every opportunity
for the kidney to defeat the of a SGLT-2 inhibitor, if it wanted
to buy where they work and what they block. But the reality is,
is that they really seem to be the carrot almost. if you think of
resetting the sodium set point of the kidney, kind of quenching
some of that salt first or sodium humidity that Justin was
referring to.


And the thing that's really interesting is when we look at trials
like DAPA-HF. So despite the fact that they do seem to have this
natural effect in blood pressure lowering effect and these
different effects, they don't tend to cause hypertension, over
diaresis, it's a much more of a natural, where the kidneys
regulatory mechanisms are still operative. we have this duality
of not causing over diaresis but causing diaresis. So it's really
when the body needs to get rid of salt, it helps it do that. And
so I think the next steps, at least for our research program is,
we want to understand taking these drugs out of the context of
stable, relatively euvolemic chronic heart failure patients. And
when we put them into the acute setting of actual volume
overload, do we see more robust diathesis and that natriuresis in
that setting.


The second thing is we want to dig into what is the internal
mechanisms that are allowing the kidney to do these things. How
is it that it's able to dump out salt when it's beneficial, but
not leaked over to uresis. Since we're digging into those
mechanisms, I think will give us some additional insight into
this class.


Dr Greg Hundley: Justin.


Dr Justin Grodin: I think Jeff really encapsulated, or at least
certainly highlighted some very important points, that are
largely in parallel with where I foresee this. Because really, if
you look at just study, a lot of these patients were quite
stable. So the questions that come along are whether or not that
this synergistic effect number one, is sustained long-term.
Because there are some data, at least in diabetic individuals,
that this might not be the case. So Jeff's paper elegantly
highlights the influence of these therapies in two weeks. Now,
whether that's sustained is certainly unclear. I think the
logical next step is, "Okay. We show that we have a therapy that
might prime the kidney for increased natriuresis" what are its
effects and individuals that might need the natriuresis even
more. So as Jeff highlighted individuals with more decompensated
heart failure, that are more congested and more hypervolemic.


And then obviously individuals that might be quite diarrheic
resistant. This is something that I think Jeff and I have given
talks on. And Jeff is clearly one of the world's experts in this
space, but it's obviously a very attractive possibility that this
might influence individuals whose kidneys are teased or trained
into just holding onto sodium, no matter what. Or really no
matter what therapies we give the kidney. I don't know if Jeff
mentioned this, but at least in his analysis, they also showed
through indicator dilution methods that there was a reduction in
plasma volume in these individuals. And I think that's really
important because we at least hypothesize that in many heart
failure phenotypes, plasma volume is certainly a component of
decompensation. So whether these kidneys have a more pleiotropic
effect on the fluid balance from your status between the
interstitium and the vascular space, long-term is really unknown.


Dr Greg Hundley: I want to thank both Jeff and Justin. What an
incredible, exciting discussion. And this paper, Jeff, were so
thrilled to have the opportunity to publish it in circulation.
And the clarity, helping us understand some of the mechanism of
the efficacy of SGLT-2 inhibition. And then this unique
combination of SGLT-2 with loop diuretics, potentiating, dieresis
natriuresis without some of the harmful effects on serum
electrolytes. And then I really appreciate both of you giving us
an insight into the future where more work is needed to
understand, is this a sustainable beyond two-week effect? And
then, can these therapies, this combination, be helpful in those
with decompensated heart failure.


On behalf of Carolyn and myself, we wish you a great week and we
look forward to catching you next week on the Run.


This program is copyright, the American Heart Association 2020.