Circulation September 29, 2020 Issue

This week’s episode includes author Finnian Mc Causland and
Associate Editor Justin Ezekowitz as they discuss
angiotensin-neprilysin inhibition and renal outcomes in heart
failure with preserved ejection fraction.


TRANSCRIPT BELOW



Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly
podcast summary and backstage pass to The Journal and its
editors. I'm Dr Carolyn Lam, Associate Editor from the National
Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley Associate Editor, director
of the Pauley Heart Center at VCU Health in Richmond,
Virginia.
Dr Carolyn Lam: Greg, we're going to be talking about RNEs and
renal outcomes in HFpEF. Oh, you got to hold me back this is
going to be such an interesting discussion. But maybe let's grab
our coffees. Are you ready to talk about some of the papers in
today's issue?
Dr Greg Hundley: You bet.
Dr Carolyn Lam: Well the first paper I have really represents a
novel gene therapy approach to atrial fibrillation. So doctors
led by Dr Arora from Northwestern University Feinberg School of
Medicine and colleagues used a novel gene therapy approach in a
canine rapid atrial pacing model of atrial fibrillation to
demonstrate that NADPH oxidase-2 or NOX2 generated oxidative
injury by causing upregulation of a constitutively active form of
acetylcholine-dependent potassium current, or IKH is an important
mechanism underlying electrical remodeling in the fibrillating
atrium.


Dr Greg Hundley: Wow, Carolyn, very interesting. Tell us a little
bit more about this gene therapy approach.


Dr Carolyn Lam: They performed targeted expression of anti-NOX2
short hairpin RNA in the intact atria of the dogs, and then
subjected those animals to rapid atrial pacing for a period of
several weeks to months. The novel atrial gene therapy approach
prevented the development of electrical remodeling and sustained
atrial fibrillation thus demonstrating for the first time a
clearer causative role for NOX2 generated oxidative injury in the
creation, as well as the maintenance of electrical remodeling in
atrial fibrillation. Furthermore, they demonstrate that a likely
cellular and molecular mechanism by which oxidative injury
created a vulnerable substrate for atrial fibrillation, the
results of this study yield therefore valuable mechanistic
insights into the pathogenesis of atrial fibrillation and have
important therapeutic implications for this clinical management.


Dr Greg Hundley: Very nice, Carolyn. We need more therapies for
AFib. Boy, that's so informative. Well, the next paper that I
have sort of merges the world of electrophysiology with the world
of imaging and it comes to us from Dr Michela Casella from Centro
Cardiologico Monzino. Among 162 consecutive patients, this study
evaluated the combined utility of electroanatomic voltage mapping
coupled with cardiovascular magnetic resonance imaging to guide
endomyocardial biopsies.


Dr Carolyn Lam: Oh, so interesting. A combined noninvasive and
invasive electrical guide to perform cardiac biopsies, wow. So
what did they find Greg?


Dr Greg Hundley: So they found that the sensitivity of pooled
electroanatomic voltage mapping and cardiovascular magnetic
resonance was as high as 95%. EVM and CMR together conferred an
endomyocardial biopsy positive predictive value of 89%.
Endomyocardial biopsy analysis allowed to reach a new diagnosis
different from the suspected diagnosis in 39% of patients,
complication rates were low, mostly vascular access related, with
no patients requiring urgent management. Most impressive for this
manuscript are the illustrative figures that are provided. It's
really a great article for those performing biopsies, doing
imaging, or the EP procedures that guide the biopsy process.


Dr Carolyn Lam: Really nice, Greg, thanks. Now for the last
paper, have you ever thought about atherosclerosis as an
autoimmune disease?


Dr Greg Hundley: Well, I wonder, we're learning so much about our
immune systems these days, perhaps.


Dr Carolyn Lam: Indeed, throughout the inflammatory response that
accompanies atherosclerosis auto-reactive CD4 positive T helper
cells do accumulate in the atherosclerotic plaque. Apolipoprotein
B-100 or Apo B is the core protein of LDL really serves as the
auto antigen that drives the generation of pathogenic T helper
one cells with pro inflammatory cytokine secretion. Yet there may
also exist Apo B specific CD4 positive T cells with an athero
protective regulatory T cell phenotype in healthy individuals.
And that relationship between the protective Apo B reactive T
regulatory cells and the pathogenic T helper one cells really has
remained unknown until today's paper.
And this is from Dr Ley from the La Jolla Institute for
Immunology and colleagues is really the first report to
characterize CD4 positive T cells recognizing Apo B in the mouse
with a combination of a novel MHC II tetramer and single cell
transcriptomics immuno receptor sequencing and functional
evaluation, and their results demonstrated an unexpected mixed
phenotype of Apo B reactive auto-immune T cells in
atherosclerosis and suggest an initially protective auto immune
response against Apo B with a progressive derangement in clinical
disease. These findings really identify Apo B auto-reactive T
regulatory cells as a novel cellular target in atherosclerosis.


Dr Greg Hundley: Very nice Carolyn, boy that was a beautiful
summary. I've got in the mail bag just a couple of things to talk
about before you get to the discussion of some research letters.
There's an ECG challenge from Dr Gunaseelan involving a young
patient with chest pain. And then Theresa Wang has a very nice
case series involving pulmonary hypertension, entitled Pressures
at an All Time High.


Dr Carolyn Lam: There's also an On My Mind piece by Dr Perman on
overcoming fears to save lives. So COVID-19 and the threat to
bystanders CPR in out-of-hospital cardiac arrest. There's a
research letter by Dr Myhre on cardiovascular hospitalizations,
influenza activity, and COVID-19 measures, another by Dr Gurbel
on the first inhuman experience with inhaled acetylsalicylic acid
for immediate platelet inhibition, the comparison with chewed and
swallowed acetylsalicylic acid. A final research letter by Dr
Zurek rounds us up regarding neuregulin one inducing cardiac
hypertrophy and impaired cardiac performance in post myocardial
infarction rats, very surprising because we thought this was
protected. So there you have it for this issue, Greg, shall we go
on to our future discussion?


Dr Greg Hundley: Absolutely.


Dr Carolyn Lam: In patients with heart failure, chronic kidney
disease is really common and associated with a higher risk of
renal events than in patients without chronic kidney disease. In
fact, these renal events are really increasing in prominence in
the heart failure literature. And so I'm really welcoming the
discussion of today's feature paper, which looks at the renal
effects of angiotensin neprilysin inhibition in patients with
heart failure with preserved ejection fraction in the PARAGON
trial. I'm so pleased to have with us the first and corresponding
author of this paper, Dr Finnian Mc Causland from Brigham and
Women's hospital, as well as our associate editor Dr Justin
Ezekowitz from University of Alberta. Finnian, congratulations on
this beautiful paper. Could you please tell us a little bit about
the overview? What motivated it, what you found?


Dr Finnian Mc Causland: It's long been a passion of mine to look
at this interaction or intersection between cardiology and renal
events. And if the truth be told, I had a moment in my life where
I thought about being a cardiologist but I was swayed in other
directions during my training in Ireland. Well, I've always been
very much interested in this intersection, like I said, and so
I've had the opportunity to work very closely with Scott Solomon
and others at the Brigham who lead many of the heart failure
trials that you are all aware of much more than I have
been.
And this particular subset of patients with heart failure with
preserved ejection fraction is a very unique population that were
studied in the PARAGON-HF trial. And we thought it was a unique
opportunity to look at some of the pre-specified secondary end
points, which were the renal outcomes in terms of trying to
figure out what the effect of this was compared to valsartan
therapy in this patient population. So I think looking at this
intersection between heart failure and preserved ejection
fraction and the deterioration of kidney function was the primary
driver to look at this in the PARAGON heart failure trial, and to
really
look at the comparison between sacubitril-valsartan with
valsartan in this patient population.


Dr Carolyn Lam: Indeed, thanks so much Finnian, and here's a
confession too. I really liked nephrology during my training.
(laughs) I thought it was really cool and with all the
interventions, and so I really admire the many things you think
about, especially in these patients, who've got multisystem
disease, but okay. Moving on with PARAGON, I know that the
secondary outcomes were reported and it was really a striking
effect on the renal events. And so glad that you're shedding more
light in it. Could you tell us what this paper added?


Dr Finnian Mc Causland: Yeah, so here we really got into I
suppose the depths of the renal composite outcome and just to
remind everybody that was a composite of a 50% or greater decline
in eGFR, the development of end stage renal disease, or death
from renal causes, so this was the composite outcome that was
examined. We really evaluated this in a lot more detailed
breaking our composite down into its individual components, as
well as looking at it in totality. And I think the big take away
point was that we found there was an almost 50% reduction in this
primary renal composite outcome for patients on
sacubitril-valsartan compared with valsartan.


Dr Carolyn Lam: And what about the components and the sort of
further analyses?


Dr Finnian Mc Causland: Yeah, so getting into the, I suppose the
details in a little bit more granularity, the major driver of
those events will be 50% or greater decline in eGFR. And that's
where the majority of these events really came from over the
follow-up of PARAGON. And so this was assessed that various study
business throughout the course of the few years that the patients
followed up with PARAGON. And I think if we look at this slope
and this was clarified in terms of the overall slope analyses of
the eGFR. And we thought this relatively early separation in
favor of sacubitril-valsartan so that there was less decline in
eGFR over time compared with valsartan. So I think this was a
supportive finding from the slope analysis that really got to
this 50% threshold and that many people have examined in greater
detail than they had the cardiovascular literature. So it takes a
fair degree of kidney function decline to really reach that
threshold of 50%. And so I think this was a very repulsed finding
supported by the slope analyses.


Dr Carolyn Lam: Yeah, and to the audience that's listening, you
have to grab hold of figure three of this paper, and that shows
the eGFR slopes, which is something that's I think really
important in current heart failure literature, the concept of the
eGFR decline. So really nice work. Congratulations again,
Finnian. Justin, could you put these findings in context for us?


Dr Justin Ezekowitz: Finnian once again, congratulations on
getting this analysis. Pretty complex area to try to analyze and
analyze properly, given that there's an expansive renal
literature out there about looking at eGFR and how you look at
it. So I think there's a couple of questions that come to mind
when we think about the PARAGON trial overall. When we think
about the protection of the kidneys over three, four, five years,
my sense was from your analysis and perhaps you could expand on
it is there seems to be very few events in those people with
pretty preserved eGFR, but a greater number of events in those
less than 60 mils per minute, and I'm wondering if you think that
there's more of a unique place for medications such as
sacubitril-valsartan and that cohort and if so is it really,
that's where all the action is, but there's no real difference?
Or do you think there's an interaction there that we should
explore?


Dr Finnian Mc Causland: Thinking back to the entry criteria for
PARAGON-HF, one had to have an eGFR more than 30 mils per minute
at baseline. And you had to go through this kind of complex
running period where you didn't have elevations of creatinine or
potassium that went inside the pre-specified ranges. So after you
took that element of what many people would consider hemodynamic
changes, acute hemodynamic changes out of it, you were left with
participants who entered the double blind randomized period. And
there, I think that's where again, we started to kind of see most
of the end points in terms of follow-up, which again were mostly
the eGFR decline. If you go to table two of the paper, you'll see
the composite, the components of the renal composite broken out
into those with eGFRs of less than 60 or 60 or greater at
baseline.
And even in both groups, I think you'll find that again they were
both driven by the 50% decline, but you only really saw the end
stage renal disease events or very few deaths from renal causes
in those with eGFR of less than 60 mils per minute of baseline.
And I think really what that speaks to is that these are the
patients with quote unquote, chronic kidney disease at baseline
are the ones who have that detrimenting kidney function to begin
with. And so we're more likely to progress as we know than those
with more preserved kidney function. And so if you followed
patients both for really good kidney function over time, it's
going to take a long time before they get that really severe
decline due to the compensating mechanisms that the kidney has to
preserve eGFR in the face of decline. So I think once you get
into the more advanced disease, you really start to see the
deterioration where there's very little renal functional reserve
to cope with any additional damage or hemodynamic changes.
So to me, it wasn't particularly surprising that that's where the
action was. To answer your second point of should we be focusing
therapy here? If you look at the median eGFR in the PARAGON heart
failure study was around 63 mils per minute. So about half of
these patients I suppose could be classified as having impaired
kidney function. If you look at it by CKD criteria it's eGFR of
less than 60. And so I think there's a huge opportunity there to
really think about this population in terms of trying to look for
interventional studies and potentially protect patients as we've
seen with this molecule, and but also with others such as SGLT-2
inhibitors, what I'm really intrigued about is if this was
persistent at eGFRs below 30, because of course, one of the most
devastating icons for patients with kidney disease that we deal
with is the development of end stage renal disease and those who
go on to hemodialysis.
So if there was some mechanism to prevent those even higher risk
patients from progressing, I think that would be a huge
opportunity for further research in this area.


Dr Justin Ezekowitz: Thanks for that very complete and thorough
answer Finnian, and that actually maybe leads to putting this in
context for the majority of people who will read Circulation and
the audience will most likely be cardiovascular specialists and
understand a lot of what you said, but could you put this in
context with other studies that really are nearby to this trial,
such as CREDENCE where the eGFR slope might be slightly
different, or even the UK HARP-III trial where the same molecule
was used, but in a different population, I wonder if you could
give us some context for these findings.


Dr Finnian Mc Causland: Sure, yeah. I mean, I think the UK
HARP-III trial maybe is the first one to discuss since this was a
comparison of sacubitril-valsartan versus irbesartan. This was a
study performed in the United Kingdom and they recruited patients
with chronic kidney disease, a small proportion of those patients
had heart failure, but this was not any of the pre-specified
entry criteria for this study. And their primary outcome was the
change in measured glomerular filtration rate after 12 months.
And really they found that there was no significant difference at
the 12 month mark between sacubitril-valsartan versus irbesartan.
And so we were asked a similar question when we presented this
study in abstract form at the American Society of Nephrology
meeting in Washington last year. And I think a lot of the
differences potentially relate to the difference in entry
criteria for the patients. But also one might argue that 12
months of follow-up may not have been enough to see these
differences in eGFR slope, which tend to occur, I suppose, rather
later in the course of progressive kidney disease and heart
failure.
And so that may be part of the reason that we didn't see the
differences with UK HARP-III. In terms of CREDENCE, obviously
it's a different molecule. And if you look at our main eGFR
decline over time in PARAGON-HF, it was around 0.7 mils per
minute, per 1.7, three meters squared per year. And so this
compares with the about 1.5 mils per minute in CREDENCE, remember
CREDENCE recruited patients with chronic kidney disease.
PARAGON-HF recruited patients with heart failure and preserved
ejection fraction. So differences in terms of the inclusion
criteria right off the bat. I think other big differences where
the CREDENCE compared, and it kind of flows in versus placebo,
there was an active comparator in PARAGON-HF in terms of it was
sacubitril-valsartan versus valsartan. So we saw differences in
eGFR slope, despite an active comparator, I think was also quite
telling and that there appears to be some additional renal
benefit in the additional sacubitril versus blast inhibition
alone.
And so I think the mechanisms is a whole other area, right? For
research, I don't think we're entirely clear of the underlying
mechanisms of this potential renal benefit, but I think we're
pretty excited in the kidney community. Where now we have several
molecules that may have potential to slow kidney functional
decline, SGLT-2 inhibitors being one class potentially
sacubitril-valsartan in another, and the top line results from
their number are just out as well. And so there's ongoing trials
that are looking at kidney function outcomes there. So we're
getting pretty excited and we're not quite as jealous of the
cardiology community as we used to be.


Dr Carolyn Lam: I couldn't think of a better way to summarize
those findings and to put it into context of other very hopeful
medications for the cardio renal outcomes. Thank you so much
Finnian for joining us today and for publishing such a great
paper with us at Circulation. And thank you, Justin, for your
perspectives.


Dr Justin Ezekowitz: Thanks Carolyn, and Finnian congrats to your
team as well. This has been a terrific paper to be able to handle
and read and look at figure three, and it tells a lot of the
story of what you saw.


Dr Finnian Mc Causland: Thank you very much again for the
opportunity and a big shout out to everybody that worked in
PARAGON-HF and especially to the support from Scott Solomon and
John McMurray for getting me involved. It's a pleasure to be part
of this.


Dr Carolyn Lam: Thank you so much from Greg and I for joining us
today, tune in again, next week.


Dr Greg Hundley: This program is copyright of the American Heart
Association 2020.