Circulation March 16, 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 and director of the
Pauley Heart Center, VCU Health in Richmond, Virginia. Well,
Carolyn, this week's feature involves interleukin-6 and a
phenome-wide association study. So we have a lot to look forward
to, but before we do that, how about we grab a cup of coffee and
jump into the other articles in this issue? I could start first
because I've got to tell you about some results from the ODYSSEY
outcomes trial. And Carolyn, this comes to us from Professor
Gregory Schwartz at the University of Colorado School of
Medicine. Well, Carolyn, this study pertains to LDL lowering. As
you know, recent international guidelines have lowered the
recommended target levels of LDL cholesterol for patients at very
high risk for major cardiovascular events or MACE.


Dr. Greg Hundley:


However, uncertainty persists as to whether additional benefit
results from achieving LDL-c levels below some of these
conventional targets. Now inferences from prior analyses are
limited because patients who achieve lower versus higher LDL-c on
lipid lowering therapy differ in other characteristics prognostic
for MACE, and because few achieved very, very low LDL-c levels.
So to overcome these limitations, these authors performed a
propensity score matching analysis of the ODYSSEY outcomes trial,
which compared alirocumab with placebo in 18,924 patients with
recent acute coronary syndrome receiving intensive or maximum
tolerated statin treatment.


Dr. Carolyn Lam:


Sensible question, and what did they find?


Dr. Greg Hundley:


Well, Carolyn, the main finding of the study was that after
accounting for differences in baseline characteristics and
adherence, patients treated with alirocumab who achieved LDL-c
levels less than 25 milligrams per deciliter did not appear to
derive further reduction in the risk of MACE compared to those
who achieved LDL-c levels of say 25 to 50 milligrams per
deciliter. So, Carolyn, the take-home message is that recent
international guidelines have lowered LDL-c goals for patients at
very high risk for MACE to levels less than 55 milligrams per
deciliter, and in some cases, maybe less than 40 milligrams per
deciliter. However, any potential benefit of achieving LDL-c
levels significantly below these goals to those very low, less
than 25 really remains uncertain.


Dr. Carolyn Lam:


Very interesting. Thanks Greg. Well, my paper is about the
HOST-REDUCE-POLYTECH-ACS trial. Got your attention? All right.
I'll tell you what it is. It's an investigator-initiated,
randomized, open-label, adjudicator-blinded, multicenter,
non-inferiority trial, which compared the efficacy and safety of
durable polymer versus biodegradable polymer, drug-eluting
stents. And these investigators led by Kyung Woo Park from Seoul
National University Hospital looked at 3,413 patients with acute
coronary syndrome. At 12 months, the primary endpoint of patient
oriented composite outcome, which was a composite of all-cause
death, nonfatal myocardial infarction, and any repeat
revascularization, occurred in 5.2% of the durable polymer group
and 6.4% of the biodegradable polymer group. And so that met the
non-inferiority P value of less than 0.01. the key secondary end
points of device oriented composite outcome, which is a composite
of cardiac death, target vessel MI, or target lesion
revascularization occurred less frequency in the durable polymer
versus biodegradable polymer groups, and this was mostly due to a
reduction in target lesion revascularization. The spontaneous
nonfatal MI and stent thrombosis rates were very low with no
significant difference between the groups.


Dr. Greg Hundley:


Well, Carolyn, you know one of my favorite questions, so what's
the take-home message here?


Dr. Carolyn Lam:


In patients with acute coronary syndrome receiving PCI durable
polymer drug-eluting stents were non-inferior to biodegradable
polymer drug alluding sense with regards to patient-oriented
composite outcome at 12 months. I think that's the significant
take-home message, and it's accompanied by an editorial where all
this is discussed, and this editorial is by Doctors Byrne and
Hanratty from Dublin.


Dr. Greg Hundley:


Very nice, Carolyn. Well, Carolyn, I am going to turn to the
world of basic science and discuss phospho-lamin phosphorylation
and how that may regulate vascular tone, blood pressure, and
hypertension in both mice and men. And it comes to us from Dr.
Michael Shattuck from King's College, London. So Carolyn, it's
long been recognized that smooth muscle Na,K-ATPase modulates
vascular tone and blood pressure. However, the role of its
accessory protein phospho-lamin has not been characterized. So
Carolyn, the aim of this study was to test the hypothesis that
phospho-lamin phosphorylation regulates vascular tone in vitro,
and this mechanism plays an important role in the modulation of
vascular function and blood pressure in experimental models, both
in vivo and in man.


Dr. Carolyn Lam:


Okay. So what did they find?


Dr. Greg Hundley:


Carolyn, these authors found that in aging wild type mice,
phospho-lamin was hypo-phosphorylated, and this correlated with
the development of aging induced essential hypertension. In human
subjects, they identified a non-synonymous coding variant, a
single nucleotide polymorphism RS-61753924, which causes the
substitution of R-70 C and phospho-lamin. The R-70 C mutation
prevented phospho-lamin phosphorylation at searing 68. This
variance rare Alleo was associated with increased blood pressure
in middle-aged men. So Carolyn, taking together these
translational animal and human studies demonstrate the importance
of phospho-lamin phosphorylation in the regulation of vascular
tone and blood pressure and suggest a novel mechanism for
aging-induced essential hypertension.


Dr. Carolyn Lam:


Interesting. And I suppose opening the door to translationally
preventing this hypertension. Very interesting. Well from the
next paper we switch to cardiac troponins, and you know these are
the cornerstone of diagnosing acute myocardial infarction. But
have you ever wondered, what is the duration of ischemia
necessary to induce a measurable release of the cardiac
troponins, or the very early release kinetics of cardiac
troponins following an ischemic event? Well, this study is the
first to report the early release kinetics of cardiac troponin
concentrations, following different durations of experimental
coronary balloon occlusion in humans.


Dr. Greg Hundley:


Ah, Carolyn. So how did they do this?


Dr. Carolyn Lam:


So 34 patients with N geographically normal coronary arteries
were randomized into four groups with different durations of
induced myocardial ischemia from zero to 30, 60, 90 seconds.
Ischemia was induced by inflating a balloon in the left anterior
descending artery between the first and second diagonal branch.
Blood was collected prior to balloon inflation and every 15
minutes for the first three hours and every 30 minutes for the
next three hours. Cool, huh?


Dr. Greg Hundley:


Yeah. So did any of the patients suffer complications?


Dr. Carolyn Lam:


So the first thing to report is none of the patients had any
complications, but what they found, and this was from authors,
Dr. Iverson from Copenhagen, Denmark and colleagues. This is what
they found increased cardiac troponin concentrations were
detected by all three high sensitivity assays, be they high
sensitivity troponin T by the Roche assay, high sensitivity
troponin I by the Siemens essay, or high sensitivity troponin I
by the Abbot essay. All assays detected a cardiac troponin
increase after only 30 seconds of ischemia. High sensitivity
troponin I by Siemens rose faster and reached a higher peak.
Copeptin levels did not significantly change. So these
interesting findings are accompanied by an editorial by
Christopher deFilippi and Nicholas Mills discussing how the
findings challenged some of our assumptions and may help shape
future care pathways and the classification of ACS.


Dr. Greg Hundley:


Carolyn, so more in the evolution of high sensitivity troponins.
Well, I'm going to shift to my last article of the day, and it
focuses on eccentric remodeling and ischemic cardiomyopathy, and
comes to us from Professor Konstantinos Drosatos at the Lewis
Katz School of Medicine at Temple University. So Carolyn, these
authors have shown that cardiomyocyte Krüppel-like factor or
(KLF)-5 regulates cardiac fatty acid oxidation, and as heart
failure has been associated with altered fatty acid oxidation,
they now investigated the role of cardiomyocyte (KLF)-5 in lipid
metabolism and the pathophysiology of ischemic heart failure.


Dr. Carolyn Lam:


Wow, Greg. What did they show?


Dr. Greg Hundley:


Well, Carolyn, they found that (KLF)-5 is induced during the
development of ischemic heart failure in humans and mice and
stimulates ceramide biosynthesis. Genetic or pharmacological
inhibition of (KLF)-5 in mice with myocardial infarction prevents
ceramide accumulation, alleviates eccentric remodeling, and
increases left ventricular ejection fraction. Thus, the authors
suggest that (KLF)-5 may emerge as a novel therapeutic target for
the treatment of ischemic heart failure. Well, Carolyn, we've got
some other articles in the issue, and I'm just going to tell you
quickly about an in-depth article entitled, “Cardiovascular
Disease and Chronic Kidney Disease: Pathophysiological Insights
and Therapeutic Options” that come to us From Dr. Marx, and then
I'm going to turn it over to you.


Dr. Carolyn Lam:


Yes, we've got an exchange of letters between Doctors Grace and
Mital regarding the article, “A Validated Model for A Sudden
Cardiac Death Risk Prediction in Pediatric Hypertrophic
Cardiomyopathy.” There's an ECG challenge by Dr. Peng on an
irregular complex tachycardia. And there's this very interesting
on-my-mind paper by Dr. Skolnik simply entitled, Gratitude. And I
just have to tell you a bit about it, and I'm quoting from it
now, “…having two surgeries for a large aortic aneurysm and
aortic regurgitation, I am also left with an overwhelming sense
of gratitude for living in the age in which I'm living. While
some focus on what is wrong in the world, at least for today, my
focus is on what is right.” Now, please read that paper. It's
just such a beautiful piece. And, finally, there's a perspective
piece by Dr. Sandhu entitled, “The Affordability of
Guideline-Directed Medical Therapy, Cost Sharing, and How Cost
Sharing is a Critical Barrier to Therapy Adoption.” Well, looks
like it's a wrap. Greg, let's get on to our feature discussion,
shall we?


Dr. Greg Hundley:


You bet. Well, listeners, we are now coming to our feature
discussion today, and we're very fortunate to have with us today,
Dr. Martin Dichgans and Dr. Marios Georgakis both from Munich,
Germany. And we also have Dr. Svati Shah from Duke University,
one of our associate editors. Welcome to you all. And I'll start
with you Martin, could you explain to us a little bit of the
background behind this study and what was the hypothesis that you
wanted to test?


Dr. Martin Dichgans:


Yes, of course. We are interested in stroke, and more broadly, in
cardiovascular disease, and inflammatory cytokines and
inflammatory mechanisms in general play a major role in
cardiovascular disease and particularly in arthrosclerosis, which
connects a cardiac disease and stroke and also multiple other
disorders. So that was our starting point. And we previously
noted the importance of specific inflammatory cytokines in
stroke, which is all primary area of research. We then quickly
became aware of the central position of IL-6, which is downstream
of IL-1β in the inflammatory cascade, and recognized not only
that there's a lot of data on IL-6 in cardiovascular disease
already, but that IL-6 actually is implicated in multiple
inflammatory conditions, including autoimmune diseases, vascular,
as I mentioned, and also metabolic disorders. And we noted that
IL-6 receptor inhibition is already in use in some of these
disorders, particularly in the treatment of autoimmune diseases,
but not yet in use in cardiovascular disease.


Dr. Martin Dichgans:


So we asked ourselves whether there would be any repurposing
potential, and also whether there would be an opportunity to
explore the safety profile in its full width using genetic data
because, and this I didn't mention, we have a background in
genetics, a large interest in genetics, and you might have
noticed that previously there has been a wealth of genetic data
coming out, both on stroke, but also on cardiovascular disease in
general. So also including other phenotypes, like for instance,
and it has now become possible via a methodology called Mendelian
randomization to utilize these genetic data and explore causal
relationships between exposures such as IL-6 levels or specific
cytokines and outcomes such as ordinary-after disease or stroke,
and even go one further and explore the therapeutic potential,
and also the full width phenotypes that could be relevant in such
a scenario. So what we did is we took advantage of large scale
genetic data from the UK biobank and data on specific outcomes
available in the UK biobank to dive into the questions we were
interested in.


Dr. Greg Hundley:


Martin, that was a wonderful explanation. So could you describe,
what was the aim of your study?


Dr. Martin Dichgans:


In brief, the aim was to use large scale genetic data to explore
the repurposing potential and safety profile of IL-6 receptor
inhibition in the general population.


Dr. Greg Hundley:


Very nice. Describe your study design.


Dr. Martin Dichgans:


So the study population was the UK biobank, which is a
population-based sample of, in this case, 340,000 unrelated
individuals. And what we did is we performed the phenome-wide
association study. So we looked across all available phenotypes
that are systematically encoded in the UK biobank, and which
included both clinical outcomes and biomarkers, in this case
about 1,400 clinical outcomes and 360 or 70 biomarkers and
endophenotype of human disease in this biobank. And again,
explored relationships between IL-6 receptor inhibition and the
effect on these outcomes.


Dr. Greg Hundley:


Very nice. Well, Marios, let's turn to you. Could you describe
the results? What did you find?


Dr. Marios Georgakis:


Yes. Hello from my side as well. So, as Martin mentioned, we
explored associations between genetically down-regulated IL-6
signaling and 1,400 clinical outcomes, as well as with 360
biomarkers in another, I would say hypothesis reapproach. So,
following corrections from output testing, we found significant
associations with genetically down-regulated IL-6 signaling
activity with 16 clinical outcomes and 17 biomarkers. As we had
shown in the past, genetically down-regulated IL-6 signaling
activity was associated with several cardiovascular phenotypes,
specifically atherosclerotic phenotypes, primarily including
coronary artery disease manifestations, but also for example,
abdominal aortic. Interestingly though, we also found a
significant association with a lower risk of type two diabetes,
as well as with a lower glycated hemoglobin, another finding that
was consistent not only in the UK biobank, but also in two
cohorts that we use for validation. So in the past, there have
only been data from small observational studies and small case
series in patients with rheumatoid arthritis supporting these
findings, but to date, no data from large clinical trials.


Dr. Marios Georgakis:


Furthermore, we find significant associations between genetically
down-regulated IL-6 signaling and higher total cholesterol, but
also higher HDL cholesterol levels, but no association with LDL
cholesterol. This further supports associations of IL-6 signaling
downregulation with, let's say more favorable argument among the
profile. Now, why is this important? This is a very interesting
finding because previous clinical trials had suggested that IL_6
receptor inhibitors might lead to increases in total cholesterol
levels, which would, of course, be an undesired side effect for
people who'd ever envisioned using IL-6 receptor inhibitors in
the context of lowering cardiovascular risk.


Dr. Marios Georgakis:


Here, however, we show, and our results support, that this
increases primarily the results of the effects of IL-6 signaling
bar down-regulation on HDL and not LDL levels. On the negative
side, and finally, we found significant associations between
genetically down-regulated IL-6 signaling and the number of
potential side effects, particularly strong associations with
bacterial infections, such as cellulitis and urinary tract
infections, which is probably also related to the identifed
association with the lower risk of neutropenia. So while these
are well-described side effects of IL-6 signaling and condition
in the context previous clinical trials, this, we believe,
disagreement with our findings adds additional confidence to,
let's say, the validity phenome-wide association state.


Dr. Greg Hundley:


Very nice Marios. Really appreciate this exciting work. And now
we want to turn to our associate editor, Doctor Svati Shah. And
Svati, you have many papers come across your desk, what attracted
you to this paper? And then how do you put the results that these
men have presented into context with other papers in this area of
investigation?


Dr. Svati Shah:


Yeah. Great question, Greg, and thanks for having me. I thought
this paper was really important, but I want to start at a broader
level, and that's why it's attracted my attention is, I think
genetics can not sort of inherently appeal to the broad
Circulation reader. It can feel somewhat esoteric. We do these
genome-wide association studies, these whole-exome association
studies, and we find new genes and we're really excited about
them as people who live in the genetic epidemiology realm. But
when we think about the broader circulation readership and the
broader cardiology readership, how does this really relate to how
I take care of patients, and what might be important for me in my
cardiovascular realm? And I think this paper really highlights
the power of human genetics and how we really understand things
that have clinical utility.


Dr. Svati Shah:


And let me just expand on that really briefly. And that is, in
the human genetics realm, we can look at what we call human
knockouts. We're not actually doing gene editing in humans, but
looking at people who have loss of function variants. They're
emulating a drug for example. And we also have PheWAS, which is a
phenome-wide association study, where we say, "We're just going
to look at lots of different clinical things and biomarkers and
try to understand things that are associated." And then finally
we have Mendelian randomization, which allows us at a very
statistical level to really assess causality. We know there are
things that are correlated with each other, but we don't
necessarily know that they're causal, and this is a statistical
way for us to potentially assess causality. I say that very
carefully because it's a statistical way to do that.


Dr. Svati Shah:


And what's really cool about this paper is they combine PheWAS
and Mendelian randomization, but with a very clinically important
aspect. What are the potential good side effects, the on-target
things that we want to try to address with these potential drugs,
like tocilizumab, and what are potential side effects of these
potential drugs. And in this case, because they combined PheWAS,
they're able to look across all kinds of things. So the things
that we already know about, they're not looking at a drug per se,
but they're emulating a drug by looking at these genetic variants
to say, "Okay. Well, we're going to look across all these
different clinical factors." So it's not only things that have
been evaluated in these clinical trials, but even just beyond
that. And then the Mendelian randomization piece allows them to
be able to say, again, statistically, are these causal. So if you
antagonize these receptors, does it 'cause' these downstream
effects. So, that's what was really cool to me about this paper.
Is it really highlights the potential for human genetics in a
very short term translational clinical potential.


Dr. Greg Hundley:


What a wonderful explanation for our listeners here. Well, let me
ask each of you, Martin, Marios, and then Svati, what do you see
as the next research endeavor in this space? Martin, you first.


Dr. Martin Dichgans:


And I completely agree with Svati that we have to utilize
genetics in order to improve our means of treating patients, and
I think that's obviously our aim here. And what this study shows,
and let me just briefly also confirm what you said, we were
intrigued by how the genetic data reflect what we see, for
instance, in clinical trials. Just to expand a little bit on that
aspect, the seven genetic instruments, which consisted of seven
snips, single nucleotide polymorphism, when we looked at the
effects of genetic lowering in this context on upstream and
downstream, known upstream and downstream biomarkers of IL-6
signaling, this really very much matched what we know from
clinical trials with tocilizumab so with pharmacologically
lowering IL-6 signaling. Again, giving us confidence that it's
informative and we will see with genetics what we are going to
expect in the future in clinical trials.


Dr. Martin Dichgans:


So now getting to your point here and providing an answer, what
we see as the next step, we should, for instance, combine the
genetic data we have here with genetic data on other approaches
to see whether, and maybe Marios can be more specific about this,
whether by combining two different approaches, for instance, LDL
lowering and targeting residual inflammatory risk, whether we
could in future clinical trial provide additional benefits to
high-risk patients with a cardiovascular disease. And I think
that will be a very important area. Also, I think we should
extend this approach to other inflammatory cytokines that have
come up in Mendelian randomization analysis to explore their
potential in future clinical trials.


Dr. Greg Hundley:


Marios?


Dr. Marios Georgakis:


Yeah. So just to add a little bit on Martin's summary, I would
say here that now that we have established the efficacy of
anti-inflammatory approaches in lowering cardiovascular risk,
both with clinical trials, but also with showing genetic and
clinical evidence, I think that the next step is first to
identify the proper clinical scenario where anti-inflammatory
approaches targeting IL-6 signaling would be used for reducing
cardiovascular risk in order to design the proper clinical
trials. And secondly, as Martin mentioned, to explore whether
targeting IL-6 signaling would, one, pass additive benefits on
Kruppel available approaches such as lipid-lowering approaches,
and second, to see whether the risk-benefit balance of
anti-inflammatory targeting IL-6 signaling would be acceptable in
the clinical setting.


Dr. Greg Hundley:


And Svati.


Dr. Svati Shah:


Yeah. It's hard to follow up on those comments. I'll say, since I
am very interested in diabetes and insulin resistance, the
cholesterol story is fantastic, but I think the fact that they
see effects on, again, statistical lowering of hemoglobin A1C and
type two diabetes is fascinating to me. I would take it even a
little step further. I think we need clinical trials. These data
are very suggestive. It sort of flips the story almost. We've
seen, even in some of the clinical trials of these drugs, that
there are beneficial metabolic effects with regards to glucose,
although some of the data are contradictory. So flipping it and
saying, we know that inflammation is complex and we know that
IL-6 has pro and anti-inflammatory roles in inflammation, and we
know that diabetes with regards to inflammation is very complex,
but maybe these drugs potentially are useful in type one and type
two diabetes. So I think we need carefully designed clinical
trials, potentially, to understand the role of blocking
inflammation, and in particular IL-6 signaling, in patients who
have diabetes.


Dr. Greg Hundley:


Excellent. Well, listeners, we want to thank Dr. Martin Dichgans,
and Dr. Marios Jojakas, and our own associate editor, Dr. Svati
Shah for bringing us this study incorporating phenome-wide
association and Mendelian randomization to identify a
relationship between down-regulated IL-6 signaling with
subsequent clinical cardiovascular outcomes. Well, 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.