Circulation March 03, 2020 Issue

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 Dr Greg Hundley, director of the Pauley
Heart Center at VCU Health in Richmond, Virginia. You know that
problem we have with the development of calcification of the
aortic valve, the aorta, etcetera with hemodialysis? Well, our
feature is going to talk about the results of a randomized phase
2B study to address this. But first, how about if you get us
started with a couple of your papers?


Dr Carolyn Lam: In fact, it is a couple of papers and they're
both related to hypertension. So in the first one, we know that
exercise is associated with a lower incidence of hypertension,
but what's the association of excessive levels of exercise in the
incidence of hypertension? This question was examined by Dr
Andersen from Uppsala University Hospital and colleagues, who
compared the incidence of hypertension among almost 207,000
participants in a long-distance cross-country skiing event and
more than 505,500 persons randomly sampled from the general
population who are matched to the skiers on age, sex, and place
of residence.


Dr Greg Hundley: I love skiing! I want to be in the match group.
Tell me, now, how long was this distance that they had to cover?


Dr Carolyn Lam: Ah ha. Now the long distance event was really
long. It was the Vasaloppet. I hope I pronounced that right, but
it's a 45 to 90 kilometer skiing race. So participation, I'm sure
you want to hear this, participation was associated with a 41%
lower incidence of hypertension over the next eight years,
compared to non-participation. And the better the performance in
terms of percent of winning time, the lower the incidence of
hypertension. If the observed associations are causal, it really
adds to the list of beneficial effects of high, or even very high
physical fitness. I can see you smiling, Greg.


Dr Greg Hundley: This is your confirmation that the AHA wants to
send us to Norway to do one of these recordings.


Dr Carolyn Lam: Well, this next paper asked the question, what is
the association of cumulated blood pressure exposure from young
adulthood to midlife with gait and cognitive function in midlife.
This is from Dr Mahinrad from Northwestern University Feinberg
School of Medicine and colleagues who included 191 participants
from the coronary artery risk development in young adults’ study,
which is a community-based cohort of young individuals followed
over 30 years. Cumulated blood pressure was calculated as the
area under the curve for baseline up to year 30 exam and gait and
cognition were assessed at the year 30 exam. Cerebral white
matter hyperintensity was available at year 30 in a subset of
participants who underwent MRI.


Dr Greg Hundley: I heard that MRI word. So what did they find
Carolyn?


Dr Carolyn Lam: They found cumulative exposure to higher blood
pressures from young adulthood to midlife, even at levels below
the clinical definition of hypertension, was associated with
worse gait and worse cognitive function in midlife. The impact of
cumulative levels of blood pressure exposure was independent of
other vascular risk factors during a follow-up period of over 30
years, and the higher burden of midlife cerebral white matter
hyperintensity on MRI, Greg, moderated the association of
cumulated blood pressure exposure with gait but not with
cognitive function.


Dr Greg Hundley: You've got me convinced we now have to go to
Norway. But what did the authors think were the clinical
implications of their study?


Dr Carolyn Lam: Well, here it is. The deleterious effect of
elevated blood pressure on brain structure and function may begin
during early adulthood and this really emphasizes the need for
all primordial, if you may, prevention of high blood pressure.
But also reconsidering individual levels of blood pressure for
the diagnosis of hypertension. Furthermore, gait may be an
earlier measure of hypertensive brain injury than cognition. Now
these issues are discussed an editorial by Angela Jefferson from
Vanderbilt University Medical Center.


Dr Greg Hundley: Very nice, Carolyn. Well, I'm going to take
another sort of twist on hypertension. My paper is from Dr Thomas
Thum from the Hanover Medical School and is really looking at the
relationship between cardiac fibrosis and diastolic dysfunction.
So the study sought to identify anti-fibrotic drug candidates by
functional screening of 480 chemically diverse natural compounds
found in human cardiac fibroblasts.


Dr Carolyn Lam: Ooh, interesting. And what did they find?


Dr Greg Hundley: What they found is using multiple in vitro
fibrosis assays and stringent selection algorithms, the authors
identified the steroid bufalin, also seen in Chinese toad venom,
and the alkaloid lycorine, from the Amaryllidaceae species, to be
effective anti-fibrotic molecules, both in vitro and in vivo,
leading to improvement in diastolic function in two hypertension
dependent rodent models of cardiac fibrosis. In addition,
administration of these agents at effective doses did not change
plasma damage markers, nor the morphology of the kidney and
liver. And therefore, it's kind of an early first toxicological
safety study.


Dr Carolyn Lam: Fascinating. Not just in the findings and the
methods, and who knew we'd be talking about Chinese toad venom on
this podcast, Greg? Okay. But let me tell you about what's more
in this issue. So, there is a research letter by Dr Djoussé, and
it is entitled Supplementation with Vitamin D and/or Omega-3
Fatty Acids and the Incidence of Heart Failure Hospitalization.
And this one is a letter from the VITAL-Heart Failure ancillary
study of the parent VITAL trial. I'm sure I've got everyone's
attention. (You) Got to read that letter.


The next is an On My Mind, by Dr Joe Hill, and is entitled, very
intriguingly, Can HFpEF and HFrEF Co-exist? Basically
accumulating evidence has revealed that the pathophysiologic
mechanisms driving HFrEF and HFpEF are distinct, but this On My
Mind paper asks can they coexist? Is it possible to identify
subjects who harbor pathophysiological elements of both syndromes
simultaneously, and if so, we may find that targeting specific
pathways is beneficial and in depth characterization of specific
subsets of patients might help overcome the limitations of an
ejection fraction driven approach.


Dr Greg Hundley: Very interesting, Carolyn. I've got some letters
from the mailbox, and the first letter is regarding SGLT2
inhibitors in cardiac hypertrophy and the corresponding author is
Professor Kazushi Tsuda from Kansai University of Health
Sciences. Another letter, from the corresponding author Dr Renato
Lopes from Duke University Medical Center in Durham, evaluates
stent thrombosis in patients with atrial fibrillation undergoing
coronary stenting from the AUGUSTUS trial. And our own Tracy
Hampton provides an update on cardiology news features. And John
Warner, from UT Southwestern, the prior American Heart
Association president, discusses his journey through healthcare
reform. And then finally, our own Sarah O'Brian provides
highlights from other journals in the Circulation family related
to high points in cardiovascular disease. Well, Carolyn, how
about on to dialysis and calcification?


Dr Carolyn Lam: Can't wait. Let's go.


Our feature discussion today, we will be focusing on patients
with end-stage kidney disease. And we know that in these
patients, the high cardiovascular morbidity and mortality could
partially be due to extensive cardiovascular calcification. Well,
our feature paper today is the first double blind
placebo-controlled phase 2B trial that tests intravenous
myo-inositol hexaphosphate, a novel strategy to inhibit the
formation and growth of hydroxyapatite and therefore reduce
calcification in these patients. I won't tell you more. I'll
leave that to the corresponding author, Professor Paolo Raggi,
from University of Alberta, and I'm also so pleased to have with
us our editor for digital strategies and associate editor Dr Amit
Khera from UT Southwestern. So Paolo, please tell us about SNF472
and your very novel trial.


Prof Paolo Raggi: As you correctly stated, patients with end
stage renal disease have phenomenally high morbidity and
mortality, particularly cardiovascular, and they also manifest
extreme calcification on the cardiovascular system. Both the
valves and the vessels are very heavily calcified. There's a very
clear impression throughout the literature that calcification
contributes, no doubt, to the high morbidity mortality with these
patients. SNF472 is a derivative of a natural product that is
only present in nature in sub molecular quantities and
essentially is administered intravenously and the mechanism of
action is quite simple. It keeps calcium and phosphorous
molecules separate. In other words, it doesn't allow
crystallization of calcium and phosphate into what we call
hydroxyapatite, or amorphous calcium crystals. This, hopefully,
was developed, this product was developed, to inhibit the final
step of calcification. Everything comes down, no matter what the
promoting event is, to crystallization of calcium and phosphorus.
Therefore, if we were able to stop the final event, hopefully you
will be able to inhibit further calcification, and that's what we
tested in this particular article, in this particular study.


Dr Carolyn Lam: Oh Paolo, I just love the way you described that.
Very, very crystal clear, if you don't mind the pun. But could
you please let us know, so a phase 2B trial, does that mean a
surrogate outcome, duration of treatment, number of patients? How
about telling us a little bit about the trial?


Prof Paolo Raggi: So, the trial involved recruiting three
different groups of patients. One would be treated with placebo
and two other cohorts would be treated with either 300 milligrams
of SNF472 three times a week or 600 milligrams of SNF472 three
times a week. The product is injected intravenously into the
dialysis line. Therefore, the patients do not have to remember to
take a pill or inject themselves. Actually, it's perfect, if you
will, compliance because all they have to do is come to their
dialysis session and they receive it during dialysis.


The study therefore, it was a relatively small study, but enough
to prove our point. Three groups were recruited, about 90
patients each, and the two treatment arms at 300 milligrams and
the 600 milligrams, were combined as a single group for the
purpose of reporting the primary results. The follow up was at
one year, so these patients were submitted to CT scanning of the
chest without contrast for measurement of calcification only at
baseline and then again at 52 weeks. In the intention to treat
group, patients were included if they had a baseline scan and at
least one follow-up scan at some point during the study. These
are very sick patients and sometimes are referred for transplant.
Sometimes they withdraw from studies. So, we asked everybody to
have a second scan if they needed or wanted to withdraw before
the 12 month mark was reached. That's for the intention to treat
analysis. And then we need some confirmatory analysis on patients
who actually did have the baseline in an actual 12 months scan
and received the entire year treatment with these two drugs, with
a drug or placebo.


Dr Carolyn Lam: That's great and please tell us the results.


Prof Paolo Raggi: The results were, in our minds, very exciting.
And let me first say, that in all the literature that looked at
what is the average progression of calcification in the general
population, it's anywhere between 10 to 15% per year. For the
person with calcium in the coronary arteries, there's an expected
progression about 10 to 15%. All the publications in patients
with renal failure and undergoing dialysis, show the progression
of anywhere between 25 and 35%, so these people are not only more
calcified, these patients also progressing very fast. In the
particular trial that we reported in Circulation, we demonstrated
on average, a progression of 20% in the group receiving placebo
and about 11% in the group receiving SNF472. So, there was about
a 45% slowing of progression in the treated group compared to the
placebo group.


 


Interestingly enough, we saw a slower progression unusual in the
placebo group. As of today, many more treatments are available to
patients with end stage renal disease that were not available
when the original studies that I mentioned earlier were
conducted. So, the 25 to 35% progression that we saw 15 years
ago, it's now slowed, you notice, to a 20% progression in these
patients, but SNF472 was even more effective at further slowing
that progression.


Dr Carolyn Lam: Well, congratulations first and foremost on a
very successful and really striking and novel results. Well, Amit
there's so much to discuss I don't even know where to start. But
first, maybe can I bring you in by saying, so what, is
Circulation now publishing renal papers?


Dr Amit Khera: The answer is absolutely yes. So first I want to
congratulate Dr Raggi on a fantastic paper. This was a
concomitant late breaking science at the American Heart
Association Sessions; so, we always try to think of timely and
exciting topics and appreciate working so closely with this group
to bring this across the finish line. At Circulation, one thing
we've been working on is something called Bridging Disciplines,
where purposefully we appreciate the heart is not in isolation
and not in a box by itself, but within a larger system, a body
system. So, we really enjoy these types of papers that cross
disciplines and there's an outstanding editorial by Susan
Hedayati, from UT Southwestern who's a nephrologist, who weighed
in here as well. So we certainly really value these types of
papers in Circulation.


Prof Paolo Raggi: I have to say, working with Circulation was
amazing. You know, you get a great job and so fast. It was an
incredible, actually.


Dr Amit Khera: Obviously, the results speak for themselves that
the study was positive, and we certainly see this diminishing the
vascular classification and certainly you've been, for decades
now, an expert in vascular calcification and coronary imaging.
And you know, the question that always comes up is, what are the
implications here? Now, on one side, especially with the
coronaries, you think this would be favorable, you get less
obstructive disease, perhaps less ischemic heart disease. But
there's always been this debate if calcium's a good or bad thing
in terms of plaque stabilization, so what are your thoughts on
what ends up being the clinical ramifications of this down the
road?


Prof Paolo Raggi: Well of course, as we clearly stated in the
paper, this has to be followed by some sort of clinical outcome
study. So, it is only speculating at this point as to what the
benefit might be. But more specifically about your question, I
think that there is a misinterpretation of what calcification
means in general. And honestly, I would prefer not to have
calcification in my cardiovascular system if I had the choice.
Many believe, and it's possibly true to a degree, that
calcification comes in to repair the plaque and there's some sort
of repair mechanism, but we have shown very clearly that the
greater the calcification burden, the higher the probability of
cardiovascular morbidity mortality. And therefore, it is not
benign to have cardiovascular calcification in general.


 


In the case of the patients with end stage renal disease,
calcification is not limited to the atherosclerotic plaque. It
extends to the thickness of the entire vessel wall and it's well
known that patients with end stage renal disease have severe
calcification of the media as well as the intima. This obviously
causes a series of other problems, such as stiffening of the
vessels and therefore reduce compliance and in the long run, many
profusion issues to multiple organs, even in the absence of
luminal stenosis. A stiff vessel does not comply with what it's
supposed to be doing. It is not allowing proper profusion of an
end organ and many have demonstrated that also increases the work
of the heart, pumping against very rigid plumbing, if you want to
put it that way and simply, and therefore may induce left
ventricular dysfunction in the long run, arrhythmias if a patient
develops left ventricular hypertrophy and fibrosis. So, I think
that there's a cascade of events that goes beyond and above just
the single plaque, atherosclerosis, calcification. I think that
calcification in general, and especially in patients with end
stage renal disease, is a whole marker, very high risk of
complications.


Dr Amit Khera: Thanks for that clarification. I think first and
foremost, it's so helpful to think beyond just isolated luminal
stenosis and sort of all the maladaptive aspects of vascular
calcification in patients with end stage renal disease. And that
leads to the next thing in your paper, which I thought was also
really interesting, which was the aortic valve calcification. We
certainly appreciate that focus on aortic stenosis as of late
with the new therapies, but you know particularly in patients
with end stage renal disease, it becomes a very complex issue.
And you saw some abating of this vascular calcification in the
aorta as well. Tell us a little bit about what you think the
implications of that would be.


Prof Paolo Raggi: So first, a word of caution that the trial was
not powered to demonstrate specifically an effect on aortic
valve. However, we did demonstrate a beautiful effect on the
slowing of the aortic valve calcification as well. It's exciting!
I think that it's something that needs to be pursued further and
I hope future studies, and definitely is the first time that
anything has demonstrated an effect on aortic valve
calcification. I'm very well aware of other studies that have
attempted, for example, use of statins to slow the progression of
valvular calcification and in essence, were completely negative.
Patients with end stage renal disease, very severe valvular
abnormalities, very, very severe, very important valvular
dysfunction as a consequence of massive calcification on the
annulus and the leaflets more so of the aortic valve, but also
the mitral valve. So this could definitely be a signal for an
excellent potential and unexpected if you will, a secondary
outcome of this treatment. I believe that in affecting valvular
calcification in patients with end stage renal disease would be,
could have potentially a massive effect from the point of view of
lowering the cardiovascular event rate.


Dr Carolyn Lam: May I chime in with a quick question? What were
adverse effects like?


Prof Paolo Raggi: This particular drug actually was associated
with the same exact rate of adverse effect as placebo. In other
words, we didn't see anything at all that was alarming. There was
one patient that had been reported by the investigator as
potential side effect of the drug. They reported something, I
think it was like acute hepatic failure, but when the case was
clearly analyzed by the DMV, we actually assessed dictation as
being a case of cholecystitis had been incorrectly labeled, we
believe. And except for that one case, there essentially were no
side effects, no adverse effects from treatment. In fact,
although it was not powered for those outcomes, there was a lower
morbidity and mortality with the SNF472 and then with placebo.


Dr Carolyn Lam: I really like that and was really struck by your
pointing out a little bit earlier, the ease of administration as
part of hemodialysis. That was very nice. Amit, I'm going to give
you the final words and questions if I may.


Dr Amit Khera: As expected, this has been an exciting podcast and
as much as I've read this paper and looked at it in detail, I
learned a lot more as I had anticipated. My question for you,
Paolo, now, is what's the next step? This is a phase 2B study.
What's the next step in the development or evaluation of this
compound and where are you going with this?


Prof Paolo Raggi: There are a few sub analysis that we haven't
yet looked at in this particular study that we just reported. One
of the things that we are definitely interested in is to evaluate
the effect on bone. As you can imagine, it is true that this
particular drug has a wonderful effect on vascular calcification,
but the next question is, did it do anything adverse to the bone?
It's a logical question but I feel that most likely the answer is
going to be a resounding no.


But, besides that, the further development of this drug is
obvious in my mind. It will have to be addressed in a proper,
randomized clinical trial to address some of the clinical
questions that we all have. Is this reducing the cardiovascular
events? Be it when we need, we will decide together what those
cardiovascular events would look like. But obviously myocardial
infarction, congestive heart failure, admission for unstable
angina, cardiovascular deaths in general, those are going to be
very important questions to be answered in a further step. Before
we get there, there are a few other questions that we have for
the drug itself from this particular 2B study that we can still
look at.


Dr Amit Khera: Excellent. Looking forward to those subsequent
analyses.


Dr Carolyn Lam: Thank you and we look forward to the next
publication on Circulation.


Dr Amit Khera: Absolutely.


Dr Carolyn Lam: I'm sure the audience is actually looking forward
to more such discussions as these. Remember, you've been
listening to Circulation on the Run.


 


Dr Greg Hundley: This program is Copyright The American Heart
Association 2020.