Circulation August 31, 2021 Issue

This week's episode features special Guest Host Mercedes
Carnethon, as she interviews author Kypros Nicolaides and
Associate Editor Karol Watson as they discuss the article
"Pravastatin versus Placebo in Pregnancies at High Risk of Term
Preeclampsia."


Dr. Carolyn Lam:


Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and its editors. We are 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, VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


We have a really important feature discussion today. It's on
pravastatin versus placebo in pregnancies at high risk of term
preeclampsia. Very important condition. And I'm just so glad that
we will be discussing this issue, coming right up. But first, I
want to start on the other papers in this issue. And this first
study, which is the first study to assess the effects of aerobic
exercise training with and without caloric restriction on changes
in the proximal aortic stiffness using cardiovascular magnetic
resonance imaging. Now the corresponding author is Dr. Brinkley
from the Sticht Center of Healthy Aging and Alzheimer's
Prevention in Wake Forest School of Medicine. But guess what? Our
very own Dr. Greg Huntley is a co-author. So whether you know it
or not, Greg, we're going to do a mini feature, right now. So Dr.
Huntley, could you please give us some background to your study,
it's so cool?


Dr. Greg Hundley:


Oh, Carolyn, thank you so much. It's quite a privilege to be,
actually being interviewed by you. So about the paper. Aortic
stiffness is really a prominent manifestation, as we know, of
vascular aging. And it's an independent predictor of
cardiovascular events and mortality. And risk factors such as
hypertension, diabetes, obesity, they can promote vascular
changes that lead to accelerated vascular aging. Now, on the
other hand, lifestyle factors such as healthy diet, regular
physical activity, they may attenuate age related increases and
aortic stiffness.


Dr. Greg Hundley:


And both cross-sectional and longitudinal studies indicate that
exercise is associated with lower aortic stiffness. However, some
data suggests exercise alone may not be sufficient to improve
aortic stiffness in certain subpopulations of older adults. And
so what Tina did, she worked in combination with all the
co-authors and determined the effects of aerobic exercise
training, with and without moderate to high caloric restriction
on the structure and function of the proximal aorta in a 160
older, so 65 to 79 year old men and women with obesity that had a
body mass index of 30 to 45 kilograms per meter square.


Dr. Carolyn Lam:


Wow. Okay, cool. But how do you assess this by MRI? Isn't that
part of the novelty of the study, right?


Dr. Greg Hundley:


Right, Carolyn. So kind of two ways magnetic resonance imaging
assesses aortic stiffness. First is to look at the
distensibility. What is this distensibility? That's the change in
the area of the aorta, relative to the distending pressure. And
you can't measure that distending pressure noninvasively. So what
we do is use a surrogate, your cuff pressure at your brachial
artery. So that's one measure. Area change divided by basically
the pulse pressure indexed for the resting area. And the second
is pulse wave velocity. And for the listeners, remember pulse
wave velocity, the faster the blood moves around through the
aorta, the stiffer the artery is. And so we measured both aortic
distensibility and pulse wave velocity.


Dr. Carolyn Lam:


I love it. You're such a good decentral educator. Okay. So what
are the results real quick?


Dr. Greg Hundley:


Thanks Carolyn. So there were significant treatment effects for
descending aortic distensibility and strain. And aortic arch
pulse wave velocity with the aerobic exercise training plus the
moderate caloric restriction group, having a 21% increase in
distensibility, and an 8% decrease in pulse wave velocity. And
none of the aortic stiffness measures changed significantly in
the aerobic exercise training. Only, or in the aerobic exercise
training plus very intensive caloric restriction.


Dr. Carolyn Lam:


So how do you put that all together? What does this mean for us
clinically?


Dr. Greg Hundley:


Right, Carolyn. So I think the findings that Tina and everyone
here in this group are showing, they suggest that exercise alone,
that is in the absence of significant weight loss, has minimal
effects on proximal aortic stiffness in older adults with
obesity. Second, although obesity likely blunts the beneficial
effects of regular aerobic exercise on aortic stiffness in older
adults, these data support a growing number of studies indicating
that intentional weight loss can be safe for older adults with
obesity. And then finally, Carolyn, the addition of moderate
caloric restriction appears to maximize improvement in aortic
stiffness. Whereas higher intensity caloric restriction may not
be necessary or even really advised. And that has important
indications for weight loss recommendations to improve
cardiovascular disease risk among older adults.


Dr. Carolyn Lam:


Oh, wow. Thanks Greg. And congratulations to you and your
co-authors on this beautiful paper. Well, in the next paper, we
switch to the preclinical world and I'm going to tell us about
the WW domain containing E3 ubiquitin protein ligase 1. And I'm
not going to be able to say that again. So I'll call it WWP1. We
know that this is an important regulator of aging related
pathologies, including cancer and cardiovascular diseases.
However, the role of WWP1 in pressure overload induced cardiac
remodeling and heart failure is yet to be determined. So this
next paper looks at that with co-corresponding authors, Dr. Li
and Ling from the State Key Laboratory of Space Meds and
Fundamentals and Application, China Astronaut Research and
Training Center in Haidian district in Beijing. Now the authors
use WWP1 Knockout Mice, and adeno associated virus, serotype
nine, carrying cardiac troponin T promoters driven by small
hairpin RNA targeting WW1. And in these special mice, found that
WW1 regulated cardiac hypertrophy induced pressure overload by
stabilizing disheveled segment polarity proteins, or DVLs.


Dr. Greg Hundley:


Carolyn. So disheveled segment polarity proteins. So what are
those?


Dr. Carolyn Lam:


Well, the DVLs, which include DVL one, two, and three are
important cytoplasmic mediators, involved in canonical and
non-canonical WNT signaling. And these are pivotal in cardiac
remodeling. The authors demonstrated that WWP1 interacts with
DVL2, and stabilizes it through an atypical ubiquitin type
modification. And thus WWP1 has the potential as a therapeutic
target for cardiac hypertrophy and heart failure.


Dr. Greg Hundley:


Excellent, Carolyn. Boy, what a fantastic summary. Well, my next
paper comes from Dr. Zhao Wang from University of Texas
Southwestern Medical Center. And Carolyn, as we know, metabolic
remodeling precedes most alterations during cardiac hypertrophic
growth under hemodynamic stress. And the elevation of glucose
utilization has been recognized as a hallmark of metabolic
remodeling. However, it's role in cardiac hypertrophic growth and
heart failure in response to pressure overload remains to be
fully understood. And so these authors aim to dissect the role of
cardiac pyruvate kinase muscle iso enzyme 1 in glucose metabolic
regulation and cardiac response under pressure overload.


Dr. Carolyn Lam:


Oh. Wow. So what were the results?


Dr. Greg Hundley:


Right, Carolyn. So they found that pyruvate kinase muscle iso
enzyme 1, so let's call that PKM1 expression, is reduced in
failing human and mouse hearts. And importantly cardiomyocytes
specific deletion of PKM1 exacerbated cardiac dysfunction and
fibrosis in response to pressure overload. Now inducible over
expression of PKM1 and cardiomyocytes protected the heart against
TAC induced cardiomyopathy and heart failure. And at the
mechanistic level PKM1 is required for the augmentation of
glycolytic flux, mitochondrial respiration and ATP production
under pressure overload. And furthermore deficiency of PKM1
caused a defect and cardiomyocytes growth and a decrease in
pyruvate dehydrogenase complex activity at both the in vitro and
in vivo levels. So, Carolyn, in summary, these findings suggest
that PKM1 plays an essential role in maintaining a homeostatic
response in the heart under hemodynamic stress.


Dr. Carolyn Lam:


Oh, nice, Greg. Well, let's go on to what else is in this issue?
There's a Research Letter by Dr. Aguib on a new variant with a
previously unrecognized mechanism of pathogenicity in
hypertrophic cardiomyopathy.


Dr. Greg Hundley:


And, Carolyn, I've got three papers. First, there's an ECG
Challenge from Professor Gunnaseelan [Rajendran], “Not All Waves
Are Factual.” There's a nice On My Mind piece from one of our
associate co-editors Torbjørn Omland entitled “Cardioprotective
Therapy in Cardio-Oncology: Quo Vadis?” And finally, there's an
In-Depth article from Dr. Brilakis entitled the “Saphenous Vein
Graft failure From Pathophysiology to Prevention and Treatment
Strategies.” Well, Carolyn, how about we head off to the feature
discussion, and learn a little bit more about pravastatin versus
placebo in pregnancies at high risk of term pre-eclampsia.


 


Dr. Carolyn Lam:


Let's go.


Dr. Mercedes Carnethon:


Well, welcome to Circulation On the Run. I'm pleased to be one of
your hosts today. My name is Mercedes Carnethon. I'm an
epidemiologist and professor at the Northwestern University's
Feinberg School of Medicine, and one of the associate editors of
the journal. I'm really excited to participate in the podcast
today with our featured guests. We have a paper led by Dr.
Nicolaides, Kypros Nicolaides, from the University of Exeter in
the United Kingdom. And we have the associate editor, Dr. Karol
Watson, who handled the piece for the journal.


Dr. Mercedes Carnethon:


So I'm really pleased to have each of you with me today and good
morning.


Dr. Karol Watson:


Good morning. Thank you for having us.


Dr. Mercedes Carnethon:


Well, thank you. So why don't we jump right in? So the title of
today's piece is pravastatin versus placebo in pregnancies at
high risk of term preeclampsia. A really exciting read that I
think provides important insights to us as well as emphasizes
what we can learn from negative trials and negative studies. And
so I'll jump right in and rather than me providing a summary,
I'll turn it over to you. Kypros. Tell me a little bit about your
inspiration for carrying out this work and why you pursued this
topic.


Dr. Kypros Nicolaides:


Thank you. Well, preeclampsia is one of the major causes of death
and handicap for the mother, and the fetus, and the baby. We have
been trying for many decades to develop a method of identifying a
high risk group of women that would develop preeclampsia. And we
succeeded in doing so. And five years ago, we carried out a major
trial at 12 weeks where we gave aspirin to the high risk group.
And that study was very successful. We managed to reduce the rate
of preterm pre-eclampsia by about 60%. And it was published in
the New England Journal of Medicine.


Dr. Kypros Nicolaides:


However, screening at 12 weeks was not very effective in
identifying women that deliver with pre-eclampsia term. And
aspirin was not effective in preventing term preeclampsia and
although preterm preeclampsia individually has more serious
complications than term preeclampsia. Because three quarters of
preeclampsia happen at term, the overall contribution of term
preeclampsia is actually higher than that of preterm
preeclampsia.


Dr. Kypros Nicolaides:


So that was the rationale, the background of having to do
something to first identify the high risk group for term
preeclampsia. And secondly, see whether we could do something to
prevent it. So we, in this study involving about 30,000 women
carried out in several hospitals in England, essentially, and
Belgium, we screened at 35 to 56 weeks. We identified that 10% of
the population at high risk. And then we randomized 1,120 women
in trial with pravastatin 20 milligrams against placebo. Why
pravastatin? Because a study from the United States by
Constantine in a preliminary study, 10 women that were randomized
to try the pravastatin or placebo starting from 12 weeks showed
extremely promising results. So pravastatin studies are very
commonly used for the treatment or prevention of hypertensive
disease outside pregnancy preeclampsia and hypertensive disease
are very closely related. So we felt that perhaps pravastatins
given at this late stage would prevent the development of
preeclampsia. Unfortunately, we found that that was not the case.


Dr. Mercedes Carnethon:


You know, your final point, there is one that we often lecture
about and talk about with students. What do you do when you have
a negative trial? I noticed that you said, unfortunately, you
found that wasn't the case. But tell us about the value of the
negative trial. I think part of the reason why this is so
compelling and important is you may have ruled something out. So
tell us a little bit about your findings. Did they surprise you?
What do you make of them?


Dr. Kypros Nicolaides:


I can divide the findings into two, Mercedes. Firstly, the
ability to screen in a multicenter study using our method, it was
a method of validating our previous model. And we had found that
we could identify 75% of the women that would develop term
preeclampsia for a screen positive rate of about 10% and I think
that that was very important. And I think that Karol Watson that
was editing and dealing with the article identified that as being
an important component of the article. And to me, that is very
much so. We found, we have now a method of identifying a very
high proportion of women that will develop term preeclampsia.


Dr. Kypros Nicolaides:


We failed. The drug, it was disappointing. But we have a
background method with which we can identify the high risk group
to try new methods of intervention that perhaps would be helpful.
I think that I will have, in a sense, great success with aspirin
in the first semester. And to a great extent, elimination of
preterm preeclampsia forced us to move with optimism of
preventing term preeclampsia. But perhaps giving pravastatin
starting from 35, 36 weeks was perhaps too late. We should have
perhaps started giving treatment before that. But we couldn't be
because we did not have a good method of identifying the high
risk group. So as far as I am concerned, we learned that
pravastatin is unlikely to be beneficial, even if we try it every
year, because we cannot identify the high risk group.


Dr. Karol Watson:


I'm so sorry for interrupting, but I just -


Dr. Kypros Nicolaides:


I'm glad you did.


Dr. Karol Watson:


This was such an important trial in so many respects. I think you
under sell it a little bit. This was phenomenal to be able to
identify this high risk group. As you say, just phenomenal. You
know, 35,000 women screened, identifying this high risk group,
and then to do a randomized trial of statin therapy in pregnancy.
That is landmark. That was really very, very prescient,
thoughtful, and really important to study. And I'm so grateful
that you guys did.


Dr. Kypros Nicolaides:


Carol, thanks very much for your kind words and for accepting our
paper for publication. Thank you.


Dr. Mercedes Carnethon:


You know, Kypros, this is really exciting. And I'm glad that you
jumped in, Carol. You know, it stands out to me that part of why
I will love having this as a potential paper to add to cases
where we teach people, how to understand, how to carry out a
study and how to respond when your primary hypothesis isn't born
out. However, even if your primary hypothesis wasn't born out,
you did learn something. And it sounds as though you learned a
strategy to identify high risk individuals. And it is informing
your next steps in your next study. Carol, you are obviously very
involved. It was great to hear your feedback. What are your
thoughts about what the lessons are for the practicing
cardiologist?


Dr. Karol Watson:


Well, there are several that I took away from this. One is, I
mean, I think building on your prior work with aspirin, that was
landmark. As you know. And the first time we actually had a
viable therapy for preventing preeclampsia. So we can prevent
preeclampsia. That's the really important thing that we found
out. And then there was a really good theoretic basis for
thinking pravastatin might work. I mean, the rationale for this
study was so solid and so important. I think the timing issue is,
I think it's still an answered whether treating with pravastatin
earlier might've helped. I don't know.


Dr. Karol Watson:


But again, we'd have to be able to identify people at risk, which
is what your group is so good at doing. But I also think it was
brave and very important that you guys decided to treat pregnant
women with statin therapy. As you know, there was an FDA
contra-indication to that until about a week ago when they
removed, or a month ago when they removed it. So you guys had to
say, we have the data, we know this seems to be safe, certainly
in this time period, and we want to do this. And that was a
really important thing to do. This is just such a rare and
important trial. The randomized controlled trial of statin
therapy in pregnancy. We just don't see that. You guys are
groundbreaking


Dr. Kypros Nicolaides:


And, Carol, on that point for those that are still, I know that
in the United States, people are planning new trials, starting
from the first trimester. But as you said, they were stopped by
the FDA. We provided further evidence of the potential safety of
the drug. It was not published in the journal, but as part of the
trial, we were collecting from some women cord blood. And it had
shown that there were no adverse biochemical events. And also
there were no significant differences in adverse events between
the placebo and the pravastatin group. So in that respect, it is
a good starting point to encourage those that want to do studies
everywhere only in pregnancy.


Dr. Karol Watson:


So important, so important.


Dr. Mercedes Carnethon:


Thank you so much, Kypros. And I'm really excited that we're
featuring this in Circulation On the Run because it means that we
can get word out beyond our core audience of cardiologists. This
is really an important piece as well for the obstetrician
gynecology community to hear about given the steps that they
will, how they'll consider using these data. Certainly, and you
both touched on a really important point, which is that it isn't
as common that we do intervention studies in vulnerable groups
and protected groups. And pregnant women typically are. You
enrolled 1,100 people into this trial. That is really impressive.
Can you share with our audience a little bit, to the extent, a
little bit about that process. How did you convince the team of
the safety and were women enthusiastic and how did they respond?
I look forward to using your responses to discuss with my
trainees, how we go about carrying out this important work.


Dr. Kypros Nicolaides:


One of the issues about trials, Mercedes, is to have the
background method of identifying a high risk group. In the United
States, unfortunately, there is no method of routine screening in
pregnancy during the first trimester. In very few cultures, if I
take ultrasound scanning, for example, a few decades ago I was
instrumental in introducing a 12 week scan. Because I have
noticed that increased nuchal translucency is a marker of
chromosomal abnormalities and so on. And that created a 12 week
routine assessment in many countries of the world. It was at the
back of that assessment that we introduced first trimester
screening for preeclampsia. That led to the aspirin trial and the
successful results of prevention. We have pioneered, in my
hospital, the series of hospitals that I have under my influence,
because they are run by ex research fellows of mine, a routine 36
weeks scan in pregnancy.


Dr. Kypros Nicolaides:


I call three scans in pregnancy important. One at 12 weeks, we
find out whether the woman is truly pregnant or not, whether she
carries one baby or not, whether the babies are generally all
right. Whether we can screen at that point for chromosomal and
other abnormalities, and now screening for preeclampsia. At 20
weeks scan, where we look for the fetal anatomy again, and then
the development of the baby. In the third trimester scan, which I
call it the delivery scan. At 36 weeks, we can tell whether the
baby is developing normally or not. Whether the baby's in the
right position cephalic or breach. And now whether the baby's too
big or too small. And now whether you can identify they're high
risk group for preeclampsia. So you need that background of
routine screening of the whole population. And then of course we
are quite experienced in recruiting women into our studies.


Dr. Kypros Nicolaides:


I deliberately call my center—although it is a routine, national
health center institution—I call it an institute of research in
fetal medicine. The ideology of the center is research. There are
so many things that we do not know. And women have understood the
value arriving in a research institute. They accept the ideology
that if you participate in research, you will benefit or others
will benefit or you will benefit your next pregnancy. So I think
a successful recruitment into trials is the projection that you
have a center that is actively being involved in research. And
research is an integral part of providing a good clinical
service. That's all I can say as a general point.


Dr. Mercedes Carnethon:


That is wonderful. You know, Kypros, I've really appreciated the
time you spent with us. And I just want to end by calling on my
colleague, Carol. Any final words or comments as we wrap up
today?


Dr. Kypros Nicolaides:


I just thought from soup to nuts, beginning to end, this study
was so informative and illustrative. We were able to, thanks to
you and your group, Kypros, to understand that you can identify
this high risk group. That you can treat pregnant women with
statin therapy, with safety. And that you can get information out
of a neutral study. And I just think all of those are so
important and I am really looking forward to your next step.
Because I think your group has just been groundbreaking in so
many levels.


Dr. Mercedes Carnethon:


Well, thank you so much, Kypros, Carol. I think we've had a
really exciting discussion this morning and our listeners from
the cardiology community, to even the more broad research
community, and the OB GYN community have learned a great deal
from your work. So this is Mercedes Carnethon, one of the
associate editors at Circulation and the happy host of the
Circulation On the Run podcast. So thank you very much.


Dr. Karol Watson:


Thanks so much.


Dr. Kypros Nicolaides:


Thank you.


Dr. Greg Hundley:


Well, on behalf of Carolyn and myself, I want to thank our
speakers, and then also wish everyone a great week and we will
catch you next week on the run. 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.