Circulation April 07, 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: I'm Greg Hundley, associate editor from the VCU
Pauley Heart Center in Richmond, Virginia.


Dr Carolyn Lam: Greg today's speaker paper is all about soy
products and whether or not there is a benefit with them with
regards to risk of coronary heart disease. Now, this has been
extremely controversial and today's speech or paper is really
important in its findings. Ha ha, I bet you want to get to it
right now but I'm going to say, hold on let's get to some other
really interesting papers in this series first. Can I start off?
You got your coffee?


Dr Greg Hundley: Yes. Let's get going Carolyn.


Dr Carolyn Lam: So the first paper I want to highlight really
talks about myocardial energetics in obesity, and you're going to
love this one Greg it's got some really cool MRI techniques. We
know that obesity is strongly associated with exercise
intolerance and the development of heart failure particularly
HFpEF. Well Dr Rayner from University of Oxford and colleagues
looked at this carefully in 80 volunteers, which included 35
controls with an average BMI of 24 and 45 obese individuals with
an average BMI of 35, who did not have coexisting cardiovascular
disease. Now, these participants underwent body composition
analysis and MRI of the abdominal liver and myocardial fat
content, left ventricular function and 31 Phosphorus Magnetic
Resonance Spectroscopy to assess Phosphocreatine ATP and Creatine
Kinase Kinetics at rest and during Dobutamine Stress.


Dr Greg Hundley: Oh, wow Carolyn, this is right up my alley.
You've got MRI imaging for body composition coupled with MR
spectroscopy for metabolism, so what did they find?


Dr Carolyn Lam: Thanks for putting that simply for us Greg. They
found that in the obese resting heart, the myocardial creatine
kinase reaction rate is increase, maintaining ATP delivery
despite reduced energy stores during increased workload. While
the non obese heart increases ATP delivery through creatine
kinase the obese heart does not, and this is associated with
reduced systolic augmentation and exercise tolerance. Weight Loss
reversed these energetic changes, so these findings really
highlight myocardial energy delivery via creatine kinase as a
potential therapeutic strategy to improve symptoms in obesity
related heart disease, as well as a fascinating modifiable
pathway involved in the progression to heart failure. Now with
this paper the central illustration is so critical, everybody has
to pick up that issue and have a look. Furthermore, you must read
the elegant editorial by Barry Borlaug and Craig Malloy.


Dr Greg Hundley: Oh, you bet Carolyn. Craig always puts these MR
spectroscopy papers in such fantastic perspective, really looking
forward to that read and such an elegant study. Now, we haven't
had Carolyn's quiz in weeks and we're going to get into one. This
paper comes from Professor Nina Wettschureck, from the
Max-Planck-Institute for Heart and Lung research, and it pertains
to the infamous G-protein coupled receptors. Now, Carolyn here's
your quiz and guess what, it's just multiple choice. All you have
to do is fill in the blank.


Dr Carolyn Lam: On G-protein coupled receptors?


Dr Greg Hundley: Yeah, I know it's... we know a lot about these,
but we're going to learn. So, G-protein coupled receptors are the
largest family of transmembrane receptors in eukaryotes. They
transduce signals of numerous physio-chemical stimuli
including... and Carolyn you have to complete this sentence. So
it's neurotransmitters, hormones, local mediators, metabolic or
olfactory cues and got to complete the sentence. Is it air
resistance? Time? Or light?


Dr Carolyn Lam: Space.


Dr Greg Hundley: That's not a choice.


Dr Carolyn Lam: All right, all right let me guess light.


Dr Greg Hundley: That's awesome. Fantastic, great job Carolyn. So
in the vascular system the contract alternative vessels is
crucially regulated by these GPCRs, including basic constrictors
such as Angiotensin two and Endothelin one. In this study the
investigators studied the role of GPRC5B, and the regulation of
contractility and differentiation in human and murine smooth
muscle cells in vitro, as well as in tamoxifen inducible smooth
muscle cells Pacific knockout mice under conditions of arterial
hypertension and atherosclerosis, and these experiments were done
in vivo.


Dr Carolyn Lam: Okay, so what were the results?


Dr Greg Hundley: They found that GPRC5B regulates vascular smooth
muscle tone and differentiation by negatively regulating prostate
cycling receptor signaling. Thus, Carolyn inhibition of the
interaction between GPRC5B and the prostacyclin receptor might be
beneficial in human arterial hypertension and vascular
remodeling. What a great new insight into basic science. Well,
let me get on I have a clinical paper, and this is on the
infamous topic from the COMPASS-PCI trial, Rivaroxaban plus
Aspirin versus Aspirin alone in patients with Prior Percutaneous
Coronary Intervention from Dr Kevin Bainey at the Canadian VIGOUR
Center in University of Alberta.


So Carolyn, the cardiovascular outcomes for people using
anticoagulation strategies or COMPASS trial demonstrated dual
pathway intervention with Rivaroxaban 2.5 milligrams twice daily
plus aspirin, and 100 milligrams once daily versus aspirin 100
milligrams once daily, reduced the primary major adverse
cardiovascular event outcome of cardiovascular death, MI or
stroke as well as mortality in patients with chronic coronary
syndromes or peripheral arterial disease. Now, whether this
remains true in patients with a history of PCI is unknown.


Dr Carolyn Lam: Oh, Greg I'm so disappointed. Why didn't you give
me a quiz here? I know about the COMPASS trial. Okay, so what did
the author's find?


Dr Greg Hundley: So Carolyn of the 27,000 plus patients in
COMPASS 16,500 plus patients had chronic coronary syndrome, were
randomized to DPI or aspirin and of these 9,862 had prior PCI. So
here are the results, DPI compared with aspirin produce
consistent reductions in MACE mortality, but with increased major
bleeding with or without prior PCI. So among those with prior PCI
one year and beyond, the effects on MACE and mortality were
consistent irrespective of time since the last PCI.


Dr Carolyn Lam: Mm-hmm (affirmative) Interesting implications on
dual platelet inhibition. Well, let me tell you a little bit
about what's in the mailbag in the rest of this issue. There's a
research letter by Dr Joseph Wu on molecular signatures of
beneficial class effects of statins on human induced pluripotent
stem cell derived cardiomyocytes. We have global rounds by Dr
Annika Rosengren and Dr Lars Wallentin on the cardiovascular
medicine in Sweden. We have a White Paper by Dr Abhinav Saxena
and colleagues on the value of hemodynamic monitoring in patients
with cardiogenic shock undergoing mechanical circulatory support.
And we also have paired perspective pieces, one by Dr Salim
Virani and colleagues on secondary prevention of atherosclerotic
cardiovascular disease comparing recent United States and
European guidelines on dyslipidemia, and another by Dr Neil Stone
and colleagues on comparing primary prevention recommendations
with the focus look at the US versus European guidelines on
dyslipidemia.


Dr Greg Hundley: Very good, Carolyn. Well, I've got a research
letter Professor Do-Young Kwon from the Korea University of Ansan
Hospital, Korea University College of Medicine and discusses the
association of Parkinson's disease with the risk of
cardiovascular disease and all-cause mortality, and a nationwide
population-based cohort study. In addition, different series of
letters Dr Seung-Jung Park from Asan Medical Center at the
University of Ulsan College of Medicine, and Professor Lang Li of
The First Affiliated Hospital of Guangxi Medical University
exchanged letters regarding the article, Clinically Significant
Bleeding With Ticagrelor versus Clopidogrel in Korean patients
with Acute Coronary Syndromes Intended for Invasive Management,
that previously published randomized clinical trial. Then finally
one of those great ECG investigations from Dr Miguel Arias, and
they have an ECG quiz entitled The Hidden Reveals the Hidden, but
really, it's referring to a Brugada ECG pattern and a patient
with Wolff-Parkinson-White. I can't wait to get onto that feature
article discussing the potential benefits or harms of soy in men
and women as it relates to cardiovascular disease.


Dr Carolyn Lam: Yeah, you and I Greg let's go. Oh, boy today's
feature paper really literally cuts close to the heart for me
talking about soy products, and whether or not there's a
relationship with cardiovascular health. This remains
controversial but thankfully we've got really great data just
published in this week's issue, so proud to have the first author
with us Dr Qi Sun from Brigham and Women's Hospital, as well as
our associate editor who's also an editorialist for this paper
and that's Dr Mercedes Carnethon from Northwestern University
Feinberg School of Medicine. So welcome both I cannot wait to
just jump right into it. Please, Qi, tell us what you found about
soy products.


Dr Qi Sun: First off this is a prospective cohort study that
included three cohort studies, the Nurses’ Health Study and the
Nurses’ Health Study II and Health Professionals Follow-Up Study.
So those three big prospective cohort follow up studies. Now over
the years we have collected much data of diet which has been
repeated, reviewed, and assessed over the years, and we have
accumulated many cases of cardinal heart disease the numbers are
a solid. Now what we found is that the intake isoflavones which
are the big family are flavonoids, the higher intake of
isoflavones were associated with a lower risk of developing
coronary heart disease in those three cohorts of men and women.
And in addition because tofu and soy milk are the primary
contributor in our guide of isoflavones, we also examine the tofu
and soy milk in relation to the risk of cardinal heart disease
What we found is that tofu intake is significantly associated
with lower risk of developing heart disease, and soy milk is also
associated with lower risk of developing heart disease. It's just
the association for soy milk, soy milk is not significant. And I
think very interestingly we also found that the menopausal status
and the postmenopausal hormone use somewhat also modulated
association primarily for coffee intake with heart disease risk,
in that we found younger women who were before their menopause
and also postmenopausal women who did not use hormone will
benefit more from tofu intake.


In contrast, for postmenopausal women who are using hormone the
association was not significant. I think those are the primary
findings of our prospective cohort study.


Dr Carolyn Lam: Oh my goodness, hallelujah. That's really
marvelous and beautifully summarized, Mercedes please explain why
was this such a controversial area before? And what does this
paper add? Love your editorial by the way.


Mercedes Carnethon: We hear a lot about nutritional epidemiology
studies, and we have a lot of debates about what we should
believe, whether we should change our behavior based on these
observational studies and quite often we have discussions about
what's new. And I lean on that final point about why I like this
particular paper so much, and that's because I found the topic of
isoflavones, tofu intake and soy to be extremely relevant to a
large proportion of the world's population, whose primary protein
intake may be something made from a soybean, heavy and
isoflavones. Within the United States it's also relevant even
though a smaller proportion of our population relies primarily on
vegetarian diet, there is a very large and interested group
wondering whether soy intake is safe. There have been discussions
about whether there's harm associated with it, and the
possibility that it could have beneficial influence on our
leading causes of death of coronary heart disease.


So I was most thrilled about the innovation of this particular
topic, and its methodological rigor. When we think about what we
lean on, we lean on large studies, we lean on multiple events and
the size of the study allowed the investigators to explore
numerous subtleties. Subtleties such as that reported related to
the moderation by menopausal status, and that was the point I was
most curious about and why I'm really excited to have an
opportunity to talk to you today Chi. Can you tell me a little
more about the menopausal status finding?


Dr Qi Sun: So first off as I mentioned tofu intake was more
strongly associated with lower risk of developing heart disease
among younger pre-menopausal women, or postmenopausal women who
did not use ham. Before that I want to also mention for
isoflavones intake where I also found a similar pattern in that
isoflavones are more. Appear to be more strongly associated with
lower risk also in those two groups of women, although the past
by interaction was non-significant. Now in terms of why I think
there are a couple reasons why is that, among postmenopausal
female or in our use hormone, the isoflavone can function as
estrogen and provide at least partially the estrogenic effects
that were calculated in postmenopausal women who do not use
hormone, and for premenopausal women we think that's probably
because before menopausal, the activity of estrogen receptor may
be higher than the estrogen receptor after menopausal. So, in
reality, the other variables of isoflavones may provide estrogen
effects after menopausal. So those are the hypotheses although I
have to mention that those hypotheses, we need more evidence to
really shed light on the mechanisms underlying those interactions
between menopausal status, postmenopausal hormonal use, where's
the intake of isoflavones and tofu.


Dr Carolyn Lam: So Chi I love that explanation and giving it some
biological possibility, although as you said it's a postulation.
But may I ask so what's the implication for men? I lived with a
man who thinks if he takes soy he's going to grow boobs. So
what... did you see any sex differences and do studies like this
and able looking for the downsides of eating soy?


Dr Qi Sun: As a scientist I'm open to any kind of new findings as
long as the findings are from well conducted, rigorously designed
study. But having said that I couldn't exclude the possibility
that maybe soy intake is associated with certain adverse health
outcomes, but so far based on my experience I didn't see any such
evidence. But having said this I always say I wouldn't risk any
possibility, but coming... circling back to the coronary heart
disease we really didn't see much difference between men and
women. It's true for the younger women we saw a stronger
association but for men I also see a lower risk of heart disease.
So there's a kind of interesting image on soy intake or
isoflavones intake in the United States that people believe they
are estrogen so a man shouldn't take it, but if you look at the
group of vegetarians, the vegans. There are a lot of guys they
practice vegetarian, they practice vegan diets and we also
publish on plant-based diet in relation to coronary heart disease
and lot of men eat very healthy. And we found those people who
practice those kinds of healthy diets, soy is often mouthful of
primary sources of proteins and if you look at their risk of
developing heart disease, type two diabetes is quite low.
Something lower than other normal women who practice otherwise
omnivore diet.


Dr Carolyn Lam: It's true Qi soy intake could also be a marker of
a healthier lifestyle in general, by extension of what you just
said. But Mercedes I love that you discuss quite a number of
these issues in your editorial and at the end of the day you
asked the most important question, what does this mean for us?
Should we all be increasing our intake of soy products? Could you
give us your synthesis of that?


Mercedes Carnethon: Yes, a point that I've definitely tried to
make here, and this is really in response to what I expect to be
the media fear surrounding new dietary findings. One of the first
questions that I know that she and his colleagues will be asked
is, should I change my diet? Can I extend my life? And that's
because the media is really looking for a lot of sensational
headlines in this topic, and I think we have to focus on what we
learn from these observational studies. They're a very important
step in the scientific process that helps us provide a
justification for later clinical trials, that helps us think
about the multiple components that work together to promote
overall excellent health. And the point you were making right
before this about the individuals who eat plant based diets that
are heavily based in soy. In the paper it also describes that
those individuals exercise more, they may have lower intakes of
saturated fat, and so I think ultimately what I take from this at
least for myself and for people who would ask is that an overall
healthy diet seems to stand up very well in these well done
observational studies. And that soy in particular may be a part
of an overall healthy diet given what we're seeing here in this
very well done study.


Dr Carolyn Lam: Oh, that's beautifully put Mercedes and Chi
perhaps I can give you the last word. What would you say is the
take home message and what are next steps?


Dr Qi Sun: I think the core message is this as Mercedes very well
discussed, I think soy and especially tofu can be really good
components of the overall healthy plant based diet, and by
practicing that I think we can significantly reduce the risk of
developing coronary heart disease for both men and the women. I
think moving forward we would like to see evidence from clinical
trials that target cardiometabolic risk factors as outcome, and
to see whether increased consumption of tofu and isoflavones can
really reduce those risk markers so that they have ample evidence
to support the mechanisms. As you mentioned Carolyn that this is
an initial study, and it could be soy, intake could be just macro
how is it, through clinical trials, we can really control those
confounding factors and really provide good evidence to support
our findings.


Dr Carolyn Lam: Well, in the meantime I just have to say you made
my day this is coming from a soy eating vegetarian, so thank you
so, so much. Thank you, listeners for joining us today.


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