Circulation July 5, 2022 Issue

This week, please join author Fabian Eichelmann and
Associate Editor Svati Shah as they discuss the article "Deep
Lipidomics in Human Plasma: Cardiometabolic Disease Risk and
Effect of Dietary Fat Modulation."


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 Director at the Pauley
Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn,
this week's feature, we are going to get into the world of
lipidomics and understand how some lipid metabolites may be more
predictive of cardiovascular events above and beyond the
conventional serum lipoproteins, like HDL and LDL. But before we
get to that, how about we grab a cup of coffee and start with
some of the other articles in the issue? Would you like to go
first?


Dr. Carolyn Lam:


Sure thing. This first paper is about the basilar artery. Have
you ever heard the analogy that the basilar artery is the
neurologists' equivalent of our cardiologists' left main coronary
artery? Well put, isn't it? Well, that's from the editorial that
accompanies this paper, but basically, occlusion of either artery
can be fatal without rapid re-perfusion. So that's why the basal
artery is the neurologists' left main coronary artery.
Re-perfusion therapies for acute basilar artery occlusion include
thrombolysis or mechanical endovascular thrombectomy.


Dr. Carolyn Lam:


In today's issue, Professor Hu from University of Science and
Technology of China, and Professor Nogueira from University of
Pittsburgh School of Medicine in the US, these are the
co-corresponding authors, and their colleagues, reported the
outcome of the attention registry of more than 2000 patients with
acute basilar artery occlusion who enrolled prospectively and
consecutively at 48 sites in China from 2017 to 2021, and
followed for the primary outcome of a favorable neurological
functional outcome defined as a modified Rankin score of zero to
three at 90 days.


Dr. Greg Hundley:


Wow, Carolyn, I love that analogy. So the basilar artery is kind
of similar in the brain to the left main coronary artery in the
heart. Whoa, what did they find here?


Dr. Carolyn Lam:


So, in this nationally representative observational study, the
authors found a significant association between endovascular
thrombectomy and better functional outcomes and survival at 90
days in patients with acute basilar artery occlusion, and this
was compared to chemical thrombolysis. Now, notably, this
relationship was modified by the baseline NIH stroke scale.
Specifically, patients with baseline NIH stroke scale of 10 or
more had an increased rate of favorable outcome when treated with
endovascular thrombectomy, whereas no significant beneficial
effect was seen in patients with baseline NIH stroke scores of
less than 10. Now, all this is discussed in a beautiful editorial
by Dr. Hankey, entitled, "Endovascular therapy for acute basilar
artery occlusion."


Dr. Greg Hundley:


Oh, beautifully stated, Carolyn. What a great article. But guess
what, Carolyn? I've got a quiz for you.


Dr. Carolyn Lam:


Uh-oh.


Dr. Greg Hundley:


This one's open answer, so it's not multiple choice. Can you name
a unique feature of zebra fish pertinent to the study of
cardiovascular disease?


Dr. Carolyn Lam:


Okay. Watch me hedge there because, first of all, I'm a daughter
of a zoologist. So my dad would have a heart attack if I couldn't
say something about the zebra fish. So, what I do know is the
zebra fish is an excellent animal model for genetic studies of
heart generation, basically development. So, there must be
something really cool there about how we can observe that.


Dr. Greg Hundley:


Excellent, Carolyn. So very well done. As you know, and your dad
knows, certain non-mammalian species like zebra fish, have an
elevated capacity for innate heart regeneration. Now,
understanding how heart regeneration occurs in these contexts can
help illuminate cellular molecular events that can be targets for
heart failure prevention or treatment, your area of expertise.
The epicardium, the mesothelial tissue layer that encompasses the
heart, is a dynamic structure that is essential for cardiac
regeneration in zebra fish, and these authors, led by Dr. Jinhu
Wang from Emory University performed single cell RNA sequencing
and identified seven epicardial cell clusters in adult zebra
fish, three of which displayed enhanced cell numbers during
regeneration.


Dr. Carolyn Lam:


Oh, interesting, Greg. So did these cell clusters provide some
clues that could be applied clinically?


Dr. Greg Hundley:


Yes. Carolyn. So these authors identified that these subsets of
epicardial cells emerge in post embryonic, zebra fish and sponsor
regions of active cardio myogenesis during cardiac growth and
regeneration. And as the heart achieves its mature structure,
these cells facilitate extracellular matrix hyaluronic acid
deposition to support formation of the compact muscle layer of
the ventricle. These cells associate with the function of the
hyaluron and proteoglycan link protein 1 or HAPLN1 paralogue in
production and organization of hyaluronic acid containing matrix
in cardiac injury sites and thereby enable normal cardiomyocyte
proliferation and muscle generation. And so Carolyn, potentially
in the future targeting hyaluronic acid regulation by
manipulation of HAPLN1 in human epicardial cells could
potentially modulate cardiac repair after myocardial infarction.


Dr. Carolyn Lam:


Well, thanks, Greg. That was awesome. Well, the next paper I want
to tell you about is one in which a novel ECG based machine
learning approach was used to determine and predict multiple
structural heart conditions. So the authors led by Dr. Chen from
Department of Translational Data Science and Informatics at the
Geisinger Health System in Danville, Pennsylvania. So these
colleagues hypothesized that a composite model would yield higher
prevalence and positive predictive value to facilitate meaningful
recommendations for echocardiography.


Dr. Greg Hundley:


Oh wow, Carolyn. Machine learning, it's just emerging everywhere
these days. So don't we need a large data set to do this?


Dr. Carolyn Lam:


Absolutely, and listen to how large this is. So using more than
2.2 million ECGs linked to electronic health records and
echocardiography reports from almost 500,000 adults between 1984
and 2021, the authors trained machine learning models to predict
the presence or absence of any of seven echo confirmed diseases
within a year, and the composite model and the composite label
that they used included moderate or severe valve disease and
reduced ejection fraction. So their composite recommend model
where reco is E-C-H-O we used age, sex ECG traces, and had an
area under the receive operating curve of 0.91 and a positive
predictive value of 42% at 90% sensitivity with a composite label
prevalence of 17.9%. Whereas the individual disease models had
area under curve ranging from 0.86 to 0.93 and lower positive
predictive values from about 1% to 31%.


Dr. Carolyn Lam:


So in summary, they showed that an ECG based machine learning
model using a composite endpoint can identify a high risk
population for having undiagnosed clinically significant
structural heart disease while outperforming the single disease
models and improving practical utility with higher positive
predictive values. So this approach may facilitate targeted
screening with echo to improve under diagnosis of structural
heart disease.


Dr. Greg Hundley:


Wow, Carolyn, really great article from the world of machine
learning. Well, how about we jump to some of the other articles
in the issue and I can go first. There are two Research Letters.
The first Research Letter comes from Professor Adlam entitled
"Pregnancy and Spontaneous Coronary Artery Dissection Lessons
from Survivors and Nonsurvivors." And our own Dr. Joe Hill, our
Editor-in-Chief also has a Research Letter entitled “Impaired AMP
Kinase Signaling in HFpEF Associated Atrial Fibrillation.”


Dr. Carolyn Lam:


Wow, what an issue filled with great stuff. There's an AHA update
by Dr. Churchwell on promoting nutrition security through
policies and programs. And there are highlights from the
circulation family of journals by our own Molly Klemarczyk, now
known as Molly Robbins. I'd love to tell you a little bit about
it. The association of new onset AF with cardiovascular outcomes
in patients hospitalized with COVID-19 are described in Circ
Arrhythmia, and EP. Rates of cardiovascular and cerebral vascular
disease mortality among Asian subgroups are presented in Circ CV,
Quality and Outcomes. Blood pressure and glycemic control are
presented in patients with heart failure in Circ Heart failure.
The associations of atrial update with technetium 99
pyrophosphate scans for transthyretin amyloid cardiomyopathy with
incident atrial fibrillation and possibly earlier diagnosis of
amyloid is presented in Circ Cardiovascular Imaging.


Dr. Carolyn Lam:


And finally the outcomes associated with larger burdens of
residual thrombus after aspiration thrombectomy for STEMI are
presented in Circ CV Interventions. Isn't that cool? And finally,
we've got an On My Mind paper by Dr. Arany on “It’s Time to Offer
Genetic Testing to Women with Peripartum Cardiopathy”. So that
wraps it up, Greg. Let's go to our feature discussion, shall we?


Dr. Greg Hundley:


You bet.


Dr. Greg Hundley:


Welcome listeners to this feature discussion on July 5th, and we
are very fortunate today. We have with us Dr. Fabian Eichelmann
from the German Institute of Human Nutrition in Potsdam, Germany,
and our own associate editor, Dr. Svati Shah from Duke University
in Durham, North Carolina. Welcome to you both. Fabian, we're
going to start with you. Can you describe for us some of the
background information that went into the preparation of your
study and what was the hypothesis that you wanted to address?


Dr. Fabian Eichelmann :


Yeah, sure. So first of all, thanks for the invitation to speak
here. So this project was basically comes from a collaboration
between us and a group in Redding, UK and we are part of a
consortium called FAME, which is short for fatty acid metabolism.
And there, we are interested in the health effects of fatty acid
metabolism in general. And in this paper that we did, this was
particularly cardiometabolic diseases. And I think this is no
surprise that we look at lipid metabolism in this context,
because there's so many really now also causal factors,
lipoproteins, total triglycerides for specific cardiometabolic
outcomes. So this is the reason why we wanted to look at it. And
through this collaboration, we were also able to harness the
potential from two different study designs that I probably will
go into later, but which really gave us an opportunity to really
generate I think, quite interesting insights.


Dr. Greg Hundley:


Very nice. And so what was that hypothesis?


Dr. Fabian Eichelmann:


So the hypothesis was that since the lipid metabolism has
formally only been mostly in the clinic, at least been measured
by lipoproteins and total triglycerides, for example, but the
lipidome of plasma, for example, is really rich. It's really
heterogeneous and it contains many different lipid classes and
different fatty acids. And through novel technologies and in this
case, lipidomics, you can really dive in really deeply and look
at this in a specific manner. And then the idea was to really
look at this and potentially identify lipids that would be
associated or could surface as biomarkers for cardiometabolic
diseases and at the same time, if those lipids were also
sensitive to a dietary intervention that really tried to modulate
the dietary intake of a fat.


Dr. Greg Hundley:


Very nice. And so how did you set this up? What was your study
design and what was your study population?


Dr. Fabian Eichelmann:


So we had two different study populations for this. So the first
one was the EPIC-Potsdam, which is a cohort study, a large scale
cohort study here in Potsdam, which started in the nineties. And
there, we basically associated baseline concentrations of these
lipid measurements with later on occurring incident cardio
metabolic outcomes. And in this case, this was type two diabetes
and primary CVD and CVD in our case meant myocardial infarction
and stroke. And we did that we checked which lipids would be
statistically significantly associated after multiple testing
with at least one of these outcomes. And then we took those
lipids further into intervention trial, which is called the DIVAS
trial in Redding, as I said, UK. And there, they had basically a
dietary intervention trial that really wanted to assess if the
change in the fatty acid proportions in the diet affects the
lipids. So there we had the lipidomics measurements at baseline
and after four months, and then we compared three different
trials to each other.


Dr. Greg Hundley:


Very nice. And so how many patients did you include and who were
these patients? Men and women? And did they have, for example,
prior cardiovascular disease?


Dr. Fabian Eichelmann:


So in EPIC-Potsdam, that's a population based cohort study. All
of the participants were drawn from the registries and invited.
So these were apparently healthy people. And in those we did
these association analyses and those we used the design, which is
a case cohort design, which is a sub sample of the whole cohort,
which is a really effective way and efficient way of analyzing
biomarker projects. And there we had in total 1,262 control
participants, and then later on additionally, a 775 type two
diabetics and 551 CVD cases. In the DIVAS trial, that was a trial
where participants also men and women, which was also the case in
EPIC-Potsdam were invited, and they were at a higher risk of at
the higher cardiovascular disease risk, which was measured by
score, but they didn't have any prior cardiovascular diseases.
And those were 113 participants that were randomized to one of
these diets.


Dr. Greg Hundley:


Right. So it sounds like two studies. One, a large case control
study and looking at different plasma lipid concentrations in two
separate groups. And then the second was a randomized trial, a
smaller trial of 113 individuals looking at a dietary
intervention. So with that established, tell us your study
results.


Dr. Fabian Eichelmann:


Yeah. So in the first step, as I said, where we associated lip
concentrations to later occurring disease, we found from the 282
lipids that we looked at, 69 were really associated to at least
one of these outcomes. And interesting here we saw that only
eight were associated to both outcomes and 49 were specific to
cardiovascular disease and 12 for specific to type two diabetes.
And from those 69, we found 19 were also sensitive to the dietary
intervention, and what was really striking here was that of these
19, 17 were perfectly in agreement with a suggested beneficial
effect, meaning that those lipids that were associated in the
EPIC-Potsdam studies on the cohort study with a higher disease
risk were reduced by these diets or in the opposite direction, we
saw those lipids that were associated with lower risk were
increased by these diets. So this was quite a striking
observation there.


Dr. Greg Hundley:


So it sounds like from the lipidomics analysis, there was a
construct of certain blood lipid markers that were associated
with cardiovascular events, and then in your randomized trial,
you were able to modify those by different dietary interventions?


Dr. Fabian Eichelmann:


Exactly.


Dr. Greg Hundley:


So listeners, now we're going to turn to our own associate
editor, Dr. Svati Shah. And Svati, you see many papers come
across your desk. What attracted you to this particular paper and
how do we put this study's results in the context with other
studies that have been published in really the sphere of
lipidomics research?


Dr. Svati Shah:


Yeah. Thank you, Greg. I just want to point out that this is a
really elegant translational study. I think these papers can be
very complicated to understand, and I think the authors did a
fantastic job of really laying out how you can combine cutting
edge what we call omics, using these cutting edge technologies,
but applying them to human cohorts with a very strong clinical
lens. So it's not just what do we learn about biology, but also
what do we learn about biomarkers that might be relevant to how
we take care of patients? And that's really one of the biggest
things I loved about this study is sort of, you get to have your
cake and eat it too. You get to learn about biology, but with a
very strong clinical lens towards identifying clinically relevant
biomarkers. I think another really important strength of this
study, which differentiates it is this sort of use of really
cutting edge lipidomics.


Dr. Svati Shah:


So this is a subset of omics where we're really looking at these
granular lipid classes. And some of the clinicians might say,
well, we measure cholesterol, why is this different? And you
know, Greg, really what lipidomics allows us is a much more
granular snapshot of these complex lipid species that are only
grossly captured by the cholesterol levels that we would measure
normally if we were seeing a patient in clinic. So to be able to
get this really granular snapshot of what is happening to lipid
biology and how it might relate to cardiovascular events,
diabetes, I think is really important. And finally, I think the
coolest part about this study is, in other studies we always have
a little bit of a hard time with what we call confounders. And
what does that mean? That means there may be other things for why
you're seeing these biomarkers associated with your disease and
those might be uncaptured things, things that you didn't measure
in this study. And we call that residual confounding.


Dr. Svati Shah:


And I think the authors in this study, not only statistically
adjusted for those potential confounders, but also importantly,
the DIVAS study, where they took the biomarkers that they found
from EPIC-Potsdam and said, do they change with the dietary
intervention? And in fact, they did find that many of these
lipid, these granular lipid species improved, meaning they went
in the proper direction in terms of your health with a diet that
was higher in unsaturated fats. So really proving not only the
potential biology of the benefit of diets enriched in unsaturated
fats, but also that these particular biomarkers are modifiable,
so they're able to be changed even in this case within 16 weeks
with just a dietary intervention. So to me that really was just a
beautifully laid out study that highlights really what
translational omics and these biomarker studies can do as we
think about the clinical care of patients.


Dr. Greg Hundley:


Very nice. And so it sounds like listeners, moving beyond the
lipoproteins, LDL, maybe total cholesterol and these granular
lipid species cholesterol esters, free fatty acids, fingo-lipids,
glycerophospholipid, et cetera, that's what we were studying in
this particular manuscript. So, well, let's turn back to Fabian.
And Fabian, what do you see is the next study to really be
performed in this sphere of research?


Dr. Fabian Eichelmann:


I think what would be really interesting and what would really
kind of prove what we saw is if you could find a way that an
intervention, be it like a drug intervention and not diet because
we looked at dietary intervention, that kind of shows the same as
we saw, but also that really specifically only alters these
lipids and how obviously not really feasible, but if that would
be going on for a long enough period, if you also saw these
effects that we now saw after four months would also affect the
health outcomes instead of just only these proxies.


Dr. Greg Hundley:


Very nice. And Svati, how about you? What do you see as the next
study that might be informative in this sphere of research?


Dr. Svati Shah:


Yeah. Great question, Greg. I mean, to me, I really think about
this gap that we have in actually translating these findings in
how we take care of patients. So again, really provocative
results here. We have really significant P values, strong effect
sizes, biomarkers that are modifiable, but in the paper they show
that it adds on top of a clinical model, so what we might use as
clinicians in the clinic that these biomarkers may help on top of
what we already know about patients. But we really need to
implement these findings and study that implementation for how
this might in a real world setting actually change outcomes in
patients and how we can actually help explain to clinicians how
these results might be beneficial for clinical care.


Dr. Svati Shah:


So on top of what Fabian already said, I think really
implementation science is a huge gap in how we take these
translational omics discoveries and use them in support of
improving patient care. We have lots to learn about these lipid
biomarkers and lots more discovery science that can be done. As
Fabian said, can we find drugs that might beneficially modified
these lipid subspecies? But again, I think this gap in
implementation science is really important.


Dr. Greg Hundley:


Very nice. Well listeners, we want to thank Dr. Fabian Eichelmann
from the German Institute of Human Nutrition in Potsdam, Germany,
and our own associate editor, Dr. Svati Shah from Duke University
in Durham, North Carolina for bringing us these really
provocative results, highlighting the identification of several
lipids and their association with cardiometabolic disease risk.
And then also nested within the same paper, a subset of
individuals undergoing a randomized clinical trial demonstrating
benefit by a dietary fat intervention, and there possibly
supporting the substitution of dietary saturated fatty acids with
unsaturated fatty acids perhaps as a potential tool for primary
disease prevention.


Dr. Greg Hundley:


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.


Dr. Greg Hundley:


This program is copyright of the American Heart Association,
2022. 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, please visit
ahajournals.org.