Circulation January 19, 2021 Issue

In this issue, author Monika Safford and Associate Editor discuss
the article “Number of Social Determinants of Health and Fatal
and Nonfatal Incident Coronary Heart Disease in the REGARDS Study
(Reasons for Geographic and Racial Differences in Stroke).” Then
authors Jennifer Ho and Timothy Churchill discuss their Research
Letter “Evaluation of 2 Existing Diagnostic Scores for Heart
Failure With Preserved Ejection Fraction Against a
Comprehensively Phenotyped Cohort.”


 


TRANSCRIPT BELOW:


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 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.


Dr. Carolyn Lam:


Guess what, Greg? We're going to talk to a lovely friend and
wonderful colleague Dr. Jennifer Ho soon regarding her research
letter on the HFpEF diagnostic scoring criteria.


Dr. Greg Hundley:


Very nice, Carolyn. Well, I've also got another feature
discussion in this issue involving the reasons for geographic and
racial differences in stroke. It's from the REGARDS study. But
first, how about we grab a cup of coffee and jump into the next
articles in the issue.


Dr. Carolyn Lam:


I've got my coffee, Greg and I'm ready to tell you about acute
infection and endotoxinemia. We know that infections are a
well-established risk factor for cardiovascular inflammation,
increasing the risk for a cardiovascular complication within the
first weeks after that infection. However, what is the mechanism
underlying such an association? Well here, Dr. Soehnlein from
Germany and colleagues utilized a model of endotoxinemia to link
acute infection and subsequent neutrophil activation with
acceleration of vascular inflammation. Acute infection was
mimicked by injection of a single dose of lipopolysaccharide into
hypercholesterolemic mice.


Dr. Greg Hundley:


So, Carolyn, what did they find?


Dr. Carolyn Lam:


Well they found that neutrophils and specifically neutrophil
extracellular traps controlled accelerated atherosclerosis during
endotoxinemia. These neutrophil extracellular traps or
NET-resident histone H2a, heightened arterial monocyte
recruitment in endotoxinemia in a mechanism involving
electrostatic charge interaction. The clinical implications are
that therapeutic neutralization of NET-resident cationic
molecules, including histone H2a by use of antibodies or peptides
may protect patients at cardiovascular risk during an acute
infection from secondary events.


Dr. Greg Hundley:


Wow, Carolyn. Really interesting. Well, my paper comes from Dr.
David Park from New York University School of Medicine. Carolyn,
elevated intracardiac pressure due to heart failure, induces
electrical and structural remodeling in the left atrium that
begets atrial myopathy and arrhythmias. The underlying molecular
pathways that drive atrial remodeling during cardiac pressure
overload are poorly defined. The authors sought in this study to
characterize the response of the ETV1 signaling axis in the left
atrium during cardiac pressure overload in humans and mouse
models and explore the role of ETV1 in atrial electrical and
structural remodeling.


Dr. Carolyn Lam:


Nice. And so what did they find, Greg?


Dr. Greg Hundley:


Well Carolyn, using the Cleveland Clinic Biobank of human left
atrial specimens and their mouse models, these authors found that
ETV1 is down regulated in the left atrium during cardiac pressure
overload, thereby contributing to both electrical and structural
remodeling of the left atrium.


Dr. Carolyn Lam:


Nice. Well Greg, let's talk about what else is in today's issue.
There's a Perspective piece from Dr. Delgado on “Changing the
Paradigm in the Management of Valvular Heart Disease: In Addition
to Left Ventricular Ejection Fraction, Focus on the Myocardium.
There's a Research Letter from Dr. Lurz on closure of iatrogenic
atrial septal defect following transcatheter mitral valve repair,
the randomized MITHRAS trial. There's an exchange of letters
between Dr. McAvoy and Dr. Kim regarding the article,
Cardiovascular Risk of Isolated Systolic or Diastolic
Hypertension in Young Adults. And an ECG challenge by Dr. Avila
on complete AV block cured by atrial pacing.


Dr. Greg Hundley:


Very nice, Carolyn. Dr. David Saadoun has an In Depth review on
medium and large vessel vasculitis and Dr. Christy Avery has a
Research Letter reporting on the trends in US cancer and heart
disease mortality from the period of 1999 through 2018. Well,
Carolyn, how about now we jump into those feature discussions?


Dr. Carolyn Lam:


Yep, double features. Here we go.


Dr. Greg Hundley:


Well listeners, this is the first of our double feature on this
January 19th and we're so fortunate today to have Monika Safford
from Weill Cornell in New York and our own associate editor,
Mercedes Carnethon from Northwestern University in Chicago.
Monika, we'll start with you. Could you tell us a little of the
background information pertaining to this study and what
hypothesis did you want to address?


Dr. Monika Safford:


Sure. Well, thank you first of all, for the opportunity. We've
been studying social determinants of health. I think there's a
lot of attention that has come on social determinants of health
from health system perspectives in recent years but I think
there's less of a recognition of individual practicing physicians
of what they can do. What's happened is that there are population
managers at most health systems and it seems like it's a fairly
distant undertaking compared to day to day clinical care. We
wondered whether there was a way to begin to integrate social
determinants of health more in the day to day management of
patients. And that was really the major motivation here was to
take this fairly late recognition, I think, compared to the
sociology world of the importance and the relative importance of
social determinants to see if we could help clinicians actually
use this information to inform their clinical management.


 


Dr. Greg Hundley:


Very nice. And so what was the study population that you worked
with? And what was your study design?


Dr. Monika Safford:


Sure. The REGARDS study, REGARDS stands for reasons for
geographic and racial differences in stroke, is a large national
cohort, more than 30,000 people who live all over the 48
contiguous United States. About 44% of them are African-Americans
and the rest are whites. Everybody was 45 and older at the time
of their recruitment between 2003 and 2007. And we're now
following them longitudinally for outcomes and among the outcomes
are coronary heart disease and a causes of death. It's a terrific
cohort to study racial disparities, if you're interested in
differences between African-Americans and whites.


Dr. Greg Hundley:


And what did you find?


Dr. Monika Safford:


We did find, which was our initial hypothesis, that the greater
the burden of social determinants that an individual is exposed
to, the greater the independent risk. There's a definite graded
risk. If you just simply count up social determinants, that
should really be part of the social history that we're all taught
to take in medical school. The greater the number, the higher the
risk. And what was really quite concerning was that once you
adjusted for all of the things that are available in a typical
cohort study, physiologic measures, past medical history, health
behaviors. There still was this massive, independent effect, 50%
greater after accounting for all of those wonderful phenotypic
markers that we have available in a cohort study.


Dr. Greg Hundley:


And what were some examples of these social determinants that we
should all be thinking about?


Dr. Monika Safford:


Sure. Educational level. We all ask our patients, what was their
educational attainment? Income has come a little bit under
scrutiny. We don't typically ask our patients what's your annual
household income? But there are lots of proxy markers so we are
aware of what our patients can afford and can't afford when we
prescribe medications. We have to know whether or not this is
something that is within the realm of possible for individual
patients. We should get a very good sense of what their financial
situation is. Their social circumstances. Are they isolated? Do
they live alone? Are we living in a state that is one of those
states that doesn't really have a robust public health
infrastructure? Are we living in a rural area? Are we in a health
professional shortage area? Most physicians are aware of these
types of variables.


Dr. Greg Hundley:


Very nice. Well, Mercy, let's turn to you. Can you help us put
these findings that Monika is sharing with us today in the
context with other studies that have performed really related to
this topic?


 


Dr. Mercedes Carnethon:


Certainly. I'd love to summarize that as well as ask the
question. We've known for some time that social determinants of
health are associated with many different health outcomes,
primarily cardiovascular diseases. We know that the access that
individuals have to resources to promote their health and protect
themselves really do influence what happens to them in the long
run. I was extremely pleased to read this paper prepared by
Monika and her group in the REGARDS study because it had many
strengths that exceed those of prior studies, namely the large
sample size, the significant representation of both Blacks and
whites, as well as the ability to study both fatal and non-fatal
outcomes. And I think that the summary provided by Monika was
excellent and I would love to follow with a few questions if I
might. Namely, were the social determinants similarly associated
with outcomes in Blacks and whites? We know certainly in this
country that the two are correlated. And I just wondered whether
or not you saw similar patterns of association whereby those who
had adverse social determinants of health also had higher rates
of mortality in both Blacks and whites?


Dr. Monika Safford:


Yeah. Wow, what a great question. There's only so much that you
can cover in one paper. In this paper, we were really focused on
this concept of the burden and a simple count of social
determinants of health. And we actually did not stratify by race.
We didn't examine this separately by race, but that is exactly
what we're doing in another similar study right now. That is a
really, really important question because some of these
determinants may not be similarly associated for Blacks and
whites.


Dr. Mercedes Carnethon:


I'd like to follow as well, so what surprised you about the
findings in this study?


Dr. Monika Safford:


Probably the biggest surprise was the difference in the
association or the strength of the association between incident
fatal CHD. This is primarily sudden death and this is what we all
want to try to avoid because this is people who we don't yet
recognize having coronary disease. And then when they die at
their presentation, it's very frustrating. We sure would love to
be able to intervene. We have gotten very good at intervening
after people survive a myocardial infarction but the surprising
thing was that the strength of this association was really much
more pronounced for incident fatal CHD than it was for non-fatal
MI. We don't understand the reason for that. That's a puzzling
finding that we're definitely diving into as we speak.


Dr. Greg Hundley:


Monika, what do you see is the next study to be performed in this
space?


Dr. Monika Safford:


What we're doing right now is we are demonstrating that this is a
robust finding across a number of different endpoints. We have a
very similar study on stroke, showing large magnitude of exactly
the same finding. And we have one that's about to come out on
diabetes, hypertension. We are really looking to demonstrate that
this approach, this very simple approach of just counting up the
number of social determinants, really is a cross cutting
observation across a number of different cardio-metabolic
outcomes, which would then lend credence to the possibility that
physicians could really integrate this into their clinical care
management. There's a whole host of studies that need to be done
to better understand nuances such as those that Mercedes
mentioned. We are really taking a deep dive into how to integrate
social determinants of health on the ground into clinical care
management, not just for larger health system population
managers, but for individual clinicians.


Dr. Greg Hundley:


Mercedes, would you like to add anything?


Dr. Mercedes Carnethon:


I'm very pleased to see this work and I think that I really like
the practical nature of it and with the counting of the social
determinants of health. I think you're right that we often can go
very deep in cohort studies and look at things in very nuanced
way. However, I like that this presents an opportunity for
clinicians interfacing with patients to have a quick and easy
tool to recognize some of the background risks that they face.
Thank you for this important work.


Dr. Greg Hundley:


Yes. Well listeners, we really appreciate the opportunity to
speak today with Monika Safford from Weill Cornell in New York
and our own associate editor, Mercedes Carnethon from
Northwestern in Chicago and helping us to understand how social
determinants can be used clinically to help identify those at
increased risk of adverse cardiovascular events.


Dr. Greg Hundley:


Well, now we're going to turn to our second in our double feature
and we'll get to that in just a moment.


Dr. Greg Hundley:


Well listeners, we're now on to our second feature discussion.
It's a double feature on this January 19th. And we have with us
Dr. Tim Churchill and Dr. Jennifer Ho, both from Massachusetts
General Hospital in Boston, Massachusetts. Well Tim, we're going
to start with you. Could you describe for us a little bit of the
background related to your study? And what hypothesis did you
want to address?


Dr. Timothy Churchill:


Absolutely. The background behind this study that we wanted to
look at was the recent emergence of the H2PEF score and the
HFA-PEFF diagnostic algorithm coming out of the European Society
just about a year ago. And we wanted to look at how these two
diagnostic tools perform in terms of diagnosis of HFpEF, which as
we all know, is a really challenging and complicated, varied and
challenging to diagnose condition. And so our specific question,
as more than a hypothesis per se, was really to investigate the
diagnostic performance of both of these tools against what we
consider really a gold standard hemodynamic definition of HFpEF
using the patients who were undergoing comprehensive level three
cardiopulmonary exercise testing with invasive hemodynamics.


Dr. Greg Hundley:


Very nice. Tell us a little bit, how did you configure your study
population? And what was your study design?


Dr. Timothy Churchill:


At our institution, we have a large cardiopulmonary exercise
testing program and we took patients coming in from there and who
had a preserved ejection fraction, which we defined in line with
guidelines as 50% or above and then available transthoracic
echocardiography that we could review. And we performed a
detailed research over read on the clinical transthoracic echo
that had been performed. And we coupled that with the lab data
that was drawn on the day of the exercise test, coupled that with
the medical history that was previously collated and we tried to
look at a population that had all of the necessary score
components to assess each of these two scores.


Dr. Timothy Churchill:


And then what we did was we calculated each of the two scores and
compared their outputs against, again, as I said, what we
consider our gold standard definition of HFpEF, which is a
invasively defined definition that accounts for both filling
pressures, as well as the relationship of the pulmonary capillary
wedge pressure to cardiac output with exercise. Trying to account
for the changes in the wedge with increases in flow, increases in
cardiac output with exercise.


Dr. Greg Hundley:


Very nice. And just quickly, how many patients did you include in
this study? And did you have an equal representation of men and
women?


Dr. Timothy Churchill:


We ended up including a 156 patients and there was a female
predominant in line with the overarching with both our
overarching exercise testing cohort, but also in line with, I
would say, the overarching prevalence of HFpEF in many other
studies. We ended up with 67% women with an average age of 59
years old.


Dr. Greg Hundley:


Very nice. What did you find?


Dr. Timothy Churchill:


I would say our biggest message, our biggest takeaway was that we
found that both of these scores performED quite well overall and
performed in a broadly similar fashion. We did note however, that
there was a significant under ascertainment of HFpEF at some of
the lower scores, which we highlighted as a potential weakness in
terms of using these scores for the diagnosis of community HFpEF
in that there was a certain number of patients with low scores
who would be classified as either not having HFpEF or a low
probability HFpEF, who we found to fit our hemodynamic
definition. And so we highlighted that as a potential weakness or
potential consideration of these. That's one area where these
scores might potentially miss people.


Dr. Greg Hundley:


Very nice. Well, let's turn to Jennifer. Jennifer you are
spending much of your career helping the world understand more or
bringing to light more information really in this field of heart
failure and specifically focusing on patients with preserved
ejection fractions. How do you put your findings here in the
context with some of the other world's literature relative to
patients with heart failure preserved ejection fraction?


Dr. Jennifer Ho:


Thank you, Greg. First off, I just want to say that we greatly
appreciate the opportunity to participate in this podcast and on
behalf of all of our coauthors, we're just thrilled to be here. I
guess there are a couple of points that I would take away to try
to place our study within the clinical context of HFpEF in
general. Number one, we know that HFpEF diagnosis is challenging,
which I think is something so fundamental to our field and needs
a lot further work. But a lot of other groups have really
struggled with trying to define HFpEF and really figuring out who
these patients are. There's a lot of work going on there.


Dr. Jennifer Ho:


I would say that our findings really show that these non-invasive
tools developed by other groups do help enrich for individuals
with HFpEF and that they perform quite well with some potential
of misclassification in these lower risk individuals. I'll also
say that what's new in our study is that we were able to show a
direct relationship of these scores and functional implications
that really affect how our patients feel. And so we were able to
show that these noninvasive scores really enrich for patients
with lower exercise capacity as measured by peak VO2, two worse
chronotropic response to exercise, and also worse hemodynamic
responses to exercise. And so I think that that's really powerful
in taking these noninvasive scores that have been developed by
other groups and really showing that there are direct functional
consequences for our patients depending on where you're scoring.


Dr. Greg Hundley:


Very nice. Jennifer, where do you think we take these scoring
systems next? What do you think is the next research that needs
to be performed in this particular space?


Dr. Jennifer Ho:


That's a great question, Greg. I think we do recognize that our
sample may be subject to referral bias. These are all patients
who were referred for clinical indications for a cardiopulmonary
exercise test with invasive hemodynamic monitoring. And so I do
think that validation of these scores is necessary across wider
samples so we can really affirm generalizability overall. I think
on a more fundamental level, so much more work is needed in the
HFpEF space in general to better understand disease pathogenesis.
We recognize that there's heterogeneity with respect to clinical
presentation, with respect to cardiac and extra cardiac organ
involvement, with respect to how we even define the disease in
the first place. I think a lot of work needs to really focus on
potential deep phenotyping approaches and other approaches to
tease apart potential subgroups of individuals that have HFpEF
that might be more uniform so we can understand all the
contributors that really lead to this disease.


Dr. Greg Hundley:


Very nice. Tim, would you like to add anything?


Dr. Timothy Churchill:


I would really echo. I think the biggest immediate question in my
mind would be replicating this model and or similar approaches to
really using invasive validation in other contexts that may or
may not have the same referral population. One of the biggest
things that drove this original study originally was that many of
the other validation efforts that have formed so far have been
based on consensus. And so we think there's a lot of value added
by the invasive hemodynamics. And so I think extending that
approach, I think can offer a lot of additional value as well in
different contexts.


Dr. Greg Hundley:


Very nice. Well listeners, we really want to thank both Dr.
Jennifer Ho and Dr. Tim Churchill for bringing us this very
informative study and helping us evaluate these new noninvasive
scoring methods and comparing them with really well done invasive
measures to best characterize patients with HFpEF. And then as
Dr. Ho said, perhaps identify groups that further phenotyping may
be indicated in other research studies to identify those that are
best suited for specific therapies to improve their overall
condition.


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,
2021.