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.