Circulation October 19, 2021 Issue

Please join author Khurram Nasir and Associate Editor Sandeep Das as they discuss the article "Social Vulnerability and Premature Cardiovascular Mortality Among US Counties, 2014-2018."

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 in Duke-National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center, VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I'm really excited about today's feature discussion. It's really meaningful on so many levels. It discusses social vulnerability. In other words, social determinants of health and its association with premature cardiovascular mortality among US counties. Now, even as an ex-US person I learned a lot, so everyone is going to want to listen in. But now let's start with going through some exciting papers in today's issue, shall we?

Dr. Greg Hundley:

You bet Carolyn. So, I'm going to grab a cup of coffee and we'll get started with the first article. And really gets into the world of cardiovascular risk and prostate cancer management.

Dr. Greg Hundley:

So, Carolyn in the light of improved prostate cancer survivorship, and the competing risk of cardiovascular disease, there's an ongoing need for rigorous cardio oncology clinical trials. As you probably know, androgen deprivation therapy is a cornerstone of prostate cancer therapy. Through different pituitary gonadotropin releasing hormone receptor mediated mechanisms both GnRH agonists, as well as antagonists, either indirectly or directly inhibit luteinizing hormone secretion, consequently inhibiting testosterone production. These GnRH agonists are the most commonly prescribed form of androgen deprivation therapy with only 3 to 4% of patients receiving a GnRH antagonist.

Dr. Greg Hundley:

So, Carolyn the relative cardiovascular safety of gonadotropin releasing hormone antagonists compared with gonadotropin releasing hormone agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains somewhat controversial. And therefore these authors led by Dr. Renato Lopes from both Brazil, as well as the Duke University Medical Center in Durham, conducted an international multicenter, prospective randomized open label trial, and men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomized one to receive gonadotropin releasing hormone, antagonist degarelix or the gonadotropin releasing hormone, agonist leuprolide for 12 months and the primary outcome was time to first educate major adverse cardiovascular event that combined the endpoints of composite death MI and stroke over these 12 months.

Dr. Carolyn Lam:

Nice Greg, and what did they find?

Dr. Greg Hundley:

Right Carolyn, due to slower than projected enrollment and fewer than projected primary outcome events enrollment was stopped before the 900 plan participants were accrued from May 3rd, 2016 to April 2020, a total of 545 patients from 113 sites across 12 countries were randomized. Baseline characteristics were really balanced between the two study groups. Now Mace occurred in 5.5% of the patients assigned to degarelix and 4.1% assigned to leuprolide and so in summary, Carolyn, this pronounced study is the first international randomized clinical trial to prospectively compare the cardiovascular safety of a gonadotropin releasing hormone antagonist as well as agonist in patients with prostate cancer. And the study was terminated prematurely due to smaller than planned number of participants and events. And so no difference in mace at one year was noted between the two groups and this pronounced study really provides a model for interdisciplinary collaboration between urologists, oncologists and cardiologist with a sheer goal of evaluating the impact of cancer therapies on cardiovascular outcomes.

Dr. Carolyn Lam:

That's so cool, Greg. I heard the presentation of these results at the ESC by Dr. Renato Lopes and it's a really cool and important study, but a paper I want to present is an analysis from Emperor preserved on inpatient and outpatient heart failure events.

Dr. Greg Hundley:

Great. Carolyn, so remind us, what did the Emperor preserved trial show?

Dr. Carolyn Lam:

Emperor preserved showed that in patients with heart failure and preserved ejection fraction empagliflozin reduce the primary endpoint of cardiovascular death or hospitalization for heart failure, primarily related to a lower risk of hospitalizations for heart failure. Greg you're smiling, because you can see me beaming because we finally have a robustly positive outcomes trial in have pep in this trial. Nonetheless in the current analysis, Dr. Milton Packer from Baylor Heart and Vascular Institute and others used prospectively collected information on inpatient and outpatient events, reflecting worsening heart failure, and pre specified their analysis in individual and composite end points.

Dr. Greg Hundley:

I've been in suspense here. What did they find?

Dr. Carolyn Lam:

Empagliflozin reduced the risk of severe hospitalizations as reflected by admissions requiring the use of ionotropic or vasopressor drugs and the need for intensive care. Empagliflozin also reduce the risk of outpatient worsening heart failure events, including the need for urgent care visits, diuretic, intensification, and unfavorable changes in functional class. So, basically benefit across the spectrum. Furthermore, because there's controversy about the effect across the spectrum of ejection fraction. The benefit on total heart failure hospitalizations was found to be similar in patients with an ejection fraction of above 40, but less than 50% and between 50 to 60%, although it was attenuated at the higher ejection fractions and we'll hear a lot of discussions about this.

 

Dr. Greg Hundley:

Wow, Carolyn. Just more information that keeps coming out about SGLT-2 inhibition. My next paper comes from the world of preclinical science and angiogenesis is a dynamic process, involves expansion of a preexisting vascular network that can incur in a number of physiologic and pathologic settings. But despite its importance, the origin of the new angiogenesis vasculature is really poorly defined in particular, the primary subtype of endothelial cells, whether they be capillary, Venus or arterial that might be driving, this process really remains undefined. These authors led by Dr. Michael Simmons at Yale University school of medicine, fate mapped endothelial cells using genetic markers specific to arterial, Venus and capillary cells.

Dr. Carolyn Lam:

What did they find Greg?

Dr. Greg Hundley:

This team study results found that Venus endothelial cells were the primary endothelial subtype responsible for the normal expansion of vascular networks, formation of arterial, venous malformation, and pathologic angiogenesis. And these observations highlight the central role of the Venus endothelium in normal development and disease pathogenesis.

Dr. Carolyn Lam:

Wow. That's really interesting. I don't think I've ever really paid attention to that bit. Venus endothelium. Thank you for that. Now what else is in today's issue? Well, there's an exchange of letters between Doctors Zhang and Liao regarding the article anti hypertrophic memory after regression of exercise induced physiologic, myocardial hypertrophy is mediated by the long noncoding RNA M heart 779, then ECG Challenge by Dr. Ahmed on challenges of interpreting smart watch and implantable loop recorder, tracings. There's cardiology news by Tracy Hampton and Highlights from the Circulation Family of journals by Sara O'Brien. These regular articles are just really worth a read. You learn so much from just these short lovely summaries. There's On My Mind paper by Dr. Meyer on a targeted treatment opportunity for taking advantage of diastolic tone. And there's also a Research Letter by Dr. Brozovich on a rat model of heart failure with preserved ejection fraction changes in contractile proteins, regulating calcium cycling and vascular reactivity.

Dr. Greg Hundley:

These journal issues, there's so much information. I'm in a close out with an in depth piece from professor entitled antithrombotic therapy in patients undergoing transcatheter interventions for structural heart disease. I really look forward to your feature discussion on the social vulnerability and premature cardiovascular mortality in US countries.

Dr. Carolyn Lam:

Thanks Greg. It's good.

Dr. Carolyn Lam:

Today's feature discussion focuses on an extremely important topic of social vulnerability and premature cardiovascular mortality. So pleased to have the corresponding author of the feature paper, Dr. Khurram Nasir from Houston Methodist and Dr. Alana Morris, who is the editorialist for this paper. And she's joining us from Emory University in Atlanta, Georgia. So thank you both of you for joining and Alana if you don't mind, I'm going to borrow some of the words from your really-excellent editorial to bring us into the discussion. You very nicely brought up that early race and ethnic disparities and a death toll from COVID 19 really, laid the foundation for us having Frank conversations about vulnerable populations and has really brought to light social determinant of health and social economic inequality as risk factors. Now that's, COVID 19. And frankly, if we put everything in a global view of what kills most of us, it's still cardiovascular disease, which is why this paper is just so important, but current recognizing I'm not from the US, lots of our audience are not from the US. Could you please walk us through what your paper looked at and what it means?

Dr. Khurram Nasir:

Sure. Klan, thank you so much for having us today and what a wonderful editorial by Dr. Morris on this. As you pointed out about the COVID challenges, we were all touched by the significant disparities, really in a one of the lifetime crisis, such as COVID. But the reality is that even in times of calm the benefits, for example, cardiovascular disease prevention access have not been shared equally among vulnerable groups. So I'm a preventive cardiologist, and it gives me immense pride that despite being the number one cause of morbidity mortality for so long as a cardiology community, we have made significant strides over the last three decades, cutting into our losses. And if you look at the trends it's appeared and I'm very hopeful that we'll soon be losing the number one killer tag in US. At the same time we are seeing that those cuts are being lost, especially in the young individuals.

Dr. Khurram Nasir:

And at one point while we celebrate these decline. But the thing that bothers many of us that unfortunately these gains have not been equal, especially for our more vulnerable patients. And apart from the well documented, I think racial disparities that we all know and are becoming more aware. I think health disparities also form across various fourth lines and I believe the deepest and more persistent divides is around income. And you can even go a step further in US, unfortunately for our international group is unfortunate fact that in US, your zip code may hold more sway than your genetic code. And an example was made famous in St. Louis, Missouri Del marble award, which is known as the Delmer divide, a title that was made famous by a four minute BBC documentary that showed, that a sharp dividing line between the poor predominantly African American neighborhoods in the north and more affluent, largely white neighborhood in the south with health falling across this divide.

Dr. Khurram Nasir:

And in our practice, we see this phenomenon clearly in our own backyard. So, inspired by this sterling. We wanted to determine that a mirror geographical measure, where we can get insights of conditions where people live, learn, work, play, grow, and age, and commonly now known as the social determinants of health. Can that explain some of these rising risks, especially in the premature cardiovascular disease. So to design this study, we reached out to the CDC social vulnerable, the index that has been created that ranks communities and zip codes based on 15 factors across food domains, socioeconomic status, household composition of disability, that in includes single parents, elderly or children, minority status and language and housing type and transportation, all of them are put together and for each census. And then eventually at the county level, you can classify what their social vulnerability is. And as you know, this was really developed in to identify places where in times of disaster and emergencies, you can focus a little bit more, but we thought about how do we connect this to, for example, our data on mortality from CDC wonder.

Dr. Khurram Nasir:

And once we did that, we found very interesting patterns that across the scale social vulnerability, there is a risk dose dependent fashion and the age adjusted mortality rates for premature cardiovascular disease, which we define as less than 65, went from the least vulnerable and became the worst across the most vulnerable. At the same time, we also found this double jeopardy issues where this association was varied by race, gender, and ruler. And what we found that specifically Non-Hispanic lack individuals were more likely for certain types of cardiovascular, premature, such as stroke and heart failure, mortality, as compared to the rest, even if you were from the least vulnerable to the most women also unfortunately had a twofold higher risk of CBD mortality. And what is becoming clearly this whole ruler urban that a two to five fold risk of CBD mortality was seen among the least vulnerable. So this is in just the motive of our study, what we did and what we found.

Dr. Carolyn Lam:

That is so wonderful. Thank you for setting the context and then just to reiterate, so this was all within the US. Alana, could you maybe help frame how important these findings are for us?

Dr. Alana Morris:

Yes. I think that this analysis is so important, particularly within the context of some of the things that we see happening politically in our country and our landscape right now. And I think we tried to touch on some of those issues in the editorial. Again, I think that the COVID 19 pandemic, if you want to put that against this landscape has really brought into the forefront of our minds, this issue of disparities. Of course, there are many of us who have been thinking about researching and writing about disparities for a long time, but the issue of disparities really, came into the public mindset with the COVID 19 pandemic. The question now is how do we address these as we go forward? And what we're seeing politically is this question of how do we address inequalities that have been present for really since the beginning of time and maybe are widening and perhaps threaten many of the advances that we've made in terms of cardiovascular disease, morbidity, and mortality.

Dr. Alana Morris:

I think we have to think about in the US, universal healthcare coverage, because we have to be able to prevent disease and treat disease. And as current addressed, there are neighborhood zip codes where people not only don't have access to healthcare, but they don't even have access to the ability to promote health. They don't have access to things like parks, where they can exercise. They don't have access to healthy foods or grocery stores and in a country like the United States where there's so much wealth, you need to think about the fact that certain individuals, don't have the ability to access a grocery store, to access healthy food. It's just really striking and mind boggling that we have this, the difference in rural versus urban locations where some of our US residents, unfortunately don't have access to primary care clinicians, certainly not specialty clinicians is really very mind boggling. And we've seen this play out with the pandemic, but hopefully once we get past the COVID 19 pandemic, we still have to come back to a place where again, we're taking care of not only preventives or services to prevent the onset of cardiovascular disease, but certainly once people are diagnosed with cardiovascular disease, we want to get them access to specialty care. So we have to think as a community, how do we prevent disease, but also treat disease once disease is diagnosed within our country.

 

Dr. Carolyn Lam:

What you just said about the zip code being more powerful about, than the genetic code, that's like a quotable code. It's incredible. And for those of us coming outside of the US, we don't even realize how much that plays a role, even just within the US. But now let's get to exact point that Alana pointed out, which is what are the next steps. And could you maybe suggest Khurram, and Alana maybe come first, but what's the one thing you want to get out or the one next thing that should happen after this

Dr. Alanna Morris:

We put a figure in to the editorial that I think really gets to the heart of the matter, I think that those of us who are in healthcare or those of us who think about public health really would ask the question of, why in a country that has as much wealth as the United States, do we not have universal healthcare, most countries across the world that are in an economic position similar to the United States do have universal healthcare coverage for their residents. And you see much better statistics in terms of longevity for their residents as compared to what we have in the United States. And what you see when you look at the United States is that where there is the most vulnerable residents as per analysis identifies those states are the ones that actually don't have, Medicaid expansion.

Dr. Alanna Morris:

They don't have a safety net for their residents. And so there's really contrast and this disparity that just does not make sense. It does not make sense where there are residents in the United States, which need the most help and they just don't have it. They just are not able to get access to preventive services as well as diagnostic services. And it really just doesn't make sense what we're doing in the United States, in my humble opinion. And I think in the humble opinion of many of us who want to take care of patients, but just cannot, Kern and I both practice in states where this is an issue. And I think that's one big driver. But again, I think when we also think about the built environment in the US and how we think about promoting health and how we talk to patients, when we talk about individuals in the US, we try to give them advice about therapeutic lifestyle changes, how to exercise, how to eat healthy, to prevent disease. That's easier for certain individuals as compared to others, depending upon where you live, depending upon those five digits that make up your zip code. So if we really want our residents to be healthy, we have to create an environment that enables them to do that.

Dr. Carolyn Lam:

Wow, thank you very much. And as I let Khurram have the final words even about where you think mixed research should be. I just want to highlight that incredible figure from your editorial Alana. I mean, it is really started, there are three panels to it, everyone. The first one chose the social vulnerability index, the second, the premature cardiovascular disease mortality, and then the third, the status of Medicaid expansion. And you can see the colors are just vivid in, how it all makes sense and goes together. So pick up our journal and have a look, but then finally Khurram?

Dr. Khurram Nasir:

So, Alana, your figure was fantastic and so much add perspective to our findings. As you were saying, it took me back to 35 years back when, where we are before Medicare disparities, even in access to hospitals were dramatic. So where we practice in the south one third of the hospitals would not admit African Americans even for emergency. Now, this is where the policy comes in and suddenly in 1965 using the carrot of Medicare dollars, the federal government virtually ended the practice of racially segregating patients, doctors, and medical staffs, blood supplies so that is the direction that we need to go from the policy perspective and trying to affect the upstream determinants. Now moving forward, as I think more, and especially as a physician, I think while the census level measures are extremely useful to help refine these policy and focus programs in vulnerable areas.

Dr. Khurram Nasir:

I also think that there is a parallel need to start focusing on similar efforts at the individual level. The first thing is how do we even identify social determinants at this patient level? Are there three main categories, income, education, possibly healthcare, but I think that we need to broaden this. And in the past we have been challenged because we didn't have a set of consensus of the defined SDUH framework. But thankfully now in 2021, we have the healthy people, 2020. Actually for international community, the WHO there is a WHO framework of identifying SDOH at an individual level and in US a more comprehensive Kaiser family foundation. And not only that, we looked at superficially broadly, but we have to go deeper beyond these components of economic instability, education, housing, social context on healthcare beyond insurance, and even food.

Dr. Khurram Nasir:

For example, income and employment are predominant pillars of income stability, but it may not capture the full picture. For example, difficulty paying bills out of pocket cost and death related to medical care, same in education, where we captured the highest degree, but issues around health and digital literacy and language proficiency may be even more important. So not only we have to broaden the scope, but we have to go in depth. And thirdly, what I've realized from these kind of studies that we have to go a step further, that social disparities don't occur in silos. And we have to look at the aggregated information. And maybe it's time to potentially learn from advances in genetics, in what we have learned that manifestation of disease, especially cardio metabolic rather than being influenced by few major genes is manifested secondary to multiple interacting genes. So can we create similar to a poly genetic risk score, which is an aggregation of genetic smaller risk to a relevant something similar called poly social risk score.

Dr. Khurram Nasir:

Now, this is an area that our group has been extensively working. And over the last 12 months, we have tried to construct a comprehensive poly social risk score at an individual level based on almost about 50 sub components of the social determinants. And we have suddenly finding very interesting associations with premature CAD stroke. Almost one in two young individuals with stroke, have the worst poly social risk code at the individual level. I think so the next steps will be definitely validation of this tool, incorporation in practice, whether it's adoption and effective interventions can be tied. But the final thing, what I truly want to say is that I'm hopeful that these efforts, the census level at an individual level, at a societal level and the health system are waking up to the importance of social determinants that we can think outside the box and have strong community partnerships. Multi Pro strategies driven largely by social economic environmental factors. So we can all make a lead towards the mission of achieving social justice and equity that eventually cascades through the health system and beyond. So we had enough time to illuminate the issues and challenges. Now it's the time to act.

Dr. Carolyn Lam:

Thank you so much Kern for a beautiful paper. We are so proud to be publishing it in circulation. And thank you, Alana lovely, editor that we've said so many times. Thank you audience for joining us today. You've been listening to Circulation on the Run from Greg and I please tune in again. Next week,

Dr. Greg Hundley:

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.