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.