Circulation June 16, 2020 Issue

Today’s episode discusses issues pertaining to the management of
ST-elevation myocardial infarction in low and middle-income
countries.


Dr Carolyn Lam and Dr Greg Hundley also discuss the following:


Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to
Severe Mitral Regurgitation by Sadek et al.
Autoantibody Signature in Cardiac Arrest by Li et al.
Cardiovascular Risk of Isolated Systolic or Diastolic
Hypertension in Young Adults by Kim et al.
TRANSCRIPT


Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly
podcast summary and backstage pass to The Journal and its
editors. I'm Dr Carolyn Lam, associate editor from the National
Heart Center and Duke National University of Singapore.


Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from
the Pauley Heart Center at VCU Health in Richmond, Virginia.
Well, Carolyn, our feature article this week is a little bit
different from what we've done in the past with original
manuscripts, we're going to focus on issues pertaining to the
management of ST-elevation myocardial infarction in low- and
middle-income countries. Oh my Carolyn, there's so many different
things to consider. There are knowledge gaps, how we manage
patients, how we get from one center to another, even just
defining those centers. And this could be a very nice blueprint
for future governments to use in managing these patients. But
before we get to that feature, how about we have a little bit of
a chat on some of the other articles in the issue?


Dr Carolyn Lam: You bet, Greg. Now, have you ever wondered why do
some but not all patients with severe aortic stenosis develop
otherwise unexplained reduced systolic function?


Dr Greg Hundley: Yes, I have Carolyn. And I wonder if it happens
to do with one of our favorite magnetic resonance spectroscopy
measurements, including creatine kinase.


Dr Carolyn Lam: You are just too smart, Greg Hundley!


Dr Greg Hundley: I had the opportunity to manage this one through
the whole editorial board review.


Dr Carolyn Lam: Well, Dr Ryder and colleagues from University of
Oxford hypothesized that reduce creatine kinase capacity and or
flux would be associated with the transition to reduce systolic
function in severe aortic stenosis. So they looked at 102
participants recruited into five groups. One, those with moderate
stenosis. Two, severe aortic stenosis with ejection fraction
above 55%. Three, severe aortic stenosis with ejection fraction
less than 55%. Four, healthy volunteers with non-hypertrophied
hearts with normal systolic function. And five, patients with
non-hypertrophied, non-pressure loaded hearts with normal
systolic function who are undergoing cardiac surgery and donating
left ventricular biopsies.


Now, all these groups underwent CMR, cardiac magnetic resonance
imaging, and 31 phosphorous magnetic resonance spectroscopy from
myocardial energetics. And they also had left ventricular
biopsies. So Greg, I know you know what they found, and so let me
lunge right into it. They found that total creatine kinase
capacity was reduced in severe aortic stenosis with median values
lowest in those with systolic failure, consistent with reduced
energy supply reserve.


Despite this, in vivo magnetic resonance spectroscopy measures of
resting creatine kinase flux suggested that ATP delivery was
reduced earlier at the moderate aortic stenosis stage, but where
left ventricular functions still remain preserved. These findings
thus suggest that significant energetic impairment is already
established in moderate aortic stenosis and a fall in creatine
kinase flux is not per se the cause of transition to systolic
failure. However, as ATP demands increase with aortic stenosis
severity, this could increase susceptibility to systolic failure.
As such, targeting creatine kinase capacity and our flux may be a
new therapeutic strategy to prevent or treat systolic failure in
aortic stenosis.


Dr Greg Hundley: Very nice, Carolyn. That is a very challenging
explanation. And boy, you walked us through it just perfectly.
And I'm so glad you're here as an expert in heart failure and
transplantation to get us through this next quiz. So Carolyn, can
you name several of the primary causes of heart transplant
related mortality?


Dr Carolyn Lam: All right. Rejection, infection, malignancy and
allograph vasculopathy, of course.


Dr Greg Hundley: Thank you very much, Carolyn. What a wonderful
job. So this paper comes from Dr Alexandra Loupy, and the study
focused on the etiology of transplant related vasculopathy, the
last one that you just named, from a population-based
perspective. So 1,310 heart transplant recipients from four
academic centers spread across Europe and the United States
underwent prospective protocol-based monitoring consisting of
repeated coronary angiographies together with systematic
assessments of clinical histological and immunological
parameters. The main outcome was prediction for cardiac allograph
vasculopathy trajectory.


Dr Carolyn Lam: Interesting. So what did they find?


Dr Greg Hundley: So Carolyn, over a median follow-up
post-transplant of about six and a half years, 4,710 coronary
angiograms were analyzed, and four distinct profiles for
allograph vasculopathy trajectories were observed. These four
trajectories were characterized by one, patients without
allograph vasculopathy at one year and non-progression over time.
And that was about 56% of the patients. Second, patients without
allograph vasculopathy at one year and late onset slow allograph
vasculopathy progression. And that was about seven and a half
percent of patients. Third, patients with mild allograph
vasculopathy at one year and mild progression over time. And that
was about 23% of patients. And finally, a fourth category,
patients with mild allograph vasculopathy at one year and
accelerated progression. And that was about 13% of patients.


Dr Carolyn Lam: Huh? So what most predictive?


Dr Greg Hundley: Well Carolyn, six early independent predictors
of these trajectories were identified. One, donor age. Second,
donor male gender. Third, if the donor used tobacco. Fourth,
recipient dyslipidemia. Fifth, class two anti-HLA donor-specific
antibodies. And finally, acute cellular rejection greater than
2R. The four allograft trajectories manifested consistently in
the US independent cohort with similar discrimination, and in
different clinical scenarios, and showed gradients for all caused
mortality.


Dr Carolyn Lam: Wow. Okay. So what's the take home message, Greg?


Dr Greg Hundley: Well, because this study identified these four
trajectories and their respective independent predictive
variables, they provide the basis for a trajectory-base
assessment of heart transplant patients for early risk
stratification. And therefore, we might be able to develop
monitoring strategies and form clinical trials around those to
determine the efficacy of perhaps these predictive models.


Dr Carolyn Lam: Thanks. Okay. Well, this next paper focuses on
Tet-methylcytosine dioxygenase 2, or TET2.


Dr Greg Hundley: Carolyn, what is that?


Dr Carolyn Lam: Well, I'm glad you asked me before I asked you.
So TET2 is a key enzyme in DNA demethylation. And the gene TET2
encodes an epigenetic regulator that demethylates cytosine.
Somatic mutations of TET2 occur in cardiovascular disease and are
associated with clonal hematopoiesis inflammation and at first
vascular remodeling.


The current paper by Dr Archer from Queens University Kingston in
Ontario, Canada, and colleagues, is novel because it's the first
to examine the role of TET2 in pulmonary arterial hypertension.
And they did this by evaluating exome sequencing data from the
largest PAH cohort assembled to date, including 2,572 patients in
the PAH Biobank. Unlike prior genetic studies, the biobank
includes patients with associated PAH. Now, this is important.
This is the category that includes patients with connective
tissue disease such as scleroderma. This biobank also included
non-European ancestry. So these are the novel aspects.


The authors performed gene-specific rare variant association
analyses using up to 1,832 cases of European origin from the PAH
Biobank, and transcriptomic analysis in an independent cohort to
assess TET2 expression.


Dr Greg Hundley: Carolyn, so what did they find regarding to
TET2?


Dr Carolyn Lam: In the entire cohort, they identified 12
predicted deleterious variants of TET2 novel to PAH. 75%
predicted germline and 25% predicted somatic variants. None of
the variant carriers were responsive to acute vasodilator
challenge. Now, this is the first time that putative germline
TET2 mutations have been associated with a human disease. They
also identify ubiquitous downregulation of the expression of TET2
in the peripheral blood mononuclear cells of idiopathic PAH and
associated PAH patients.


Finally, they evaluated TET2 depleted mice and demonstrated that
they spontaneously developed inflammation, pulmonary vascular
obliteration and pulmonary hypertension, thus providing
biological plausibility that disorders in this pathway can indeed
cause PAH. This is discussed in an editorial by Dr Soubrier from
INSERM, entitled, TET2: A Bridge Between DNA Methylation and
Vascular Inflammation.


Dr Greg Hundley: Oh wow, Carolyn. Well, let me tell you about a
couple other articles in our issue. First, Dr Amr Abbas has a
letter to the editor regarding actuarial versus echocardiographic
outcomes following TAVR, evaluating gradients, leaks, areas and
mortality with responses by Flavin Vincent and from Laurent
Fauchier. We have Dr Miguel A. Arias again presenting another EKG
challenge for us. Next, professor Giovanni Esposito has a
research letter involving PCI rates for ACS during this COVID-19
pandemic. Next, Dan Roden from Vanderbilt has a consensus report
related to QTC prolongation during the coronavirus pandemic. And
finally, professor Marco Roffi has an on my mind piece related to
STEMI and COVID-19 pandemics.


Dr Carolyn Lam: Oh, there is a series of on my mind papers in
this week's issue. “The Future of Cardiovascular Prevention:
Unprecedented Times,” by Laurence Sperling. “Primary and
Secondary Prevention Of Cardiovascular Disease in the Era of
Coronavirus Pandemic,” by Erin Michos. “Reperfusion of STEMI in
the COVID-19 Era: Is it Business as Usual?” by Dharam Kumbhani.


And finally, we also have a research letter by Dr Lili Jong,
addressing immune checkpoint inhibitors which are increasingly
applied to a broader range of cancers and their potential
toxicity causing myocarditis. And this letter describes the
association of timing and dose of cortical steroids in immune
checkpoint inhibitor associated myocarditis and cardiac outcomes.


Dr Greg Hundley: How about we discuss how we might want to manage
ST-elevation myocardial infarctions in low- and middle-income
countries?


Dr Carolyn Lam: You bet. Let's go, Greg.


Dr Greg Hundley: Well listeners, now we get to turn to our
feature article. And we're very privileged today to have Dr
Chandrashekhar from The University of Minnesota. And he and a
large group of authors have put together a paper discussing the
resources and infrastructure really necessary to manage
ST-elevation myocardial infarction in low- and middle-income
countries. Welcome Chandra. So we're going to call him Chandra
for short as he is known internationally. Chandra, can you tell
us a little bit about this prevalence of STEMI in low- and
middle-income countries, and then also about the constitution of
your writing group and what you were trying to do to address this
issue?


Dr Chandrashekhar: The issue we are trying to address is, as you
know, the low- and middle-income countries, there are about 80
plus countries constituting this group, and they account for
something like 5.8 billion people around the world. And it's so
interesting that 80% of the MIs that happen on the face of this
earth are probably happening there, in areas which don't have
resources to effectively deal with this condition, unlike the US
or European countries and developed countries.


So this group got together to create some outlines of how to
optimize care in low- and middle-income countries. And we got
together groups which have extensive experience in dealing with
this problem. It was a coalition of frontline clinicians as well
as major organizations, including the Indian Council of Medical
Research, the premier research body in India, a public health
foundation of India which is a nongovernmental organization
extensively involved in this, The Population Health Research
Institute in Canada, the Latin America Telemedicine Infarct
Network called LATIN, The Pan African Society of Cardiology and
The South African Society of Cardiac Interventions, and an NGO in
India called STEMI India. So we took experienced people from a
number of different countries and created this group.


Dr Greg Hundley: Very good. Now, were there knowledge gaps or
implementation gaps, maybe help distinguish those two terms for
us, that you had to address when just starting your effort?


Dr Chandrashekhar: Yeah, absolutely. So let's start with the
knowledge gap. As you know, there are excellent guidelines both
in the United States, as well as Europe. Of course, there are
STEMI guidelines in the UK and Australia and New Zealand, but
these guidelines are not very applicable to low and middle income
countries due to a number of reasons, due to porosity of
resources, due to poverty, overcrowding, lack of infrastructure,
and a bunch of other reasons that you can imagine.


So if we recommend somebody needs total balloon time under
certain threshold, it's nearly impossible to meet this in most
places in the low- and middle-income countries. And so there is a
significant amount of implementation gap as well as knowledge
gap, because the guidelines that are tailored to Western
societies don't fit very easily in low- and middle-income
countries. It's like fitting a round peg in a square hole.


So that's why we thought we should create something very focused,
right? And there are implementation gaps in the sense
infrastructure-based as well as resource-based. And knowledge
gaps, for example, we don't know what the dose of dual
antiplatelet therapy is optimal in these patients, for example,
ticagrelor may have a higher effect in some Asian populations
with small body habitus.


Similarly, as you know, statin doses, especially in the far east
are much lower than what are prescribed here. So these are the
kinds of challenges that we are applying and try to suggest some
solutions.


Dr Greg Hundley: It sounds like definitions could differ,
management strategies could differ, pharmacologic versus
invasive, even centers that would manage the patients. Can you
describe some of those issues for us?


Dr Chandrashekhar: Right. So that was the biggest challenge we
had. So we had to create some resource infrastructure appropriate
management paradigms for low- and middle-income countries. To
give you an example, primary PCI, which is something we take for
granted within our milieu, if you think about it, you and I
probably didn't give thrombolytic therapy in the last 15 years.
So this is a day-to-day thing in low- and middle-income
countries. Most of the patients either they come so late that
they don't get any reperfusion therapy for STEMI, or if they do,
thrombolytic therapy is are very common mode of treatment there.


And so we had to create a way for them to get the optimized care.
And so we divided the localities into different levels, from
level one to level five. Level one being the most remote area and
five being the one which is most equipped and can implement all
the Western standards and guidelines.


And so we suggest a system of hub and spoke to transfer people
from the smaller centers to the big centers, and outline what
therapies need to be done at what stage. And one of the things
that we emphasize so much is called pharmaco-invasive therapy,
where you give thrombolytic therapy if you cannot reach a PCI
center in time, and then in the next three to 24 hours, you
transport the patient to a center where they can do PCI. And this
has been studied in a number of trials showing that it's a very
effective strategy. And so these are the kinds of solutions that
we try to emphasize.


Dr Greg Hundley: And how about the patients themselves and the
doctors that would implement, in terms of education, does your
document cover how to reach out to both patients and physicians
in these countries to emphasize these new protocols that you and
your group have developed?


Dr Chandrashekhar: Absolutely. That's the crucial issue, right?
No matter how many guidelines we create, if we can't implement
it, they're useless, right? And so we have two parts to this
guideline. There's a section devoted to governmental agencies as
well as NGOs interested in improving care, STEMI care in low and
middle income countries, as well as a section for frontline
clinicians, which includes very focused flashcards with
definitions and what exactly each level of this center in the hub
and spoke model should be doing and how do they transport
patients and how do they ensure that adequate pharmacotherapy is
instituted? And so we keep repeating this and we also provide
some other options of how to communicate with the hub facilities,
from the spoke facilities, including use of mobile and social
media apps like WhatsApp.


Dr Greg Hundley: Do you have certain recommendations that
physicians in the field and patients at home should be aware of,
for example, administration of aspirin and things like that?


Dr Chandrashekhar: Absolutely. These are all codified in
flashcards, which are going to be printed for distribution to the
frontline physicians. And they are also created as wall posters
and plastered in this peripheral health centers where essentially
the only thing they may have is an old EKG machine and a few
drugs like aspirin. And so we have tried to cater to each of
this, both in the informational material and what basic
pharmacotherapies and equipment these centers should be having.
And that's where the governmental part comes. So when governments
have to decide how they invest their scarce dollars, they can
divide it appropriately based on these recommendations.


Dr Greg Hundley: I like that last statement, it sounds like in
addition to physicians and patients that your document may even
be useful for governments and organizations delivering the care
in these countries, do you want to talk a little bit about where
you think this document may go next in that regard?


Dr Chandrashekhar: The best use of this document would be for
agencies in different parts of the countries to take this up. And
at the last count, there are at least five or six governments
which are actively looking at the blueprint that is provided from
this document, and to see what parts of this are locally
implementable within their environment. And eventually, if it
appears that it's applicable to multiple jurisdictions, then
perhaps something like WHO could take this and modify it suitably
for different localities. We see a lot of potential in this.


Dr Greg Hundley: Well, we are very privileged to have the
opportunity to publish this important work. And I wonder here,
just in closing, on behalf of your entire author group, are there
any words you'd like to leave us with regarding this just
monumental effort?


Dr Chandrashekhar: The thing that we can say is we should thank
Circulation and its editorial board for working with us. It went
through, I think, three revisions and it really made the document
much better. And we really thank all of you for allowing us this
platform. As you know, this is going to reach a huge part of the
medical establishment as an open access article. And hopefully it
will help us implement some progressive changes in healthcare in
the low- and middle-income countries. And so we really thank
Circulation for providing us this platform.


Dr Greg Hundley: Well, listeners, we're going to wrap up here and
we're most appreciative to Chandra from The University of
Minnesota and his entire author group. On behalf of Carolyn and
myself, we wish you a great week and look forward to chatting
with you next week. This program is copyright to The American
Heart Association, 2020.