Circulation March 9, 2021 Issue

This week features two Feature Discussions. In our first feature
discussion, Nikkil Sudharsanan and Associate Editor Ntobeko Ntusi
as they discuss the article "Variation in the Proportion of
Adults in Need of BP-Lowering Medications by Hypertension Care
Guideline in Low- and Middle-Income Countries: A Cross-Sectional
Study of 1,037,215 Individuals from 50 Nationally Representative
Surveys." Then in our second feature discussion, join author
Aloke Finn and Associate Editor Jeffrey Saffitz as they discuss
the article "Microthrombi As A Major Cause of Cardiac Injury in
COVID-19: A Pathologic Study."


One addendum to the Feature Discussion with Drs. Sudharsanan and
Ntusi:


·       Dr. Sudharsanan wanted to
clarify that treatment needs were determined for each
country based on multiple blood pressure measurements taken
on the day of the survey; however, all the estimates were based
on BP measured on just one day, rather than over several weeks as
is done in clinical practice. This is related the final question
posed in the first Feature Discussion.


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 Dr. Carolyn Lam, Associate Editor from the National
Heart Center and Duke National University of Singapore.


Dr. Greg Hundley:


And I'm Greg Hundley Associate Editor for the Pauley Heart Center
in Richmond, Virginia at VCU Health.


Dr. Carolyn Lam:


Guess what, Greg, it's another issue with a double feature. We
are going to be discussing microthrombi as a major cause of
cardiac injury in COVID-19.


Dr. Greg Hundley:


Yes, Carolyn and our second discussion will be centered on blood
pressure lowering in low and middle-income countries. But how
about you and I both grab a cup of coffee and jump into the other
articles in this issue.


Dr. Carolyn Lam:


Sure thing. I got my coffee and let's start with gestational
diabetes. Now, we know that leads to an earlier onset and
heightened risk of type 2 diabetes, which is a strong risk factor
for cardiovascular disease. But Greg, do you think that attaining
normal glycemia following gestational diabetes can ameliorate the
access risk?


Dr. Greg Hundley:


Carolyn, that's a really great question. I would think so but how
about you tell me what these authors found.


Dr. Carolyn Lam:


Yep. This next paper it's from Dr. Gunderson from Kaiser
Permanente, North California and colleagues. They exactly sought
to answer the question and realize that it was unclear whether
attaining normal glycemia can ameliorate the excess
cardiovascular disease risk that's associated with gestational
diabetes. So they evaluated gestational diabetes history and
glucose tolerance after pregnancy and found out whether or not it
was associated with coronary artery calcification in women. The
obtained data from the CARDIA study which is a US multicenter
community-based perspective cord of young black and white adults
age 18 to 30 years at baseline.


Dr. Carolyn Lam:


This is what they found. Women without previous gestational
diabetes showed a greater increase in the risk of coronary artery
calcification associated with worsening glucose tolerance.
However, women with a history of gestational diabetes had a
twofold higher risk of coronary artery calcification across all
subsequent levels of glucose tolerance. Midlife atherosclerotic
cardiovascular disease risk among women with previous gestational
diabetes is therefore not diminished by attaining normal
glycemia. And this is discussed in an accompanying editorial by
Dr. Jennifer Green from DCRI entitled Cardiovascular Consequences
of Gestational Diabetes.


Dr. Greg Hundley:


Carolyn, well, sounds like I was wrong but our next paper, it's
going to review for us a little bit about IgE. Remember that
immunoglobulin associated with itching. So Carolyn immunoglobulin
E or IgE belongs to a class of immunoglobulins involved in immune
response to specific allergens. However, the roles of IgE and IgE
receptor in pathological cardiac remodeling and heart failure or
a non. So in this study, the investigative team measured serum
IgE levels and cardiac IgE receptor expression in diseased hearts
from humans and mice.


Dr. Carolyn Lam:


Oh, Greg, I'm itching to find out what this study showed.


Dr. Greg Hundley:


Yes, Carolyn, going from the quizmaster now to is it comedy now?
Serum IgE levels were significantly elevated in patients with
heart failure as well as in two mouse cardiac disease models
induced by chronic pressure overload via transverse aortic
constriction and chronic angiotensin two infusion. Now,
interestingly Carolyn, IgE receptor expression levels were also
significantly up-regulated and failing hearts from human and the
mouse model.


Dr. Greg Hundley:


Carolyn, the authors found that IgE induction plays a causative
role in pathological cardiac remodeling at least partially via
the activation of IgE receptor signaling in cardiac myocytes and
cardiac fibroblasts. So future studies are needed to determine if
therapeutic strategies targeting the IgE receptor axis and as to
whether they may be effective for managing IgE mediated cardiac
remodeling.


Dr. Carolyn Lam:


Fascinating. I never thought of IgE involved in cardiac
remodeling. Now, this next paper really interesting. Regulators
are always evaluating the use of non-interventional real-world
evidence studies to assess the effectiveness of medical products.
The RCT DUPLICATE Initiative was formed to use a structured
process to design real-world evidence studies to emulate
randomized control trials and compare results. Now, this paper
represents the first 10 trials emulations in RCT DUPLICATE, and
it's from Dr. Jessica Franklin from Brigham and Women's Hospital
and Harvard Medical School in Boston and her colleagues. And they
did this to evaluate cardiovascular outcomes of antidiabetic and
antiplatelet medications.


Dr. Greg Hundley:


Wow, Carolyn. So how does they do this?


Dr. Carolyn Lam:


So they use patient level claims data from US Commercial and
Medicare-PEERS and implemented inclusion exclusion criteria of
the trial selected primary endpoints and compare the populations
to emulate those of each of the corresponding randomized
controlled trials within the trial mimicking populations, they
then conducted propensity score matching to control for more than
120 pre-exposure con founders.


Dr. Greg Hundley:


So Carolyn, were they able to emulate their randomized clinical
trial results?


Dr. Carolyn Lam:


Now, despite the attempts to emulate the trial design as close as
possible, there were still differences between the randomized
control trial and the corresponding real-world evidence study
population. The regulatory conclusions were equivalent in six of
10 studies. The real-world evidence emulations achieved a hazards
ratio estimate that was within the 95% confidence interval from
the corresponding trial in 8 of 10 studies. Agreement between the
trial and real-world evidence findings varied depending on which
agreement metric was used.


Dr. Carolyn Lam:


Interim findings indicated that selection of active comparative
therapies with similar indications and use patterns enhance the
validity of the real-world evidence. And so, even in the context
of active comparators concordance between trial and real-world
evidence findings was not guaranteed partially because trials
were not emulated exactly. More trial emulations are needed to
understand how often and in what context real-world evidence
findings will match the trials. And yet these initial findings of
RCT DUPLICATE really indicate circumstances when real-world
evidence may offer causal insights where trial data is either not
available or cannot be quickly or feasibly generated


Dr. Greg Hundley:


Well, Carolyn, that is really interesting findings there because
we're all trying to decide what to do with these large data sets
and combining the results of millions and millions of data points
and very interesting findings in this study. How about we see
what else is in the issue?


Dr. Carolyn Lam:


Absolutely. Well, let me start. There's an exchange of letters
among doctors Villarreal, Cárdenas Suri, [and]
Navarro-Castellanos regarding the Multi-system inflammatory
syndrome in children. The ECMO needs and Kawasaki disease
likeness. There's also an ECG challenge by Dr. Pillai entitled "A
Tale of Two Blocks".


Dr. Greg Hundley:


Well, Carolyn, I've got a very nice In-Depth review from Dr. Van
Belle regarding transcatheter aortic valve replacement in
bicuspid aortic valve stenosis. And there's a Research Letter
from Dr. Lew entitled “Short-Chain Enoyl-CoA Hydratase Mediates
Histone Crotonylation and Contributes to Cardiac Homeostasis.”
And then finally, Dr. Nordin Hanson from Amsterdam has a very
nice piece on the Clinical Implications of Basic Science Research
entitled “DAMPening Mortality in COVID19: Therapeutic Insights
from Basic Cardiometabolic Studies on S100A8/A9.” Well, Carolyn,
how about we check out the double feature.


Dr. Carolyn Lam:


Definitely let's go, Greg.


Dr. Greg Hundley:


Well listeners, we are here for our first feature discussion on
this March 9th issue and we have with us Nikkil Sudharsanan from
Heidelberg and also our own Associate Editor Ntobeko Ntusi from
Cape Town. Welcome gentlemen. Nikkil, could you please describe
for us the hypothesis that you wanted to test your study
population and your study design?


Dr. Nikkil Sudharsanan:


Yeah, so for our hypothesis, we really wanted to know, depending
on which hypertension treatment guideline you chose, what
implications does it have at the population level for the number
of people in low and middle-income countries that would require
treatment or that you would want to place on treatment. And we
were really looking at not just one country, but a whole range of
50 low and middle-income countries. And so our study population
is actually from this pretty remarkable data source that combines
the World Health Organization surveillance data for many
countries with other sources of data, to try to create a
comparable almost low and middle-income country super dataset
that's specifically designed to answer questions around
cardiovascular disease. So our study population was really based
on population representative samples for each of the 50 countries
we considered. And in most of the countries we focused on the
adult population. So those ages 30 and above.


Dr. Greg Hundley:


And your total sample was over a million participants, correct?


Dr. Nikkil Sudharsanan:


Yeah, it's a really huge sample. And I think it's a testing to
some of these data sources, especially the ones in India and
Brazil, but collected just really large sample sizes that
contributed to this huge global population.


Dr. Greg Hundley:


Very nice Nikkil. And what did you find?


Dr. Nikkil Sudharsanan:


So the big finding is we actually went into it not knowing how
the choice or how strong the choice of a blood pressure treatment
guideline would be on the number of people that required
treatment and were really surprised to see that we took more
treatment guidelines, the 2018 American College of Cardiology,
American Heart Association guidelines, the kind of typical 140 by
90 blood systolic diastolic blood pressure threshold that you see
as part of a lot of guidelines. The UKs NICE guideline and then
the WHO Hearts guideline, which is based on their pen and package
of essential non-communicable disease interventions.


Dr. Nikkil Sudharsanan:


And we started a really, really pronounced difference in the
proportion and size of the adult population that you would
recommend or place under hypertension treatment, depending on
which of these guidelines used to decide who gets treatment
across these countries. So at the top, we found the American
College of Cardiology, American Heart Association guidelines, and
for the countries we were considering it put about 27% of women
and a really high 35% of men as recommended for blood pressure
treatment.


Dr. Nikkil Sudharsanan:


And then very closely followed to that was the 140, 90 threshold.
So it was still high, but not as high, I would think it was
around 26% of women and 31%. And then between these two
guidelines and the UK NICE and WHO Hearts, there was a really big
drop-off in how many people would actually be recommended for
blood pressure treatment.


Dr. Nikkil Sudharsanan:


The NICE guideline, for example, only have 12% of women and about
16% of men and the WHO Hearts is by far the lowest, which only
about 10% of women and 11% of men. So I think our first really
striking finding was that this choice is not trivial. And
depending on which guideline you actually choose to decide who
gets treatment in that country, it has really big implications
for how many people in that country are going to need treatment.


Dr. Greg Hundley:


Very good. And Ntobeko, how do you put the results of this study
in the context with other research perform to study hypertension?


Dr. Ntobeko Ntusi:


Thank you, Greg. So we know that although more than 80% of the
global battle of Cardiovascular Disease, okay. As in low and
middle-income countries, the data around respecters for
cardiovascular disease has largely come from high-income
countries. And the INTERHEART study was really the first
publication about 15 years ago to try and address this question.
And it was very apparent both in the INTERHEART study as well as
the INTERHEART Africa study of hypertension was one of the key
respecters not only for my myocardial infraction, but for
cardiovascular disease in general.


Dr. Ntobeko Ntusi:


In the INTERHEART study hypertension having a hazard ratio of two
and the population attributable risk of 17%. And then the
INTERHEART Africa study having a hazard ratio of over six. And
this paper is really an important application in my view, showing
that in a comparison of over a million individuals from 50
countries, there is great variation in the proportion of
individuals that need to be treated for hypertension, based on
the choice of guideline and definition of hypertension. And if
you look at figure one, this is variable from anywhere from 9% to
35%.


Dr. Ntobeko Ntusi:


The other important contribution of this paper is that the
proportion of the population that needs to be treated for
hypertension increases with age, which is something that we know
but strikingly more than 60% in those over the age of 60 years.
And for me, they are really great core key messages that I think
are important contributions from this publication. The first one
being that the choice of hypertension treatment guideline
significantly influences the denominator of what you consider to
be hypertensives in your population. The second one is that many
people in low and middle-income countries are still unaware of
their status of elevated blood pressure and the need for
treatment. And I think this is a key point to emphasize.


Dr. Ntobeko Ntusi:


The third important message is that these first two points I've
made have got huge implications for the scale-up costs and
healthcare system capacity and that countries need to choose
definitions for diseases. And this needs to be aligned with
national health policy as well as available resources. And then
finally, a key part of the discussion, which I asked the author
to address was really around our understanding of the barriers to
optimal management of blood pressure in low and middle-income
countries and how these gaps can be oppressed. And they speak to
the economic and human resources, the health policy, the
importance of population screening and importantly education at
every level.


Dr. Greg Hundley:


Very good. Nikkil I'd like to come back to you and then maybe 20
seconds or so, what do you think is the next study that needs to
be performed really in this area of research?


Dr. Nikkil Sudharsanan:


I think there may be two, one is to really build on this in terms
of what we showed this is the proportion of people that would
require treatment and that's how it varies across these
guidelines. I think it's important to also tie that to the
resource implications directly, like Dr.Ntusi said, to actually
show this guideline would require this many resources versus this
many for that guideline. I think that will really help countries
in deciding what's actually feasible guideline to implement.


Dr. Nikkil Sudharsanan:


And the second one, which is I think a much more challenging
study to do is just a study of all these guidelines are based on
mostly data from high-income countries. And even among these high
income countries, there's these discussions on what the
appropriate level for treatment is and what point you should
initiate treatment. And it seems like this really has not been
done with low and middle-income country populations. So we're
arguing about four different guidelines that were built for
high-income country populations. And I think it would be really
important to see some sort of trial or long-term observational
study actually in terms of averting cardiovascular disease events
which guidelines actually makes the most sense for these
countries.


Dr. Greg Hundley:


Very good. Ntobeko, anything to add to that?


Dr. Ntobeko Ntusi:


I think I agree completely with Nkkil and I think this paper has
a number of really important strengths, and I think those
strengths and key contributions have to be taken in the context
of one significant limitation and how we interpret these results.
And that's the fact that when we normally see a patient in the
clinic to diagnose hypertension, we would take two or three blood
pressure measurements. In this study, they only took a single
blood pressure measurement and that's the basis for the
conclusions and for me a key limitation, but nonetheless, I think
a very important contribution.


Dr. Greg Hundley:


Very nice. Well listeners, we want to thank Nikkil Sudharsanan
from Heidelberg and Ntobeko Ntusi from Cape town for bringing us
this important study, indicating that worldwide there's
substantial variation really in the proportion of adults in need
a blood pressure lowering medication, depending on which
hypertension guideline is used. Well, let's move on now to our
second feature discussion.


 


Dr. Greg Hundley:


Listeners, we are now to our second feature discussion and we
have with us Dr. Aloke Finn from the Cardiovascular Path
Institute in Gaithersburg, Maryland and our content editor expert
for pathology, Dr. Jeff Saffitz from Beth Israel Deaconess.
Welcome gentlemen. Aloke, could you describe for us, what was the
question you wanted to address with this researching? What was
your study design and your study population?


Dr. Aloke Finn:


Great. Greg, thanks for your interest in our article and for
highlighting it. We were really interested in understanding what
the pathologic causes for cardiac injury were in people
hospitalized with COVID-19, as you know, it's been reported in
the literature that people with COVID-19 with cardiac injury do
worse than those without cardiac injury, but the mechanism is not
still well understood. So the study design was really based upon
a collaboration with a group from Italy in the Lombardy region,
where they had had a terrible outbreak in 2020, as you remember
in February. And they had a number of hospitalized. People die
from COVID-19 infection, and they too were interested in
understanding the pathologic causes of chronic injury. We got IRB
approval and those hearts were sent to us during the middle of
this pandemic in the February, March time. And we were able to
examine 40 of those hearts and report our pathologic findings.
And these were unselected cases of hospitalized patients dying of
COVID-19.


Dr. Greg Hundley:


That was great. And tell us a little bit what were your study
results?


Dr. Aloke Finn:


So we, first of all, did an analysis based upon the presence of
myocardial necrosis. So that was the sort of the selection
factor, which hearts had myocardial necrosis which parts didn't
have myocardial necrosis. We found that 35% of the hearts in this
40 cases had myocardial necrosis. Now, we divided those into the
type or pattern of myocardial necrosis. Was it acute myocardial
infarction? Was there a large area of infarction greater than one
centimeter squared or was there focal myocardial necrosis less
than one centimeter squared. It's small areas of focal myocardial
necrosis. We've found that most cases of patients dying of
COVID-19 with myocardial necrosis had focal myocyte necrosis. Not
large areas but small areas of myocyte necrosis. And we looked
for the cause of those necrosis, majority of those cases with
focal myocyte necrosis had microthrombi as the cause of that
necrosis. So that suggests the major mechanism of myocardial
injury in COVID-19 patients is microthrombi.


Dr. Greg Hundley:


Very nice. Well, Jeff, let's turn to you. How do we put the
results of this study in the context with perhaps other
pathologic studies that have been obtained from hearts of
individuals that succumb to COVID-19?


Dr. Jeffrey Saffitz:


It's a very important question. And I want to say that at the
outset, there have been many papers published focused on the
pathologic findings of COVID-19 patients who have come to
autopsy. And I have to say that the quality of these papers has
been quite variable. In many cases, the pathology being shown is
actually post-mortem artifact. In other cases, the interpretation
of the pathology is incorrect. And so I think we have to be very
careful in a study like this to make sure that what is being
reported is actually valid and meaningful in the context of the
important clinical questions being posed. And in this case, I can
say the pathology was really extremely impressive and very
convincing.


Dr. Jeffrey Saffitz:


Another important aspect of this study has to do with the
comparison of the composition of the microthrombi that were
identified in patients dying from COVID-19 versus patients who
have other types of coronary thrombosis, but in a different
setting. And here, there were some interesting observations that
provide insights, not only into mechanism of thrombosis, but also
potential information about how one might want to target
antithrombotic therapy in these patients. So I would really like
to hear more from Dr. Finn on this interesting aspect of this
study.


Dr. Aloke Finn:


Jeff, thanks for your comment and your question. I think I agree
with you, this was another interesting aspect of the study. What
was done was that were able to examine the constituents of
thrombi, different types of thrombi both in the setting of
patients who had COVID-19 and non COVID-19 STEMIs as well as
microvascular thrombi described in the COVID-19 patients, as well
as embolized thrombi that embolized a small microvascular within
the heart. And what we essentially found was that these thrombi,
that are COVID microthrombi are distinct in their constituents.
Distinct in that they had more fibrin and more compliment
activation than the other types of thrombi that we're studied. So
I do think this begins to unravel the question about how are
these thrombi forming and are they different from the type of
thrombi we normally treat? And the answer is, yes.


Dr. Greg Hundley:


Very nice, Aloke. What study do you think needs to be performed
next in this space? And after you, I'll ask Jeff the same
question.


Dr. Aloke Finn:


Greg, I would like to know whether or not therapies like
anticoagulant, anti-compliment, antiplatelet therapies can
decrease the risk or the effect of the COVID-19 on myocardial
injury. Is will we see a benefit to anticoagulant or
antithrombotic strategies in the study? I think that is the
natural next question to ask.


Dr. Greg Hundley:


Very nice. And Jeff, anything to add?


Dr. Jeffrey Saffitz:


Yeah, well, I'm an experimental pathologist, so I'm always
interested in disease mechanisms. And I would like to understand
more about how these microthrombi form, the role of endothelial
cell injury, the role of cytokine storm and other factors which
we know are contributing. I think in the end having a more
fundamental understanding of these mechanisms will provide
important insights, not only in trying to manage heart disease,
but in fact, other organ system disease, which is likely being
mediated by a similar mechanism in the kidney and potentially in
the brain and other organs as well. So I think this is a great
example about how autopsy can provide really critically important
information in a new human disease and set the stage for
subsequent studies that will really provide important dew
information.


Dr. Greg Hundley:


Excellent. Well listeners, we want to thank Dr. Aloke Finn from
Gaithersburg, Maryland, Dr. Jeff Savitz from Boston,
Massachusetts for this excellent discussion and revealing the
pathologic results of 40 hospitalized patients from Italy that
expired after COVID-19 highlighting the cause of myocardial
necrosis and how it was related to the presence of microthrombi.


Dr. Greg Hundley:


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.