Circulation October 20, 2020 Issue

This week's episode includes author Daniel Lackland and Associate
Editor Mercedes Carnethon as they discuss the article "Forty-year
Shifting Distribution of Systolic Blood Pressure with Population
Hypertension Treatment and Control."


TRANSCRIPT BELOW



Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly
podcast summary and backstage pass to the journal and it's
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 Greg Hundley associate editor, Director
of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Well, Carolyn, this week's feature is good news. What do I mean
by good news? It's going to be a tale of how hypertension has
evolved in the Southeastern United States. And it's going to
review how that's progressed its treatment efficacy in both those
of white, and men and women of black race. But before we get to
that, how about we grab a cup of coffee and jump into some of the
other articles in this issue.



Dr Carolyn Lam: Man, you got my attention, Greg. You definitely
got my attention.



Dr Greg Hundley: Very good. Well, Carolyn, my first paper is from
the world of basic science, and it's from Dr Maya Kumar from
Stanford University School of Medicine. This group maps the step
wise remodeling of pulmonary arteries in a robust chronic
inflammatory mouse model of pulmonary hypertension. A model that
demonstrates pathologic features of human disease, including
right ventricular pressures, medial thickening, neointimal lesion
formation, elastin breakdown, increased anastomosis within the
bronchial circulation and perivascular inflammation, all of those
combined. And the author sought to define the cell behaviors
underlying each stage of vascular remodeling, and identified a
pathway required for neointima formation with the premise being
that this understanding could be pivotal in modulating
progression of disease in pulmonary hypertension.



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



Dr Greg Hundley: Well, Carolyn, they found surprisingly. The
neointima arises from smooth muscle cells and not the
endothelium. Medial smooth muscle cells proliferate broadly too
thick in the media, after which a small number of smooth muscle
cells are selected to establish the neointima. These neointimal
founder cells subsequently undergo massive clonal expansion to
form occlusive neointimal lesions. The normal pulmonary artery
smooth muscle cell population is heterogeneous, and the authors
identify a Notch3-marked minority subset of smooth muscle cells
as the major neointimal cell of origin. Notch signaling is
specifically required for the selection of neointimal founder
cells, and Notch inhibition significantly improves pulmonary
artery pressure in animals with pulmonary hypertension, thus
perhaps providing a new mechanism from which to test therapies to
thwart the progression of disease in those with pulmonary
hypertension. Very interesting basic science work.



Dr Carolyn Lam: Yeah. And very important too. Thanks Greg. Well,
I've gotten another basic science paper too. First, let me ask
you, do you think of DNA methylation much?



Dr Greg Hundley: We hear a lot about that, Carolyn. Methylation
and changing DNA and how it might be transcribed. Tell us more.



Dr Carolyn Lam: DNA methylation is indeed a mechanism of gene
transcription regulation. It's recently gained a lot of attention
as a possible therapeutic target in cardiac hypertrophy and heart
failure. However, its exact role in cardiomyocytes remains
controversial. Thus, the authors Dr Stenzig from University
Medical Center, Hamburg-Eppendorf and colleagues knocked out the
main de novo DNA methyltransferase in cardiomyocytes. Also,
called DNMT3A in human induced pluripotent stem cells. They then
assess the functional consequences of DNA methylation deficiency
under control and stress conditions in human engineered heart
tissue from these knockout derived cardiomyocytes.



Dr Greg Hundley: Wow, Carolyn. So what did they find here?



Dr Carolyn Lam: Three main consequences of DNMT3A knockout.
Number one, there were gene expression changes of contractile
proteins, such as higher atrial gene expression. Number two,
there was ever an activation of the glucose lipid metabolic
regulator PPAR gamma, which was associated with accumulation of
lipid vacuoles in these knockout cardiomyocytes. And number
three, HIF-1 alpha protein instability occurred, which was
associated with impaired glucose metabolism and lower glycolytic
enzyme expression rendering the knockout engineered heart tissues
sensitive to metabolic stress such as serum withdrawal and
restrictive feeding. So in conclusion, these results suggest an
important role of DNA methylation in the normal homeostasis of
cardiomyocytes and during cardiac stress, which could make it an
interesting target for cardiac therapy.



Dr Greg Hundley: Wow, Carolyn. That was really fascinating,
especially helping us understand how DNA methylation is
operative, great summary there, and it's just organized so well.
Learned a lot from that. I'm going to switch back and move into
the world of clinical science on this next article. And it really
fascinating, projecting outcomes using some biomarkers that I
hadn't heard of previously. This paper is from Dr Alan Maisel
from University of California, San Diego School of Medicine, and
it evaluated the utility of advanced biomarkers for
discriminating type one versus type two MI in patients presenting
to the emergency room. In the study, two cardiologists
adjudicated type one and type two MIs and six biomarkers were
analyzed cardiac troponin I, copeptin, mid-regional pro-atrial
natriuretic peptide, C-terminal proendothelin-1, mid-regional
pro-adrenal Mendelian, and finally procalcitonin. And the
prognostic utility of these biomarkers for all-cause mortality
and major adverse cardiovascular events or mace included the
composite of acute MI, unstable engine of petrous, re-infection,
heart failure, and stroke at 180 days of follow-up.



Dr Carolyn Lam: So what did they find with these very interesting
biomarkers, Greg? Were they able to distinguish type one from
type two MI?



Dr Greg Hundley: Great question, Carolyn. So among 2,071 patients
type one MI and type two MI were adjudicated in 94 and 176
participants, respectively. Patients with type one MI had higher
levels of cardiac troponin I while those with type two MI had
higher baseline levels of all of the other biomarkers. Next,
combining all the biomarkers resulted in a similar accuracy to a
model using clinical variables and cardiac troponin I, and the
addition of the biomarkers to the clinical model yielded the
highest AUC, under the curve. Next, other biomarkers, but not
cardiac proponent was associated with mortality and mace at 180
days among all the patients with no interaction between the
diagnosis of type one or type two MI. Then conclusion, Carolyn,
the assessment of these new biomarkers, reflecting
pathophysiologic processes occurring with type two MI may help
differentiate it from type one MI. Additionally, all the
biomarkers measures except cardiac troponin I were significant
predictors of prognosis regardless of the type of MI, both type
one and type two.



Dr Carolyn Lam: That's really cool, Greg. Thanks. I'm going to
end with a clinical paper too, and maybe ask you, Greg, you know
so much about AI playing a role in cardiac MRI. Do you think it
could do that in echo too?



Dr Greg Hundley: Leading question, Carolyn. Now, you have
expertise in this area as well. I bet it could be helpful. Tell
us what you've got in this paper.



Dr Carolyn Lam: Well, automated interpretation of
echocardiography with deep neural networks and AI could support
clinical recording and improve efficiency. Now while prior
studies evaluated spatial relationships using still frame images
and echo these authors who were led by Dr Tsai from National
Cheng Kung University Hospital and college of medicine in Taiwan,
these author's aim was to train and test a deep neural network
for video analysis by combining spatial and temporal information
to automate the recognition of left ventricular regional wall
motion abnormalities on echo.
So they collected a series of transthoracic echocardiogram
examinations performed between July 2017 and 2018 in two tertiary
care hospitals. Regional wall abnormalities were defined by
experienced physiologists and confirmed by train cardiologists.
First, the authors developed a 3D convolutional neural network or
CNN model for view selection to ensure stringent image quality
control.
Second, a unit model segmented the images to annotate the
location of each left ventricular wall, and third, a final 3D CNN
model evaluated echo videos from four standard views before and
after segmentation and calculated a wall motion, abnormality
confidence level for each segment.



Dr Greg Hundley: Very nice, Carolyn. So a lot going on to
identifying the wall and then performing analysis on those walls'
segments. So what did they find?



Dr Carolyn Lam: So when a series of more than 10,600 echoes,
their view selection model identified 6,454 or 61% of exams with
sufficient image quality. The external validation was performed
in 1,756 exams from an independent hospital. The final model
recognizes regional wall motion abnormalities, and the cross
validation and external validation datasets with an area under
receiver operating characteristic curve of impressive now 0.91
and 0.89 respectively. In the external validation dataset, the
sensitivity was almost 82% and specificity also almost 82%. And
so in echo exams of sufficient image quality, it is feasible from
this work for deep neural networks to automate the recognition of
regional wall motion abnormalities using temporal and spatial
information from moving images, further investigation is required
to optimize the model performance and evaluate clinical
application.



Dr Greg Hundley: Sounds very exciting. Helping facilitate the
identification of regional wall motion abnormalities. Well, how
about if we jump into some of the other articles in the issue,
would you like to go first?



Dr Carolyn Lam: I'd love to Greg. There's Research Letter from Dr
Wu on patient-specific induced pluripotent stem cells and how
they implicate intrinsic impaired contractility in the
hypoplastic left heart syndrome. There's an In-Depth paper by Dr
McEvoy on lifelong aspirin for all in secondary prevention of
chronic coronary syndrome. Is this still sacrosanct or is
reappraisal warranted? In our Cardiovascular Case Series, Dr
Grodin talks about an uncommon disease in a rare location, the
mystery of the rapidly progressive cardiomyopathy. A very
interesting one. You have to read it. We have a Research Letter
from Dr Golbus on changes in type of temporary mechanical support
device use under the new heart allocation policy. There's an ECG
challenge by Dr Choxi entitled entitle, 􀍞􀁞how me the P wave.􀍟
Very interesting title. You got to pick it up. And there's an On
My Mind paper by Dr Thibodeau on telehealth for uptight titration
of guideline directed medical therapy and heart failure.



Dr Greg Hundley: Very nice, Carolyn. Well, I've got a couple of
letters. First, there's an exchange of Letters to the Editor
regarding the article 􀍞􀀾ow Attenuation Noncalcified Plaque to
Predict Myocardial Infarction: Are We There Yet?􀍟 And it's from
Dr Alfonso and then a response from Dr Williams, and finally, a
Research Letter entitled The Effectiveness of Deep Sedation for
Patients with Intractable Electrical Storm Refractory to
Antiarrhythmic Drugs. And it comes from Dr Raphaël Martins. Well,
Carolyn, how about we move on to that feature article and learn
more about hypertension in the Southeastern United States?



Dr Carolyn Lam: You had me waiting right from the start, Greg.
Let's go.



Dr Greg Hundley: Well, listeners, welcome to our feature
discussion today. And we're going to be reviewing a paper
regarding hypertension and with us, we have Dr Daniel Lackland
from Medical University of South Carolina and our own
associate
editor, Mercedes Carnethon from Northwestern University. Welcome
to you both. Well, Dan let's get started with you. Can you tell
us a little bit about the background information pertaining to
your paper? And then what was the hypothesis that you wanted to
test?



Dr Daniel Lackland: For decades, we've known that the
Southeastern portion of the United States is a disadvantaged
area, but a great geographic diversity where you had these great
rates of disease. In 1960, there was NIH-supported the Charleston
Heart Study and the Evans County Georgia Heart Study. And these
were two databases that were trying to actually look for some
type of a factor that was in this population that was leading to
the great risk, we became the custodians of this database. And
then the regard study focused in or structured around 2000 began
to also look at areas of the Southeast. And so the question that
we had was using these cohorts, looking at 40 years, have we seen
a difference in blood pressure? We did see a difference in
outcomes, but have we seen also the difference in blood pressure
in this high-risk group?



Dr Greg Hundley: It sounds like your hypothesis was to determine
whether blood pressure had diminished. And you've told us a
little bit about your study design, but perhaps can you describe
a little more of the study population.



Dr Daniel Lackland: In the Charleston Heart study, Charleston,
South Carolina, it was basically the County and there was a
random sample SLED it in that area and Evans County, Georgia
Friday it was just everybody that was in the County. Curtis Hames
was the individual at that time and put together these two nice
cohorts. These were individuals, obviously in 1960 a time before
we were treating blood pressure and recognizing pressure. So
there was a blood pressure measurement, there was a cholesterol
measurement and basically, a general overall assessment that was
having in both of these cohorts in 1960. These individuals again
were followed, and then when the regard study was started in the
late 1990s, it did also again, blood pressure measurements, but
with a focus in the Southeastern portion of the United States.
And so you were able to see this population. So it was an
opportunity to look at some cohorts that were readily available
and using them for a unique way to consider it in this particular
high-risk area.



Dr Greg Hundley: Very good. And so how many total subjects did
you have?



Dr Daniel Lackland: In the Charleston Heart Study and Evans
County, Heart Study you were looking at several thousand and you
were comparing it to a slightly higher group from the regards
where you're looking at 5,000 or so.



Dr Greg Hundley: So what did you find, Dan?



Dr Daniel Lackland: We found some wonderful things. Certainly,
the blood pressures had come down just like national studies have
shown. The top of the list was these excessive blood pressures,
these severe blood pressures of where 10% of the African-American
men and women in 1960 had systolic blood pressures greater than
2000. These were virtually eliminated. We didn't see this later
on 40 years later, I think a wonderful accomplishment. The other
piece is that while all the blood pressures came down, blood
pressures came down significantly greater for African-American
men and women and all facets. So those blood pressures that we
would have considered high 140, whatever, those all came down
there, and they came down greater than we saw among white men and
women. We were seeing the gap that was so huge in 1960. The
racial gap, starting to come together with a very positive type
of sign.
The other piece excitingly, we saw the blood pressures in the
lower percentiles coming down suggesting that maybe some of the
lifestyle that we've been implementing around the country were
also being implemented successfully in this high-risk
Southeastern population.



Dr Greg Hundley: Very good. So Dan, in 1960, 10% of the men and
women had systolic blood pressures greater than 200 millimeters
of mercury. And you saw mark declines after the year 2000, and
then also you saw declines for those that had mild elevations in
blood pressure, systolic blood pressures in the 140-millimeter
mercury range. And one quick question, was this true for both men
and women?



Dr Daniel Lackland: Yes, indeed. Both men and women, everybody's
blood pressure came down.



Dr Greg Hundley: So Mercedes, let's turn to you help us put this
paper in the context with other manuscripts that we review at
circulation, but also the world's literature.



Mercedes Carnethon: I'm really excited about the opportunity to
feature these findings and circulation, because I think they
provide a very unique contribution to the literature about the
population trends and levels in blood pressure, in the United
States and around the world. And one thing that's really
important is we don't often talk about our population level
successes. And as we know, hypertension is one of the leading
drivers of cardiovascular disease. And particularly when we think
about reasons for disparities in some of the diseases that Dan
mentioned earlier, heart failure, renal disease, hypertension as
a primary driver of this, as well as stroke.
I certainly can't leave that out. And so to hear that over time a
population levels of blood pressure are shifting downward or are
certainly shifted downward is really heartening news. It does
back certain questions. We certainly still see disparities in
blood pressure levels between blacks and whites in this country,
but are most likely a primary driver of the disparities that we
see in stroke, in renal failure, in certain cardiovascular
diseases, and as well as heart failure.
And so it's wonderful to see this. And I asked Dan and his
colleagues, this particular study data was from the baseline of
the regard's cohort and extremely well-designed study that's
captured individuals from across the United States. I have two
questions, Dan. One is, were you able to tease out any
differences in blood pressure between those in rural versus more
urban areas in the Southeast and the second, because this ended
in 2005, what do you project would happen today? Do you think
these trends are holding? Have we gotten better? Where do we
stand?



Dr Daniel Lackland: That's wonderful questions. As far as the
rural urban, in one sense or certainly Evans County, Georgia is
all rural. And if you compared a little bit teasing out, as
you've suggested, the Evans County rates were just exceptionally
higher than the of the urban sides. If you will allow me for a
moment to call Charleston, South Carolina is somewhat urban
community. You did see some differences, but they were relatively
subtle. Where we are today, if we look at the clinical data, it
looks like the top of the list, those excessive, severe blood
pressures that particularly we saw in black men and women in 1960
are gone. Now we're working on the moderate blood pressures that
Greg had referred to. And I think that, that's fun on that. Those
are also coming down. The exciting piece though, although also
those lower blood pressures that you refer to, so that in that
prevention side of it, those blood pressures are coming down. And
that lifestyle, maybe our messages are gradually getting there to
all of the population.
Dr Greg Hundley: Very good. Let me ask you here in closing, maybe
30 seconds for each of you, what do you think is the next study
that needs to be performed in this particular area? Dan, we'll
start with you.



Dr Daniel Lackland: I think we know that the interventions work
for everybody. So I think we're one of the pieces. Again, is to
look at the groups that we've been referring to now with the new
guidelines and the new classifications of hypertension, looking
at those people that we used to call prehypertension and now have
become stage one hypertension, and also elevated blood pressure.
Can we implement lifestyle interventions and get down a lower
blood pressure? The other piece on the global side that we have
mentioned, I think there are global populations around the world
that actually unfortunately were similar to what 1960 South
Eastern populations are. And I think this is a good model to make
sure that we can take what we've done here and take it to other
populations around the world.



Dr Greg Hundley: Very good, Mercedes?



Mercedes Carnethon: What I'm most curious about going forward is
what proportion of this decline is due to pharma-cotherapies and
what proportion is due to shifts in lifestyle behavior? As a data
type of person, I would be very interested in teasing this out
because there are multiple contributions to high blood pressure,
some of which need to involve interventions at the individual
level and others that can be implemented on a population scale.
And those population scale interventions, for example, reducing
sodium and certain foods have the potential to reach all
populations, including vulnerable populations, and are less
dependent on one's ability to adopt lifestyle changes
individually. And so I would be most curious about trying to
tease that out so that we can appropriately target resources that
will reach the largest and most vulnerable populations.



Dr Greg Hundley: Well, listeners we're most appreciative to have
this opportunity to speak with Dan Lackland from Medical
University of South Carolina and Mercedes Carnethon from
Northwestern University. And listen to them describe these very
encouraging results from the regard study, showing that there
have been detriments in both severe and mild to moderate
hypertension over the last 40 years in the Southeastern United
States. So on behalf of both Carolyn and myself, we wish you a
great week, and we'll catch you next week on the run. This
program is copyright the American Heart Association, 2020.