Oct 19, 2020
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.