Circulation November 10, 2020 Issue

This week’s episode features author Kazuomi Kario and Associate
Editor Wanpen Vongpatanasin as they discuss the article
"Nighttime Blood Pressure Phenotype and Cardiovascular Prognosis:
Practitioner-Based Nationwide JAMP (Japan Ambulatory Blood
Pressure Monitoring Prospective) Study."


TRANSCRIPT BELOW:



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,
Director of the Pauley Heart Center at VCU Health in Richmond,
Virginia. Carolyn, when is the best time to check your blood
pressure if you have a home monitoring device? Morning?
Afternoon? Nighttime? And what do those nighttime fluctuations
infer? Well, we'll hear a lot more in our feature discussion
today, but first let's grab a cup of coffee and jump into some of
the other papers in the issue. I'm going to start first this
week, and my first paper comes from Dr Joe Wu at Stanford
University. Carolyn, a quiz. Are all endothelial cells alike?



Dr Carolyn Lam: Jeez, Greg. Okay, I'm going to hedge. I bet a lot
of them share similarities, but there may be some differences.



Dr Greg Hundley: Yes, Carolyn. Dr Wu and his associates perform a
series of elegant experiments involving mice, and they found that
certain tissue-specific endothelial cells cluster strongly by
tissue, like those in the liver or the brain, whereas others
from, for example, adipose tissue or the heart have considerable
transcriptomic overlap with endothelial cells from other tissues.
They identified novel markers of tissue-specific endothelial
cells and signaling pathways that may be involved in maintaining
their identity, and sex was a considerable source of
heterogeneity in the endothelial transcriptome.
In addition, they found that markers of heart and lung
endothelial cells in mice were conserved in human fetal heart and
lung endothelial cells and identified potential angiocrine
interactions between tissue-specific endothelial cells and other
cell types by analyzing ligand and receptor expression patterns.



Dr Carolyn Lam: So interesting, Greg. You especially had me at
sex differences. So, what's the take home message?



Dr Greg Hundley: Right, Carolyn. So this group discovered a
series of transcriptional networks that maintain endothelial cell
heterogeneity, and that angiocrine and functional relationships
exist between tissue-specific endothelial cells. These findings
open the door for future studies that can manipulate these
pathways and perhaps modify processes, like atherosclerosis, that
impact the endothelium.



Dr Carolyn Lam: Wow, that's cool, Greg. Well, from your paper,
I'm going to a mechanistic paper too, and the next study really
aimed to define cardiac fibroblasts' heterogeneity during
ventricular remodeling, as well as the underlying mechanisms that
regulate their function, so important questions here. And
co-corresponding authors, Drs Prósper and Lara-Astiaso from
Clinica Universidad de Navarra in Pamplona in Spain, as well as
Dr Lindner from Maine Medical Center Research Institute in
Scarborough, Maine in the U.S., and their co-authors, basically
characterized cardiac fibroblasts after myocardial infarction
using a whole host of very novel techniques like single-cell and
bulk RNA sequencing, ATAC sequencing, and functional assays.
Swine and patient samples were studied using bulk RNA sequencing.



Dr Greg Hundley: Very intriguing. What did they find?



Dr Carolyn Lam: They identified and characterized a unique
cardiac fibroblast subpopulation that emerged after myocardial
infarction in mice. These activated fibroblasts exhibited a clear
profibrotic signature expressing high levels of collagen triple
helix repeat containing 1 and localized into the scar. Moreover,
the absence of this regulator resulted in pronounced lethality
due to ventricular rupture. Finally, a population of cardiac
fibroblasts with a similar transcriptome was identified in a
swine model of myocardial infarction, as well as in heart tissues
from patients with myocardial infarction and dilated
cardiomyopathy.



Dr Greg Hundley: Ah, so important information on how fibroblasts
start the scar formation after infarction. So, Carolyn what's the
take home message here for this research?



Dr Carolyn Lam: Well, this paper really provides important
information on cardiac fibroblast heterogeneity, their dynamics
during the course of myocardial infarction, and the authors also
redefine the cardiac fibroblasts that respond to cardiac injury
and participate in myocardial remodeling. This study identifies
collagen triple helix repeat containing 1 as a novel regulator of
the healing scar process, and as a target for future
translational studies.



Dr Greg Hundley: Great, Carolyn. You're doing such a great job.
This is an issue for double quiz. Have you ever heard of
treatments for hypertension incorporating Chinese herbal formula
gastrodia-uncaria granules?



Dr Carolyn Lam: What? Are you trying to speak Chinese, Greg?



Dr Greg Hundley: Yeah (affirmative) Okay.



Dr Carolyn Lam: I'm sure you're going to tell us about it.



Dr Greg Hundley: Right. So this study is from Professor Yan Li
from Ruijin Hospital in Shanghai, Jiao Tong University School of
Medicine. Gastrodia-uncaria granules Carolyn, is a mixture of
Chinese herbs that dates back many years, I think thousands, and
in this study was used in patients with masked hypertension. So
in the study, patients with an office blood pressure of less than
140/90 millimeters of mercury, but a daytime ambulatory blood
pressure of 135 to 150 millimeters of mercury systolic or 85 to
95 millimeters of mercury diastolic, were randomized one-to-one
to receive the treatment of, and I'm going to abbreviate it, GUG
versus placebo, 5 to 10 grams twice daily for four weeks. The
primary efficacy variable was the change in daytime ambulatory
blood pressure.



Dr Carolyn Lam: Ah. (affirmative), so did it work?



Dr Greg Hundley: Well, in their intention-to-treat analysis,
daytime systolic-diastolic blood pressure was reduced by 5 and 3
millimeters of mercury in the GUG group, and 3 and 1.6
millimeters of mercury in the placebo group, respectively. The
between group difference in blood pressure reductions was
significant, 2.5 and 1.7 millimeters of mercury, and 24-hour
blood pressure by 2 and 1.5 millimeters of mercury, but not for
the clinic and nighttime blood pressures. The per protocol
analysis in 229 patients produced similar results. Only one
adverse event, sleepiness during the day was reported and no
serious adverse events occurred. So Carolyn, a potentially
inexpensive regimen found useful in China for patients with
masked hypertension. To learn more of the results of this
interesting study, listeners are suggested to review the article
in this particular issue.



Dr Carolyn Lam: Wow, interesting Greg. Okay. So from hypertension
to CABG. Now we know that approximately 15% of saphenous vein
grafts occlude during the first year after coronary artery bypass
graft surgery, or CABG, despite aspirin use. So can ticagrelor
added to standard aspirin improve saphenous venous graft patency
at one year after CABG? Now this is the question that Dr ten Berg
from St. Antonius Hospital from Nieuwegein in Netherlands, and
colleagues sought to answer in the popular CABG trial, which was
an investigator-initiated randomized double-blind
placebo-controlled multicenter trial of 499 patients with one or
more saphenous vein grafts, who were randomly assigned after CABG
to ticagrelor or placebo added to standard aspirin.
The primary outcome was saphenous vein graft occlusion at one
year assessed with coronary CT angiography occurred in 10.5% of
the ticagrelor group, versus 9.1% in the placebo group, so that's
an odds ratio of 1.29, and it was not significant. The secondary
outcome of one year saphenous vein graft failure, which was a
composite of vein graft occlusion, revascularization, myocardial
infarction in the myocardial territory supplied by the vein
graft, or sudden death, well, that occurred in 14.2% of patients
in the ticagrelor group, versus 11.6% in patients in the placebo
group. Again, not a significant difference.



Dr Greg Hundley: So Carolyn, a negative study? What's our take
home here?



Dr Carolyn Lam: In this randomized double-blind
placebo-controlled trial, the addition of ticagrelor to standard
aspirin after CABG did not reduce the rate of saphenous vein
graft occlusions at one year. Now, this conclusion differs from
some other studies that investigated this research question, and
this is discussed in this editorial that you got to pick up. It's
by Dr Goldman from the University of Arizona.



Dr Greg Hundley: Wow, Carolyn. Great job. Well, we've got a
couple more articles in this issue, and I'll start by describing
a research letter by Dr Daviet regarding heparin-induced
thrombocytopenia in COVID-19, and then Carolyn there's a second
research letter from our own Torbjørn Omland regarding
established cardiovascular biomarkers provide limited prognostic
information in unselected patients hospitalized with COVID-19.
And then finally, from Dr Chonyang Albert, a case series
entitled, The Enemy Within: Sudden Onset of Reversible
Cardiogenic Shock with Biopsy-Proven Cardiomyocyte Infection by
SARS-CoV2.



Dr Carolyn Lam: We've also got an ECG challenge by Dr Sreenivasan
entitled, A Red Flag ECG, also known as, and have you heard of
this, South African flag pattern. Okay, here's a hint. It's an
important, but subtle ischemic ECG change. You got to look it up.
There's an On My Mind paper by Dr Alexander on at risk of
depriving patients’ life-saving cardiac surgery, and those are
the implications of the ischemia trial for CABG. A Research
Letter shared by Dr Susen entitled, Endotheliopathy is Induced by
Plasma from Critically-ill Patients and Associated with Organ
Failure in Severe COVID-19. And finally, in Cardiology News,
Tracy Hampton reviews the most recent literature in top journals
like Nature, Metabolism, Cell, Stem Cell, and Circulation
Research. Wow. Bonanza issue. So cool, but I really want to hear
about the different blood pressure patterns now. Let's go to our
feature discussion, shall we?



Dr Greg Hundley: Absolutely. Here we go. Well, listeners we are
excited to get to this feature discussion to learn more about the
use of ambulatory blood pressure measures, particularly those
that are collected 24 hours and during the nighttime. We have
with us, Dr Kazuomi Kario from the Jichi Medical University in
Japan, and our own Associate Editor, Dr Wanpen Vongpatanasin from
University of Texas Southwestern Medical Center in Dallas.
Welcome to you both. And Kazuomi, could you start us off please
and just describe some of the background that led you to perform
this study? And what hypothesis did you want to address?



Dr Kazuomi Kario: The old guidelines management of the
hypertension and now recommend instead of the office blood
pressure, now the ambulatory blood pressure management. So for
example, the ABPN and also home blood pressure monitoring, but
the 24-hour blood pressure reduction is very much important, all
prefer the values, but also our hypothesis took on the 24-hour
blood pressure quantity reduction, but also, we should normalize
our circadian rhythm. Usually blood pressure reduced by 10 to 20%
at night during the sleep compared to the daytime. But the other
group, is exhibited and predicated known six bars and also is
either higher at night during the nighttime period compared to
the daytime. And also home blood pressure variability, that hurts
blood pressure in the morning. So circadian rhythm normalization
and also, I recreate blood pressure variability especially is
more precise.
It's important for the quality control over for the hypertension
management. So my hypothesis is that blood pressure reduction,
the other most blood pressure, and the normalized circadian
rhythm, under agitate, to keep agitate among as such. All the
three components I did try to optimize 24-hour blood pressure
control, so I want to confirm our hypothesis. To optimize 24-hour
blood pressure control consists of these three components,
24-hour pressure reduction, and the normalize circadian rhythm
and the keeping the other keep such, it shouldn't be; I have,
have you left your prevention or not? That's my hypothesis and
background.



Dr Greg Hundley: So with our 24-hour ambulatory monitoring
evaluating in this study, do we have the normal dip during the
evening? Do we have a rise associated with the circadian rhythm?
What is the variability of the blood pressure over time? Tell us
what study population, and how did you design this study to
address your hypothesis?



Dr Kazuomi Kario: This population is the hypertension patients,
90% or more on the out-patients who keep the adequate, the active
daily readings, and they are medicated, or usually conventional
hypertension medication is the effective to reducing the office
blood pressure and they can. But the other hypotension treatment
may not be sustained to be reducing the nocturnal blood pressure
and next morning people are taking pills. So it may be that the
picture of the nighttime blood pressure and the morning blood
pressure. So our hypothesis targets is already mitigated
hypotension patient, but we should find out control for the
current hypotension treatment. It should be the nighttime and
next morning.


 



Dr Greg Hundley: So we're addressing whether the efficacy of or
any hypertensive medications are maintaining low blood pressures
at night and avoiding a surreptitious rise in blood pressure when
we wake up. So how many patients did you enroll and what were
your study results?



Dr Kazuomi Kario: The total study population number is 6,359
patients or enrolls. And we find out, compared to the daytime.
Daytime also where the risk of the nighttime blood pressure other
age, was more the precise this predictor of cardiovascular
events. So, cardiovascular events consist of the atherosclerosis
cardiac events consists of stroke and coronary artery disease.
And also the nighttime blood pressure associated with the risk of
the heart failure. And very interestingly, disrupted circadian
rhythm, it rises at night higher during the nighttime compared to
the daytime, it was independent of risks for the cardiovascular
event, especially for the heart failure. So even after
controlling for the daytime, even on the nighttime blood
pressure, this pattern nighttime riser was an independent risk,
so very interesting results.



Dr Greg Hundley: So elevations of systolic blood pressure during
nighttime, during sleep were associated with future
atherosclerotic cardiovascular disease, as well as heart failure.
And one more quick point, was there a particular magnitude of
rise of that systolic blood pressure at night was important. And
did you find similar results for men and for women?



Dr Kazuomi Kario: Yes, similar results for men and the women.
Theo other factor was age was increased. The almost the higher
during the nighttime or other age of the rising pattern was 10
allowed during the nighttime compared to the daytime.



Dr Greg Hundley: So even a 10% increase in systolic blood
pressure at night relative to daytime was important for
forecasting these adverse cardiovascular events. So Juan pen, can
you help us take these results from this elegant ambulatory
monitoring study and put those in the context of other study
results that have evaluated 24 ambulatory monitoring of blood
pressure?



Dr Wanpen Vongpatanasin: I think the notion of nighttime blood
pressure as the independent predictor of cardiovascular outcome
has been shown in other cohort, but usually not this large
magnitude, that is an international registry. I had call that in
different countries around the world that demonstrate this. But
again, like I said, it compiled from a smaller dataset, there's
even fewer data sets in the United States. There's a cohort from
Jackson Heart, but again, it's less than a thousand and most of
other cohorts have looked at mostly a target organ level, not at
the heart CV outcome.
So I think this add to an important observation, and I think that
the results from the nighttime it's similar, but extended from
previously that look at individual outcome using a adjudicated
data committee that also a very distinctive feature of the study
that is a committee that look at this and look at a specific
outcome rather than just a retrospective using the death index
from different countries. The other part is slightly different
perhaps, and they learn from reading it is the extreme dipping,
also dropped a lot. Initially people think that it might be
associated with the worst outcome, but even to me I wasn't sure
what this mean, but in this study the most extreme dip, maybe
not, not as much that shouldn't be worried as much compared to
the actual nighttime blood pressure itself or not dipping itself.



Dr Greg Hundley: Kazuomi what do you see as the next study that
needs to be performed in this area of research?



Dr Kazuomi Kario: Oh, it's the observational study of the current
medical situations maybe kind of situations. So next step, we
should focus on that nighttime blood pressure; regardless of the
office and the daytime, so even there are controls, if we should
target the nighttime blood pressure and the toxicity controls,
organ damage should be decreased and the subsequent
cardiovascular events should be decreased. So observational study
targeting the nighttime blood pressure is the next topic.



Dr Greg Hundley: And Wanpen do you have anything to add to that?



Dr Wanpen Vongpatanasin:I'd like to see more large observational
study from the US with the diverse population, because the salt
consumption in Asia, particularly in Japan, are probably among
the highest. So perhaps the nighttime blood pressure, it's
confounded by high sodium and something, and we're not too far
behind obviously, but it'd be nice to know what it means in the
US. And obviously they're targeting nighttime blood pressure,
it's the hot topic and that's by itself is probably another 30
minutes to an hour of discussion. But I think that that's very
important area of research.



Dr Greg Hundley: Listeners, what a really wonderful discussion.
And in this study from Japan of over 6,000 individuals treated
for high blood pressure, those with 24-hour monitoring and
exhibiting a rise in systolic blood pressure during the nighttime
was associated with future cardiovascular events and an increase
in the risk of heart failure. Moving forward from these experts,
performing additional observational studies to confirm these
findings and other populations, and perhaps a randomized trial,
trying to target therapeutic interventions that would lower
nighttime blood pressure may be warranted. Thank you Dr Kario and
Dr Vongpatanasin. We wish you a great week and we look forward to
catching you on the run next week. This program is copyright The
American Heart Association, 2020.