Nov 9, 2020
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.