Circulation March 1, 2022 Issue

This week, join author Makoto Hibino and editorialist
Christoph Nienaber as they discuss the article "Blood Pressure,
Hypertension, and the Risk of Aortic Dissection Incidence and
Mortality: Results From the J-SCH Study, the UK Biobank Study,
and a Meta-Analysis of Cohort Studies" and accompanying editorial
"Taming Hypertension to Prevent Aortic Dissection: Universal
Recognition of a "New Normal" Blood Pressure?"


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 Dr. Greg Hundley, associate editor, director of the Poly
Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn
this week's feature discussion. Oh, very interesting. We are
going to delve into results from the Japan specific health
checkup study, as well as the UK Bio bank study and also a
meta-analysis of several cohorts and investigate the relationship
between hypertension and the future risk of aortic dissection.
Well, Carolyn, but first, how about we grab a cup of coffee and
delve into some of the other articles in this issue, and I'll go
first?


Dr. Carolyn Lam:


Please do.


Dr. Greg Hundley:


I'm going to discuss with you the AVATAR trial.


Dr. Carolyn Lam:


Hold on, Greg, remind us, the AVATAR trial?


Dr. Greg Hundley:


Right, Carolyn. So the aortic valve replacement versus
conservative treatment in asymptomatic, severe aortic stenosis or
the AVATAR trial is an investigator initiated international
prospective randomized control trial that evaluated the safety
and efficacy of early SAVR or surgical aortic valve replacement
in the treatment of asymptomatic patients with severe aortic
stenosis, according to common criteria.


Dr. Greg Hundley:


So for example, the valve area is less than one centimeter
squared with an aortic jet velocity of greater than four meters
per second, or a mean trans aortic gradient of greater than 40
millimeters of mercury. They also, all of the patients had normal
LV function and negative exercise testing was mandatory for
inclusion.


Dr. Greg Hundley:


And so these authors, led by professor Marco Banovic from the
University Clinical Center of Serbia, tested the primary
hypothesis that early SAVR would reduce the primary composite
endpoint of all cause death, acute myocardial infarction, stroke,
or unplanned hospitalization for heart failure as compared to a
conservative strategy, according to guidelines. And the trial was
designed as event driven to reach a minimum of 35 pre-specified
events. The study was performed across nine centers in seven
European countries.


Dr. Carolyn Lam:


Wow. A big important study. What did they find?


Dr. Greg Hundley:


Right, Carolyn? So they had 157 patients and they age average, 67
years and 57% were men and they were randomly allocated to early
surgery, so 78 were in that group, or conservative treatment, and
79 were in that group. The follow-up was completed in May of 2021
and the overall medium follow was 32 months, 28 months in the
early surgery group and 35 months in the conservative treatment
group.


Dr. Greg Hundley:


There was a total of 39 events, 13 in early surgery and 26 in the
conservative treatment arm. So Carolyn, in asymptomatic patients
with severe aortic stenosis, early surgery reduced the primary
composite all cause death, acute myocardial infarction, stroke,
or unplanned hospitalization for heart failure compared to the
conservative treatment. And so, Carolyn, this randomized trial
provides preliminary support for early SAVR once aortic stenosis
becomes severe, regardless of symptoms.


Dr. Carolyn Lam:


Wow. Interesting. Well, this next paper that I'm looking at
describes a novel therapeutic target that, listen up, can lower
plasma cholesterol and prevent thrombosis simultaneously.


Dr. Greg Hundley:


What? Are you sure about this? All right, Carolyn. All right.
Describe this for us.


Dr. Carolyn Lam:


Well, I'll tell you what that target is. It is the coagulation
factor prekallikrein, which I'm going to call PK, prekallikrein.
Okay. Now, as a reminder, coagulation cascades are activated by
tissue factor initiated extrinsic pathway and the contact system
initiated intrinsic pathway. Both of which converge into the
common pathway. Plasma kallikrein is a serine protease playing a
crucial regulatory role in the intrinsic pathway and is generated
from the liver expressed prekallikrein, a pro enzyme encoded by
the KLKB one gene.


Dr. Carolyn Lam:


Now that was the background. In the current study, Drs. Song and
Luo from Wuhan University in China and their colleagues
identified that the plasma coagulation factor prekallikrein or PK
interacts with the LDL receptor and induces its degradation in
the lysosomes. In young Chinese Han adults serum PK
concentrations positively correlate with LDL cholesterol levels.
In hamsters genetic ablation of the KLKB one decreases plasma
lipid levels through up-regulating LDL receptor in a manner
additively to the PCSK nine inhibitor cyclocumarol.


Dr. Carolyn Lam:


Injections of the anti PK neutralizing antibody in mice and knock
down of the KLKB one gene in rats also increased hepatic LDL
receptor levels and reduced plasma cholesterol levels.
Furthermore, in mice with ample E deficient background PK absence
arrested the progression of atherosclerotic lesions. So in
totality, these results suggest that PK, remember that's
prekallikrein, regulates both LDL and thrombosis, and that PK
inhibition can be an attractive therapeutic strategy to lower
plasma cholesterol and prevent thrombosis simultaneously.


Dr. Greg Hundley:


Very nice, Carolyn. Well, before we get to our feature discussion
on aortic dissection, I've got a paper that pertains to
preclinical science and involves the study of aortic dissection.
And it comes to us from Professor Aijun Sun from the Shanghai
Institute of Cardiovascular Diseases at the Song Hang Hospital in
Futon University, the Institute of Biomedical Science in Futon
University.


Dr. Greg Hundley:


So Carolyn, the development of thoracic aortic dissection is
closely related to the extracellular matrix degradation and the
vascular smooth muscle cell transformation from contractile to
synthetic type and legumin degrades the extracellular matrix
components directly, or by activating downstream signals.
However, the role of legumin in the vascular smooth muscle cell
differentiation and the occurrence of thoracic aortic dissection,
that remains elusive or unsolved.


Dr. Carolyn Lam:


Oh, so what did this study show?


Dr. Greg Hundley:


Right, Carolyn. So these authors found that the elevation of
legumin is observed in thoracic aortic dissection tissues of both
human subjects and in mice and deletion or pharmacologic
inhibition of legumin rescues BAPN induced thoracic aortic
dissection development in mice by alleviating extracellular
matrix degradation and the vascular smooth muscle cell
transformation. Carolyn, legumin depletion may represent a novel
therapeutic strategy for thoracic aortic dissection and further
studies are required to explore the diagnostic value of serum
legumin as a novel biomarker for thoracic aortic dissection.


Dr. Carolyn Lam:


Wow. That's cool. Thanks, Greg. Well, there are other really cool
papers in today's issue. There's a Cardiovascular Case Series by
Dr. Bockus on a “Heart of Gold: A Scintillating Leading
Pericardial Effusion. And I'll give you a hint, it's a case of
cholesterol pericarditis. There are letters by Drs. Lucas and
Taegtmeyer regarding the article “One Year Committed Exercise
Training Reverses Abnormal Left Ventricular Myocardial Stiffness
in Patients with Stage B HFpEF” with a response by Dr. Levine.
There are highlights from the Circulation Family of Journals by
Sara O'Brien.


Dr. Greg Hundley:


Well, Carolyn, I have some other papers to discuss in this issue
as well. First, there's an On My Mind piece from Professor Lawler
entitled, “What Are Adaptive Platform Clinical Trials, and What
Role May They Have in Cardiovascular Medicine?” Next, there's an
In Depth piece from Professor Damman entitled Evidence Based
Medical Therapy in Heart Failure Patients With Reduced Dejection
Fraction and Chronic Kidney Disease. And then finally, Professor
Yoshida has a Research Letter entitled The Efficacy and Safety of
Edoxoban 15 Milligrams According to Renal Function in Very
Elderly Patients With Atrial Fibrillation, a Sub-Analysis of the
Elder Care AF Trial. Wow, Carolyn, how about now we get onto that
feature discussion.


Dr. Carolyn Lam:


Oh, let's go Greg.


Dr. Carolyn Lam:


For our feature discussion today, we are talking about aortic
dissection and the association with hypertension or elevated
blood pressure. Now at first sight, you may think, well, we all
know that hypertension and elevated blood pressure is an
important risk factor for aortic dissection, but I'd like you to
question, do we really know?


Dr. Carolyn Lam:


Surprisingly few prospective studies have been published. We know
that aortic dissection is an extremely important and serious
complication, but it's low incidence means we need huge numbers
to be able to answer questions such as, what blood pressure does
the start taking off at? For example, is it systolic or diastolic
blood pressure and so on? Well, guess what? We finally, I think,
have some of the best evidence on this topic published in today's
issue of Circulation.


Dr. Carolyn Lam:


And I'm so proud to have the first and corresponding author with
us, Dr. Makoto Hibino from the University of Toronto to discuss
his fantastic paper. As well as an editorialist, Dr. Christoph
Nienaber from Imperial College, London, who will discuss the
significance of this paper. Well, let's start with you, Dr.
Habino or Makoto, if you don't mind, could you please tell us
what you did and what you found?


Dr. Makoto Hibino:


Thank you, Carolyn. So it's my honor to be here to present my
case in this podcast. So first, some of the recent data shows
that the number of aortic dissection operation and this
increasing trend, depending on countries and given the critical
nature of aortic dissection preventive strategy against aortic
dissection is expected. On the other hand, hypertension is still
global issue and is responsible for constant number of deaths
from cardiovascular diseases, including aortic dissection, but
due to the relatively rare instance of dissection and acute
critical nature of the disease, the available epidemiological
evidence has been limited. So this time we wanted to investigate
how the relationship of hypertension and blood pressure with the
instance of the aortic dissection is, in terms of strengths
association and the shape of the association.


Dr. Makoto Hibino:


We also hypothesized that association may not be leading a
relationship. And what we did is our study is consist of three
parts. The first two parts are original cohort studies using a
Japanese specific health checkup study and UK Bio bank study in
both of which we prospectively followed about half a million
general population and analyzed the hazard risk of other aortic
dissection instance for hypertension and systolic and diastolic
blood pressure using Cox proportional analysis. And the last part
is meta-analysis including eight cohort studies and examine the
robustness and shape of the association between hypertension and
systolic and diastolic blood pressure and the risk of aortic
dissection.


Dr. Carolyn Lam:


Wow. So a huge study across diverse cohorts. What did you find?


Dr. Makoto Hibino:


Yes. So in both of our cohort studies, there was significant risk
of aortic dissection for hypertension and systolic and diastolic
blood pressure as a continuous variable. Also, there was
increasing trend in hazard ratios for categorical systolic and
diastolic blood pressure with two to five, for higher risk in the
highest systolic blood pressure category and four to 12 for
higher risk in the highest diastolic blood pressure category in
the meta-analysis. The summary relative risk shows that those
with hypertension has threefold risk of aortic dissection and the
robustness of the result confirmed with the sensitivity and
subgroup analysis. Lastly, in the non-linear dose response,
meta-analysis, there was very strong dose response relationship
between systolic blood pressure and aortic dissection with
evidence of non-linearity. And similar, but still, those response
relationship was found between diastolic blood pressure and
aortic dissection. This analysis showed that the risk of aortic
dissection was significant at systolic blood pressure more than
132 millimeter mercury, and diastolic blood pressure more than 75
millimeter mercury suggesting a risk of aortic dissection, even
in non-hypertensive population.


Dr. Carolyn Lam:


Wow. That last part really grabbed me. And I think I should
repeat that the risk was significant at the systolic blood
pressure of only 132 and a diastolic blood pressure of 75. That's
really striking. Chris toff, would you agree with me when I said,
I think this is like the best data that we have now, sort of
correlating blood pressure and hypertension with aortic
dissection. I loved your editorial by the way.


Dr. Christoph Nienaber:


Thank you very much. I'm pleased to have the chance to write this
editorial. Because, when I reviewed the article, I was thrilled
of the data and the fact that somebody some consortium had
managed to pool data from two different, let's say population
studies in two different gene pools in Japan and in the UK
together. And finding in a very granular way, that even within
the normal spectrum of blood pressures, up to let's say 140
systolic, we find an increasing risk of dissection with a high
normal blood pressure as compared to a low normal blood pressure.
This has been very convincingly shown by Makoto's analysis. The
entire group has to be congratulated for that fantastic idea.
Collaboration from two different ends of the world, and then
coming up with a similar conclusion in both populations, tells us
that this is a general principle at work, that works in both gene
pools in both Asian, as well as European populations, and tells
us how important it is to keep an eye on blood pressure and even
manage blood pressure within the normal range to a low normal in
the future.


Dr. Carolyn Lam:


And I love the way you articulated that in that beautiful
editorial, but could I now ask your thoughts, both of you, what
are the clinical implications of this? I love Chris toff, that
you discussed in your editorial, well, do we now lower the
thresholds for treatment? Because aortic dissection is not the
most common of incidences, right? So does lowering the blood
pressure even more or targets come at a price? Or what should we
be thinking of now, clinically?


Dr. Christoph Nienaber:


We are not treating dissection. We are trying to prevent
dissection by gauging or gouging to a low normal blood pressure
with various drugs and combinations of drugs in patients that are
considered to be at risk with a slightly elevated blood pressure.
So in the future, it's not enough to accept 140 systolic or 90
diastolic we should really pay attention to strictly lowering
blood pressure in the idea of preventing vascular events.


Dr. Christoph Nienaber:


And that was considered to come at a price, but we have of
course, reassuring data from Hope, from Sprint recently published
that showed that even the low normal doesn't hurt. I mean, you
have a lower risk of cardiovascular events, generally speaking,
shown in Sprint with a low normal blood pressure. It comes a
little bit at the expense of watching renal function, but that
doesn't contribute to kind of prognostic sequelae. You just have
to pay attention to it. You would not run any additional risk by
lowering the blood pressure to a normal low blood pressure. And
that's, I think, the convincing message, and even with a low
incidence of the most important vascular accidents, such as
dissection, you could prove that, or the group could prove that
in almost 3000 patients that suffered from dissection, that whole
pool of analyzed data. So again, I have to congratulate to this
fantastic and convincing results.


Dr. Carolyn Lam:


Thank you. And Makoto, what do you think are the most important
clinical take home messages from your study?


Dr. Makoto Hibino:


Yes. So let me, a little bit, step back to the summary of our
findings. So our findings is so that this is a study is a fast
summary of the evidence from the prospective stakeholder studies
on the association of blood pressure and hypertension with the
risk of aortic dissection. And this study improves the evidence
base from being based on the case studies or single study to
actual estimate of the relative risk. So also, with further study
are needed, the current results suggests that the reducing blood
pressure either through a healthier lifestyle or medication may
reduce the instance of aortic dissection and furthermore the
optimal target blood pressure may even lower than the current cut
for hypertension. So from my perspective given the little rare
instance of aortic dissection, intensive blood pressure
management may be more effective or efficient in high risk
population, such as those with bicuspid aortic valve or those
with very ill medical follow for aortic aneurysm and those with
genetic background. So further study in a specific subgroup, is
warranted.


Dr. Carolyn Lam:


Thank you. And Chris toff, that's very interesting because I buy
your argument too, that on the other hand, going lower, even in
non-high risk, doesn't really come at a price as far as we can
see. So what do you think Chris toff, what do you think are the
further studies that are needed?


Dr. Christoph Nienaber:


Well, I was intrigued to see in their analysis that even the
subgroups of patients, including patients with hereditary
connective tissue disorders, survivors of previous dissection,
patients with other conditions, including diabetes, et cetera,
they're all across the board, benefited from low blood pressure
adjust or adjustment to a low blood pressure. That gives me
confidence to recommend to my colleagues, not only here, but in
my further environment to follow those patients that are
identified either as risk groups or with a slightly elevated
blood pressure to definitely lower the blood pressure to lowest,
lower to blood pressure with those side effects.


Dr. Carolyn Lam:


Nice. These are association studies just to take a step back
rather than sort of treatment target studies, although we've
discussed some of the treatment target studies, but I have to
really agree that it's some of the strongest association data
that I can frankly think of for blood pressure and aortic
dissection. We're just so grateful that it has been published in
Circulation. And thank you so much, Chris toff, for your elegant
editorial, that really puts things in perspective with a very
important final key take home message.


Dr. Carolyn Lam:


And with that, well listeners, you heard it right here on
Circulation on the Run from Greg and I thank you for joining us
this week. And, don't forget to tune in again next week.


Speaker 5:


This program is copyright of the American heart association in
2022. The opinions expressed by speakers in this podcast are
their own and not necessarily those of the editors or of the
American Heart Association for more, please visit
ahajournals.org.