Circulation April 4, 2023 Issue

This week, please join authors Tatsuhiko
Naito and Kosuke Inoue
as well as Associate Editor Wendy Post as they discuss
the article "Genetic Risk of Primary Aldosteronism and Its
Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of
Genome-Wide Association Study."


Dr. Greg Hundley:


Welcome listeners, to this April 4th discussion of Circulation on
the Run. I am one of your co-hosts, Dr. Greg Hundley, Associate
Editor, Director of the Pauley Heart Center at VCU Health in
Richmond, Virginia.


Dr. Peder Myhre:


And I'm Dr. Peder Myhre from Akershus University Hospital and the
University of Oslo in Norway. So Greg, today we have the feature
paper, discussing the genetic risk of primary aldosteronism and
its contribution to hypertension. So this is such an interesting
topic and av very important cost on hypertension. And in this
paper, they use cross-ancestry meta-analysis from GWAS studies to
assess this very interesting discussion.


But first, Greg, I have a paper that comes to us from the DELIVER
trial, and it is about dapagliflozin to patients with HFpEF, and
assessing the association with the duration of the heart failure.


So Greg, it is important to understand how the effects of new
treatments vary by the duration of heart failure. Because on one
hand, physicians may think that a patient who has longer standing
heart failure represents a stable survivor where new treatment is
unnecessary. On the other hand, the view has been expressed that
patients with long-standing heart failure may have more advanced
disease, and there may come a point where they no longer respond
to or tolerate the addition of new therapies, particularly
because of hypotension, kidney dysfunctional and electrolyte
abnormality. So the investigators from the DELIVER trial, led by
corresponding all author John McMurray from University of
Glasgow, therefore, aimed to assess the efficacy and safety of
the SGLT2 inhibitor dapagliflozin, according to the duration of
heart failure with EF above 40%. So that is mildly reduced or
preserved.


Dr. Greg Hundley:


Wow, Peder, very timely, very timely article. So what did they
find?


Dr. Peder Myhre:


So Greg, the authors categorized patients by duration of heart
failure, one category less than six months, and then six to 12
months, and then one to two years, two to five years, and
finally, more than five years. And longer duration heart failure
patients were older, and more comorbid with worse symptoms, and
the rate of the primary outcome increased with heart failure
duration. And so, the benefit of dapagliflozin was consistent
across heart failure duration categories with hazard ratios 0.67,
0.78, 0.81, 0.97, and 0.78. And that gives a P4 interaction of
0.41. So the absolute benefit was therefore since there was no P4
interaction, greatest among those with highest risk, and that it
was the longest duration heart failure. So there was a number
needed to create for heart failure above five years of 24, versus
32 for those with the shortest duration of heart failure. And the
authors therefore conclude, that even in patients with
long-standing heart failure and generally mild symptoms cannot be
considered stable, and it is not too late for such patients to
benefit from an SGLT2 inhibitor.


Dr. Greg Hundley:


Ah, very practical information, Peder, beautiful description.
Well Peder, this next paper comes to us evaluating low density
lipoprotein cholesterol. And as you know, low density lipoprotein
cholesterol is an important causal risk factor for
atherosclerotic cardiovascular disease. However, a sizable
proportion of middle-aged individuals have not developed coronary
atherosclerosis as assessed by the presence of coronary artery
calcification. Now whether the presence of coronary artery
calcification modifies the association of LDL cholesterol with
atherosclerotic cardiovascular disease risk, well, that's
unknown. So these authors, led by the corresponding author of
Martin Mortensen from Aarhus University Hospital, evaluated the
association of LDL cholesterol with future atherosclerotic
cardiovascular disease events, in patients with and without
coronary artery calcium, from 23,132 consecutive symptomatic
patients evaluated for coronary artery disease, using coronary
commuted tomography angiography, or CTA, that were included in
the Western Denmark Heart Registry, which is a semi-national
multi-center based registry with longitudinal registration of
both patient and procedural data.


Dr. Peder Myhre:


Oh, that is so important, Greg. So we're looking at LDL
cholesterol and the association with ASCVD in patients with and
without coronary artery calcification. So what did they find?


Dr. Greg Hundley:


Right, Peder. So during a median follow up of 4.3 years, 552
patients experienced a first cardiovascular disease event. In the
overall population, LDL cholesterol per 38.7 milligrams per
deciliter increase, was associated with cardiovascular disease
events during the follow-up period. Now, when stratified by the
presence or absence of a baseline coronary artery calcium score,
LDL cholesterol was only associated with a cardiovascular disease
event in the 47% of patients with a coronary CAC score greater
than zero. While no association was observed in the 53% of
individuals with a coronary artery calcium score equal to zero.


Now similarly, very high LDL cholesterol, so greater than 193
milligrams per deciliter, versus an LDL cholesterol of less than
116 milligrams per deciliter, was associated with a
cardiovascular disease event in patients with a CAC score greater
than zero, but not in those without coronary artery calcium.
Next, Peder, in patients with coronary artery calcium equal to
zero, diabetes, current smoking, and low HDL cholesterol levels,
were associated with future cardiovascular disease events. This
principle finding was replicated in the multiethnic study of
atherosclerosis.


And so, Peder, LDL cholesterol appears almost exclusively
associated with a cardiovascular disease event over the ensuing
five years of follow-up in middle-aged patients with versus
without evidence of coronary atherosclerosis, as identified by
coronary artery calcium scores. This information is quite
valuable for individualized risk assessment among middle-aged
patients.


Dr. Peder Myhre:


Oh, that is so important, Greg. So really, LDL seems to be more
predictive of atherosclerotic cardiovascular disease than those
with calcium in their coronaries, while there was no association
in those with no calcium in their coronaries. Very interesting.


Dr. Greg Hundley:


Absolutely. And there's a very nice editorial by Professor
Sniderman entitled, “Cholesterol Coronary Calcification and
Cardiovascular Prevention: Lessons We Can Learn from the Western
Denmark Heart Registry.”


Dr. Peder Myhre:


Thank you, Greg, that was a beautiful summary. And we are going
to stay in clinical science, but we're going to move to aortic
disease and look at gut microbiota. Now, Greg, large scale human
and mechanistic mouse studies indicate a strong relationship
between the microbiome dependent metabolyte,
Trimethylamine-N-oxide, abbreviated TMAO, and several
cardiometabolic diseases. And in this study, which comes to us
from corresponding author Philip Owens from University of
Cincinnati, the investigators aim to assess TMAO's role in the
pathogenesis of AAA and targeting its parent microbes as a
potential pharmacologic intervention.


Dr. Greg Hundley:


Ah, very interesting, Peder. So what methodology did they use?


Dr. Peder Myhre:


So Greg, this is one of those fantastic studies combining
clinical and preclinical science. And the investigator measured
TMAO in two independent patient cohorts, with a total of 2,129.
And in addition, they used the murine AAA model, and fed the mice
a high choline diet, which is a diet that markedly augment plasma
levels of TMAO. And these mice were then treated with broad
spectrum antibiotics, targeted inhibition of a gut microbial
enzyme with fluorometer chloroquine, called FMC, or utilizing
mice genetically deficient of Fmo3.


Dr. Greg Hundley:


Very nice. So what did they find, Peder?


Dr. Peder Myhre:


So the authors found that elevated TMAO was associated with
increased AAA incidence and growth in both patient cohort
studies. And dietary colon supplementations augmented plasma TMAO
and aortic diameter in both mouse models of AAA, which was
suppressed with poorly absorbed oral broad spectrum antibiotics.
In treatment with FMC ablated TMAO production attenuated colon
augmented aneurysm in the initiation, and halted progression of
an established aneurysm model. And additionally, the Fmo3
knockout mice had reduced plasma TMAO, aortic diameters, and were
protected from AAA rupture compared to wild type mice.


So Greg, in conclusion, this study defined a role for gut
microbiota generated TMAO in AAA formation, and additionally,
increased microbiome derived TMAO may serve as a novel
therapeutic approach for AAA treatment where non currently
exists.


Dr. Greg Hundley:


Beautifully described, Peder. And another one of their articles
in Circulation that, as you indicated, very nicely complying the
world of preclinical and clinical science.


Well, we've got some other articles in the issue, and how about
we jump into some of those? So first, there's a very nice Letter
to the Editor from Professor Wong entitled, “Frailty and Age
Correlation in Clinical Trials.” And there is another reply to a
prior Letter to the Editor from Professor McMurray entitled,
“Efficacy and Safety of Dapagliflozin According to Frailty in
Patients with Heart Failure, a Pre-specified Analysis of the
DELIVER Trial.” And then next, Peder, Michelle A. Albert has a
very nice synopsis of the American Heart Association Presidential
Address, entitled, “Economic Adversity and Healthcare.”


Dr. Peder Myhre:


Nice. And finally, there's a Research Letter from Dr. Baggish
entitled, “Association Between Concussion Burden During
Professional American-style Football and Post-career
Hypertension.”


Dr. Greg Hundley:


Very good, Peder. Well, what a packed issue we have this week,
and how about we jump next to that feature discussion with our
colleague Carolyn? Ah.


Dr. Peder Myhre:


Let's go.


Dr. Carolyn Lam:


Primary aldosteronism, or, we're going to say PA for this
discussion, is one of the most common causes of secondary
hypertension, and it is also a particularly morbid form of
secondary hypertension. So identifying this subgroup of
hypertensive patients with primary aldosteronism, again PA, would
allow us to perhaps, direct more aggressive management to their
cardiometabolic risk. Now, is a genetic approach the way to do
it? Well, we're about to find out in today's very special paper.


We're very honored to have the first author, Dr. Tatsuhiko Naito,
from Osaka University Graduate School of Medicine, and his second
and co-author Dr. Kosuke Inoue, from the Graduate School of
Medicine in Kyoto University, as well as our associate editor,
Dr. Wendy Post, from Johns Hopkins University School of Medicine,
here to discuss this very important paper. Perhaps I could start
with you, Dr. Tatsuhiko. Could you please, perhaps, tell us a
little bit about what made you do this study, what you did, and
what you found?


Dr. Tatsuhiko Naito:


I would like to thank you for inviting us to present the
information from our paper. In terms of genetic, germline genetic
factors behind the development of PA has not been isolated. And
in addition, the PA is the cause of hypertension, but the genetic
relationship between hypertension and PA has not been discussed
previously. That is why we conducted a genome-wide association
study, GWAS, of PA here. Our GWAS consisted of three defined
cohorts of our Japanese cohort, UK Biobank, and FinnGen. In our
Japanese cohort, we collected samples in Hiroshima University,
and we used controls from Biobank Japan, which is the largest
Japanese biobank. And we also used two publicly available
biobanks, UK Biobank and FinnGen. So they can be used upon
registration. By utilizing these resources, we conducted a
cross-ancestry, meta-analysis of GWAS.


Dr. Carolyn Lam:


Thank you. And the results, please?


Dr. Tatsuhiko Naito:


In the meta-analysis, we identified five genetic loci that were
significantly associated with the risk of PA satisfied in the
genome world significant threshold. The strongest association was
observed at WNT2B, which is located in chromosome 1. And in
addition, we identified one near the genome-wide association
locus CYP11B1 and B2, which is located on chromosome 8. So
CYP11B2 is the key enzyme that acts in producing aldosterone in
the adrenal gland, thus, we consider that resource. This locus
would be also our PA risk associated locus with a high
probability.


Of interest, these loci were reported to be associated with
hypertension, but we thought this results is resemble, because PA
occupies around five to 10% of causes of hypertension. Does the
PA associated loci could be reported as hypertension associated
loci in previous GWAS with large sample size?


So to support our assumption, we compared the risk effect of
these genetic loci between PA and hypertension. So if there are
risk effects who are coming from PA, these loci should present
higher effect on PA than on hypertension. And expectedly, these
loci presented significantly higher effect on PA here.


And lastly, inspired by these results, we hypothesized that some
of other loci, that had been reported to be associated with
hypertension, might come from the primary effects on PA. To
investigate this, we picked up blood pressure rated genetic loci
from previous GWAS of blood pressure, and compared their risk
effects between PA and hypertension. The result was that, 66.7%
presented a higher risk effect for PA than for hypertension. And
two strictly demonstrates the result. We also performed the
adjustment of blood pressure values, and even in this adjustment,
61.9% showed a higher effect on PA than on hypertension. So
considering the prevalence of PA among hypertensive individuals,
this result is little bit surprising, we think. So PA may explain
an unexpectedly large amount of genetic background of
hypertension, we think.


Dr. Carolyn Lam:


Wow, thank you so much, Tatsuhiko. So first, genome-wide evidence
for genetic predisposition to PA susceptibility, and then,
revealing that two thirds of previously established BP associated
variants were in fact a higher risk effect for PA than for
hypertension. Wow. So Wendy, could you help us put these findings
into perspective, please?


Dr. Wendy Post:


Thank you, Carolyn. Congratulations to the authors. This was a
really interesting paper that we enjoyed discussing in our
meetings. We were especially interested in the clinical
potential, clinical implications of your study. We all see
patients with hypertension, whether we're cardiologists, or
endocrinologists, or primary care physicians. And so, trying to
understand more about what is potentially the underlying causes
for hypertension, from a biological standpoint, that might help
us to identify and treat our patients appropriately, is really so
important. And so, I was wondering, Kosuke, if you could tell us,
from your perspective as an endocrinologist and a researcher, how
you interpret these studies in a way that our readers might be
able to use these results to think about the next patient we're
seeing in our clinic with hypertension?


Dr. Kosuke Inoue:


Yeah. Thank you very much for asking this important point, Wendy.
We're, first of all, I'm very pleased that our research is
published in Circulation, and thank you very much for your
consideration. And I think there are two major implications of
our findings, treatment and a diagnosis.


First of all, for treatment, well, our findings advance our
current state of knowledge about PA pathogenesis. Like Wendy
said, what is the causes? And what is the genetic causes of
primary aldosteronism ? And particularly, it'll be helpful for
better precision medicine in the future. And therapy involving
genetic information, this may not be the clinical practice
tomorrow, but this would advance our clinical practice in the
future.


And the second point is diagnosis. Well, primary aldosteronism is
really important to diagnose, because treating only blood
pressure, or hypertension, is not enough for patients with
primary aldosteronism. Like Tatsu said, aldosteronism itself has
a direct effect on organ damage beyond blood pressure, elevated
blood pressure. So diagnosis of primary aldosteronism is
critical, and our findings showed 10%, the current percentage of
10% primary aldosteronism, may not be fully diagnosed patients,
given that 67% of PA associated variants presented higher
alteration for the PA. So I think, we needed to be more careful
about diagnosing primary aldosteronism. So for those who have a
resistant hypertension, or who are suspected to have primary
aldosteronism, we needed to screen more for such patients.


Dr. Wendy Post:


Thank you, that was really helpful. Can I ask you a little bit
more about what you recommend in clinical practice? I've been
asking around, we actually just had our American College of
Cardiology meeting in New Orleans, and I knew this paper had just
been published online, and the editorial is about to come out.
And so, I noticed that there's a lot of variability in practice,
as to whether we screen for PA, or just treat with aldosterone
blocking medications, such as spironalactone. So can you tell me
a little bit more about what you recommend? And maybe your
practice is different as an endocrinologist, but should we just
presume people have primary aldo, and aldosteronism, and treat
them for that? Or should we be searching for aldosterone
producing adenomas, and surgically removing them? If you could,
tell us a little bit more about what you recommend.


Dr. Kosuke Inoue:


Thank you very much for asking this, Wendy. So to be honest, I
don't think we can conclude something only from our result, of
course. But what I can recommend is, from our findings, it is
better to always thinking about primary aldosteronism when
treating patients with hypertension. So those may have and those
may not have that. I think thinking about primary aldosteronism
is important, and if there's a possibility they have, or if their
clinicians have trouble treating hypertension, then I would
recommend screening for such patients about primary
aldosteronism.


Dr. Wendy Post:


In order to find an adenoma, is that the purpose of the
screening?


Dr. Kosuke Inoue:


I think, whether they have an adenoma or, there are two types of
primary aldosteronism, aldosteronism producing adenoma, and BAH
bilateral adrenal hypocardia. And rather does not have adenoma
itself, but they have a hyper aldosteronism in their blood. So we
cannot tell whether they have a PA or BAH. But anyway, we needed
to think about whether they have excess level of aldosterone, and
if they have, we needed to think about the proper treatment, such
as medication therapy or surgical treatment.


Dr. Wendy Post:


Thank you. So if they have bilateral adrenal hyperplasia, then
medical therapy.


Dr. Kosuke Inoue:


Yes.


Dr. Wendy Post:


If they had an adenoma, you might consider surgical excision.


Dr. Kosuke Inoue:


Generally, yes.


Dr. Wendy Post:


Thank you.


Dr. Carolyn Lam:


Wendy, I love that clinical focus, because much as PA is a highly
morbid cause of secondary hypertension, it's also sometimes seen
as potentially curable, or at least targetable with specific
medical therapy. And thank you for inviting that beautiful
editorial, I'd love to quote from it. Because the final sentence
of it really does say that this paper really reminds everyone
treating hypertension, to maintain a high clinical suspicion for
PA, and hopefully, such a high clinical suspicion will lower the
threshold for biochemical testing. Will motivate the pursuit of
localization studies, to determine if a surgical cure is
possible. And at minimum, allow for early initiation of
mineralocorticoid-receptor blockade. How beautifully put, huh?


So thank you for inviting that editorial. And if I may, are there
any final take home messages from anyone? May I start with Dr.
Tatsuhiko? Any take home messages or next steps you'd like to
mention?


Dr. Tatsuhiko Naito:


Okay. Yeah. I think the future advances in this study first, as
Kosuke said, of PA is mainly classified into aldosterone
producing adenoma and bilateral adrenal hyperplasia. However, we
couldn't identify subtype specific risk associated loci, due to
the lack of statistical power. And specifically, we know that
histopathological features of aldosterone producing adenoma are
reported, vary depending on the causative somatic mutations. So
further insights may be obtained by investigating the genetic
risk of aldosterone producing adenoma, according to the causative
somatic mutations. But anyways, we are happy to present the
genome-wide association genetic loci that associated with PA in
the cross-ancestry cohort for the first time. Thank you.


Dr. Carolyn Lam:


Thank you. Kosuke?


Kosuke Inoue:


Sure. So I totally agree with what Tatshu said, and also,
aldosterone is a nasty hormone. So as a clinician, I would
recommend, for all clinicians who treat patients with
hypertension, please always consider aldosterone, and whether
their aldosterone should be treated or not. And thank you.


Dr. Carolyn Lam:


Wendy?


Dr. Wendy Post:


I also wanted to get back to your statements, Kosuke, about
precision medicine. And this was a genetic study, and you did
mention how this could potentially lead to precision medicine,
practical approaches to identifying patients who might be treated
with specific therapies, based on their genetics. And of course,
we're not there yet, but thanks for helping us to get closer to
that vision in the future.


Dr. Carolyn Lam:


Indeed, thank you so much for publishing this very important
paper in Circulation, and for coming online to discuss it today.


You've been listening to Circulation on the Run. Thank you
listeners for joining us today, and don't forget to tune in again
next week.


Dr. Greg Hundley:


This program is copyright of the American Heart Association 2023.
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.