Circulation November 23, 2021 Issue

Please join first author Yuan Lu and Guest Editor Jan
Staessen as they discuss the article "National Trends and
Disparities in Hospitalization for Acute Hypertension Among
Medicare Beneficiaries (1999-2019)."


Dr. Carolyn Lam:


Welcome to Circulation on the Run: your weekly podcast, summary
and backstage pass to the journal and it's 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, and director of
Pauley Heart Center at VCU health in Richmond, Virginia.


Dr. Carolyn Lam:


Greg, today's feature discussion is about the national trends and
disparities and hospitalizations for hypertensive emergencies
among Medicare beneficiaries. Isn't that interesting? We're going
to just dig deep into this issue, but not before we discuss the
other papers in today's issue. I'm going to let you go first
today while I get a coffee and listen.


Dr. Greg Hundley:


Oh, thanks so much, Carolyn. My first paper comes to us from the
world of preclinical science and it's from professor Christoff
Maack from University Clinic Wursburg. Carolyn, I don't have a
quiz for you, so I'm going to give a little break this week, but
this particular paper is about Barth syndrome. Barth syndrome is
caused by mutations of the gene encoding taffazin, which
catalyzes maturation of mitochondrial cardiolipin and often
manifests with systolic dysfunction during early infancy. Now
beyond the first months of life, Barth syndrome cardiomyopathy
typically transitions to a phenotype of diastolic dysfunction
with preserved ejection fraction, one of your favorites, blunted
contractile reserve during exercise and arrhythmic vulnerability.
Previous studies traced Barth syndrome cardiomyopathy to
mitochondrial formation of reactive oxygen species. Since
mitochondrial function and reactive oxygen species formation are
regulated by excitation contraction coupling, these authors
wanted to use integrated analysis of mechano-energetic coupling
to delineate the pathomechanisms of Barth syndrome
cardiomyopathy.


Dr. Carolyn Lam:


Oh, I love the way you explained that so clearly, Greg. Thanks.
So what did they find?


Dr. Greg Hundley:


Right, Carolyn. Well, first defective mitochondrial calcium
uptake prevented Krebs cycle activation during beta adrenergic
stimulation, abolishing NADH regeneration for ATP production and
lowering antioxidative NADPH. Second, Carolyn, mitochondrial
calcium deficiency provided the substrate for ventricular
arrhythmias and contributed to blunted inotropic reserve during
beta adrenergic stimulation. And finally, these changes occurred
without any increase of reactive oxygen species formation in or
omission from mitochondria. So Carolyn what's the take home here?
Well, first beyond the first months of life, when systolic
dysfunction dominates, Barth syndrome cardiomyopathy is
reminiscent of heart failure with preserved rather than reduced
ejection fraction presenting with progressive diastolic and
moderate systolic dysfunction without relevant left ventricular
dilation. Next, defective mitochondrial calcium uptake
contributes to inability of Barth syndrome patients to increase
stroke volume during exertion and their vulnerability to
ventricular arrhythmias. Lastly, treatment with cardiac
glycosides, which could favor mechano-energetic uncoupling should
be discouraged in patients with Barth syndrome and left
ventricular ejection fractions greater than 40%.


Dr. Carolyn Lam:


Oh, how interesting. I need to chew over that one a bit more.
Wow, thanks. But you know, I've got a paper too. It's also
talking about energetic basis in the presence of heart failure
with preserved ejection fraction, but this time looking at
transient pulmonary congestion during exercise, which is
recognized as an emerging and important determinant of reduced
exercise capacity in HFpEF. These authors, led by Dr. Lewis from
University of Oxford center for clinical magnetic resonance
research sought to determine if an abnormal cardiac energetic
state underpins this process of transient problem congestion in
HFpEF.


Dr. Carolyn Lam:


To investigate this, they designed and conducted a basket trial
covering the physiological spectrum of HFpEF severity. They
non-invasively assess cardiac energetics in this cohort using
phosphorous magnetic resonance spectroscopy and combined real
time free breathing volumetric assessment of whole heart
mechanics, as well as a novel pulmonary proton density, magnetic
resonance imaging sequence to detect lung congestion, both at
rest and during submaximal exercise. Now, Greg, I know you had a
look at this paper and magnetic resonance imaging, and
spectroscopy is your expertise. So no quiz here, but could you
maybe just share a little bit about how novel this approach is
that they took?


Dr. Greg Hundley:


You bet. Carolyn, thanks so much for the intro on that and so
beautifully described. What's novel here is they were able to
combine imaging in real time, so the heart contracting and
relaxing, and then simultaneously obtain the metabolic
information by bringing in the spectroscopy component. So really
just splashing, as they might say in Oxford, just wonderful
presentation, and I cannot wait to hear what they found.


Dr. Carolyn Lam:


Well, they recruited patients across the spectrum of diastolic
dysfunction and HFpEF, meaning they had controls. They had nine
patients with type two diabetes, 14 patients with HFpEF and nine
patients with severe diastolic dysfunction due to cardiac
amyloidosis. What they found was that a gradient of myocardial
energetic deficit existed across the spectrum of HFpEF. Even at
low workload, the energetic deficit was related to a markedly
abnormal exercise response in all four cardiac chambers, which
was associated with detectable pulmonary congestion. The findings
really support an energetic basis for transient pulmonary
congestion in HFpEF with the implication that manipulating
myocardial energy metabolism may be a promising strategy to
improve cardiac function and reduce pulmonary congestion in
HFpEF. This is discussed in a beautiful editorial by Drs.
Jennifer Hole, Christopher Nguyen and Greg Lewis.


Dr. Greg Hundley:


Great presentation, Carolyn, and obviously love that MRI/MRS
combo. Carolyn, these investigators in this next paper led by Dr.
Sara Ranjbarvaziri from Stanford University School of Medicine
performed a comprehensive multi-omics profile of the molecular.
So transcripts metabolites, complex lipids and ultra structural
and functional components of hypertrophic cardiomyopathy
energetics using myocardial samples from 27 hypertrophic
cardiomyopathy patients and 13 controls really is the donor
heart.


Dr. Carolyn Lam:


Wow, it's really all about energetics today, isn't it? So what
did they see, Greg?


Dr. Greg Hundley:


Right, Carolyn. So hypertrophic cardiomyopathy hearts showed
evidence of global energetic decompensation manifested by a
decrease in high energy phosphate metabolites (ATP, ADP,
phosphocreatine) and a reduction in mitochondrial genes involved
in the creatine kinase and ATP synthesis. Accompanying these
metabolic arrangements, quantitative electron microscopy showed
an increased fraction of severely damaged mitochondria with
reduced crystal density coinciding with reduced citrate synthase
activity and mitochondrial oxidative respiration. These
mitochondrial abnormalities were associated with elevated
reactive oxygen species and reduced antioxidant defenses.
However, despite significant mitochondrial injury, the
hypertrophic cardiomyopathy hearts failed to up-regulate
mitophagic clearance.


Dr. Greg Hundley:


So Carolyn, in summary, the findings of this study suggest that
perturbed metabolic signaling and mitochondrial dysfunction are
common pathogenic mechanisms in patients with hypertrophic
cardiomyopathy, and these results highlight potential new drug
targets for attenuation of the clinical disease through improving
metabolic function and reducing myocardial injury.


Dr. Carolyn Lam:


Wow, what an interesting issue of our journal. There's even more.
There's an exchange of letters between Drs. Naeije and Claessen
about determinants of exercise capacity in chronic thromboembolic
pulmonary hypertension. There's a "Pathways to Discovery" paper:
a beautiful interview with Dr. Heinrich Taegtmeyer entitled,"A
foot soldier in cardiac metabolism."


Dr. Greg Hundley:


Right, Carolyn, and I've got a research letter from Professor
Marston entitled "The cardiovascular benefit of lowering LDL
cholesterol to below 40 milligrams per deciliter." Well, what a
great issue, very metabolic, and how about we get onto that
feature discussion?


Dr. Carolyn Lam:


Let's go, Greg.


Dr. Greg Hundley:


Welcome listeners to our feature discussion today. We have a
paper that is going to address some issues pertaining to high
blood pressure, or hypertension. With us, we have Dr. Yuan Lu
from Yale University in New Haven, Connecticut. We also have a
guest editor to help us review this paper, Dr. Jan Staessen from
University Louvain in Belgium. Welcome to you both and Yuan, will
start with you. Could you describe for us some of the background
that went into formulating your hypothesis and then state for us
the hypothesis that you wanted to address with this research?


Dr. Yuan Lu:


Sure. Thank you, Greg. We conducted this study because we see
that recent data show hypertension control in the US population
has not improved in the last decades, and there are widening
disparities. Also last year, the surgeon general issued a call to
action to make hypertension control a national priority. So, we
wanted to better understand whether the country has made any
progress in preventing hospitalization for acute hypertension.
That is including hypertension emergency, hypertension urgency,
and hypertension crisis, which also refers to acute blood
pressure elevation that is often associated with target organ
damage and requires urgent intervention. We have the data from
the Center for Medicare/Medicaid, which allow us to look at the
trends of hospitalization for acute hypertension over the last 20
years and we hypothesize we may also see some reverse progress in
hospitalization rate for acute hypertension, and there may
differences by population subgroups like age, sex, race, and dual
eligible status.


Dr. Greg Hundley:


Very nice. So you've described for us a little bit about perhaps
the study population, but maybe clarify a little further: What
was the study population and then what was your study design?


Dr. Yuan Lu:


Yeah, sure. The study population includes all Medicare
fee-for-service beneficiaries 65 years and older enrolled in the
fee-for-service plan for at least one month from January 1999 to
December 2019 using the Medicare denominator files. We also study
population subgroups by age, sex, race and ethnicity and dual
eligible status. Specifically the racial and ethnic subgroups
include Asian, blacks, Hispanics, North American native, white,
and others. Dual eligible refers to beneficiary eligible for both
Medicare and Medicaid. This study design is a serial cross
sectional analysis of these Medicare beneficiaries between 1999
and 2019 over the last 20 years.


Dr. Greg Hundley:


Excellent. Yuan, what did you find?


Dr. Yuan Lu:


We actually have three major findings. First, we found that in
Medicare beneficiaries 65 years and older, hospitalization rate
for acute hypertension increased more than double in the last 20
years. Second, we found that there are widening disparities. When
we look at all the population subgroups, we found black adults
having the highest hospitalization rate in 2019 across age, sex,
race, and dual eligible subgroup. And finally, when we look at
the outcome among people hospitalized, we found that during the
same period, the rate of 30 day and 90 day mortality and
readmission among hospitalized beneficiaries improved and
decreased significantly. So this is the main findings, and we can
also talk about implications of that later.


Dr. Greg Hundley:


Very nice. And did you find any differences between men and
women?


Dr. Yuan Lu:


Yes. We also looked at the difference between men and women, and
we found that actually the hospitalization rate is higher among
females compared to men. So more hospitalizations for acute
hypertension among women than men.


Dr. Greg Hundley:


Given this relatively large Medicare/Medicaid database and
cross-sectional design, were you able to investigate any
relationships between these hospitalizations and perhaps social
determinants of health?


Dr. Yuan Lu:


For this one, we haven't looked into that detail. This is just
showing the overall picture, like how the hospitalization rate
changed over time in the overall population and by different
population subgroups. What you mentioned is an important issue
and should definitely be a future study to look at whether social
determine have moderated the relationship between the
hospitalization.


Speaker 3:


Excellent. Well, listeners, now we're going to turn to our guest
editor and you'll hear us talk a little bit sometimes about
associate editors. We have a team that will review many papers,
but when we receive a paper that might contain an associate
editor or an associate editors institution, we actually at
Circulation turn to someone completely outside of the realm of
the associate editors and the editor in chief. These are called
guest editors. With us today, we have Dr. Jan Staessen from
Belgium who served as the guest editor. He's been working in this
task for several years. Jan, often you are referred papers from
the American Heart Association. What attracted you to this
particular paper and how do you put Yuan's results in the context
with other studies that have focused on high blood pressure
research?


Dr. Jan Staessen:


Well, I've almost 40 years of research in clinical medicine and
in population science, and some of my work has been done in
Sub-Saharan Africa. So when I read the summary of the paper, I
was immediately struck by the bad results, so to speak, for black
people. This triggered my attention and I really thought this
message must be made public on a much larger scale because there
is a lot of possibility for prevention. Hypertension is a chronic
disease, and if you wait until you have an emergency or until you
have target organ damage, you have gone in too late. So really
this paper cries for better prevention in the US. And I was
really also amazed when I compared this US data with what happens
in our country. We don't see any, almost no hospitalizations for
acute hypertension or for hypertensive emergencies. So there is
quite a difference.


Dr. Jan Staessen:


Going further on that, I was wondering whether there should not
be more research on access to primary care in the US because
people go to the emergency room, but that's not a place where you
treat or manage hypertension. It should be managed in primary
care with making people aware of the problem. It's still the
silent killer, the main cause of cardiovascular disease, 8
million deaths each year. So this really triggered my attention
and I really wanted this paper to be published.


Dr. Greg Hundley:


Very nice. Jan, I heard you mention the word awareness. How have
you observed perhaps differences in healthcare delivery in
Belgium that might heighten awareness? You mentioned primary
care, but are there any other mechanisms in place that heighten
awareness or the importance?


Dr. Jan Staessen:


I think people in Belgium, the general public, knows that
hypertension is a dangerous condition. That it should be well
treated. We have a very well built primary care network, so every
person can go to a primary care physician. Part of the normal
examination in the office of a primary care physician is a blood
pressure measurement. That's almost routine in Belgium. And then
of course not all patients are treated to go. Certainly keeping
in mind the new US guidelines that aim for lower targets, now
recently confirmed in the Chinese study, you have to sprint three
cells. And then the recent Chinese study that have been published
to the New England. So these are issues to be considered. I also
have colleagues working in Texas close to the Mexican border at
the university place there, and she's telling me how primary care
is default in that area.


Dr. Jan Staessen:


I think this is perhaps part of the social divide in the US. This
might have to be addressed. It's not only a problem in the US,
it's also a problem in other countries. There is always a social
divide and those who have less money, less income. These are the
people who fell out in the beginning and then they don't see
primary care physicians.


Dr. Jan Staessen:


Belgium, for instance, all medicines are almost free. Because
hypertension is a chronic condition prevention should not only
start at age 65. Hypertension prevention should really start at a
young age, middle age, whenever this diagnosis of high blood
pressure diagnosis is confirmed. Use blood pressure monitoring,
which is not so popular in the US, but you can also use home
blood pressure monitoring. Then you have to start first telling
your patients how to improve their lifestyle. When that is not
sufficient, you have to start anti hypertensive drug treatment.
We have a wide array of anti hypertensive drugs that can be
easily combined. If you find the right combination, then you go
to combination tablets because fewer tablets means better patient
adherence.


Dr. Greg Hundley:


Yuan we will turn back to you. In the last minutes here, could
you describe some of your thoughts regarding what you think is
the next research study that needs to be performed in this sphere
of hypertension investigation?


Dr. Yuan Lu:


Sure. Greg, in order to answer your question, let me step back a
little bit, just to talk about the implication of the main
message from this paper, and then we can tie it to the next
following study. We found that the marked increase in
hospitalization rate for acute hypertension actually represented
many more people suffering a potential catastrophic event that
should be preventable. I truly agree with what Dr. Staessen said,
hypertension should be mostly treated in outpatient setting
rather than in the hospital. We also find the lack of progress in
reducing racial disparity in hospitalization. These findings
highlight needs for new approaches to address both the medical
and non-medical factors, including the social determinants in
health, system racism that can contribute to this disparity. When
we look at the outcome, we found the outcome for mortality and
remission improved over time.


Dr. Yuan Lu:


This means progress has been made in improving outcomes once
people are hospitalized for an acute illness. The issue is more
about prevention of hospitalization. Based on this implication, I
think in a future study we need better evidence to understand how
we can do a better job in the prevention of acute hypertension
admissions. For example, we need the study to understand who is
at risk for acute hypertensive admissions, and how can this event
be preempted. If we could better understand who these people are,
phenotype this patient better and predict their risk of
hospitalization for acute hypertension, we may do a better job in
preventing this event from happening.


Dr. Greg Hundley:


Very nice. And Jan, do you have anything to add?


Dr. Jan Staessen:


Yes. I think every effort should go to prevention in most
countries. I looked at the statistics, and more than 90% of the
healthcare budget is spent in treating established disease, often
irreversible disease like MI or chronic kidney dysfunction. I
think then you come in too late. So of the healthcare budget in
my mind, much more should go to the preventive issues and
probably rolling out an effective primary care because that's the
place where hypertension has to be diagnosed and hypertension
treatment has to be started.


Dr. Greg Hundley:


Excellent. Well, listeners, we've heard a wonderful discussion
today regarding some of the issues pertaining to hypertension and
abrupt admission to emergency rooms for conditions pertaining to
hypertension, really getting almost out of control. We want to
thank Dr. Yuan Lu from Yale New Haven and also our guest editor,
Dr. Jan Staessen from Louvain in Belgium. On behalf of Carolyn
and myself, we want to wish you a great week and we will catch
you next week on the run. This program is copyright of the
American Heart Association, 2021. The opinions express by
speakers in this podcast are their own and not necessarily those
of the editors or of the American Heart Association for more
visit aha journals.org.