Circulation May 26, 2020 Issue

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: I'm Greg Hundley, Associate Editor, Director of
the Poly Heart Center at VCU Health in Richmond, Virginia.


Dr Carolyn Lam: Today's feature discussion is the first huge look
at the global, regional and national burden of calcific aortic
valve disease and degenerative mitral valve disease over a huge
period, from 1990 to 2017. Very important discussion coming right
up after this coffee chat.


Greg, do you mind if I go first?


Dr Greg Hundley: Go ahead, Carolyn.


Dr Carolyn Lam: The first paper I want to talk about applies
novel single cell transcriptomics to unveil new insights into
pressure overload cardiac hypertrophy. Here's your quiz, Greg,
ready?


Dr Greg Hundley: Well, I'm choking on my coffee here, but go
ahead.


Dr Carolyn Lam: All right, I was thinking of asking you about
single cell transcriptomics but let me just tell you the results.
Single cell RNA sequencing is a new and rapidly advancing
technique that can comprehensively characterize gene expression
and relationships among individual cells.


Dr Wang from Fuwai Hospital, National Center for Cardiovascular
Diseases, Chinese Academy of Medical Sciences, and Peking Union
Medical College and colleagues analyze the transcriptomes of
11,492 single cells and identified major cell types, including
both cardiomyocytes and non-cardiomyocytes based on their
molecular signatures. They did this at different stages during
the progression of pressure overload induced cardiac hypertrophy
in a mouse model.


Their findings not only illustrated dynamically changing cell
type crosstalk doing pathological cardiac hypertrophy, but also
shed light on strategies for cell type and stage specific
interventions in cardiac disease. For example, subtype switching
of macrophages was found to be a key event underlying the
transition from normal to decline dejection fraction in cardiac
hypertrophy.


Thus, targeting macrophages in hypertrophy for example, during
the switch could attenuate disease progression. All of this is
discussed in an editorial by doctors, Zhang and Zhou from
University of Alabama in Birmingham.


Dr Greg Hundley: Oh wow. Carolyn very important macrophage
infiltration and another role for those, that cell type. Well, my
first paper gets at the topic of reversal of these factor Xa
inhibitors.


In this particular patient population, it's the situation where
we're dealing with intracranial hemorrhage. The article comes
from Dr G Morgan Jones and colleagues from the University of
Tennessee Health Sciences Center. Since the approval of oral
factor Xa inhibitors, there have been few papers published really
regarding the ability to neutralize the anti-coagulate effects of
these agents, particularly after intercranial hemorrhage.


Dr Carolyn, this is a multi-center, retrospective, observational
cohort study of 433 patients. Then it received apixaban, or
rivaroxaban, and then developed an intercranial hemorrhage. They
then subsequently received prothrombin complex concentrates in
that period of time between 2015 and 2019.


Dr Carolyn Lam: Wow. How did these participants who had
intracranial hemorrhage, how did they fare after receiving these
prothrombin concentrates?


Dr Greg Hundley: Yeah, well, administration of the prothrombin
complex concentrates after, apixaban or rivaroxaban in the
setting of intracranial hemorrhage, provided a high rate of
excellent or good hemostasis. That was in nearly 82%, coupled
with an adverse consequence of 3.8% of those experiencing a
thrombosis.


Thrombosis occurred in 25 patients who had a total of 26
thrombotic events of which 22 occurred in the first 14 days,
following the prothrombin complex concentrate administration. One
patient had documentation of an infusion related reaction. For
the full cohort of patients, in the hospital mortality was 19%
and the median ICU care and hospital length of stay were two and
six days respectively.


Carolyn, these cohort analyses seemed to demonstrate the
possibility of success and similar to other observational cohort
studies. The results of this study suggest that future randomized
control trials evaluating the clinical efficacy of these
prothrombin complex concentrates in patients with factor Xa
inhibitor related intercranial hemorrhage are needed.


Dr Carolyn Lam: Nice, Greg. You know what? I'm going to start
with a quiz. True or false, heart failure with reduced ejection
fraction is characterized by blunting of the positive
relationship between heart rate and left ventricular
contractility known as the force frequency relationship?


Dr Greg Hundley: Well, Carolyn, this is one of those where if I
go 50/50, you'll knock out the wrong answer. Let's say, I'm going
to go, true.


Dr Carolyn Lam: You're so right, Greg. This next paper really
deals with this. It's from corresponding author, Dr Witt from
Leeds Institute of Cardiovascular and Metabolic Medicine,
University of Leeds in UK and colleagues who previously described
that, tailoring the rate responsive programming of cardiac
implantable electronic devices in patients with HFrEF based upon
individuals noninvasive force frequency relationship data, really
improves exercise capacity. Addressing this reduce force
frequency relationship and HFrEF.


 Now in the current paper, they sought to examine whether
using force frequency relationship data to tailor heart rate
response in HFrEF with inpatients, with HFrEF and cardiac
implantable electronic devices would favorably influence exercise
capacity and left ventricular function six months later.


They conducted a single center, double blind, randomized parallel
group trial in 83 patients with HFrEF. With a cardiac implantable
electronic device and randomized to tailored rate response
programming based on these individuals force frequency
relationship versus conventional age guided rate response
programming. The primary outcome measure was changed in walk time
on a treadmill walk test.


Dr Greg Hundley: Wow, Carolyn. So this is a really detailed
analysis. What did they find?


Dr Carolyn Lam: They found that rate adaptive cardiac implantable
electronic device programming taking into account the at normal
force frequency relationship in these patients, was associated
with improved exercise time.


Force frequency relationship guided heart rate settings had no
adverse effects on left ventricular structure and function. While
conventional settings were associated with a reduction in left
ventricular ejection fraction.


Out of the box age guided rate adaptive pacing, might be a sub
optimal choice in patients with heart failure and an assessment
of the force frequency relationship might be of clinical benefit
in facilitating personalized rate adaptive programming.


Dr Greg Hundley: Very nice.


Dr Carolyn Lam: Thanks Greg, but there's other stuff I want to
tell you about in this issue. There's a research letter by Dr
Gambier on Molecular Imaging of Infective Endocarditis with
Floral Multiple Trials PET-CT. This is the first time that a
Florine 18 PET tracer has been used to specifically image
bacterial infection of the heart valves with high sensitivity and
specificity in an animal model.


Dr Greg Hundley: Oh, good job, Carolyn. Those flooring tracers,
very interesting. Another application perhaps. Well, in a
perspective piece, I have an article Carolyn from Dr Orly Vardeny
from University of Minnesota Medical School in Minneapolis and
remembers the prior cardiovascular complications from influenza.
And how those experiences may be useful in anticipating some of
the cardiovascular complications that we may see from SARS-CoV-2.


In a separate article, Dr Aatish Garg and collaborators from VCU
Health, present an ECG case of syncope in an individual with
severe aortic stenosis status post bioprosthetic aortic valve
replacement and coronary artery bypass grassing. Who also has
paroxysmal AV block?


Then finally, Carolyn, Professor Concepcion Peiró from
Universidad Autónoma in Madrid. Has an on my mind pace discusses
ACE inhibition and our abuse in relation to the SARS-CoV-2 to
virus bonding to ACE two binding sites within the respiratory
epithelium.


Well, Carolyn, how about we get on to that feature discussion? I
can't wait to hear about aortic and mitral valve disease over
nearly 30 years.


Dr Carolyn Lam: Let's go Greg. Nondramatic valvular heart disease
is really common throughout the world. However, no studies have
previously estimated their global or national burden, that is
until today's feature paper. That's part of the Global Burden of
Disease, or GBD, 2017 study. I am so pleased to have with us a
corresponding author, Dr Greg Roth from University of Washington.
As well as Victoria Delgado, our associate editor from Leighton
University Medical Center.


What a great topic to discuss. Nondramatic valvular heart
disease, meaning calcific aortic valve disease, degenerative
module valve disease, all the stuff we see and have to deal with
now. Greg, could you please tell us about this GBD effort and
really what you found?


Dr Greg Roth: Let me tell you a little bit about the Global
Burden of Disease Study and then why we wanted to explore this
question and then what we found. I am the lead for cardiovascular
research at the Institute for Health Metrics and Evaluation in
Seattle at the University of Washington. We're the coordinating
center for the Global Burden of Disease Study. It's now in its
second decade, and it's a large-scale effort to quantify the lost
health due to early death and disability for every country in the
world.


This is a huge effort with over 5,000 people around the world
working on it. We work closely with governments around the world,
as well as the World Health Organization, as well as county,
state, and other authorities in the US.


Our goal is really to bring together all of the evidence in the
world to bear on important health policy questions. One of the
areas that I've had a long interest in is valve disease.


I'm a practicing cardiologist at our county hospital here in
Seattle, as well as an echocardiographer. I was really excited by
the idea of bringing together my passion for taking care of
patients with valve disease and looking at how to use diagnostic
imaging to take better care of them and the disease modeling
research that I do at the institute.


We decided a couple of years ago after exploring the global
patterns of rheumatic heart disease, that we would turn our focus
towards these really important questions of non-rheumatic valve
disease. There's obviously a very large literature and lots of
active research around the clinical pathways that we need to
follow for patients with calcific valve disease and mitral valve
disease that's not due to rheumatic causes. Obviously in recent
years, we've got amazing technologies and interventions that
we're using more and more frequently like percutaneous
interventions.


However, we had not done the work to turn this really interesting
tool, the Global Burden of Disease Study, towards looking at
these important causes. We pulled together every data source we
could find on the population level burden of nonrheumatic valve
disease and then using a range of techniques, and we rely heavily
on tools that come out of data science.


These include computer disease modeling tools that we've
developed as well as ensemble models and other sort of big data
approaches to pull all of this together into comparable,
consistent estimates of death and prevalence. Then we're also
really interested in using those to estimate what we call summary
metrics of health, like disability adjusted life years. We do
this for a very long time series. So we went back all the way to
1990 and we looked all the way to 2017.


Then we're able to get a really good sense of not only what the
impact of these diseases are, but how they compare to the 350
other diseases that we estimated in exactly the same way for the
Global Burden of Disease Study. Also, where is the burden of
these particular conditions going up? Where is it going down?


We're really excited to be able to pull that together into this
paper. In which we report the global, regional, and national
burdens of calcific aortic valve disease and degenerative mitral
valve disease. As well as a right sided valve disease that's not
due to congenital endocarditis causes, which we estimate
separately in the study.


Dr Carolyn Lam: Greg, you say, you're excited. I can definitely
speak, I think on behalf of both Victoria and Augie, that we're
the ones excited publishing this really great piece of work here
in circulation. You know personally, I'm a great fan of your work
in GBD. Tell us the results.


Dr Greg Roth:  What we found was that in 2017, there was an
estimated 12.6 million cases of calcific aortic valve disease in
the world and 18.1 million cases of degenerative valve disease
globally. With higher rates of calcific valve disease, among men
and higher rates of degenerative valve disease among women. Now
that is an aggregate.


We've produced estimates for every country in the world and for
larger countries with more than 200 million people, we've gone
down to what we call the first administrative level. So, US
states, Chinese provinces, and we do this in the larger
countries, but when you add it all up, you get those numbers.


We also found that there were just over a hundred thousand deaths
globally each year due to calcific aortic valve disease and about
35,000 deaths reported due to degenerative mitral valve disease.
I think this is really interesting because of course, as
clinicians, we have a lot of experience with sources like cohort
studies, and trials, and registries, but we have not actually
looked at what's actually the world's largest public health
reporting system, which is vital registration, meaning death
certificates.


Now, most of us have filled out that certificates and we always
wonder, how reliable are there? And there's clearly limitations.
In fact, a huge amount of our work at the Global Burden of
Disease Study is dealing with the limitations of death
certificates, looking for bias, and adjusting that bias when we
can, but these are death certificates where somebody's entered
these causes as the underlying cause of death.


I think when that actually shows up on a death certificate,
that's actually a real signal to us that there was a physician
out there who felt pretty strongly that that was the sort of
trigger that led to the patient's death.


We also found that aging and population growth are leading to
about a hundred percent increase over this period of time over
the last 25 years in the number of deaths due to these
nonrheumatic valve diseases. If we age standardized, we see that
the trend is flat, but if you're running a health system or a
minister of health, you need to hear that message that with aging
and population growth affecting almost every country in the
world, you're going to see dramatic rises in the number of cases
of both of these conditions showing up on the doorstep of all of
your hospitals.


Dr Carolyn Lam: Fantastic Victoria, could you put these findings
in context for us and maybe take us behind the scenes a little
bit at what the editors thought?


Dr Victoria Delgado: These are very important data, because so
far, for example, we have, as Greg said, registries and one of
the most known registries was for example, in Europe, The
Valvular Heart Survey that was done in 2001, if I remember well.
Has been redone recently, it was last year published in
circulation. The other one with a very large data is coming from
counties. With similar data to the results that are publishing
now.


For example, if you compare those two registries with much
smaller populations, in US, they always report much, much
frequently the genetic mitral valve regurgitation. While in
Europe, aortic stenosis is the most frequent one, calcific aortic
stenosis. Here, I was again surprised with in the global
population that again, degenerative mitral valve regurgitation is
much more prevalent than calcific aortic stenosis, but you can
see that there was an increase of 124% in the prevalence of
calcific aortic valve disease in 2017.


I wonder if this is related to the awareness of the risk
associated with aortic stenosis and they invent of a new
therapies, transcatheter therapies, with the TAVI for example, or
transcatheter aortic valve replacement, which has opened the door
for an effective treatment for many patients that before were
simply denied for surgery. I don't know if you have further
insights into that.


Dr Greg Roth: Yes. I think that's a really important point, that
we see a lot of variation in the data. While we have millions of
death certificates to look at all around the world. Really scores
of millions, where we can look for trends and patterns. The
population level data on nonrheumatic valve disease is actually
quite limited compared to most diseases.


We did a very aggressive perspective review of the published and
gray literature and found about 50 sources reporting prevalence
for these conditions that were usable in our study. For the most
part, those studies are not long time series. We have to estimate
trends, piecing together data from different populations.


Now, there are a couple of places in the world where you can get
a long trend of time where they've gone back repeatedly in the
same population and looked with echo, which you obviously need
here to make these diagnoses.


As far as we can tell, and these are just a handful of studies,
the trend is flat. We don't see large increases. Now, the
increases in our study were completely driven by aging and
population growth and the age standardized rates. The
epidemiologic pattern for this disease is that it's flat and for
mitral valve disease, maybe trending down a little bit.


I think it's clear that in places where there's been a lot of
attention paid either because of new therapies, like TAVR or new
access to diagnostic screening with the growth of echo
cardiography and other screening methods, that is a limitation of
the study, for sure. I think what it really focuses me on is the
idea that we need better data. We need to think about ways and
probably more cost effective ways of surveilling for these
conditions, but I'll tell you something that was really
interesting, that we found is that, in the United States where we
relied heavily on administratively coded data, because we have
that in a uniform format for every state and we have a long time
series for that, and we have complete vital registration.


We looked at the state level and we found that the all ages rate,
was actually going up. Meaning it wasn't just population growth
and aging, but in about a third of the states, the true
epidemiologic rate of the disease was going up. Meaning it's
becoming more common even if you control for the change in age
structure of a country like the United States over time.


I think that given the fact that we're seeing this explosion of
obesity around the world, and we know that atherosclerotic risk
factors can be a major driver of let's say calcific aortic valve
disease. I mean, an interesting question is, is valve disease
going to be sort of a canary in the coal mine? Are we going to
see more of it at younger ages?


Traditionally it's been the oldest patients who actually survived
the longest and tend to be healthier, who we can actually find
having the disease, but I wonder, are we going to see more of
that as patients present with more obesity. Unfortunately we know
that reversing or controlling those atherosclerotic risk factors
hasn't paid off in big ways for preventing calcific aortic valve
disease. It's complex and like mitral valve disease, clearly
there's likely to be a very strong genetic component as well.


Dr Carolyn Lam: Greg, you mentioned a little bit more about the
age effect, but you did mention some sex differences. Could you
just clarify a little bit about that and maybe the interaction
between the two?


Dr Greg Roth: What we've all been taught, or at least what I was
always taught, was that there was more mitral valve disease in
women. We actually did find that in the study and that was
reassuring because when we went back to look for the source of
that sort of common teaching, actually, it's pretty hard to find.


I think it actually comes, my guess is, from a lot of people's
clinical practice. To see that match-up between what we thought
was going to be true in terms of the relative prevalence by sex
for these two major diseases, calcific aortic valve disease and
degenerative mitral valve disease was reassuring. It suggested
that the data we have is actually picking up on real patterns and
patterns that match sort of our clinical experience as well.


One of the interesting things about the interaction between age
and sex, is that women live much longer on average than men. As
women age into those oldest years, what we actually see is a
decline in the burden of disease. There's an increase in stroke,
but for everything else, those women are truly survivors.
Actually we see less bowel disease and cardiovascular disease in
general, in the oldest old women.


What we do see is a massive rise in cognitive impairment and
dementia. That's a very active area of research for us right now.
The interaction between atherosclerotic risks, which can drive
things like valve disease and of course, coronary disease and
stroke and then the cognitive impact is a really important area
of research. There are a couple of great papers that have come
out even just in the last few weeks.


I think this question of how risk is going to impact people in
those oldest age groups? Is really important. We know the
population is aging. We know that in some places, life expectancy
is increasing to the point where we really need to rethink what
the disease patterns are going to be in the oldest old.


Dr Carolyn Lam: Indeed. So the feminization of aging is kind of
what I like to call it, but yikes Victoria. Could I maybe ask you
to please give the final words of advice and maybe the take home
messages?


Dr Victoria Delgado: I think that this data are really welcomed
because as Greg said, we need to understand better how we can
modify the prognosis of these prevalent and how we can tackle it
and for that we need data. I think that these are very welcomed
data.


Now, how we are going to do it in the future? That's a great
question. I don't have the answer right now, but I think that
increasing the awareness that nonrheumatic valvular heart disease
can impact as well on the outcomes of the population, is
important to know. I think that people need to have access to
diagnostics best particularly echo cardiography is very available
imaging technique and very feasible. We can have right now
developments where we can do the echo cardiography with our phone
by adding one of the probes.


I think that in the future, we may see more and more valvular
heart disease that probably was already there, but we just need
to increase the awareness. From those data, learn how we can
treat those individuals if they need and how we can improve the
outcome of these individuals.


Dr Carolyn Lam: Thank you, Victoria. Thank you, Greg. More
awareness and more good data needed.


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


Dr Greg Hundley: This program is copyright the American Heart
Association, 2020.