Circulation November 13, 2018 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.


                                               
This week's feature discussion focuses on first and man pilot
study results of pericardiotomy and its influence on left
ventricular diastolic reserve with volume loading. Very
fascinating implications for heart failure with reserved ejection
fraction, coming right up after these summaries.


                                               
Cardiac dysfunction is a major component of sepsis-induced
multi-organ failure in critical care units. But what are the
underlying mechanisms and potential therapeutic approaches to
this? Well, in today's paper from co-first authors Drs Sun and
Yao, corresponding author Dr Chang, and colleagues from UT
Southwestern Medical Center, the authors examine the status of
cardiac autophagy and its role during sepsis pathogenesis using a
rodent lipopolysaccharide-induced sepsis model. They've found
that forced overexpression of Beclin-1 in the heart promoted
autophagy and mitophagy, protected mitochondria, improved cardiac
function, and alleviated inflammation and fibrosis after a
lipopolysaccharide challenge. Whereas, haplosufficiency for
Beclin-1 resulted in the opposite effects. For the more injection
of a cell permeable Tat-Beclin-1 peptide improved outcomes in
lipopolysaccharide-challenged animals. Thus promoting
Beclin-1-dependent signaling may be a novel and effective
intervention to alleviate organ dysfunction caused by maladaptive
autophagy during severe sepsis.


                                               
The next paper presents important experimental data that causes
us to consider the potential cardiovascular hazards of anti
B-cell activating factor immunotherapy, which is currently
approved for the treatment of autoimmune systemic lupus
erythematosus. You see, genomic data has shown that B-cell
activating factor receptor pathway is specifically essential for
the survival of conventional B lymphocytes, which is a key driver
of coronary heart disease. However, in today's paper from
co-first authors, Drs Tsiantoulas and Sage, corresponding author
Dr Binder and colleagues from Medical University of Vienna, the
authors reported an unexpected finding that B-cell activating
factor neutralization increased atherosclerotic plaque size and
complexity despite efficient depletion of mature, conventional B
lymphocytes. Furthermore, the authors provided evidence
suggesting a novel B-cell independent anti-inflammatory property
of B-cell activating factor. They showed that the expression of
the alternative B-cell activating factor binding receptor,
transmembrane activator and CAML interactor in myeloid cells
limited atherosclerosis thus showing novel atheroprotective
pathways. Thus, these results introduce a new perspective with
respect to the potential cardiovascular hazards that may be
associated with the long term blockade of B-cell activating
factor in chronic inflammatory settings. There is a need for more
refine therapeutic approaches targeting the B-cell activating
factor pathway.


                                               
Vascular smooth muscle cells are known to possess remarkable
plasticity undergoing fundamental phenotypic switches from a
differentiated to a dedifferentiated state in response to
vascular injury or remodeling. However, what are the underlying
cellular processes by which vascular smooth muscle cells maintain
their cell identity? Well, in today's paper from co-first authors
Dr Yao, Yu and Li, corresponding Dr Wang from Fu Wai Hospital
National Center for Cardiovascular Diseases, Chinese Academy of
Medical Science and Peking University Medical College. The
authors applied single cell RNA sequencing to analyze disease
human arteries and identified histone variant H2A.Z as a key
histone signature that maintains vascular smooth muscle cell
identity. H2A.Z occupied genomic regions near vascular smooth
muscle cell marker genes and it's occupancy was decreased in
vascular smooth muscle cells undergoing dedifferention. H2A.Z
expression was dramatically reduced at both messenger RNA and
protein levels in diseased human vascular tissues compared to
those in normal arteries. Notably, in vivo overexpression of
H2A.Z rescued injury-induced loss of vascular smooth muscle cells
identity and new intima formation. Together, these data
introduced dynamic occupancy of a histone variant as a novel
regulatory basis contributing to cell fate decisions and implied
that H2A.Z may be a potential intervention known for vascular
diseases.


                                               
What is the causal role of body mass index and cardiovascular
health in young adults? In the next paper from first and
corresponding author Dr Wade from University of Bristol in United
Kingdom and her colleagues. The authors used a combination of
conventional multivariable regression analyses, Mendelian
randomization and subsample recall by genotype methodologies.
Recall by genotype is a novel approach that exploits the random
assortment of alleles through meiotic cell division at conception
to inform genetically base recall and enables the collection of
precise phenotypic measures in smaller studies while maintaining
statistical power and ability for causal inference. The authors
use these methods to estimate the causal effect of body mass
index on gross level and detail cardiovascular health in healthy
participants from the Avon longitudinal study of parents and
children at age 17 years as well as in an independent sample from
the same cohort study at age 21 years.


                                               
Their results showed that higher body mass index was likely to
cause worse cardiovascular health specifically higher blood
pressure and higher left ventricular mass index even in youth.
Higher body mass index also resulted in increased cardiac output
in the recall by genotype study which appeared to be solely
driven by stroke volume, as neither the Mendelian randomization
nor the recall by genotype analyses suggested a causal effect of
body mass index on heart rate. These consistent results support
efforts to reduce body mass index from a young age to prevent
later adverse cardiovascular health and illustrate the potential
for phenotypic resolution with maintained analytical power using
a recall by genotype methodology.


                                               
Older adults undergoing aortic valve replacement are at risk for
malnutrition, however, what is the association between
pre-procedural nutritional status at midterm mortality? First
author, Dr Goldfarb, corresponding author Dr Afilalo from McGill
University in Montreal, Quebec, reported results of the
FRAILTY-AVR prospective multicenter international cohort study
conducted between 2012 and 2017 in 14 centers in three countries.
This study included patients 70 years and older who underwent
transcatheter aortic valve replacement or surgical aortic valve
replacement. The mini nutritional assessment short form was
assessed by trained observers pre procedure with scores seven or
less out of 14 being considered to be malnourished. The short
performance physical battery was simultaneously assessed to
measure physical frailty. The authors found that malnutrition was
associated with higher one-year mortality and 30-day adverse
events following aortic valve replacement via a transcatheter or
surgical approach. While malnutrition and frailty were
interrelated, the integration of nutritional assessment resulted
in improved predictive value for frail patients. Clinical trials
are needed to determine whether pre and post procedural
nutritional interventions can improve clinical outcomes in these
vulnerable patients.


                                               
Do newer generation ultra-thin strut drug-eluding stents improve
clinical outcomes over contemporary thicker strut stents? First
and corresponding author, Dr Bangalore from New York University's
School of Medicine and colleagues search PubMed, Embase and
Central and identified 10 trials that randomized more than 11,650
patients and evaluated three newer generation ultra-thin strut
drug-eluding stents, that is defined as a strut thickness less
than 70 microns, versus thicker strut second generation drug
eluding stents and reported clinical outcomes. They found that
newer generation ultra-thin strut drug-eluding stents were
associated with a 16% reduction in target lesion failure, which
was a composite of cardiovascular death, target vessel myocardial
infarction or ischemia-driven target lesion revascularization
evaluated at one year follow-up. Ultra-thin strut drug-eluding
stents reduced the risk of target-lesion failure driven by a
reduction in myocardial infarction and also a qualitatively lower
rate of stent thrombosis compared to contemporary thicker strut
second generation drug-eluding stents.


                                               
Ambient air pollutants are known to be associated with increased
cardiovascular morbidity and mortality, however, what is the
association between air pollution and cardiac structure and
function? First and corresponding author Dr Aung from Queen Mary
University of London and colleagues performed a cross-sectional
analysis of a large population free of preexisting cardiovascular
disease in the UK Biobank population study. They found that
higher past exposure to fine particulate matter and nitrogen
dioxide were associated with larger cardiac biventricular
volumes. Proximity to major roads, a surrogate for chronic air
pollution exposure, was additionally associated with higher left
ventricular mass. These associations between ambient air
pollution and at first cardiac phenotypic changes, in individuals
without prevalent cardiovascular disease, suggest that air
pollution should be recognized as a major modifiable risk factor
which needs to be targeted by a public health measures.


                                               
The final original paper this week is the first study to
demonstrate a causal link between atrial fibrillation and the
NLRP3 inflammasome, which is an innate inflammation signaling
complex. Co-first authors, Drs Yao and Veleva, corresponding
author Dr Li from Baylor College of Medicine and colleagues
assessed MLRP3 inflammasome activation by immunoblot in atrial
whole tissue lysates and cardiomyocytes from patients with
paroxysmal or long-standing persistent atrial fibrillation. They
found that NLRP3 inflammasome activity was increased in these
patients. To determine whether cardiomyocytes specific activation
of NRLP3 was sufficient to promote atrial fibrillation, they
established a cardiomyocyte specific knock in mouse model which
expressed constitutively active NLRP3. These mice developed
spontaneous premature atrial contractions, an inducible atrial
fibrillation, which was attenuated by a specific NLRP3
inflammasome inhibitor. Cardiomyocyte-specific knockdown of NRLP3
suppressed atrial fibrillation development in these mice. Thus,
these results establish a novel pathophysiological role for
cardiomyocyte NLRP3 inflammasome signaling with a mechanistic
link to the pathogenesis of atrial fibrillation, and suggests
that inhibition of NLRP3 may be a potential novel atrial
fibrillation therapy approach.


                                               
And that brings us to the end of our summaries.


                                               
Now for our feature discussion.


                                               
Is pericardiotomy going to be our next treatment for heart
failure with preserved ejection fraction or HFpEF? I have the
first and corresponding author of a very intriguing research
letter. Dr Barry Borlaug from Mayo Clinic in Rochester,
Minnesota, joining me today to tell today about his great paper.
Barry, welcome back to the show. You are amazing. Congratulations
on yet another wonderful publication. So, could you set us up.
Those of us who don't think about this every day. The
hemodynamics of what pericardiotomy does. Tell us what was the
rationale of doing this study?


Dr Barry
Borlaug:             
You know, it's interesting. We think about intracavitary
pressures on the left side ventricle and the left atrium causing
congestion and pulmonary hypertension. We think that this is all
related to left ventricular issues, but about 30 or 40% of the
pressure is actually related to external restraint on the heart
as mediated by the right ventricle across the septum and the
pericardium and external pericardial contact restraints. In
animals, we've known since back in the late 1970s, that with the
chest open, if you open up the pericardium, which we know in
HFpEF, on average, is shifted up and to the left. It's stiffer.
This effect really comes into play more at higher heart volumes.
It doesn't have as much of an affect at lower heart volumes like
might be absorbed with rest. It's even been rumored that in some
species like greyhounds, illicit dog racers, would actually cut
away the pericardium so these dogs could race better. It's
actually been shown that they can experimentally, in a paper in
the 1980s, that they can exercise the higher peak VO2. They have
a higher cardiac output response, because the heart is better
able to utilize the Frank-Starling relationships to augment
ventricular filling and ejection at fuller pressures.


Dr Carolyn
Lam:               
Oh my goodness. I didn't know that latter fact about the racing
dogs. Could I ask you something? We've talked about this before
back in the day. When you say the left side the filling pressures
go up when there's pericardial restraint, remember we used to
talk about a parallel shift upwards versus true intrinsic
stiffening ... diastolic stiffening. You still do mean that
parallel shift upwards, right?


Dr Barry
Borlaug:             
That's right. If it was purely an increase in stiffness, we would
expect it to sort of rotate, pivot from the bottom left up, but
what we see, and in human data, we published a number of years
ago, most of the increase in LV end-diastolic pressure is a
parallel shift upward in the diastolic pressure volume
relationship. That really suggests that there's an increase in
restraints on the heart. That's why we think that that's an
important target and it's possibly more remediable to treatment
since we're having such tough luck changing the viscoelastic
properties of the left ventricle, not that we shouldn't be doing
that, but this might be something different that we could do that
might give us a little bit more of a benefit in terms of filling
pressure reduction.


Dr Carolyn
Lam:               
True. True. But the way you describe it too, it does mean that we
may be talking about, I hate to say this but, specific subsets or
types of HFpEF, where that may play a bigger role and I'd just
like to bring the audience to your incredible paper that I think
that I've cited a gazillion times already on the obese HFpEF
phenotype. Do you want to remind everyone about that because I
think there you really [inaudible 00:16:30], didn't you that
ventricular interdependence played a big role.


Dr Barry
Borlaug:             
So, in people with obese HFpEF, which is now becoming by far one
of the most dominant. Oh God. We did a study that compared them
to non-obese and we see that the obese patients have a bit more
plasma volume expansion, a bit more cardiac remodeling, right
heart enlargements, increase of LV mass and an increase in
epicardial fat. What all this does is increases the total heart
volume in the pericardial space. Because the pericardium doesn't
appear to grow as much as the heart volume, this increases the
coupling between the right and left heart. Some people, perhaps
like the obese phenotype of HFpEF, might be more poised to derive
benefit from approaches to therapeutically remove this excess
pericardial restraint.


Dr Carolyn
Lam:               
Okay, now you just have to get down to telling us what you did.
This was a first in man pilot study. Drum roll everybody. You
gotta listen up. This was so cool.


Dr Barry
Borlaug:             
This physiology just got us thinking that maybe we could do this
to help our patients with HFpEF. First we tested this in dogs,
then with pigs with features of HFpEF and it seemed to work there
so the next step was to show that it might work in people. We
took people that were already going to get their pericardium
open, so people that were referred for cardiac surgery. We wanted
to choose people that had risk factors for HFpEF and diastolic
dysfunction but maybe not necessarily diagnosed HFpEF.


Dr Barry
Borlaug:             
We took people who were referred for aortic valve replacement for
AS, coronary artery bypass grafting or both and consented them
ahead of time, put catheters into them to measure hemodynamics
and then we measured resting hemodynamics with the chest open,
but pericardium intact, because the changes that we see occur
predominantly when there's an increase in volume load to the
heart, we then had to stress the system. Now we can't have them
exercise cause they're under general anesthesia with an open
chest. You achieve that by elevating their legs and giving them a
little saline bolus, so we had a pressure at rest, pressure with
saline load.


                                               
Then we asked our surgeons to open the pericardium, which they do
obviously to gain access to the heart for cardiac surgery and we
repeated the same assessments and intervention. What we saw was
that the resting filling pressures, again these people did have
diastolic dysfunction, the resting pulmonary wedge pressure was
about 16. With the volume load maneuver, it increased to 25 when
the pericardium was intact. After we had opened the pericardium,
the increase in wedge pressure, which was our primary endpoint,
was reduced from an increase in nine millimeters of mercury down
to an increase of only three millimeters of mercury. So that
verified our hypothesis that the pericardium contributed and that
we could prove total cardiac diastolic reserve, if you will, just
by removing that pericardial restraints.


Dr Carolyn
Lam:               
Wow. I love the figures, by the way, that you've drawn as always
they illustrate that so beautifully. And listeners, this is a
research letter, so there's that one central figure that you must
get your hands on right away. Now Barry, I think the first
question is this wasn't really HFpEF patients right? Let's be
very clear with the audience who these were though and then you
did a subset analyses though, a further analysis that showed this
may apply more to people with higher wedge at rest. Could you
elaborate?


Dr Barry
Borlaug:             
Absolutely. While these people, and Carolyn, I think you know as
well, I think a lot of people probably have HFpEF that they have
a sort of occult HFpEF, that's not been diagnosed maybe because
unfortunately, not everybody else thinks about this diagnosis.
When you look at the charts very carefully, and found out about
13 of the 19 patients complained of significant dyspnea based on
chart review. Of those 13, 10 had other indicators that according
to current criteria would give them the diagnosis. When we looked
at this at this very post hoc, sort of exploratory subset, we
actually saw that these patients, even though they didn't
necessarily have a clinic diagnosis of HFpEF, that these patients
actually responded even more favorably to the effects of
pericardiotomy in their greater reduction in the increase in
wedge pressure. When we plotted in the figure that you mentioned,
we plotted the change in the increase in wedge pressure, it was
really the patients that had the greatest increase with volume
loading initially that derived the most benefit. That makes sense
because those were the people where the pericardium and the
restraint is the becoming most operative, when the heart is most
distended and congested.


Dr Carolyn Lam
               
Maybe one quick last question. What next Dr Borlaug? Gosh, you
just keep coming up with one thing after another with the
animals. I noticed that it was a non-invasive pericardiotomy. I'm
reading between the lines here. What are you going to do next? Do
you think this is ready for prime time?


Dr Barry
Borlaug:             
As usual, you're reading correctly between the lines. We have
filed a patent awhile back for this and we have a device that can
achieve a pericardial modification or an anterior pericardiotomy
without the need for open heart surgery, so that you don't crack
the sternum. It's done from a subxiphoid approach and we've
actually just received some funding to start doing this under an
IDE, which we will need to work with the FDA. We hope to do and
start testing this in patients that have HFpEF and then look at
the acute hemodynamically affects. Then we'll also begin to
explore the safety and potential efficacy using other indices
like imaging, exercise capacity and things like that.


Dr Carolyn
Lam:               
That is just so cool. I think that one of the immediate take home
messages for me now though is when we see patients who we think
have HFpEF, have a low threshold to look for evidence of
constriction. I would say that we may miss the diagnosis of
people who legitimately have constrictive pericarditis and may
need to benefit from this. I think it's one of those hidden
diagnosis, so that's one thing. And then the next thing, if I
could just ask you, are there any patient populations that you
say should not undergo this? And I say this because I remember
back in the day again, when we were experimenting with dog
models, this is just gestalt okay, but I thought that the dogs
who had right-sided heart failure, severe right-sided heart
failure, needed that pericardium to lean on, and if you released
it, the dilatation on the right side would just be inexorable
because there is no pericardium to rein them in. Do you get what
I mean? I don't know. I'm just curious if you have any patient
population right now that you're already thinking I'm not going
to include in my trial.


Dr Barry
Borlaug:             
Yeah. That's a very important point, Carolyn. We would not want
to apply or test initially certainly this therapy where eccentric
cardiac remodeling is a problem because we know that there is a
little bit of eccentric dilatation even in people after a regular
cardiac surgery with pericardiotomy. Marty Molenter showed that,
in a paper back in the 1980s, you have a patient who already has
some dysfunction, we would hypothesize that they may get a bit
worse, so we would not want to test this in people with the right
ventricular dysfunction, right ventricular enlargement phenotype
of HFpEF. We would not want to give this to people with HFrEF.
Remember with HFrEF, we wanted to do just the opposite. We tested
this years ago with the ACORN trial or older studies wrapping the
latissimus dorsi around the heart to cause reverse remodeling so
this is really something that would maybe work more for people
with smaller stiff hearts, HFpEF, where that concern that they're
going to dilate and get low EF heart failure either on the left
or on the right side. We would want to focus more on the small
hearts and away from those people with dilation.


Dr Carolyn
Lam:               
That is so great. Thanks so much Barry for letting us under the
hood. Congratulations once again. These are just great papers.
Keep them coming. Well listeners. I'm sure you enjoyed that as
much as I did. Don't forget to tune in again next week.