Circulation March 31, 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: And I'm Dr Greg Hundley from the VCU Health
Pauley Heart Center in Richmond, Virginia. Well, Carolyn, we've
got a great feature article this week, evaluating do we wait or
do we do now ablation of ventricular tachycardia in patients with
ischemic cardiomyopathy and implantable defibrillators? But
before we get to that, how about if we grab our coffee or
whatever it may be and jump into the other articles?


Dr Carolyn
Lam:              
Sure. Well, Greg, have you ever wondered what the outcomes are of
transcatheter aortic valve replacement, or TAVR, in patients with
bicuspid aortic valve stenosis? Now, remember, patients with
bicuspid aortic valve stenosis were excluded from the pivotal
evaluations of TAVR.


Dr Greg Hundley: I wondered that yesterday, Carolyn.


Dr Carolyn Lam: Well, guess what, Greg, it's your lucky day
because we're going to get answers now from corresponding author
Dr Brennan from DCRI and coauthors who use data from the Society
of Thoracic Surgeons, American College of Cardiology, TAVR
registry from 2011 to 2018 to determine the device success
procedural outcomes, post-TAVR valve performance and in-hospital
clinical outcomes in almost 171,000 eligible procedures, of which
5,412 TAVR procedures were performed in bicuspid aortic valve
patients, including 3,705 with current generation devices.


Dr Greg Hundley: Wow. Carolyn, this sounds to me like probably
one of the largest collections of patients that have had TAVR and
bicuspid valves. What did they find?


Dr Carolyn Lam: Well, compared to patients with tricuspid aortic
valves, bicuspid aortic valve patients were younger and had a
lower STS predicted risk of operative mortality score, so you
have to bear that in mind first. With the current generation TAVR
devices, the incidence of device success was only slightly lower
for bicuspid versus tricuspid aortic valve patients and residual
two-plus aortic insufficiency remains slightly higher, though,
for bicuspid versus tricuspid aortic valve patients.


There was no difference in adjusted one-year hazard of stroke in
patients with bicuspid versus tricuspid valves, but the adjusted
one-year hazard of mortality was lower among bicuspid aortic
valve patients. Thus, using current generation technology, TAVR
appears both safe and effective for the treatment of bicuspid
aortic valve stenosis, although there remains a low incidence of
moderate or greater aortic insufficiency among both bicuspid and
tricuspid aortic valve patients.


Dr Greg Hundley: Very nice. Well, Carolyn, do you ever wonder how
white cells are recruited into areas of the heart that have
sustained a myocardial infarction?


Dr Carolyn Lam: Every day, Greg. Every day I think about that.


Dr Greg Hundley: You know, we've got so much wondering on your
side of the world and on my side of the world, but if we connect
that we will solve a lot of things. Well, this paper is from Dr
Prabhakara Nagareddy from Ohio State University. This group of
investigators used a mouse model involving ligation of the LAD
and flow cytometry to characterize the temporal and spatial
effects of myocardial infarction on different myeloid cell types,
a process termed myelopoiesis, that results in heightened
production of neutrophils.


The investigators sought to understand the mechanisms that
sustain white blood cell production in recruitment to the injured
heart using global transcriptome analysis of different cardiac
cell types within the infarct. In addition, just as these clever
circulation papers do, also a human subject study was performed
utilizing a combination of genetic and pharmacologic strategies.
The authors identified the sequela of events that led to
MI-induced myelopoiesis. Cardiac function was assessed by
echocardiography and the association of early indices of
neutrophilia with major cardiac events, or MACE, was studied in
those patients sustaining an MI.


Dr Carolyn Lam: Wow, that's a huge amount of work. What was the
bottom line results?


Dr Greg Hundley: So, first, in the patients with acute coronary
syndromes, a higher neutrophil count on admission and
post-revascularization correlated positively with major adverse
cardiovascular disease outcomes. And then, second, from the basic
science component, the study identified novel evidence for the
primary role of neutrophil-derived alarmins and, in particular in
this study, S100A8-A9 in dictating the nature of the ensuing
inflammatory response following myocardial injury.


Therapeutic strategies aimed at disruption of this S100A8-A9
signaling, or its downstream mediators in neutrophils, were shown
to suppress granulopoiesis and therefore, perhaps in the future,
could improve cardiac function in those patients sustaining an
acute coronary syndrome. Really elegant work. That combination of
the basic science in the animal model and then the translational
work in the human subject model.


Dr Carolyn Lam: Exactly what I was going to say. Translational
work. Well, hold onto your seat because this next one is super
cool, too. It is the first time a pre-clinical development and
first in human proof-of-concept of peritoneal direct sodium
removal using a zero-sodium solution as a candidate therapy for
volume overload. So, as a background, remember that loop
diuretics have been well described to have toxicities and that
loss of response to these agents are common when we try to treat
volume overload. So alternative strategies are clearly needed for
the maintenance of euvolemia in heart failure.


These authors, led by Dr Testani from Yale University
hypothesized that non-renal removal of sodium directly across the
peritoneal membrane, that is called direct sodium removal, using
a sodium-free osmotic solution should result in extraction of
large quantities of sodium with limited off-target solute
removal. So what they did is they performed porcine experiments
followed by a human study in which participants with end-stage
renal failure on peritoneal dialysis underwent randomization and
crossover to either a two-hour dwell with one liter of this
direct sodium removal solution or a standard peritoneal dialysis
solution. Sodium-free 10% dextrose, by the way, was utilized as
the direct sodium removal solution.


Dr Greg Hundley: Boy, Carolyn, this is really another one of
these elegant translational studies. So we have the animal model,
we have the human subjects and then we have different
concentrations of these peritoneal fluid that are injected and
then extracted for dialysis. I can't wait to hear. So what did
they find?


Dr Carolyn Lam: First, cycling a sodium-free osmotic solution
that's a 10% dextrose across the peritoneal cavity of swine
resulted in substantial sodium removal. So, proof of principle
there. The sodium removal increased proportionately as the volume
of 10% dextrose cycled across the peritoneum increased.
Experimental elevation of right-sided cardiac filling pressures
also resulted in substantial increased sodium removal with this
technique. Now, in the humans, a single dose of sodium-free 10%
dextrose was well tolerated in human subjects and resulted in
over four-fold greater sodium removal than the strongest
commercially available peritoneal dialysis solution.


So, direct sodium removal with a sodium-free osmotic peritoneum
solution represents a new potential therapy for non-renal sodium
and fluid removal in edematous disorders such as heart failure.
However, there is a long way to go in deploying such a procedure
in the heart failure population. And this is really highlighted
and discussed in an accompanying editorial by Dr Robert Toto from
UT Southwestern.


Dr Greg Hundley: Fantastic. Carolyn. Bob Toto always puts things
really in perspective. That'll be a great read. Well, let me tell
you about a couple other articles in this issue. Dr Bina Ahmed
from Santa Barbara Cardiovascular Group has a very nice
on-my-mind piece getting at this issue of how we should, as
physicians, be reacting to the healthcare issues. Also,
particularly in cardiovascular disease, as they occur in the face
of climate crisis. A great read. Then there's a beautiful adult
learning excerpt put together by Dr Daniel Kramer from the
Richard A. and Susan F. Smith Center for Outcomes Research in
Cardiology at Beth Israel Deaconess Medical Center.


It involves a patient that presents with some symptomatology
associated with their thoracic spine. They have to undergo an
MRI. They've got an implanted device. How do you work through
that? What do we need to do with anticoagulation? It turns out
the patient also may need a Watchman device. Who is a candidate
for that? Boy, it's just a great educational read.


Carolyn, there is a lot in the mailbag this week. Professor John
Madias from the Icahn School of Medicine at Mount Sinai and Dr
Adaya Weissler-Snir from the Hartford Hospital and University of
Connecticut exchanged some letters regarding the article
previously published on hypertrophic cardiomyopathy-related
sudden cardiac death in young people in Ontario.


Robin Woods from Monash University has a research letter
involving no modulation of aspirins effect by body weight in
healthy older men and women. And then Myra Lipes from the Joslin
Diabetes Center Harvard Medical School has a research letter
entitled the Cardiac Autoimmunity is Associated with Subclinical
Myocardial Dysfunction in Patients with Type 1 Diabetes.


Dr Carolyn Lam: And I'll add one more research letter by Dr
Dempsey on prospective associations of accelerometer-measured
physical activity and sedentary time with incident cardiovascular
disease, cancer and all-cause mortality. So something that's
really a hot topic now. Man, that has been a great issue. But
let's move on to our feature discussion, shall we?


Dr Greg Hundley: You bet. Well, listeners, welcome to this
feature discussion where we're going to understand a little bit
more about ICDs and ventricular tachycardia and we have Dr
Karl-Heinz Kuck from the University Hospital of Lübeck. We have
Francis Marchlinski from the University of Pennsylvania and we
have Dr Sammy Viskin, our own associate editor from the Tel Aviv
Medical Center. What a great study. So, Karl, I'd like to start
with you. Can you give us a little bit of background about why
you wanted to perform the study and what was your hypothesis?


Dr Karl-Heinz Kuck: There is an ongoing debate in clinical
electrophysiology, what would be the optimal timing of catheter
ablation in patients with ventricular tachycardia and ventricular
fibrillation. Now, until today, most patients come to catheter
ablation at a very late stage of the disease, mostly after
multiple ICD shocks. So the patients are in a very bad condition
and our strong feeling is the patients should undergo, much
early, a successful catheter ablation.


The study was initiated with the background that we, and others,
have shown that a very catheter ablation, which is before any
ICTD shock, a so-called preventative ablation, is superior with
respect to clinical endpoints as compared to optimal medical
treatment. That's number one. And number two is that we know from
retrospective analysis of multiple ICD studies that ICD shocks
increase mortality as compared to patients with ICDs that have no
shocks.


So, on one side we have the benefit of a preventive ablation
which has been shown in three randomized trials, and on the other
side we know that ICD shocks increase mortality. So somewhere in
between multiple ICD shocks and no shock should be the benefit of
catheter ablation and this, exactly, was the background of the
BERLIN-VT Trial to investigate whether a very only catheter
ablation study, which is after the first episode of VT/VF, before
any ICD shock, would be superior as compared to having an ICD
implanted and follow the patients and then ablate the patients
after an arbitrary taken number that we set to three ICD shocks.
We were looking then for a combined clinical endpoint to see
whether there is any benefit of prophylactic, or preventative,
ablation versus what we call deferred catheter ablation.


Dr Greg Hundley: Can you tell us about the BERLIN-VT? What was
your study population? A little bit about the design.


Dr Karl-Heinz Kuck: Yeah. The patients that we investigated were
patients only with ischemic cardiomyopathy who would had a
previous myocardial infarct, to reduce the number of
interventions that would require an epicardial access in that
patient population. That's number one. And number two, the
patients should have an ejection fraction above 35 because a
previous study that we have done, the VTACH Study showed that
there was no benefit of catheter ablation in patients with a very
low ejection fraction, so this was the patient population that we
were looking. And then patients had to have had at least one
episode of VT/VF before they were randomized either into
preventive ablation or into deferred ablation.


Dr Greg Hundley: How many participants were in your study? And
then tell us a little bit about the study results.


Dr Karl-Heinz Kuck: We randomized the 76 patients to preventive
ablation, and 83 patients do differed ablation. The number, we
originally thought to be higher, but we had redesigned interim
analysis and after the second interim analysis at the DSMV, we
commanded to terminate the trial for futility. And at that point
in time when the study was terminated, these numbers were
included, which was almost two thirds of the patients which were
originally included in to the front.


Dr Greg Hundley: What were your results?


Dr Karl-Heinz Kuck: Now, which respect to the endpoint of the
trial, which was the primary endpoint, which was a composite
endpoint of all-cause mortality and unplanned re-hospitalizations
for worsening of heart failure or ventricular arrhythmias, we did
not find any significant difference between the preventive and
the deferred ablation group. Actually, after 12 months, there
were 21% of patients in the differed, and 27% in the preventive
ablation group, and these numbers almost doubled over two years
but didn't show any difference.


So with respect to the components of the combined endpoint, we
also didn't see any significant difference with respect to
overall mortality, hospitalization for worsening of heart failure
and hospitalization for worsening of ventricular tachycardia or
ventricular fibrillation, despite the fact that there was a
strong trend to a reduction of hospitalization for VT/VF in the
preventive group as compared to the deferred group.


But this was fully compensated for the primary endpoint by an
increase of hospitalizations, early hospitalizations after
ablation for worsening of heart failure and a somewhat higher
mortality rate in the preventive group as compared to the
deferred group, which I believe was really bad luck because
almost none of the six [inaudible 00:17:12] in the preventive
group died due to cardiovascular reasons. Whereas most patients
in the deferred group died because of ventricular tachycardia,
ventricular fibrillation.


Now, what is interesting to mention is that with respect to the
secondary endpoint, which is sustained VT and VF and appropriate
ICD therapy, there was a significant benefit of preventive
catheter ablation as compared to deferred catheter ablation but,
as I mentioned before, this could not be translated into a
benefit with respect to clinical outcome in the trial.


Dr Greg Hundley: Thank you, Dr Kuck. Dr Marchlinski, could you
help us put this in perspective as we're thinking about patients
with ischemic heart disease that we are considering implantation
of an ICD?


Dr Frank Marchlinski: Yes, definitely. First, I like to
congratulate the investigators. This is a real tour de force, a
lot of effort, multiple centers involved. Dr Willems, Dr Kuck,
congratulations because this is an important effort. I think that
one needs to realize, of course, that it is our goal to try to
eliminate VT with the hope that we're going to improve mortality
outcome in addition to improving quality of life. It's a
worthwhile goal. I hope someday we will achieve it and that we'll
be able to use ablative therapy very early in the course, even in
advance of ICD implantation and potentially even to prevent ICDs.
That's a worthwhile goal and something that we all need to target
as investigators in this area.


But Dr Kuck's study demonstrated that we're not there yet to use
it as very early in the course of a disease before patients
manifest a lot of arrhythmia recurrences. One thing is for
certain, though. This study, although important in suggesting
that we need to take our time in terms of planning to do the
ablation procedure, we don't want to delay. There's enough
evidence to say that repeated shocks can increase mortality, as
Dr Kuck pointed out, and enhance a bad outcome.


It certainly provides a very poor quality of life for the patient
to experience these shocks, so we need to consider the timing of
when it's appropriate, when patients begin to experience ICD
shocks after receiving a defibrillator and not wait for repeated
shocks, not wait for excessive dosing with Amiodarone, but rather
to intervene in a timely fashion after a patient begins to get
the shock therapy. It was clear that even the BERLIN-VT
investigators didn't wait for multiple additional shocks. As soon
as patients received one or two shocks, they got enrolled in this
study, this is the deferred limb, and took advantage of the
effectiveness of ablation to reduce the number of VT episodes.


Dr Greg Hundley: Sammy, now back to you. What study do we need to
perform next in this field? How do you think the results here
guide us moving forward with research in this area?


Sammy Viskin: As Frank said, in [inaudible 00:20:25], it is very
important that patients are not referred too late for ablation
when they arrive after many shocks and they're already, sometimes
even encouraged to getting shocks. The present study shows that
perhaps they should not be referred for ablation too early at
this point, at least not until we get better with our ablation
techniques. So we need studies on how to improve our ablation
techniques. They keep getting better, but they still have a long
way to go. And then we should be able to define the optimal time
when it's not too early and when it's not too late to perform the
ablation procedure.


Dr Karl-Heinz Kuck: I agree with all of what had been said. I
just would like to mention that the study, the BERLIN-VT Study
compared, actually, very early catheter ablation versus early
catheter ablation. We just wanted to know whether very early
ablation is better than early because I think that all the three
physicians here, the three electrophysiologists, would agree that
we would be happy if most of the patients would even be sent
after the second or third shock. Many patients having multiple
more shocks before they are sent for catheter ablation.


So, in this sense, the BERLIN-VT Study was an aggressive study
because they did not allow patients to be sent after the 10th
shock, after the 15th shock, after an electrical storm. So we are
comparing very early versus early ablation and I'm not giving up,
like Frank Marchlinski was saying. I'm not giving up on the idea.


Sammy is saying we are not yet there, but we should continue to
prove that an early ablation is superior to a late ablation. But
BERLIN-VT did not look at the very late ablation component of the
strategy here. I think what this study shows and what all the
other studies also show how difficult it is, in the field of
VT/VF and severely diseased patients, to do such a randomized
trial. We have a lot of problems to enroll these patients and
therefore, I was glad that we could at least get some information
out of the trial.


I'm still supporting the idea that the international community
should work closer together in the field of catheter ablation of
ventricular tachycardia and ventricular fibrillation so that we
could increase the number of patients within a rather short
period of time that should be included in these VT ablation
trials. That's, I think, another learning that I've done from
this trial but also from some of the other trials that we and
others have done in the field.


Dr Greg Hundley: Well, listeners, we want to thank Dr Karl Kuck
from University of Lübeck in Germany, Dr Frank Marchlinski from
University of Pennsylvania, and Dr Sammy Viskin from Tel Aviv
Medical Center. We've really heard some insightful results
related to ICD placement and those with ischemic heart disease
from the BERLIN-VT Study. It really emphasizes the importance of,
as we move forward, international collaborations when we're
trying to study this patient population.


Well, on behalf of Carolyn and myself, we wish you a great week
and look forward to chatting with you and grabbing a cup of
coffee next week. Take care. Of this program is copyright of the
American Heart Association 2020.