Circulation May 14, 2019 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 Greg Hundley, Associate Editor of Circulation from the
Pauley Heart Center at VCU Health in Richmond, Virginia.


Dr Carolyn
Lam:               
Are NOACs, or non-vitamin K antagonist oral anticoagulants, safe
and efficacious in patients with extremely high or very low body
weight? Very interesting paper and discussion coming right up.
Greg, I hear that you've got a couple of papers you'd like to
highlight first.


Dr Greg
Hundley:            
You bet, Carolyn. My two papers today both focus on ventricular
dysrhythmia. The first one, from Yuki Komatsu from Tsukuba,
Japan, researches the efficacy of catheter ablation of refractory
ventricular fibrillation storm after myocardial infarction. VF
storm attributed to focally triggered VF after MI is recognized
as a distinctive, lethal, arrhythmogenic syndrome that differs
from scar mediated monomorphic VT.


                                               
This study investigated the acute and long-term outcomes of
catheter ablation for the treatment of last resort in a large
series of consecutive patients with post-MI VF storm refractory
to medical therapies. In the study, investigators enrolled 110
patients averaging about sixty-five years in age. Ninety-two were
men, and their average ejection fraction was approximately 31%.
VF storm occurred in the acute phase of MI, about four and a half
days after MI-onset, during the index hospitalization in about
39% of the patients. It was sub-acute (that is greater than 1
week later) in 44% of patients. It was remote (greater than 6
months later) in 17% of patients. And the focal triggers were
found to originate from the scar border zone in 80% of the
individuals.


Dr Carolyn
Lam:               
And what did the study show?


Dr Greg
Hundley:            
So Carolyn, during in hospital stay after ablation, VF storm
subsided in 84% of patients and overall, 27% of in-hospital
deaths occurred. The duration from the VF occurrence to the
ablation procedure was associated with in-hospital mortality,
with a P-value of 0.008. During follow-up after discharge from
the hospital, only one patient developed recurrent VF storm. Of
note though, 36% of the patients died, with a median survival of
2.2 years. And the long-term mortality was associated with a low
EF (less than 30%), New York Heart Association class greater than
3 Heart Failure, a history of atrial fibrillation or chronic
kidney disease.


                                               
So in summary Carolyn, the results of this study show that in
patients with MI presenting with focally-triggered VF storm,
catheter ablation of the culprit triggers is life-saving and
appears to be associated with short and long-term freedom from
recurrent VF storm. The overall mortality for these patients is
associated with the severity of their underlying cardiovascular
disease, and those associated co-morbidities.


                                               
Now my next paper is from one of our associate editors, Sami
Viskin from Tel Aviv University. He's looking at a new form of
polymorphic VT. Now as we think about polymorphic VT, I always
think about the long QT interval syndromes associated with
Torsades de Pointes. We have specific management strategies for
those long QT syndromes, but Carolyn, there's a second category
of polymorphic VT that's not related to QT prolongation. This
second category involves patients without structural heart
disease, who have genetic disorders like Brugada or patients that
may have experienced hypothermia. There is also a third category
of individuals with structural heart disease, during acute ST
elevation MI.


                                               
What Sami has discovered is there's now a fourth category of
non-QT prolongation, which includes those with coronary artery
disease but without evidence of ischemia.


Dr Carolyn
Lam:               
So how did they show or find this fourth category?


Dr Greg
Hundley:            
Well, this is a longitudinal cohort that he identified, and they
basically followed forty-three individuals who developed
polymorphic VT within days of an otherwise uncomplicated MI or
coronary revascularization procedure. The in-hospital mortality
was 17% with these patients with arrhythmic storm and the
patients were treated with quinidine invariably survived to
hospital discharge, just like the other categories of non-QT
prolongation polymorphic VT.


                                               
During long term follow-up of five and a half years, 16% of
patients discharged without quinidine developed recurrent
polymorphic VT and there were no recurrent arrhythmias in those
individuals that were receiving quinidine therapy long term.


                                               
So Carolyn, although quinidine therapy is usually considered
contraindicated in patients with organic heart disease who
develop ventricular arrhythmias, this therapy may be life-saving
for patients with coronary disease developed arrhythmic storms
due to polymorphic VT. Polymorphic VT storms may be a transient
phenomenon. It's unclear for how long quinidine should be
continued in these responsive patients.


Dr Carolyn
Lam:               
Wow, neat! Well, for my two papers I'm going to start off with a
basic paper and, in fact, a quiz for you this time, Greg! So,
what do cilia have to do with the heart? All right, you get to
ask me, do you remember what cilia are?


Dr Greg
Hundley:            
Aren't cilia on prokaryotes? I mean, I think of bacteria.


Dr Carolyn
Lam:               
All right, let me set us straight. The primary cilium is a
cellular organelle and it's formed by a protrusion of the plasma
membrane that functions as a signaling platform in eukaryotic
cells and is found in many cells including neurons,
pre-adipocytes and kidney tubular cells, where they have been
reported to be involved in a variety of cellular functions such
as proliferation, differentiation, cell cycle regulation as well
as mechano-chemical sensing of diverse stimuli.


                                               
Now, the importance of these cilia is highlighted by the role in
several diseases, known as ciliopathies. Polycystic kidney
disease is one such disorder with, by the way, numerous
cardiovascular manifestations. Whereas ciliated cells have been
described in the developing heart, a role for primary cilia in
the adult heart has not been reported. It was therefore the aim
of these authors and those co-corresponding authors Dr Hill from
UT Southwestern and Dr Lavandero from University of Chile, who
aimed to identify cells in the adult heart harboring a primary
cilium and to determine whether these primary cilia play a role
in disease-related remodeling.


Dr Greg
Hundley:            
Carolyn, this is so interesting. I had no idea about these cilia.
So what did they find?


Dr Carolyn
Lam:               
So, in a series of elegant experiments, these authors identified
for the first-time primary cilia in mouse, rats, and human
hearts, specifically and exclusively in cardiac fibroblasts. Now
these ciliated fibroblasts were enriched in areas of myocardial
injury. Transforming Growth Factor beta-1 signaling and SMAD3
activation were impaired in fibroblasts that were depleted of the
primary cilium. Extra cellular matrix protein levels and
contractile function were also impaired. And in vivo depletion of
PC1 inactivated fibroblasts after myocardial infarction impaired
the remodeling response.


Dr Greg
Hundley:            
So how do we use this clinically, and what does it mean for us?


Dr Carolyn
Lam:               
These findings point to a pivotal role of cilia and PC1 in
disease related pathological cardiac remodeling and suggest that
some cardiovascular manifestations of autosomal dominant
polycystic kidney disease, for example, derive directly from
myocardium autonomous abnormalities. The findings also uncover
novel fibrosis regulators and raise the prospect that this
pathway may emerge as a target with therapeutic relevance.


Dr Greg
Hundley:            
Wow, very interesting!


Dr Carolyn
Lam:               
Thanks! And the next paper is also very interesting, in dilated
cardiomyopathy and providing insights in how specific viral
function may be involved in the development of dilated
cardiomyopathy. Looking at the Group B enteroviruses, which are a
common cause of acute myocarditis and can be a precursor of
chronic myocarditis and therefore dilated cardiomyopathy leading
to heart transplantation. In fact, enterovirus-induced dilated
cardiomyopathy represents a third of idiopathic dilated
cardiomyopathy cases.


                                               
So these authors, led by corresponding author Dr Andreoletti from
University of Reims, Champagne-Ardenne and Dr Semler from
University of California, performed deep sequencing of viral RNA
from cardiac tissue from patients with enterovirus related end
stage dilated cardiomyopathy and then trans-factored viral RNA
clones, mimicking the viral genomes found in patient tissues into
primary human cardiac cells to assess their replication
activities and impact on cardiomyocyte function.


                                               
They found that the major persistent viral forms are composed of
B-type enteroviruses harboring 5' terminal deletion in their
genomic RNAs. These viruses alone, or associated with full length
populations of helper RNAs, could impair cardiomyocyte function
by viral enterovirus proteinase 2A activities in these
enterovirus-related dilated cardiomyopathy cases.


Dr Greg
Hundley:            
Very interesting, Carolyn. So what are the clinical implications
of this viral infection of the heart?


Dr Carolyn
Lam:               
Well, the findings seem to imply that it would be important for
us to develop specific inhibitors of enterovirus proteinase 2A
activity that might prevent viral replication and inhibit the
shut-off of host cell translation as well as the disruption of
dystrophin.


                                               
Furthermore, in early diagnosed enterovirus induced dilated
cardiomyopathy, the use of such protease inhibitors could
potentially decrease and stop the chronic pathological process of
dilated cardiomyopathy and therefore reduce the need for heart
transplantation in this end-stage. Very interesting, but requires
more work.


                                               
So, that wraps up our summaries Greg. Shall we move to our
feature discussion?


Dr Greg
Hundley:            
Absolutely.


Dr Greg
Hundley:            
Today we have Renato Lopes from Duke University in Durham, North
Carolina and Brian Olshansky, Professor Emeritus from Iowa now in
clinical practice in Waterloo and Mason City, Iowa. We're going
to talk about our non-vitamin K oral antagonists, or NOACs, safe
and efficacious in patients in extremely high (greater than 120
kg) or extremely low (less than 60kg) of body weight.


                                               
Renato, welcome to our podcast in Circulation on the Run. Can you
give us a little overview of your study, why you performed it and
what results did you experience?


Dr Renato
Lopes:             
The idea behind this study was to provide more data into the use
of NOACs in these extreme body weight patients, where we don't
have a lot of information. Some guidelines actually caution
against the use of NOACs in patients with extreme body weight
because of the lack of data.


                                               
We had the opportunity to look at the Aristotle database, which
was a large, randomized trial comparing apixaban versus warfarin
for patients with atrial fibrillation, over 18 000 patients. We
took advantage of this database to try to look at the extreme
body weight and how those patients at weight more than 120 kg,
more than 140 kg and less than 60 kg, performed in terms of the
treatment effect of apixaban versus warfarin. This was the
rational, to try to provide more data so people could gain
additional confidence in using apixaban in clinical practice in
those extreme body weight patients.


                                               
What we showed was, in general the treatment effect of apixaban
versus warfarin for the efficacy outcomes CHOKE, systemic
embolism and all cause death and myocardial infarction was very
consistent across the weight spectrum and preserved. Apixaban was
superior to warfarin and this was consistent regardless of the
weight category. For the low body weight patients less than 60
kg, we also found that apixaban results in terms if efficacy was
preserved.


                                               
So, going out to the bleeding and safety endpoints, apixaban was
safer than warfarin across different spectrums of weight.
Surprisingly, in patients less than 60 kg we saw an even greater
relative risk reduction in bleeding, in patients treated with
apixaban compared to warfarin. The main message was for efficacy,
apixaban was better than warfarin - the same results as the
Aristotle main trial. For bleeding and safety endpoints, we also
saw the same results and consistent results with apixaban- in
particular with patients below 60 kg, which is always a concern
that people might have in clinical practice. It seems that
apixaban was even safer with an even greater treatment effect.


Dr Greg
Hundley:            
Very nice. Can you tell us a little bit about some of the sites
where you enrolled patients and did you identify any variation in
age, sex or region specific factors? Were there any differences
in your findings related to race?


Dr Renato
Lopes:             
That is a very interesting question because we know that these
variables play an important role in body weight. We enrolled
patients from thirty-nine countries in Aristotle, in over a
thousand sites all over the world. Interestingly, I can tell you
that the heaviest weight we had in our study was 205 kg, a
patient from the United States. The lightest weight that we had
was 39 kg, from the Philippines. You lose trading the variation
that regions of the world can play out and how patients can
perform. We haven't seen any major difference in these analogies.
There were prior analogies that look at different BMIs, and we
know that the treatment effect might be attenuated depending on
race and sex. In this analogy, we did not find any significant
difference according to race, region of the world or even sex.


Dr Greg
Hundley:            
Just getting back to your body weight measurement, you mentioned
percentage of individuals were above 120 kg and briefly mentioned
some were above 140 kg. What percentage of your study cohort was
that extra-large size, above 140 kg? Do you think more work needs
to be done in that area or do you think the results were
sufficient for that very heavy body weight?


Dr Renato
Lopes:             
This is a very important question. If we look at the breakdown,
we had about 11% of the entire trial in the low spectrum of
weight, less than 60 kg in weight - almost 2000 patients. A good
number of patients. In extreme weight more than 120, we have
about 980 patients. That was 5.5% of the overall trial. When you
look at greater than 140 kg, we had 258 patients, 1.4% of the
overall trial population and about 25% of this category greater
than 120.


                                               
I think as we start getting greater than 140 kg, we had 258
patients. It is not a large number of patients. It is some
information and it is good to have some data on these patients.
Before that, we had no data on apixaban in this level of weight.
What we are seeing is that above 140 kg, the death rate are very
low. There is a trend to better bleeding endpoints and better
bleeding profile with apixaban, similar to what we have seen in
the entire spectrum of weight when we look at weight as a
continuous variable. We also saw that trend in patients greater
than 140 kg for bleeding. This is reassuring. I don't think we
can say it is definitive, it is only 260 patients that we are
talking about.


                                               
It is reassuring that we now have data in patients more than 140
and up to 205 kg, and we didn't seem to see any major concern or
any difference in the curves in terms of the direction of
efficacy and safety of apixaban. For the majority of patients it
is reassuring and gives us extra confidence that the dose we use
in clinical practice five milligrams twice daily should also work
in those heavy weight and the heaviest body weight patients.


Dr Greg
Hundley:            
Very good. Brian you've done an excellent editorial and I wonder
if you could help us put this study in perspective with what we
know about NOACs and managing patients with atrial fibrillation?


Dr Brian
Olshansky:         It
really is a fascinating study. Obesity is as growing problem for
us here in the mid-west and probably throughout the world. It
effects a variety of things including drug pharmakinetics, volume
of distribution, drug clearance etc. So knowing how NOACs work at
the extremes of body weight, either the massively obese or the
vanishingly frail, it becomes important to understand the safety
and efficacy of the use of NOACs in these individuals. There are
guidelines that caution us against use of NOACs at extremes of
body weight, particularly those patients who are over the 120 kg
mark. The one point I would like to make is, at least here in the
mid-west, 120 kg is becoming almost the norm. We are having
people that are becomingly massively obese and this is really the
question then in my mind, is what to do with those patients who
are over 140 kg or even way more than that. This gets to points
that I would like to make about some the issues we need to
consider about this study and where we are with our understanding
about the use of NOACs in the extremes of body weight.


                                               
One thing to keep in mind is, in this analysis, this was a
retrospective group analysis. That is one important point. We
don't have prospective data that look at an entire large
population, a very frail, a very low body weight population.


                                               
Another issue is that weight is not a static measure. We only
have assessment at the baseline. Variability in weight or body
mass index may be important in terms of its relationship to the
development of atrial fibrillation and sequelae. The other issue
here to consider is that there are comorbidities that are
associated with those who are at the extremes of body weight and
there was a significant variation in this study in age
composition, sex dominance, the region of enrollment, the
presence of comorbidities between the different weight groups
that could contribute to results we have seen. Those with low
body weight had more comorbidities and a higher mean CHADSVASC
score, and had the biggest difference between apixaban and
warfarin.


                                               
We have quite a bit to learn about how to understand these data,
and when we consider the individuals who are over 140 kg, indeed
there are concerns about the volume of distribution of a NOAC and
its efficacy. We would like to rely on this data. The problem is
that the number of individuals that are a part of this
retrospective analysis at the very high body weight and very low
body weights was a rather small number and so to project from
that number, what we should do with all of our patients becomes
somewhat of a concern.


                                               
Although these are interesting and provocative data, what we
really need is to have some well-designed large prospective
randomized controlled trials that specifically address those
individuals at the extremes of body weight because this is
becoming more and more of a problem as time goes on. We are
seeing more individuals that are at the extremes of body weight.
While I have not specifically noticed a difference in my own
clinical practice, what we need is a better understanding about
the dosing of and potential risks and benefits of the NOACs for
the extremes of body weight.


Dr Greg
Hundley:            
On behalf of Carolyn and myself, we really appreciate you
listening. Have a great week. We look forward to seeing you next
week.


Dr Carolyn
Lam                 
This program is Copyright American Heart Association 2019.