Circulation October 11, 2016 Issue

 


Carolyn:
Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and its editors. I'm Dr.
Carolyn Nam, Associate Editor from the National Heart Center and
Duke-National University of Singapore. Today's featured
discussion deals with the perspective piece entitled, What I Wish
Clinicians Knew About Industry and Vice Versa. Intriguing, isn't
it? I can tell you it is one of the best papers I have ever read,
so stay tuned. First, here's your summary of this week's journal.


 
 
The first study takes a step towards understanding atrial
fibrillation on a more fundamental level by demonstrating that
some patients have altered left ventricular myocardial energetics
even in the absence of other comorbid diseases. First author, Dr.
[Veejay Surendra 00:00:50], corresponding author, Dr. [Cassidy
00:00:53] and colleagues from the University of Oxford studied 53
patients with lone atrial fibrillation undergoing catheter
ablation and compared them to 25 matched controls without atrial
fibrillation. They did this using sequential studies of cardiac
function with magnetic resonance imaging as well as energetics
with phosphorus-31 magnetic resonance spectroscopy.


 
 
At baseline, there was subtle but significant left ventricular
dysfunction and abnormalities in ventricular energetics in
patients relative to controls. Following ablation of atrial
fibrillation, left ventricular function measured by ejection
fraction and peak systolic circumferential strain improved
rapidly with a switch to sinus rhythm but remained at normal at 6
to 9 months. Although pulmonary vein isolation effectively
eliminated atrial fibrillation in all the patients in the study,
the hearts continued to express an energetic profile consistent
with a myopathic phenotype meaning that the ratio of
phosphocreatine to adenosine triphosphate was lower in the atrial
fibrillation compared to controls irrespective of recovery of
sinus rhythm and freedom from recurring atrial fibrillation.


 
 
The clinical implications of these findings are that apparently
lone atrial fibrillation may actually be a consequence rather
than a cause of an occult cardiomyopathy and that this
cardiomyopathy is unaffected by ablation. Of course, future
studies are needed to prove this and to examine whether
therapeutic strategies that target the adverse cardiometabolic
phenotype could reduce atrial fibrillation recurrence. These
important issues are discussed in an accompanying editorial by
Doctors Hyman and Callans.


 
 
The next study provides experimental evidence that suggests we
may finally have an answer to heart failure preserved ejection
fraction or HFpEF, and that is the modification of titin. Titin
is a sarcomeric protein that functions as a molecular spring and
contributes greatly to left ventricular passive stiffness. The
spring properties can be tuned through post-transcriptional and
post-translational processes and their derangement has been shown
to contribute to diastolic dysfunction in patients with HFpEF.
The current paper by first author, Dr. Methawasin, corresponding
author, Dr. Granzier and colleagues from University of Arizona
provide important proof of principal investigation of the effects
of manipulation of titin isoforms as a treatment for a transverse
aortic constriction murine model of progressive left ventricular
hypertrophy leading to HFpEF.


 
 
Conditional expression of a transgene with deletion of the RNA
recognition motif for one of the splicing factor, RBM20 alleles,
resulted in reduced splicing and a substantial increase in larger
more compliant titins that were named super compliant titin. The
result was normalization of passive stiffness of isolated muscle
strips as well as normalization of left ventricular diastolic
function and chamber stiffness as assessed by echocardiography
and pressure volume analyses. There were no effects on
extracellular matrix stiffness. The authors also showed that
other spliced targets of RBM20 did not contribute to the results
and thus, the beneficial effects were almost certainly entirely
related to the changes in titin isoforms.


 
 
Furthermore, treadmill exercise was used to show that treated
animals displayed improved exercise tolerance. In summary, the
study showed that increasing titin compliance in this murine
model resulted in marked improvement in multiple measures of
diastolic function and performance, thus suggesting that titin
holds promise as a therapeutic target in HFpEF. This is the
discussed in an excellent accompanying editorial by Dr. LeWinter
and Dr. Zile.


 
 
The next study adds importantly to evidence that heavy physical
exertion and anger or emotional upset may act as triggers of
first myocardial infarction. In this paper by first author, Dr.
Smith, corresponding author, Dr. Yusuf, and colleagues from the
Population Health Research Institute Hamilton Health Sciences and
Master University, authors explored the triggering association of
acute physical activity, anger, and emotional upset with acute
myocardial infarction. They did this in the inter-heart study
which was a case control study of first acute myocardial
infarction in 52 countries. In the current analysis, the authors
used a case crossover approach to estimate odds ratios for acute
myocardial infarction occurring within 1 hour of triggers.


 
 
Of 12,461 cases, 13.6% engaged in physical activity and 14.4%
were angry or emotionally upset in the case period referring to
the 1 hour before symptom onset. Physical activity in the case
period was associated with an increased odds of acute myocardial
infarction with an odds ratio of 2.3 and a population
attributable risk of 7.7%. Anger or emotional upset in the case
period was associated with an increased odds of acute myocardial
infarction of more than 2.4 odds ratio and a population
attributable risk of 8.5%. Importantly, there was no effect
modification by geographic region, prior cardiovascular disease,
cardiovascular risk factor burden, prevention medications, time
of day, or day of onset of acute myocardial infarction.


 
 
Interestingly, the authors did find an interaction between heavy
physical exertion and anger or emotional upset with an additive
association in participants with exposure to both in the 1 hour
prior to the acute myocardial infarction. The take home message,
these findings suggest that clinicians should advice patients to
minimize exposure to extremes of anger or emotional upset due to
the potential risk of triggering an acute myocardial infarction.
While heavy or vigorous physical exertion may also be a trigger,
this did not refer to just any physical activity and the authors
cautioned that this must be balanced against the known
well-established benefits of regular physical activity over the
long term and clinicians should continue to advice patients about
the life-long benefits of exercise.


 
 
The last study provides insights in the molecular mechanism in
pulmonary hypertension. First author, Dr. Lee, corresponding
author, Dr. Stenmark, and colleagues from the Pediatric Critical
Care Meds and CVP Research University of Colorado Denver
hypothesized that metabolic reprogramming to aerobic glycolysis
may be a critical adaptation of fibroblast in the hypertensive
vessel wall, an adaptation that drives proliferative and
pro-inflammatory activation through a mechanism specifically
involving increased activity of the NADH sensitive
transcriptional corepressor, C-terminal-binding protein 1.


 
 
The authors assessed glycolytic reprogramming and measured NADH
to NAD+ ratio in bovine and human adventitial fibroblast as well
as mouse lung tissues. They found that expression of the
C-terminal-binding protein 1 was increased in fibroblast within
the primary adventitia of humans with idiopathic pulmonary
arterial hypertension and animals with pulmonary hypertension.
Furthermore, treatment of fibroblast from the pulmonary
hypertensive vessels of hypoxic mice with a pharmacological
inhibitor of C-terminal-binding protein 1 led to a normalization
of proliferation inflammation and the aberrant metabolic
signaling.


 
 
In summary, these result showed that C-terminal-binding protein
1, a transcription factor that is activated by increased free
NADH acts as a molecular linker to drive the proliferative and
pro-inflammatory phenotype of adventitial fibroblast within the
hypertensive vessel wall. Thus, this metabolic sensor may be a
more specific target for treating metabolic abnormalities in
pulmonary hypertension. Those were your summaries. Now for our
feature paper. Our feature today is special on so many levels,
and because it's so special, I actually have Dr. Joe Hill,
editor-in-chief of circulation from UT Southwestern here today
with me. Hi Joe.


 
Joe:
Sure. As always, it's a pleasure to be here with you. This is a
new type of content where we solicit thought leaders from a
variety of vantage points around the cardiovascular space to
provide their perspective on the future of cardiovascular Science
in medicine. Rob Califf, the FDA Commissioner, provided his
perspective on the regulatory role interfacing with
cardiovascular medicine and Science. Victor Dzau who presides
over the National Academy of Medicine in the United States did
the same, provided a very insightful perspective from his vantage
point now, formerly in academia, but now overseeing this advisory
board to the policy makers in Congress. Today, we're going to
talk about a perspective that emerges from industry, from someone
who also has a strong and long history in academia.


 
Carolyn:
That is a perfect lead up. The title of the paper; What I Wish
Clinicians Knew About Industry and Vice Versa. Here is the
amazing guest that we have today, it's Dr. Ken Stein, Chief
Medical Office of Rhythm Management at Boston Scientific. Hi Ken.
It is a very, very intriguing title and I'd like you to first
describe to us what makes you the person who can talk about being
a clinician and going over to the dark side of industry and vice
versa?


 
Ken:
Thanks Carolyn and Joe. I think right now just get over my
embarrassment at being called a thought leader and being
mentioned in the same as Rob Califf and Victor Dzau. I met both
of them but I don't think I've ever been mentioned in the same
sentence as either them and probably never will be again. Why me
to do this? Again very gracious of Joe to invite the submission.
My history, I've been in industry now at Boston Scientific for 7
years, and prior to that was an unreformed academic faculty at
Cornell. Ever since I did my training, eventually becoming
co-director of the EP Lab there for many years. Then 7 years ago,
the opportunity came up to leave the cloistered ivory towers of
academia and to join industry. It's been a very interesting and I
think very productive ride ever since.


 
Carolyn:
I have to tell you that your article is just one of the most
well-written pieces I have ever read and I mean that sincerely.
You began with the story that everybody asked you this question.
Why did you do it? What did you learn? I'm going to ask that of
you today. Tell us.


 
Ken:
In the 7 years, I get 2 questions all the time. One is, do you
miss practice? The answer is, there are things about practice
that I miss very deeply and that is really the engagement that
you get with patients and families. I think we always have to
remember as caregivers, we're privileged to be able to do what we
do. On the other hand is, but I do get an opportunity to
participate in decisions now that rather than affect one patient
at a time, for better or for worse, affect hundreds of thousands
of patients at a time.


 
 
The other question is, what surprised you? What have you learned?
What didn't you know about industry? As I thought about it, it's
2 things. It's one that I think in retrospect I was and I think
many of us are way too cynical about the motivations of industry,
how industry operates. The other shock, if you will, was that it
goes 2 ways and there's a lot of cynicism in industry about
physician motivations and how physicians operate on a day to day
basis.


 
Carolyn:
Really? Do you have any examples of that?


 
Ken:
I'll give you a couple of examples. First, from the point of view
of how does industry work and what are the motivations in
industry. One of the first decisions that I had to make 7 years
ago after joining the company was to issue a recall on one of our
products. It actually was a recall that had not yet failed in the
field but we had some bench testing that suggested that there was
a particular risk to some patients and novel to the industry and
the whole thing. This is not go over well with the CEO, but in
fact, really the only question people ask is, is this the right
decision for patients? That was a really gratifying piece of
education to me.


 
 
The flip side of the coin, we did introduce a new battery
technology in our fibrillators and CRT devices just before I
joined the company that basically doubled the amount of battery
capacity that we have in the devices. It's one of the funny
things. There are still editorials being written in journals
other than circulation, I'll say, that still say that industry
will never increase battery longevity of their devices but cost
us money because we lose money on device replacements. We've done
it and a lot of our competitors are in the process of doing it.


 
 
When I got to the company, what I found is there was a tremendous
amount of angst within the leadership of the company. Do doctors
do this or are they afraid in a fee-for-service environment to
give up what they get doing battery replacements on short-lived
devices. Of course that cynicism is unfounded. That doctors have
embraced longer, better battery life technology.


 
Joe:
Ken, to hear you say this is interesting and frankly inspiring.
You can't pick up a copy of the New York Times right now and not
read about some issue around drug pricing and some of the
companies that have done the wrong thing with. They've increased
prices hundreds of percentage, 400%, even more. To know from your
perspective that those are perhaps the exceptional circumstances
and that there are many, many companies who of course have to
keep a business running but at the same time they truly have the
patient at heart. You have said and you said in your piece that
as the Chief Medical Officer, you're the voice of the patient at
your organization.


 
Ken:
I aim to be. That was the lesson I learned from Don Baim who
really ... Don passed away very shortly after I joined the
company, who's really a giant in cardiology. I wish that I had
been able to spend more time with him as a mentor but that was
very important statement he made. Say he's right, there are bad
actors, there are bad actors in industry, there are bad actors
among physicians, there are bad actors among academics, but
that's not generally true. I also want to be careful not to be
misconstrued. Skepticism and doubt are important. Cogito ergo
sum, it's not just I think, therefore I am, it's probably better
understood that I doubt, therefore I think, therefore I am.
Skepticism is fundamental to scientific process, but there's this
border that you cross over where constructive skepticism turns
into destructive cynicism. I'm afraid gets in the way of our
ability to work together to better the outcomes, better welfare
of patients.


 
Carolyn:
Do you think we've swung from the United States maybe you could
give me your opinion to the wrong end of that balance between
constructive skepticism and destructive cynicism? Joe, what do
you think?


 
Joe:
As someone who has not worked in my own research closely with
industry, sometimes I think that we have. I mean, there are
certainly many examples. We all know where people have crossed
the line and that is profoundly unacceptable, but at the same
time, I worry that we've thrown the baby out with the bathwater
and some of the things that are uniquely done in academia and
some of the things that are uniquely done in industry, a synergy
between them across the divide is essential to move this field
forward. I think sometimes the boundaries and the bright lines
separating them are so distinct and defined that it prevents
those source of synergies.


 
Carolyn:
Thank you for that paper that really provides that balanced
perspective. The beautiful thing, it's just so personal almost.
It feels like we're sitting with you, having a conversation when
we're reading that paper. Like now, it's just been an amazing
experience having you on this podcast. Do you have any last
messages?


 
Ken:
My last words. I again just want to thank you and thank Joe. Has
the pendulum swung too far? Thing about pendulums are that they
oscillate and I think what's needed is a willingness to watch out
that it doesn't swing too far. Is there cynicism? I'll admit, I
was flabbergasted and I still flabbergasted that you allowed me
to write this piece but I think the fact that you welcomed the
piece from someone in industry within the intent of bringing this
out, that is the pendulum not going too far. As long as there are
voices, editors, journals who are willing to help us articulate
points like this, I think that's at least what keeps us in a
reasonable balance.


 
Joe:
As Carolyn said, you brought a uniquely human conversational
element to this piece. Not everybody would publish a piece in
circulation and acknowledge that you are intimated and
embarrassed walking into Don Baim's office. That brought us right
into your living room and that was powerful.


 
Ken:
Honestly, I wasn't looking for the job. I was more interviewing
them to find out what I can about the company, but I did not want
to make an ass of myself in front of them. I felt like I was
[pieing 00:19:53] for fellowship. I walked in the door and
honestly I'm still standing with my hand on the doorknob and he
looks up at me and I have to remember his voice, he had that deep
sort of growly voice. He said, "Stein, you have no idea what
Chief Medical Officer does, do you?" I'm just thinking, do I try
to BS my way out of this or do I just give him the God honest
truth and turn around and go back to work. I said, "No, Dr.
Baim." I couldn't call him [inaudible 00:20:22] and to the end, I
told him, "Dr. Baim," I said, "I had no idea." That's when he
said, "Your job is to be the voice of the patient within Boston
Scientific." He said after that, "You don't need to know anything
about business. We know you don't know anything about business.
We've got a lot of MBAs and hopefully they do."


 
Carolyn:
Thank you once again for the paper, for this discussion. Thank
you both for being here. For all of you who are listening, thank
you for joining us again on Circulation on the Run.