Oct 10, 2016
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.