Circulation March 7, 2017 Issue

Dr. Carolyn
Lam:              
Welcome to Circulation on the Run. Your weekly podcast summary
and [inaudible 00:00:06] of the journal and its editors. I'm Dr.
Carolyn Lam, associate editor from the National Heart Center and
Duke National University of Singapore. In just a moment we will
be discussing really fascinating preclinical data to suggest that
high fiber diet and acetate supplementation may change the gut
microbiota and thereby prevent the development of hypertension
and heart failure. But first here's your summary of this week's
issue.


                                               
The first paper describes the impact of heart transplantation on
the functional status of children with end stage heart failure in
the United States. First author, Dr. Peng, corresponding author
Dr. Almond and colleagues from Stanford University, use the organ
procurement and transplantation network to identify 1,633 US
children age less than 21 years, and surviving one year or more
post-heart transplant, from 2005 to 2014, with a functional
status score available at three time points. Namely at listing,
at transplant, and one year or more post-heart transplant. They
found that at the one year assessment 64% were fully active with
no limitations, or a functional status score of 10. 21% had minor
limitations with strenuous activity, or a functional status score
of 9. And 15% scored a functional status score lower than 9.
Compared to the listing functional status, functional status at
one year post-transplant increased in 91%, and declined or remain
unchanged in 9%. Early rejection, older age, African-American
race, chronic steroid use, hemodynamic support at heart
transplantation, and being hospitalized at transplantation, were
all associated with abnormal functional status post-transplant.


                                               
These findings may be helpful to patients, families, and
referring providers by providing a contemporary picture of the
post-heart transplant life in children as they weigh the risks
and benefits of transplantation.


                                               
The next paper brings cardiac reprogramming one step closer to
clinical translation. In this paper by first author Dr. Mohamed,
corresponding author Dr. Srivastava, and colleagues from
Gladstone Institute of Cardiovascular Disease in San Francisco,
the authors used a high throughput chemical screen in post-natal
mouse cardiac fibroblasts, and found that transforming growth
factor beta, or TGF beta, and WNT, or wint inhibition, enhanced
transcription factor based direct reprogramming of cardiac
fibroblasts to induce cardiomyocyte like cells in vitro and in
vivo. A combination of TGF beta and wint chemical inhibitors
increased the quality, quantity, and speed of direct
reprogramming, resulting in improved cardiac function after
injury as early as one week after treatment. These chemical
inhibitors enhanced human cardiac reprogramming and reduced the
number of transcription factors needed for human cardiac
reprogramming to just four factors. These findings if validated
in large animals could facilitate a combined gene therapy and
small molecule approach to heart failure.


                                               
The next study is the first report of the risks of cardiac
mortality among five year survivors of childhood cancer beyond 50
years of age. First author Dr. Fidler, corresponding author Dr.
Hawkins, and colleagues from University of Birmingham in United
Kingdom, looked at the British childhood cancer survivors study,
a population based cohort of 34,489 five year survivors of
childhood cancer that was diagnosed from 1940 to 2006 and
followed up until February 28th in 2014. The authors quantify the
cardiac mortality access risk. Overall 181 cardiac deaths were
observed, which was 3.4 times that expected. Survivors were two
and half times more at risk of ischemic heart disease, and almost
six times more at risk of cardiomyopathy or heart failure at
death than expected. Among those aged over 60 years, subsequent
primary neoplasms, cardiac disease, and other circulatory
conditions accounted for 31%, 22%, 15% of all deaths.
Specifically for cardiomyopathy or heart failure deaths,
survivors diagnosed between 1980 and 1989 had 29 times the excess
number of deaths observed per survivors diagnosed either before
1970 or from 1990 onwards. Thus the authors concluded that excess
cardio mortality among five year survivors of childhood cancer
remains increased beyond 50 years of age, and has clear messages
in terms of preventative strategies. However, the fact that the
risk was greatest in those diagnosed in 1980 to 1989, suggests
that initiatives to reduce cardio toxicity among those treated
more recently may be have a measurable impact.


                                               
The last study describes the 30 day results of the Source 3
Registry, that is the European Post Approval Registry of the
latest generation of the Sapien 3 trans-catheter heart valve. Dr.
Wendler and colleagues from King's Health Partners in London,
describe that these 30 day results of the Source 3 Registry
demonstrate that trans-catheter uratic valve implantation, or
TAVI, using the Sapien 3 resulted in high procedural success with
low procedural complications, and excellent post-implant
hemodynamics. Moderate to severe paravalvular leakage appeared to
be lower with the Sapien 3 than reported with prior versions of
this trans-catheter heart valve. Rates of pacemaker implantation
were higher with the Sapien 3 than in earlier generations of the
valve. This, in combination with the growing experience of
patient selection, procedure planning, execution, and
post-operative care has led to one of the best short-term
outcomes ever reported after TAVI. These results are discussed in
an accompanying editorial by Dr. [Altassi 00:06:58], and Dr.
[Urani 00:06:58], from the Emery Midtown Hospital in Atlanta,
Georgia, where they say that these early results from Source 3
Registry are a source of encouragement with some caveats.


                                               
Well, those were your summaries. Now for our feature discussion.


                                               
I am so honored to have two lovely ladies join me today on the
show. And they are the first author of a feature paper, Dr.
Francine Marques from Baker Heart and Diabetes Institute in
Melbourne, Australia, as well as Dr. Peipei Ping, associate
editor from the David Geffen UCLA School of Medicine. Welcome
ladies.


Dr. Peipei
Ping:                
Hi, hello.


Dr. Francine Marques:   Hi, thank you for having us.


Dr. Carolyn
Lam:              
As a clinician, I have very very often advised my hypertensive
patients to go on the dash diet. And you know, I have no had any
trouble explaining the low salt bit, right? I understand it. But
then I realize that I've always advocated as well the high fiber
bit, not actually really understanding how high fiber directly
impacts blood pressure. And I'm so excited because your paper,
Francine, shed some light on this and it actually has something
to do with the gut. So could you please explain what you did and
what you found?


Dr. Francine Marques:   So we fed a mouse model called
[adoca 00:08:25] model of habitation, that also developed heart
failure, we fed them a high fiber diet for three weeks, and then
after that we did a surgery to make them become [habitant
00:08:36] safe and we followed them up for six weeks. And what we
observed through that trajectory is that mice that were fed a
high fiber diet had significantly lower systolic and diastolic
blood pressure, and also an improvement in the heart function,
and also a decrease in both heart and brainal fibrosis. And the
reason why the fiber is so important is because although we
usually don't digest the fiber, the bacteria in our gut
absolutely love it. And that allows the bacteria, good bacteria
to grow. And with that growth we have release of the fermentation
of the fiber, releases in short chain fatty acid. So these
specific molecules can then be put back into our body and can
help us in our health. So we also fed these mice acetate, which
is one of the short chain fatty acids, directly and we also
observed very good improvements in blood pressure and
cardiovascular health.


Dr. Carolyn
Lam:              
It's just fascinating. So these are studies in mice. What do you
think of clinical translational aspects of this?


Dr. Francine Marques:   Large epidemialogical studies
have shown that there is an inverse correlation between fiber
consumption and blood pressure. And they have seen this through
very small clinical trials looking into the intake of fiber
lowering blood pressure. But our study opens the possibility of
new interventions using maybe short chain fatty acids
specifically, but are also looking into a different type of
fiber. So most studies would look into either soluble or
insoluble fiber directly. Our study, the diet that we used, is
mostly resistant starches. So these are their preferred type of
fiber for bacteria growth in our gut. And maybe they use a
[inaudible 00:10:32] type of fibers as well could be a new
[inaudible 00:10:36] opportunity.


Dr. Carolyn
Lam:              
Peipei, I remember you discussing this paper at our editorial
meetings and you so beautifully highlighted the novelty of this
paper. Could you share this with our listeners?


Dr. Peipei
Ping:                
Often within many complex studies trying to understand cellular
pathways and mechanisms of cardio protection, it's a very
important topic as we have had our research focus on in the pas t
25 years. What's very unique and provocative of this particular
study is that it simply identified critical metabolic pathways
that actually is underlying the protective effects. Many of us
have wondered about with eating, for example vegetables or high
fiber diet, it is examined specific molecules that have both a
direct as well as an endocryne path that would circulate things
back to the cardiac muscles, and having the muscles becoming more
protective because of regulation of certain transcriptomic
pathways to support cardiac muscle contraction. So we were very
impressed by both the new concept as well as the state of the art
technologies employed in this investigation.


Dr. Francine Marques:   Thank you, that's very nice.


Dr. Carolyn
Lam:              
I couldn't agree more, you put it so beautifully Peipei. I
thought that it was really nice also linking pathways as well as
linking several organ systems. Is there anything you might want
to highlight about the renal effects, not just cardiac?


Dr. Francine Marques:   Yes. Many times investigations
been focusing on if something went wrong how do we cure it? More
precious is when we find novel results telling us the healthy
individuals, what are the things we should be doing so our blood
pressure would stay at the normal level, or our cardiac function
is being protected if there's an insult or injury. And so in this
situation, the examination of the entire renal transcriptomic do
give us very valuable information on how the blood pressure
regulation system that maybe actually protected by the short
chain fatty acid acetate.


Dr. Carolyn
Lam:              
So true Francine. Anything else to add?


Dr. Francine Marques:   Just to say circulation, for
giving the opportunity to submit this paper, and share it with
the world. We're very very excited about the data.


Dr. Carolyn
Lam:              
Yeah we should be the ones to thank you. It's a beautiful paper.
We're very privileged to publish it in circulation. May I ask
what are next steps for you? What do you think needs to be done
from here?


Dr. Francine Marques:   We're validating this in other
models now. And we're also looking into the [inaudible 00:13:57]
microbiome and how that's related to habitation. So trying to
really pinpoint mechanisms and how we can move this forward into
the clinic.


Dr. Carolyn
Lam:              
That's so great. And Peipei, do you think that there's certain
gaps that urgently need to be addressed now?


Dr. Peipei
Ping:                
Yes, I think one of the most beautiful thing that ... Concept,
illustrated this investigation is we really couldn't be just
focusing on one organ, our primary interest organ, heart, alone.
What's demonstrated here is a beautiful link of both mechanism as
well as governed by transforming parbolytes with endocryne
effects. How the gut, the kidney, and the heart are all connected
together in this process, achieving a better protective condition
in the environment for the cardiac muscle.


Dr. Carolyn
Lam:              
Thank you listeners. You've been listening to Circulation on the
Run. Tune in next week for even more news.