Circulation March 14, 2017 Issue

Caroline:             
Welcome to Circulation On The Run! Your weekly podcast, summary,
and backstage pass to The Journal and it's editors. I'm Doctor
Carolyn Lam, Associate Editor from the National Heart Center in
Duke National University of Singapore. What does the gut
microbiome have to do with Cardiovascular Disease? Well to find
out you'll just have to stay tuned for our featured discussion
debate. First, here's our summary of this week's journal.


                               
The first paper seeks to answer the question "does first
trimester screening modify the natural history of Congenital
Heart Disease?" To answer this question Doctor Jasinskyl and
colleagues from the University Hospital in Masaryk University in
the Czech Republic, analyze the spectrum of congenital heart
defects and outcomes of 127 fetuses diagnosed with congenital
heart defects in the first trimester compared to 344 fetuses
diagnosed in the second trimester screening. All of these
analyzed between 2007 and 2013.


                               
They found that the spectrum of congenital heart defects
diagnosed in the first versus second trimesters differed
significantly with a greater number of comorbidities, defects
with univentricular outcomes, intrauterine deaths, and
terminations of pregnancy in those diagnosed in the first
compared to second trimester.


                               
They further analyze 532 fetuses diagnosed with congenital heart
defects in the second trimester but in an earlier period of 1996
to 2001, which is the period before first trimester screening was
introduced. In this group they found significantly more cases of
defects with univentricular outcomes, intrauterine deaths, and
early terminations of pregnancy. In comparison to fetuses also
diagnosed with congenital defects in the second trimester but in
the later period of 2007 to 2013.


                               
Thus, the authors concluded that first trimester screening had a
significant impact on the spectrum of congenital heart defects
and on the outcomes of pregnancies with defects diagnosed in the
second trimester. Early prenatal cardiac ultrasound screening may
therefore, in some countries, reduce the number of children born
with severe cardiac abnormalities and associated comorbidities.


                               
The next study sheds light on the use of intravenous recombinant
tissue plasminogen activator, or "RTPA," in patients with acute
ischemic stroke also receiving no wax or the newer oral
anticoagulants. Doctor Sienne and colleagues from the Duke
Clinical Research Institute in Durham, North Carolina use data
from the American Heart Association "Get With The Guidelines"
stroke registry in 42,887 ischemic stroke patients treated with
RTPA at 1,289 hospitals in the United States between 2012 and
2015. They basically found no statistically significant
differences in the risk of symptomatic intracranial hemorrhage
between patients who were taking Noac, Warfarin, or not taking
any anticoagulant before the stroke.


                               
This largest clinical experience of stroke thrombolysis in
patients receiving Noac before the strokes thus suggest that RTPA
is reasonably well tolerated without prohibitive risks for
adverse events amongst selected Noac treated patients. However,
the authors are quick to say that their observations must be
considered as preliminary due to the absence of coagulation
parameters, timing of the last Noac intake, and whether or not
non-specific reversal strategies may have been applied.


                               
The next paper provides experimental evidence of the unique
effects of plasminogen activation and Alpha 2 antiplasmin
inactivation on the fibrinolytic system in pulmonary embolism. In
this paper from Dr Sing, Hong, and Reed from the University of
Tennessee Health Sciences Center in Memphis, Tennessee the
authors use mouse models of experimental pulmonary emboli to show
that monoclonal antibody inactivation of Alpha 2 antiplasmin,
which is an endogenous inhibitor of plasmin, effectively
dissolved pulmonary emboli with similar potency to high dose
RTPA.


                               
Alpha 2 antiplasmin inactivation synergize with low dose RTPA to
enhance thrombus dissolution. And like RTPA, Alpha 2 antiplasmin
inactivation alone or in combination with low dose RTPA, did not
cause fibrinogen degradation or increased bleeding. The authors
therefore concluded that Alpha 2 anti plasmin is a dominant
regulator that prohibits thrombus dissolution in vivo.


                               
Therapeutic modulation of Alpha 2 antiplasmin activity may
therefore prove an effective strategy to enhance fibrinolysis
without significantly increasing the bleeding risk. These results
are discussed in an accompanied editorial by Doctor Yurano from
Hamamatsu University School of Medicine in Japan.


                               
More exciting experimental data in the next paper showing that
novel beta arrestin signaling pathways may be viable targets in
dilated cardiomyopathy. First author Doctor Reba, corresponding
author Dr Solaro, and colleagues from University of Illinois at
Chicago treated a dilated cardiomyopathy mouse model expressing a
mutant tropomyosin for three months with either a beta-arrestins
two biased ligand of the entertance and receptor or losartan and
angiotensin receptor blocker as control. Treated mice showed
improved cardiac structure and function associated with
myofilamins that had significantly improved myofilament calcium
responsiveness. Which was depressed in the untreated mice.


                               
These functional changes were mediated through beta arrestin
which may have a novel role in increasing MLC2V phosphorylation
through a previously unrecognized interaction of beta arrestin
localized to the sarcamore. Thus, long term beta arrestin 2
biased agnonism of the angiotensin receptor may be a viable
approach to the treatment of dilated cardiomyopathy. Not only by
preventing maladaptive signaling but also by improving cardiac
function by altering the myofilament calcium response via
beta-arrestin signaling pathways. The concept of a two in one
angiotensin receptor blocker and calcium sensitizer is discussed
in accompanying editorial by Doctors Wu, Ju, and Siao from Peking
university in China.


                               
The final paper asks the question "are three arterial graphs
better than two coronary artery bypass grafting?" Doctor Galdino
and colleagues from Weill Cornell Medicine in New York performed
a meta analysis of eight propensity score matched observational
studies on more than 10,000 matched patients comparing the long
term outcomes coronary artery bypass grafting with the use of two
verses three arterial graphs.


                               
They found that the use of a third arterial condo et in bypass
grafting is a associated with superia long term survival
irrespective of sex and diabetes status and without a higher
operative risk. These results therefore support a strategy of the
use of a third arterial graph and really deserve confirmation in
prospective randomized trials. Well, that's it for the summaries.
Let's welcome our guests.


                               
Our topic for discussion today is so exciting. In fact, I am
going to read from the paper describing it as an exciting, new,
and important field of investigation where we start to understand
how nutrition, our gut micro-community composition, and our
genetics actually all play a part in Cardiovascular Disease. And
to discuss this paper I have the first and corresponding author
Doctor Wilson Tang from Cleveland Clinic Foundation as well as
Doctor Nikhil Munshi, Associate Editor from UT Southwestern.
Welcome Wilson and Nik!


Nik:                       
Thank you.


Wilson:                
Thank you.


Caroline:             
Wilson, please set the stage for us! What does our gut microbiome
have to do with cardiovascular disease? I agree it's a hot area
but, you know, could you just describe what it actually means.


Wilson:                
This has been somewhat of an accidental discovery from our group
when we start encountering different types of metabolites that we
measure to kind of associate them with Cardiovascular Disease.
And unbeknownst to us, some of them are produced by the bacteria
that live inside us to which we convert and try to eliminate. So
one such metabolite that we identify is, which in many of the
foods that we tell our patients, advise our patients that have
high risk of Cardiovascular Disease. So all these connections
come together to form a scientific basis to which how one of the
biggest environmental exposures that we have which is what we eat
every day is filtered by trillions of bacteria that live inside
us and many of these metabolites become hormones that effect our
every day function and activity.


                               
And, in many ways, can actually lead to diseases that are so
remote from the gut but such as Cardiovascular Disease,
Atherosclerosis, and we further identify these process and they
impact downstream organ function like heart function and kidney
function. So these are all very excited areas and this is just
one of several metabolites. There are other metabolites that also
impact blood pressure and even brain function and so all these
areas become kind of a new avenue for us to look at potential
therapeutic targets.


Caroline:             
Yeah I think it's so completely fascinating that we can actually
each experience a given meal differently based on the different
types of gut microbial communities in our bodies isn't it? And
that that actually can effect things all the way from
atheroscleroses, to obesity, insulin resistance, and so on. Could
you give us a specific example from your research?


Wilson:                
We actually identified a metabolite, a very small molecule called
Trimethylamine N-oxide, we abbreviate it as TMAO. And TMAO is
actually formed from the bacteria from a precursor called
Trigosamine which is, you know, gas. In other words, the bacteria
taken substances of nutrients such as choline and connetine which
is actually common in many foods but particularly in red meats,
in egg yolks, and many other foods that we know are potential
contributors to Cardiovascular Disease.


                               
And actually converted into this gaseous compound that our liver
converted into a neutral compound, that we think is neutral for a
long time and nitrogenous waste, except that when we have both
animal studies and human studies patients with high levels of
this TMAO metabolite has been associated with a high risk of
Cardiovascular Disease. And in fact in animal studies we have
direct evidence that show its contributing to the mechanistic
compartment.


Caroline:             
Now extrapolating from what you just said so vegetarians, for
example, or vegans even more so, would have less TMAO levels
then?


Wilson:                
Yeah, obviously there are wide variation in these levels actually
change almost by the minute because obviously we eat different
times of the day and it comes in and out of our bodies. But in
general, yes, in other studies that we actually identified a
higher level of in carnivores which are meat eaters verses vegans
and vegetarians who do not eat meat.


Wilson:                
Yeah and we actually use... I sort of labeled choline and
connetine to actually directly show that the synthesis of TMA and
TMAO by a labeled connetine is higher in meat eaters, carnivores,
verses vegetarian or vegans.


Caroline:             
Oh, I really have to ask both you Wilson and Nik the following
question then. What do you think is the, you know, take home
message? How do you apply this clinically and even more cheeky,
perhaps, how are you applying this in your own life? I mean with
this knowledge have you become vegetarian? I'm putting you on the
spot here.


Wilson:                
I think this is basically a very scientific demonstration of how
what we eat does impact our every day bodily function. And I
think many cultures have this identification. Obviously many
Asian cultures have seen the impact of food. In fact, it actually
opens entire insight into how different medicinal food may
actively be impacting the gut microbiome that actually creates
different effects in the body. But in terms of diet and
nutrients, yeah I have totally have eaten less meat in my every
day dietary habits.


                               
I definitely think it's something that is certainly quite
insightful and probably very impactful. That being said, I think
different cultures also have different populations of microbiome
and I think it's not a one size fits all. In fact I think every
individual has his own dynamic ranges and we are still in the
very very first early stage of understanding how this impact
helps in disease. So there's a lot of excitement and there's a
lot of technology that hopefully can help us to unravel this
mystery.


Caroline:             
Exactly, a new and important field just like you said. Nik, what
do you think?


Nik:                       
From my standpoint, I'm actually not a big meat-eater so this was
very welcomed news when this all came out. But, you know, from
another standpoint it really opens up a lot of new questions. You
know, it kind of blurs the line between sort of genetics and
environmental factors. You know, so the questions of maybe a
family who shares certain genetic traits may also share certain
environmental traits. In other words, they share certain gut
microbial components and maybe this sort of complicates how we're
going to disentangle some of these risk factors going forward.
I'm interested to get Wilson's take on this.


Wilson:                
Yeah it gives us a lot of insight to the I guess what happens is
the microbiome is isolated in the family lineage because the
lifestyle exposure are very similar in each household. So, what
we thought is inherent is being inherited from both the genomic
but also a microbiome perspective.


Caroline:             
Nik, you manage this paper. I really love, for example, that
figure which I think everyone should get ahold of the journal and
have a look at. Could you tell us a little bit more about this
category of papers?


Wilson:                
I'm sort of charged with this task of bringing sort of basic
Science across the aisle to clinicians so that we can all sort of
talk the same language and perhaps interact on a higher level.
And so I was really excited reading some of Wilson's work and you
know I really wanted to bring that to some of our broad
readership just so that we could sort of appreciate what sort of
science was going and I really think that this is a really great
example of something that's on the verge of being translated.


                               
You know you can imagine that by either effecting certain
metabolite compositions or maybe by treating certain subsets of
bacteria we may be able to influence long term cardiovascular
risks not to mention obesity, diabetes, and some of these other
diseases that Wilson is actively working on. So I really read
this with a lot of excitement and I wanted to bring this to a
broader audience and you know we have a number of other articles
that are in the pipeline that I think will serve to bridge this
gap and put us on the same field so that we can kind of speak the
same language.


Caroline:             
Wilson, did you have a good time sort of writing something like
this its not long.


Wilson:                
It's actually very difficult. In fact, its just like writing
poetry. You know it's hard to write in simple and short
sentences. So it actually was a big challenge for me and I really
thank the opportunity to be able to do that but I also want to
emphasize I think it was a very insightful experience for me too.
Because as a practicing physician and a commissioned scientist
don't always merge these too few, these two areas in a way to
actually see the importance we like to learn the science and try
to explore I think clinicians really need to take charge and
learn exciting science that's occurring. I think this is a
wonderful avenue and I applaud [inaudible 00:18:10] for setting
this radio [inaudible 00:18:11]


Caroline:             
Well listeners you heard it first here on Circulation On The Run
it is poetry by Wilson Tang. So please, please pick up a copy of
today's journal and don't forget to tune in again next week!