Circulation March 14, 2017 Issue

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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!

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