Circulation August 1, 2017 Issue

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Dr. Carolyn Lam: Welcome to Circulation on the Run your weekly podcast summary and backstage pass to the Journal and it's editors. I'm Dr. Carolyn Lam associate editor from the National Heart Center and Duke National University of Singapore.

Our feature paper this week provides important mechanistic insights into oxidative stress and inflammation with aging. More of that soon right after the summary of this week's journal.

The first paper contributes to our understanding of the genetic and functional relevance of soluble guanylyl cyclase activity for coronary artery disease. As background, a chromosomal locus at 4q32.1 has been associated with coronary artery disease risk with genome wide significance. The locus encompasses GUCY1A3, which encodes the alpha one subunit of the soluble guanylyl cyclase, a key enzyme of the nitric oxide cyclic GMP signaling pathway.

In today's study from co-corresponding authors Dr. Kessler, and Dr. Schunkert from Munich, Germany and colleagues the authors showed that the GUCY1A3 locus has regulatory properties with the risk allele leading to reduced expression of GUCY1A3. The lead snip modulated finding of the transcription factor ZEB1 resulting in reduced expression of GUCY1A3 in carriers of the risk allele. As a consequence risk allele carriers demonstrated impaired inhibition of vascular smooth muscle cell migration and platelet aggregation after stimulation of the soluble guanylyl cyclase.

In summary, this study suggest that modulating soluble guanylyl cyclase activity or inhibiting the effects of reduced expression of GUCY1A3 may be promising therapeutic strategies for individuals with the high risk alleles of GUCY1A3.

The next paper reports the outcome associations between adding a radial arterial graft to single and bilateral internal thoracic artery grafts in the arterial revascularization trial or ART. As a reminder, ART was designed to compare survival after bilateral internal thoracic artery over single left internal thoracic artery bypass with about 20% also receiving a radial artery graft instead of a saphenous vein graft.

In the current paper, first author Dr. Taggert from University of Oxford and corresponding author Dr. Benedetto from University of Bristol in the United Kingdom and colleagues showed that the primary endpoint of ART which was a composite of myocardial infarction, cardiovascular death and repeat revascularization at five years was significantly lower in the radial artery group when compared to the saphenous vein graft group. This association was present when the radial artery graft was used to supplement both the single internal thoracic artery as well as the bilateral internal thoracic artery grafts.

In summary this post-hoc ART analysis showed that an additional radial artery was associated with lower risk for mid-term major adverse cardiac events when used to supplement single or bilateral internal thoracic artery grafts.

The next study addresses the questions of whether intensive blood pressure lowering beyond usual targets recommended by guidelines would lead to more lowering of left ventricular hypertrophy in patients with hypertension and whether reducing the risk of left ventricular hypertrophy explains the reported cardiovascular benefits of intensive blood pressure lowering.

To answer this question Dr. Soliman from Wake Forest School of Medicine in North Carolina and colleagues studied the 8,164 participants with hypertension but no diabetes from the Systolic Blood Pressure Intervention or SPRINT Trial. They showed that among SPRINT participants without baseline left ventricular hypertrophy, intensive blood pressure lowering was associated with a 46% lower risk of developing left ventricular hypertrophy compared to standard therapy. Similarly, among SPRINT participants with baseline left ventricular hypertrophy blood pressure lowering intensively was associated with a 66% greater likelihood for regression or improvement of their left ventricular hypertrophy. Furthermore, adjusting for left ventricular hypertrophy as a time-varying covariate did not substantially attenuate the effect of intensive blood pressure therapy on cardiovascular disease events.

In summary these findings add further evidence of the benefits of the intensive blood pressure lowering in patients with hypertension and suggest that these benefits go beyond reducing the hemodynamic stress on the cardiac structure. Further research is needed to understand the mediating factors and mechanisms by which intensive blood pressure lowering impacts the cardiovascular system.

Well that wraps it up for our summaries, now for our feature discussion.

We are going to talking about aging, oxidative stress and inflammation today and really taking a deep dive into potential mechanisms. I am so pleased to be here with the corresponding author of our feature paper in this week's issue. And that is Dr. Mustapha Rouis from INSERM University Paris six in France as well associate editor from University of Rochester Dr. Charlie Lowenstein.

Welcome gentlemen.

Dr. Charlie Lowenstein: Thank you for having us.

Dr. Mustapha Rouis: Thank you very much.

Dr. Carolyn Lam: Mustapha, what inspired you to actually look at the Thioredoxin system in looking at this aging question? What were your hypotheses?

Dr. Mustapha Rouis: Actually our laboratories working on cardiovascular diseases for several years. We have been trying to understand why oxidative stress and inflammation increase with age despite the presence of a variety of antioxidant proteins in the body. So among the antioxidant proteins the Thioredoxin-1, isoform one which is a small ubiquitous incytocylic protein called our attention because it's a multi functional protein. It can exert an antioxidant role, anti-inflammatory and anti-apositic role. So therefore we wanted to know whether the increase in the oxidative stress and inflammation with age is it due or at least in part to a deficiency of Thioredoxin-1. If so is there increases due to a decrease in protein synthesis or to increase in its degradation.

For this purpose we have constituted a cohort of young and old subject, male and female. They want to focus on this particular point because this is very important point it has not been easy to achieve and we took a lot of time to sort and to keep only subject meeting our criteria. Those who we wanted to enroll consisting of people free from any history of diseases such as cardiovascular diseases, diabetes, obesity, inflammation, any kind of inflammation, cancer et cetera. In addition we wanted subject without any risk factor for cardiovascular disease except of course the age. No smoking, no hyperlipidemia and no taking any medication.

This really very hard to achieve. Then once we have enough subject we evaluate the Thioredoxin-1 using commercially available very specific kit, ELISA kit and showed that the plasma level of Thioredoxin-1 decreased significantly with age. Since it has been described for several years that Thioredoxin-1 can be cleaved at the C terminal level, the cleavage has been described to be occur after lysine at position eight. This will generate a truncated called Thioredoxin-80. We measured the plasma concentration of Thioredoxin-80 in this sample, in this same sample of the selected subject using an ELISA method developed in our laboratory because there is no commercially kit for Thioredoxin-80.

The result showed that Thioredoxin-80 increased with age therefore the decrease in the plasma concentration of the full length Thioredoxin-1 observed in the old, in the elderly is probably due to an increase in its cleavage and not to a decrease in its synthesis. Of note we observed an increase of the expression and activity of two alpha secretases ADAM-10 and ADAM-17 two enzyme responsible for the cleavage process in the peripheral blood mononuclear cells of the old subject. Our results consolidate our interpretation.

Dr. Carolyn Lam: Wow, what a beautiful set of studies that included human samples and then also included some very elegant mouse experiments. I remember the excitement among the editors when we discussed this paper. Charlie could you just share a little bit of what went on when we looked at this?

Dr. Charlie Lowenstein: First I'd like to put this study into context which is that oxidants increase during aging and it's been known for a long time that animals that have high metabolic rates have short life spans and one of the things that goes along with high metabolic rate is a lot of radical production. And since the 1950's there's been this theory, the free radical theory of aging that radicals damage cells. And so the question is, are radicals bad? What do they do in aging? And what defenses do we have against them? So that's one of the contexts of this article.

Secondly we also know that oxidants are associated with diseases. Increased oxidants during cancer, during inflammatory diseases and during atherosclerosis so that's why this study is important. It's important for two reasons. First of all there's a theory that as you age there's more radicals and radicals might actually cause part of the problem in aging. Secondly radicals are also associated with inflammatory diseases like atherosclerosis.

When the editors got this article, it was very exciting for several reasons. First of all, the short form of Thioredoxin, TRX-80 might explain why older people have more oxidative stress. Secondly this short form TRX, TRX-80 might be a new bio-marker for aging. And thirdly, the short form of Thioredoxin might help us monitor different antioxidant therapies when people have too many radicals. So for a number of important clinical reasons our editors were very excited when we received this important manuscript.

Dr. Carolyn Lam: Mustapha, what are your next steps when it comes to this?

Dr. Mustapha Rouis: Well several studies have shown that Thioredoxin-1 can reduce inflammation and can protect the body against several pathologies which has an increased interest in its use for therapeutic purpose. However its cleavage in the generation of the Thioredoxin-80, limited research work in this direction so I just remember you that the Thioredoxin-80, the truncated form in contrast to the full length Thioredoxin-1 exerts a pro-oxidant, pro-inflammatory angiogenic and carcinogenic effect. So nevertheless in order to counter these difficulties we plan to synthesize some Thioredoxin limited peptides such as catalytic site containing peptides and these peptide used it in therapy could show significant biologic activity. This peptide could lose constitute maybe an alternative to the full length Thioredoxin.

Dr. Carolyn Lam: Wow, that is exciting. Charlie, what do think is the take home message for clinicians listening to this?

Dr. Charlie Lowenstein: Scientists and clinicians all agree that an excess of radicals is bad. But there's an antioxidant paradox which is when patients take antioxidants like vitamin E, those antioxidants don't help. In a large clinical trial suggesting that vitamin E and other antioxidants don't help. So the question is, maybe antioxidant therapy helps some patients but doesn't help others. One of the interesting aspects of this study that maybe the presence or absence of TRX-80 might determine whether antioxidant therapies will help. Furthermore, maybe TRX-80 levels might be able to guide patients as to whether or not they should take antioxidant therapy. There are many important aspects of this study that point toward future studies.

Dr. Mustapha Rouis: We thought about inhibiting the ADAM-10, ADAM-17 alpha secretase enzyme to prevent the cleavage process and I know that many drug companies are trying to find the specific inhibitors but the problem is these two enzyme are benefit in brain for enzymatic disease. So waiting to have a specific inhibitor for this enzyme that do not cross the hematoencephalic barrier to use it in humans but until that we may be the use or conceive the peptides it's better approach.

Dr. Carolyn Lam: I'm just loving this discussion because it's really bringing out a lot more to this paper than I realized as a clinician. Charlie could you end by just saying a few words about how we look at basic science papers in Circulation and the importance of the clinical translation element that we keep saying is our primary focus.

Dr. Charlie Lowenstein: Circulation is a great journal that covers important clinical topics. There's a lot of basic science that underlies some of these clinical topics so whenever we get a paper that gives us insight into a disease or reveals a new therapy and it's at the basic level we look very carefully at it. We want to know, will it help our readers understand something about the clinical process, clinical disease, diagnostics [inaudible 00:16:00] So when we get a paper we look at it very carefully and emphasize it has to be a basic paper that reveals a mechanism that's important to clinicians. That clinicians can understand and appreciate and gain insight about what's going on with their patients. I'm both a clinician and a scientist, I am charged with trying to figure out what basic concepts are relevant to our clinical audience.

Dr. Carolyn Lam: Thank you Mustapha, thank you Charlie and thank you listeners for tuning in this week. Don't forget to tune in again next week.

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