Circulation May 16, 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 its editors. I'm Dr. Carlolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. What's the link between DPP4 and aortic valve calcification? Well, to find out, keep listening because we'll be discussing this and an important new paper right after these summaries.

The first original paper in this issue tells us that high sensitivity Troponin I, may have a role in personalizing preventive strategies in patients with Type II Diabetes. Dr. Cavender and colleagues from University of North Carolina, Chapel Hill, sought to describe the relationship between changes in high sensitivity Troponin I and cardiovascular outcomes in the EXAMINE phase 3B trial, which was designed to evaluate the cardiovascular safety of alogliptin. The current analysis was restricted to patients, randomized 30 days or more after the qualifying acute coronary syndrome event, and high sensitivity Troponin I was measured using the Abbot Architect Assay at baseline and six months.

The authors found that high sensitivity Troponin I was detectable in the vast majority - 93% of patients with Type II Diabetes, stabilized within 30 days after acute coronary syndrome. One in six of these patients had high sensitivity Troponin I levels above the 99th percentile upper reference limit. High sensitivity Troponin I had a strong graded relationship with the incidence of subsequent major cardiovascular events.

Changes in high sensitivity Troponin I as small as two to six nanograms per liter over six months, were associated with a heightened risk of adverse outcomes. Particularly cardiovascular death and heart failure. Alogliptin neither increased nor decreased the risk of cardiovascular events in a high risk cohort of patients with elevated high sensitivity Troponin I levels. These findings therefore imply that serial measurements of high sensitivity Troponin may have a role in preventive strategies, either by intensifying or prolonging therapies in patients at high risk or reducing or shortening therapies in patients at low risk of cardiovascular events.

The next paper describes the effects of Pioglitazone on cardiac outcomes after ischemic stroke or transient ischemic attack in patients with insulin resistance without diabetes in the IRIS trial, which stands for Insulin Resistance Intervention after Stroke. As a reminder, the IRIS trial compared the effects of Pioglitazone with placebo on major cardiovascular events after stroke or transient ischemic attack, in patients without diabetes but who had evidence of insulin resistance. And it showed that Pioglitazone improved insulin resistance, prevented diabetes, improved CRP and reduced fatal and non-fatal stroke or myocardial infarction.

In the current paper, by Dr. Young and colleagues from Yale Cardiovascular Research Center in New Haven, Connecticut, the authors performed a secondary analysis of IRIS and examined the effect of Pioglitazone on acute coronary syndromes, mainly myocardial infarction or unstable angina. They found that Pioglitazone reduced the risk of these events by 29%, with benefit emerging after two years of treatment. Furthermore, Pioglitazone reduced the incidence of Type I myocardial infarction with a neutral effect on Type II myocardial infarction. In summary, among patients with insulin resistance without diabetes, Pioglitazone reduced the risk of acute coronary syndromes after a recent cerebrovascular event, and may serve as a useful secondary prevention therapy in addition to statins, aspirin, and other established treatments.

The next study tells us that immune complexes may be an important biomarker in the risk stratification of Antiphospholipid Syndrome. Now recall that Antiphospholipid Syndrome is characterized by recurrent thrombosis in patients with Antiphospholipid predictive antibodies. However, the predictive value of the presence of Antiphospholipid auto antibodies is low. And new markers are needed to identify carriers at higher risk.

In the current study by Dr. Serrano and colleagues from Madrid, Spain, the authors performed a historical cohort follow up study based on the Magnum 12 plus 12 cohort, that included all patients who had received a kidney transplant in their hospital in a 12 year period from 2000 to 2011. Sera used for the analysis were collected in the 24 hours before the kidney transplant surgery, and used to measure circulating immune complexes of immunoglobulin A bound to beta II glycoprotein I.

The authors then investigated the possible association of these immune complexes with thrombosis, graft thrombosis and graft loss in the six months following kidney transplant. They found that in patients with the immunoglobulin A isotope antiphospholipid antibodies, the presence of circulating immune complexes of immunoglobulin A bound to beta II glycoprotein I, pre transplant, was associated with acute thrombotic events. Patients positive for the immune complexes had a much higher risk of developing post transplant thrombotic events, and higher risk of graft thrombosis mediated graft loss. On the other hand, complex negative patients had the same thrombosis risk as the control population. These findings imply that treatment to prevent thrombosis should focus mainly on the immune complex positive patients in this setting.

The final paper addresses the issue that public reporting of PCI Outcomes may create disincentives for physicians to provide care for critically ill patients, particularly at institutions with worse clinical outcomes. In this study from first author, Dr. Waldo from the VA Eastern Colorado Health Care System in Denver, Colorado, corresponding author, Dr. Yeh from Beth Israel Deaconess Medical Center in Boston, Massachusetts, and colleagues. The authors used state reports to identify 31 out of 86 hospitals that were recognized as negative PCI outliers in two states: Massachusetts and New York, from 2002 to 2012.

They sought to evaluate the procedural management and in hospital outcomes of patients treated for acute myocardial infarction before and after a hospital had been publicly identified as the negative outlier. They found that outlier facilities were larger, treating more acute myocardial infarction patients, and performed more PCI's than non outlier hospital. The rates of percutaneous revascularization increased similarly at outlier and non outlier institutions after report of the outlier status. After outlier designation, the in hospital mortality declined at the outlier institutions to a greater extent than was observed at the non outlier facilities. Thus, public reporting of outlier status may prompt outlier facilities to improve case selection, and employ systems improvements that optimize patient care, and improve in hospital mortality among patients with myocardial infarctions.

We are going to have such a fun discussion in today's feature paper. Have you ever wondered what does dipeptidyl peptidase-4, or DPP4 have to do with aortic valve calcification? Well, you're about to learn, because in today's paper we actually learn that DPP4 inhibitors, which you might recognize from diabetes, you know drugs such as sitagliptin, could serve a potential therapeutic target in aortic valve disease. To tell us about it and discuss it, we have corresponding author, Dr. Jae-Kwan Song] from Asan Medical Center in Seoul, South Korea, as well as Dr. Thomas Eschenhagen, Associate Editor from University Hospital Hamburg Eppendorf in Germany. Welcome, gentlemen.

Dr. Jae-Kwan Song: Hi.

Dr. Thomas Eschenhagen: Hi.

Dr. Carolyn Lam: Fascinating paper. I have to congratulate you first and foremost, but please tell us, what inspired you to look at DPP4 in aortic valve disease.

Dr. Jae-Kwan Song: Yeah, actually as a clinician, I think there is two issues. One is the prevalence of calcific aortic valve disease is increasing rapidly in the developed and also developing countries. The second important issue is that we do not have effective medical treatment option. So I will say that the medical treatment of calcific aortic valve disease is a typical example of unmet clinical needs to serve this kind of troubled scientific issues, our team have focused on the reciprocal interaction between endothelial cells and interstitial cells. Because this potential mechanism was well reported by other investigators that the interaction between two cells are very critical for maintaining aortic valve tissues. So first we started with Enos knockout mouse, to go over what's going on in the aortic valve in the models. In the human tissues in patient with calcific aortic valve disease, we have found that DPP4 is specifically activated. That's the beginning of our study.

Dr. Carolyn Lam: Could you please explain to those of us who don't do basic science research everyday, I mean, your study involves tissues both from humans and mirroring models. Could you explain it very simply what you did and what you found?

Dr. Jae-Kwan Song: Yes, in the Enos Knockout mouse, we have found that those mouse showed very strong calcification process compared to the live animals. What is the mechanism of this enhanced calcification in this mouse? And we found that the loss of endothelial function is critical, and then we found that DPP4 is actively involved in the calcification process. The first test we have done is the isolation of developed interstitial cells. And then we focused on osteogenic transformation over this valvular interstitial cell both in the Enos Knockout mouse, and the human developing interstitial cells. So we have found that the endothelial dysfunction activates the DPP4 activity in these tissues, which resulted in the increase osteogenic transformation of developed interstitial cell. So that's the beginning of our observation.

Dr. Carolyn Lam: And could you describe what you did subsequently to prove the whole mechanism?

Dr. Jae-Kwan Song: As you know the DPP4 has many substrates including many peptides involved in glucose metabolism, so the hardest part of our study is what is the molecule target, or associated with DPP4 in the pathologic process of calcification in developing interstitial cells. We tested many different substrates known to the potential targets of DPP4, and we have found specifically insulin-like growth factor-1 (IGF-1) is the key proponent of all this process. With further study, we found that the DPP4 cleaves or inactivates or decrease IGF1 activity in the valvular interstitial cell, and in the normal status IGF1 is a very critical to protect osteoblastic transformation of valvular interstitial cell. We have found that the DP4 and IGF1 exercises key therapeutic target, and the key molecules involved in valvular calcification. As you know we do have a DP4 inhibitors, which were successfully clinically to reduce the diabetes control. So it's very easy to test the DP4 inhibitors in animal models. Both in the Enos Knockout mouse, and we also developed in the calcific aortic valve disease using some treatment, including Vitamin D and hypercholesterol and diet the in vivo experiment showed that [inaudible 00:13:58] inhibitors effectively prevented the development of calcification and prevented the development of calcification and prevented the developement of calcific aortic disease. This the main finding of our study.

Dr. Carolyn Lam: That is so fascinating, and really especially what you just said, that sitagliptin in this rabbit model prevented calcific aortic valve disease with the concurrent increase in plasma IGF1 levels in line with the DPP4 inhibition. That is just such a beautiful piece of work, congratulations. And congratulations Thomas on managing such a nice paper. Take us under the hood about the discussions that happened with the editors. Surely you recognized the translational impact. What do you think? Is it time to reposition DPP4 inhibitors?

Dr. Thomas Eschenhagen: We and the reviewers like the paper because first of all it describes a new, interesting biological mechanism. If we are done, and we like that it uses human samples, but also this treatment in two different animal models. This together, really makes it a strong paper, we've found perfectly suitable for Circulation. As you said Carolyn, the translation perspective is fascinating. Obviously it's very early days. There is no specific evidence yet from patients. But that could, in patients, take actually very very long. Even the big studies already been done with sitagliptin and other DPP4 inhibitors, that don't show a signal in this direction yet, but I would say that could still happen, and maybe in the long term, all of the cardiologists putting all this stuff in German it's call TAVS, in America it's called TAVR does not work anymore, obviously. That's just the speculation.

But it gives a very interesting signal, and this study certainly should stimulate research in humans and do some prospective studies in patients.

Dr. Carolyn Lam: Yes indeed. If I may ask, Jae-Kwan, do you have plans for further steps?

Dr. Jae-Kwan Song: Yeah, we are expecting some [inaudible 00:16:06]. The first process with proof of concept study as you know is DP4 inhibitors have been actually been used for the diabetic controls, so we may have a patient cohort who also underwent [inaudible 00:16:22] echocardiogram [inaudible 00:16:23] while without medication. The analysis of those later can be used for proof of concept study. But we are challenging issues that although many drugs are classified as a DP4 inhibitors, we should really focus on the tissue distribution on these drugs, specifically on the cardiac issues. It may be possible that the different drugs have a different tissue distribution even after all our medication. The second critical issue is what is the actual dose of these drugs to prevent calcific aortic valve disease. Usually these drugs are used for diabetes control. We may need different lab results of these drugs for different critical indications. So that's the two important issues to be solved.

Dr. Carolyn Lam: That's wonderfully put, and I couldn't agree more. Thomas, could we switch tracks a little bit. Because now that I have you online, and you're the first time joining us on the show too, tell us a little bit more about what it's like as an associate editor really looking at these pre clinical data, being able to parse out what you think has translational value, and especially for circulation. We have a very strong emphasis now on clinical translation. Share some of your thoughts there on how it's been for us.

Dr. Thomas Eschenhagen: It's been a great experience. I do have some experience with other journals as an associate editor, or being on an editorial board. But I have to say circulation is really quite unique. I think it's a very strong group of people. I'm amazed by the level of knowledge and also the level of engagement of the other editors and associate editors, in every single paper. What's also really rewarding is the overall quality of papers being submitted to circulation, it's really great. A lot of papers are not only presenting some beautiful, basic science, but also this translational perspective, that's actually what we are looking for. So very solid, exciting scientific work in cells, animals, but always some link, either some materials from humans or a good link to a translation perspective. That's the perfect paper for circulation and I have to say we get quite a bit of them, and it's sometimes even difficult to pick the ones we really like. But it's great, it's really been a lot of fun.

Dr. Carolyn Lam: This is actually one of the purposes of this podcast. It's hoping to share with our readers, with our listeners, what happens at these editor discussions because it's so interesting, I just wish everyone could listen to all the science and the clinical translation that we discuss. Thank you very much for sharing your thoughts today, both Thomas, and Jake Won, beautiful work. We're very proud to be publishing this work in circulation.

Thank you listeners for joining us this week. Don't forget, tell all your friends about this podcast, and tune in again next week.

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