Circulation August 8, 2017 Issue

Carolyn:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

                                Later on in this podcast, we will be meeting Dr. Nancy Schweitzer, Editor-in-Chief of the new Circulation Heart Failure. We will be discussing today's feature paper on acute myocarditis as well as hearing about her visions for the journal. All that coming right up after these summaries.

                                The first original paper this week suggests that day-to-day blood pressure variability may be a significant risk factor for dementia. First author Dr. Oishi, corresponding author Dr. Ohara, and colleagues of Kyushu University from Fukuoka, Japan, studied a total of 1,674 community-dwelling Japanese elderly without dementia, who were followed up for five years, and had home blood pressure measured three times every morning for a median of 28 days.

                                They found that the age and sex adjusted incidences of all-cause dementia, vascular dementia, and Alzheimer's disease increased significantly with increasing day-to-day variability of home systolic blood pressure. These associations remained unchanged after adjusting for potential confounding factors, including average home systolic blood pressure. The study, therefore, suggests that the measurement of day-to-day blood pressure variability, using home blood pressure monitoring, may be a useful way to assess future risk of dementia, irrespective of dementia subtype.

                                The next paper is one of the first studies to directly target a gene within the fibroblast of a mammalian heart and show a direct role in regulating cardiac fibrosis. Co-corresponding authors Dr. Molkentin from Howard Hughes Medical Center and Cincinnati Children's Hospital Medical Center and Dr. Davis from University of Washington and colleagues performed an elegant series of mouse experiments to show that the gene-encoding p38 alpha mitogen-activated protein kinase was required to mediate fibroblast activation in the mouse heart following injury.

                                They also showed that forced activation of p38 within fibroblasts, using a transgenic approach, was sufficient to drive fibrosis in multiple tissues of the mouse, including the heart.

                                In totality, their findings indicated that p38 mitogen-activated protein kinase was a nodal signaling effector within the cardiac fibroblast that drove both wound healing and long term fibrosis in heart failure. In other words, it appears to play a crucial role in the control of both physiological and pathological processes. The clinical implications are that pharmacologic inhibition of p38 mitogen-activated protein kinase in heart failure could reduce progressive fibrosis. However, the same inhibition during acute myocardial infarction injury may inhibit wound healing and be detrimental. These issues are discussed in an accompanying editorial by doctors, Stratton, Koch and McKinsey.

                                Receptors, well known for their roles in angiogenesis and cancer, may play a role in atherosclerosis, as shown in the next paper, which looked at the Eph-family of receptor tyrosine kinases. These are the largest family in the mammalian genome, which interact with ephrin ligands on adjacent cells to mediate cell adhesion repulsion signaling.

                                First author, Dr. Finney, corresponding author, Dr. Orr, from LSU Health Sciences Center, Shreveport, and colleagues assessed the role of EPHA2 in atherosclerosis by deleting the EPHA2 in a mouse model of atherosclerosis and by assessing EPHA2 function in multiple vascular cell culture models.

                                The authors identified a novel role for EPHA2 in atherosclerosis by regulating both plaque inflammation and progression to advance atherosclerotic lesions. Cell culture studies suggested that endothelial EPHA2 contributed to atherosclerotic inflammation by promoting monocyte firm adhesion, whereas, smooth muscle EPHA2 expression regulated the progression to advanced atherosclerosis by regulating smooth muscle proliferation and extracellular matrix deposition.

                                The clinical implications are that blunting EPHA2 ligation may selectively reduce plaque-associated inflammation. Since the effect of EPHA2 on smooth muscle proliferation appears to be largely ligand independent, unlike its effect on inflammation, the blunting of EPHA2 ligation may limit inflammation while leaving smooth muscle fibroproliferative remodeling intact.

                                Well, that wraps it up for our summaries. Now, let's go to our feature discussion.

                                Our feature paper today may cause us to think a little bit differently about fulminant versus non-fulminant acute myocarditis because the findings are actually in contrast with previous studies and are extremely insightful.

                                And, to discuss this, I am so pleased to have the corresponding author, Dr. Enrico Ammirati from Niguarda Hospital in Milan, Italy, as well as Dr. Nancy Sweitzer, Associate Editor of Circulation from University of Arizona, who managed this paper. But importantly, also, the Editor In Chief of Circulation Heart Failure. Welcome, Enrico and Nancy.

Enrico:                  Hello.

Nancy:                  Thank you, Carolyn.

Carolyn:               Enrico, could I ask you to start by clarifying the conditions that we're talking about here? When we say acute myocarditis or fulminant myocarditis, and non-fulminant myocarditis, what exactly are we referring to?

Enrico:                  We refer to an acute condition and fulminant myocarditis is a myocarditis inflammation of the myocardium that's a media anatomic or mechanical support due to an anatomic instability, while non-fulminant myocarditis it's a condition where the patient remains hemodynamically stable. Previous records have suggested that despite their dramatic presentation of patient with a fulminant myocarditis might have better outcome than those with acute fulminant myocarditis.

                                Now in this study we have over 55 patients with fulminant myocarditis and in particular, 34 patients with fulminant myocarditis with viral genomes within two weeks from the onset of symptoms, whereas in the previous record, in particular from [inaudible 00:07:38] we have shown in 15 occasions of fulminant myocarditis, that fulminant myocarditis as quite a good prognosis.

                                But what we believe it is that gives disparity between our results that connected all acute patients admitted to the emergency department with [inaudible 00:08:01] and symptoms onset within one month to two weeks before. Is the main difference comparing [inaudible 00:08:11] this study [inaudible 00:08:13] patient with onset of symptoms since one year before the onset of symptoms. And we believe that we enroll acute patients.

                                Whereas in the other study, there was sort of selection by us. It was true that in those previous studies, they have all just patients who we were endomyocardia biopsied performed whereas in our study we did not perform endomyocardia biopsies in that case. But we feel that we have a snapshot of the acute stage of a fulminant myocarditis, so we connected all the patients, whereas in previous study, maybe some of the patients they had acute symptoms died before evaluation from the other researchers.

Carolyn:               Indeed, it makes a lot of sense that there may be some survival bias involved. For example, if the sickest patient didn't get a biopsy, for example.

                                Nancy, when you were managing this paper, what were the kind of the discussions that occurred at the editorial discussions?

Nancy:                  I think that Dr. Ammirati pointed it out really well. The editors felt that this was a very important paper because it really looked inclusively at myocarditis in the modern era, and showed us where perhaps bias in prior studies had led us astray in terms of our beliefs about, particularly the outcomes in this syndrome. Not only the outcomes in the fulminant patients, who have a very profound and important early mortality risk, but also the outcomes in the non-fulminant patients, who in this study, really do extremely well and do not progress to LV dysfunction, which has been a long-held belief, I think. So understanding much better the full spectrum of myocarditis was made much easier because of the comprehensive look Dr. Ammirati and his colleagues took.

Carolyn:               Enrico, I do congratulate you on a beautiful paper. As I said, as a heart failure cardiologist myself, it has changed my thinking. Could you maybe share just a bit more details of what your study found and how this is important clinically?

Enrico:                  What we have found it is that hospital deaths or heart transplantation was about 25 percent in fulminant myocarditis compared to ten percent in non-fulminant myocarditis and despite greater improvement in the left ventricle injection fraction [inaudible 00:10:56] in fulminant myocarditis compared to non-fulminant forms. The proportion of patients with the left ventricle injection fraction below 55% [inaudible 00:11:09] was higher in fulminant myocarditis comparing it to non-fulminant myocarditis. So we have to pay great attention to do this form of myocarditis not thinking that this is a condition that can simply recover with time but we have to aggressively manage this condition, and we have to see about trials designed [inaudible 00:11:39] in this specific setting to improve the [inaudible 00:11:50] outcome and to reduce myocardial injury during the acute phase.

Carolyn:               True. And Nancy, I mean you see tons of these patients too. How has this impacted you?

Nancy:                  It's interesting, it definitely has impacted me. I like everyone, taught and taught on my teaching rounds for many years that the fulminant patients we were seeing, despite how ill they were, would have better outcomes than those who were non-fulminant. And also, many patients who present with dilated cardiomyopathy who are non-ischemic are told after searching for some viral illness in the year prior to their presentation that probably they had a virus attack the heart or an inflammation of the heart. I've stopped saying those things, and I continue to see review of papers that I'm handling about myocarditis refer to these misconceptions. So I think this is going to be a really important paper, and clarifying our understanding of how this disease evolves over time.

Enrico:                  I fully agree, I fully agree with this message, and [inaudible 00:12:54] but I believe that the traditions that are involved in [inaudible 00:13:00] maybe can be misleading for other cardiologists.

Carolyn:               Nancy, I'm gonna switch tracks a little bit, I mean your explanation of that already gets me so excited about the kinds of papers that are gonna get to be seen at the new Circulation Heart Failure under your leadership. So could you just tell us a little bit more about your vision as editor-in-chief.

Nancy:                  Well Carolyn, Circulation Heart Failure is an excellent journal Dr. [inaudible 00:13:33] has stewarded it beautifully in its first decade of life. In many ways I don't want to change the journal, I want the very best science that's helping us have a deeper understanding of the disease processes and therapies that affect our patients. That said, I would say we have a couple new initiatives, or sort of slight differences in how we're going to manage the journal going forward. I must say, the content we get is spectacular, and we're so fortunate to be able to look through the papers we get, and try to choose the very best science. It's an amazing privilege for me and the new team.

                                We're really interested in young investigators and those people who are starting out in their career. The emerging scientists who are producing the best heart failure science. Early in your career you might not have the weight of data behind you to merit publication and circulation proper, but we hope that with good science well thought out excellent hypotheses, Circulation Heart Failure will be an appropriate target for those emerging investigators.

                                We found some great pleasure in approaching young scientists at meetings, and discussing their work, and asking them to send it to our journal. And that's been great fun and we've seen wonderful yield from that. We've been getting submissions from people we've spoken to whose work we admire, and we really hope to build that part of the journal up. Hand in hand with that is an effort at building our social media presence. We're an entirely online journal. We're very interested in visually appealing content. We do have an images in case report section. And we're going to work to try to build an online community for our young investigators who may not have the money to travel internationally, but who really needed global community of heart failure research colleagues, and we hope to be a place to build that.

                                And finally, we're interested in some areas that maybe, are emerging or underrepresented in other journals. Areas like ... the way technology is transforming heart failure mechanical circulatory support devices, wearable devices, the other technologies we're using increasingly in our patients. And the world of pulmonary hypertension, and right ventricular dysfunction, which is sort of searching for a journal home, and we hope that we can be that journal home. And of course representing the full spectrum of therapies for heart failures including transplantation. I already mentioned mechanical circulatory support, you know, all the richness that is the evolving field of heart failure, and how we ... I think as professionals in that field think about and treat our patients a little differently than other people caring for heart failure.

Carolyn:               Listeners, you just heard it right here, on Circulation on the Run.

                                Thank you so much for joining us this week. Tune in again next week for even more exciting news.