Circulation May 23, 2017 Issue

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. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. In just a moment we'll take a deep dive into hemo-compatibility-related outcomes in the MOMENTUM 3 trial of a fully magnetically levitated pump in advanced heart failure. But first, here's your summary of this week's journal.

                                                The first paper sheds light on the biological mechanisms underlying cardioprotective effects of the Mediterranean diet. First author, Dr. Wang, corresponding author Dr. Hu and colleagues of Harvard, TH Chan, School of Public Health in Boston, Massachusetts studied 980 participants from the PREDIMED Trial including 230 incident cases of cardiovascular disease and 787 randomly selected participants at baseline followed up for 7.4 years.

                                                Participants were randomized to a Mediterranean diet supplemented with extra virgin olive oil, a Mediterranean diet supplemented with nuts, or a controlled diet. Plasma ceramide concentrations were measured and the primary outcome was a composition of non-fatal acute myocardial infarction, non-fatal stroke or cardiovascular death.

                                                The authors found a novel positive association between baseline plasma ceramide levels and incident cardiovascular disease. In addition, the association between baseline ceramides and incident cardiovascular disease varied significantly by treatment groups where a Mediterranean dietary intervention appeared to mitigate the potential deleterious effects of elevated plasma ceramide concentrations on cardiovascular disease.

                                                These findings, therefore, strengthen the evidence base for recommending the Mediterranean diet for cardiovascular disease prevention and suggest that plasma ceramides have the potential to serve as markers of future cardiovascular disease risk.

                                                The next paper describes a novel therapeutic approach against hypertensive cardiac remodeling and provides the first evidence of the cardio protective effect of cardiofibroblast-specific activating transcription factor 3 or ATF3. In this study from first author Dr. Li, co-corresponding authors, Dr. Du from Beijing Anzhen Hospital in China, and Dr. Ma from Thomas Jefferson University in Philadelphia and colleagues, the authors used a discovery-driven unbiased approach to identify increased ATF3 expression in mirroring hypertensive hearts and the human hypertrophic heart, expressed primarily by cardiac fibroblast cells. ATF3 knockout markedly exaggerated the hypertensive ventricular remodeling, a state rescued by lentivirus mediated microRNA aided cardiac fibroblast selective ATF3 over-expression.

                                                Conversely, cardiac fibroblast specific ATF3 over-expression significantly ameliorated ventricular remodeling and heart failure. The authors further identified MAP2K3 as a novel ATF3 target, and that p38 was the downstream molecule of MAP2K3, mediating the profibrotic hypertrophic effects in ATF3 knockout animals.

                                                In summary, this study provides the first evidence that ATF3 up-regulation in cardiac fibroblasts in response to hypertensive stimuli, protects the heart by suppressing MAP2K3 expression, and subsequently p38 TGF-beta signaling. Thus, identifying molecules mimicking endogenous ligands or inhibiting microRNA that down-regulate ATF3 expression, may represent novel therapeutic approaches against hypertensive cardiac remodeling. These, and other issues, are discussed in an accompanying editorial by Dr. Jennifer Davis of University of Washington.

                                                The next paper tells us that clinical frailty score may need to be part of the pre-operative assessment of patients undergoing transcatheter aortic valve replacement, or TAVR. First author, Dr. Shimura, corresponding author, Dr. Yamamoto and colleagues of Toyohashi Heart Center in Japan, utilized the optimized catheter valvular intervention or OCEAN Japanese Multicenter Registry of 1215 patients undergoing TAVR and found that clinical frailty score correlated with other markers of frailty, such as body mass index, albumin, gait speed and grip strength. Furthermore, the clinical frailty score was an independent predictive factor of increased late-cumulative mortality risk. Thus, in addition to reflecting the degree of frailty, the clinical implications of these findings are discussed in an accompanying editorial by Dr. Jonathan Afilalo from McGill University in Montreal.

                                                In the final study, we learned that long-term anabolic androgenic steroid use may be associated with myocardial dysfunction and accelerated coronary atherosclerosis. Dr. Baggish and colleagues from Massachusetts General Hospital in Boston, used a cross-sectional cohort design of 140 experienced male weight lifters, age 34-54 years, comprising 86 men reporting at least two years of cumulative lifetime anabolic androgenic steroid use, and 54 non-using men. Compared to non-users, steroid users demonstrated relatively reduced left ventricular systolic function and diastolic function on transthoracic echocardiography. Furthermore, steroid users demonstrated higher coronary artery plaque volume on coronary CT angiography compared to non-users. In summary, this is the first large controlled study of its type to demonstrate that long-term anabolic androgenic steroid use is associated with both systolic and diastolic myocardial dysfunction, as well as coronary atherosclerosis. Thus, when clinicians encounter young or middle-aged men who exhibit evidence of unexplained left ventricular dysfunction or premature coronary artery disease, the possibility of cardiotoxicity due to long-term anabolic androgenic steroid use should be considered in the differential diagnosis.

                                                Well, those were your summaries. Now, let's move on to our featured discussion.

                                                For our featured discussion today, we are actually reviewing a secondary analysis of the MOMENTUM 3 Trial, which is a multicenter study of the mag lev technology in patients undergoing mechanical circulatory support, with the HeartMate 3. And to discuss today's findings I'm so pleased to have the corresponding author, Dr. Mandeep Mehra from Brigham and Women's Hospital in Boston, Massachusetts, as well as Dr. Biykem Bozkurt, Associate Editor from Houston, Texas.

                                                Welcome Mandeep and Biykem.

Dr. Mandeep Mehra:     Thank you. It's a pleasure to be with you all.

Dr. Biykem Bozkurt:        Thank you.

Dr. Carolyn Lam:               Let's start by getting a few definitions right, shall we, just for our audience. This specific article, and congratulations Mandeep, it's just so great, it speaks of hemo-compatibility-related outcomes. Could you start by telling us what that is, and maybe reminding us what the original MOMENTUM 3 short-term results showed.

Dr. Mandeep Mehra:     Sure. As our listeners are aware, left ventricular assist devices have really transformed the management of refractory advanced heart failure, by the introduction of a form of flow, called continuous flow, in the devices, which tend to render patients, relatively low pulsatiles to non-pulsatile. Now what we've seen is that the interface between this very unnatural physiology from continuous flow in concert with the patient's biology tends to create a constellation of problems that we sort of refer to as hemo-compatibility-related adverse events.

                                                For example, we have seen a very curious development of recurrent gastrointestinal bleeds that tend to occur in a manner similar to what was observed with critical aortic stenosis, the so-called Heyde's Syndrome. Similarly we see stroke-related problems and we also see evidence of thrombosis that can sometimes develop within the pump. So we refer to the conglomeration of these unique complications that arise from the abnormal interface between the device and the patient as hemo-compatibility-related adverse events.

Dr. Carolyn Lam:               And this is a secondary analysis, a six-month secondary analysis, right? So could you give a little bit of background of why you would hypothesize that these events might be different with the HeartMate 3 versus 2? I mean, it's quite unique that we're going back to creating a pulse.

Dr. Mandeep Mehra:     Yes. Let me fist define for our audience what the MOMENTUM 3 Trial was designed to initially do, and is still doing. MOMENTUM 3 is a randomized controlled trial of two devices: one, a conventionally available continuous flow device called the HeartMate 2, and the second device, the novel pump called the HeartMate 3. The HeartMate 3 is a pump that took two decades to engineer. And it took that long because it is very unique, based on the following principles.

                                                First, it's a small profile, so the entire pump can be placed intrathoracically. Second is that the way in which it moves blood, its rotor, is fully magnetically levitated, which means that it has no friction when it rotates. The third is that despite its small profile, this device has wide blood flow gaps, meaning that as blood is moving in this centrifugal flow pump, it does not expose the blood elements to as much of sheer stress as one sees with other conventionally available devices. And then finally, what this device has uniquely is a intrinsic pulse, and what that means is that we program this device in a fixed program to actually ramp its speed up and ramp it down so that it creates an intrinsic pulse of about 30 beats per minute, which is engineering-wise designed to improve pump wash out; that's the intention.

                                                So the MOMENTUM 3 Trial was constructed to really compare these two devices and we recently reported, on the primary end point of the six-month outcomes of this trial. And the trial primary end point was set at survival free of a disabling stroke, or the need for re-operation because of pump malfunction. And what we found was that this pump, the HeartMate 3, clearly met its non-inferiority end point, versus the HeartMate 2, but also demonstrated superiority on the primary end point at six months. We were certainly not expecting to see superiority at this early time point, but we were very fortunate to see that.

                                                Now what is unique about this is that for the first time ever, we saw no cases of suspected or manifest established pump thrombosis, as a result of de novo pump thrombosis requiring re-operations with the HeartMate 3 device. And this is a frequency of about 10% that we normally observe with pumps. That is one in 10 pumps will clot off within about six months, and require re-operation. So we were very gratified to see this observation in the short-term data of the primary MOMENTUM 3 database.

                                                Now as a result of that observation, Carolyn, we thought that the hard end points, as are typically adjudicated for the primary basis of these clinical trials, missed the entire constellation of hemo-compatibility-related outcomes because these are patients who develop both bleeding and clotting complications. And the net burden of hemo-compatibility is not entirely available for review, which is the basis of this important secondary analysis that was published in Circulation.

Dr. Carolyn Lam:               What striking findings. So tell us the bottom line.

Dr. Mandeep Mehra:     What we found in the secondary analysis was evidence that the burden of hemo-compatibility-related adverse events is lower in patients with the HeartMate 3, compared to the HeartMate 2 device. And that was the basis of the bottom line that we found.

                                                In particular, we knew that there were no episodes of de novo pump thrombosis with the HeartMate 3, but we also found that there was evidence of a reduction in non-disabling strokes with the HeartMate 3 device. So we now have evidence that thrombotic complications, minor strokes, as well as pump thrombosis, seem to be abrogated by this new pump.

                                                What we should keep in mind, however, is that this is still early data from the ongoing MOMENTUM 3 Trial, and the trial is actually designed to enroll and observe over a thousand patients, over two years. And we are basically showing in this a very early look at six months of about 300 of these patients. And so that needs to be kept in mind. But we are extremely encouraged by these early trends suggesting that we may have started to break the issues related to the barriers of implementation of such therapy in the hemo-compatibility domain.

Dr. Carolyn Lam:               Yeah, and as a heart failure doc, I can tell you that I share that excitement and I know that Biykem does too, as did the editors.

                                                Biykem, tell us a little bit about what we talked about as editors about this paper.

Dr. Biykem Bozkurt:        Indeed. Mandeep, the hemo-compatibility concept which is being addressed in this new publication is quite novel and is exciting, and addresses the continual spectrum of the pathology, ranging from the GI bleed, to the stroke spectrum. The question I have, in this study, the overall scores were not different in the absolute number that we saw as a score from the hemo-compatibility ranking.

                                                Do you think we would continue to use this approach as a quantitative score, given the fact that there may be bidirectional impact from different devices on the different spectrum, especially with the recognition that HeartMate 3 seemed to be protective against the thrombotic, perhaps events, or should we use it more of a qualitative score card looking at which perhaps spectrum the device tends to be a little bit more risky or beneficial. So shall we color code this score and try to perhaps focus on the spectrum of thrombosis versus bleeding and then try to strategize?

Dr. Mandeep Mehra:     Thank you for that very erudite question, Biykem. You hit right at the heart of the matter. So let me make a few comments about that. The first issue is that so far, the field has not had a clear definition of hemo-compatibility. Hemo-compatibility has been more of a engineering term. When someone said hemo-compatibility, they thought of biomaterials, rather than a clinical definition of hemo-compatibility. So for the first time, we have actually introduced the term hemo-compatibility into the lexicon of definition, managing patients with LVAD, so that's one important point.

                                                The second important point is that we, until this day, until this analysis, have not had the ability to really provide people with a full picture of the entire burden of experience of hemo-compatibility-related complications that an individual patient experiences as they are on this device, because you know that patient's going to have a GI bleed, and then they may have a stroke, because we may change, dynamically we may change anticoagulation for instance if someone has one event then the other, and the traditional way in which studies are done, hey do not give you a clear picture into the burden of hemo-compatibility. So the most innovative thing about this clinical hemo-compatibility definition, is that we've not introduced a score that reflects the burden of disease, and we have also created tiers of severity of the burden of disease experience into three quantitative tiers that include various subsets which are hierarchal.

                                                So for example, is one gastrointestinal bleeding the same as non-disabling stroke? Well, no. One gastrointestinal bleeding may be a milder form a hemo-compatibility-related problem. So our early look at this clearly shows that survival free of a hemo-compatibility-related event is clearly lower in the patients with a HeartMate 3. However, as you astutely pointed out, when you examine purely the burden of hemo-compatibility-related complications experienced by the survivors, one actually sees a trend in favor of the HeartMate 3, but not a statistically significant difference, largely because we have not yet abrogated problems related to bleeding complications on the side of the hemo-compatibility.

                                                Why is that? Well, it's because we still treat all patients in both groups with the HeartMate 2 or the HeartMate 3 with the same intensity of anticoagulation. What this sort of data points out to us in the future, first of all, is that it allows us to compare apples to apples, as we are looking at different device platforms, that's number one. Second is it gives a much more robust look into the total patient experience. And third, it actually gives us insight into whether altering one component of the equation, so let's say there's a bleeder, if you actually react to that clinically, will you start to see problems on the clotting side.

Dr. Biykem Bozkurt:        This is a very, very important study that addresses the whole spectrum of hemo-compatibility in a more comprehensive fashion, and also points out perhaps the differences that we see in overall others, centrifugal flow, left ventricular assists, support systems such as the Heartware HVAD study that showed increase in hemorrhagic stroke, especially hemorrhagic stroke in the first six months in the ENDURANCE Trial, whereas the HeartMate 3 has shown in the MOMENTUM 3 publication, as well as the Circulation secondary end point study demonstrates a reduction in disabling strokes and absence of any pump thrombosis.

                                                So there are differences, despite both of the pumps are centrifugal, there are differences in the profile, and the spectrum of the risk and hemo-compatibility. And one other interesting finding from this study is that the predictors for hemo-compatibility outcomes are complementary to what has been known in the sense that lower antiplatelet and anticoagulation management strategies are associated with increased risk of hemo-compatibility adverse events.

                                                And surprisingly, the control of blood pressure did not appear to correlate with the hemo-compatibility outcomes. So from that perspective, it differs from the ENDURANCE Trial where the uncontrolled blood pressure or hypertension was associated with hemorrhagic strokes, in the ENDURANCE Trial, whereas in the MOMENTUM 3, the blood pressure did not appear to correlate with the hemo-compatibility outcomes or pump thrombosis.

                                                So these are very interesting findings and I think are complementary to the evolving field of the risk benefit ratios in patients with LVAD support. And from that perspective, we in Circulation felt that this will be a very valuable publication for our readership as well as for the whole heart failure and transplant community.

Dr. Carolyn Lam:               Thank you, so much for joining us today, don't forget to tune in next week.