Circulation on the Run

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Circulation March 24, 2020 Mar 23, 2020

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Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast soiree and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor for the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Greg Hundley, Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week we're going to talk about carotid stenosis, and you remember how we measure those a lot with ultrasound, and what that thickness is, and IMT? Well, we're going to talk about getting some thresholds and an update in that with our feature discussion today. But before we get there, how about grab a cup of coffee and we get started with other papers. Dr Carolyn Lam: All right. Well, I've got my coffee and I'm ready to tell you about two papers. They're both on left ventricular hypertrophy. One is basic and one is clinical. I will start with the basic paper because it is a super cool one that uncovers a novel mechanism underlying myocardial hypertrophy. And this involves S-nitrosylation, a prototypic, redux-based post-translational modification, S-nitrosylation. So this is from co-corresponding authors, Drs Xie, Han, and Ji from Nanjing Medical University, who performed a series of elegant experiments using myocardial samples from patients and animal models exhibiting myocardial hypertrophy, and they demonstrated that S-nitrosylation of muscle limb protein plays a crucial role in myocardial hypertrophy. This muscle limb protein modification enhanced binding to toll-like receptor 3 and receptor interacting protein kinase 3, which stimulated NOD-like receptor pyrin domain containing 3 or NLRP3 inflammasome activation and consequent caspace-1 and interleukin 1 beta activation, ultimately promoting myocardial hypertrophy. They further showed that the deficiency of S-nitrosylated muscle limb protein governed toll-like receptor 3 really alleviates pathological myocardial hypertrophy. Okay Greg, I can see the look on your face. You're like what? That was a lot. What are the clinical implications, right? Dr Greg Hundley: Yeah, Carolyn, you are taking me back to molecular biology course 410, that I would take as a senior in college. Wow. So tell me what are the clinical implications? Dr Carolyn Lam: All right, here's a take-home. The data really identify that S-nitrosylated muscle limb protein is a key regulator, which together with toll-like receptor 3 made therefore serve as putative therapeutic targets in treating pathological myocardial hypertrophy in heart failure. That's the take-home. Before any further comments, let's go to the clinical study. Now, this one focuses on a malignant subphenotype of left ventricular hypertrophy in which minimal elevations of cardiac biomarkers identify individuals with left ventricular hypertrophy at high risk for developing heart failure. And this is from corresponding author Dr James de Lemos from UT Southwestern. He and his colleagues tested the hypothesis that a higher prevalence of the malignant left ventricular hypertrophy phenotype among blacks may contribute to racial disparities in heart failure risk. So they pooled data from three large multi-ethnic cohorts, that is Eric, Dallas Heart Study, and MESA, totaling more than 15,700 participants. These participants were then classified into three groups: One, those without ECG left ventricular hypertrophy; two, those with ECG left ventricular hypertrophy but normal biomarkers; and three, those with ECG left ventricular hypertrophy and at normal levels of two biomarkers, high sensitivity troponin T above six nanogram per liters, or NT-proBNP above 100 picograms per milliliter. And that last group were the malignant left ventricular hypertrophy group. They found that the prevalence of malignant left ventricular hypertrophy was threefold higher among black men and women versus white men and women. Compared to participants without left ventricular hypertrophy, the adjusted hazard ratio for heart failure was 2.8 in those with malignant ventricular hypertrophy and only 0.9 in those with left ventricular hypertrophy and normal biomarkers. And these were similar findings in each race and sex subgroups. Mediation analysis indicated that 33% of the access hazard of heart failure among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant left ventricular hypertrophy in blacks. Dr Greg Hundley: So Carolyn, race could be a really important issue in left ventricular hypertrophy. What did the authors conclude? I mean, how should this help us perhaps manage these patients? What was the take-home? Dr Carolyn Lam: So this really shows that a higher prevalence of the malignant hypertrophy phenotype may in part, explain the higher risk of heart failure among blacks compared to whites. And what it means too is that when left ventricle hypertrophy is detected by ECG or cardiac imaging, perhaps we should consider measuring high sensitive troponin T or NT-proBNP, which will help distinguish those in whom risk for heart failure is favorable from those at a much higher risk. Dr Greg Hundley: Very, very interesting. Well Carolyn, I'm going to switch. I've got a basic paper and it's going to focus on dysfunctional adipocytes and how they might talk to cardiomyocytes in the situation of ischemia reperfusion injury. And the corresponding author is Xin-Liang Ma, from Thomas Jefferson University in Pennsylvania. So Carolyn, do you have any thoughts regarding how patients with diabetes might experience a greater degree of myocardial ischemia reperfusion injury in the setting of an MI? Dr Carolyn Lam: Oh my goodness, you're really putting me on this spot here. Well, I know things that come to mind would be oxidative stress, microvascular disease. Dr Greg Hundley: Very good. Open-ended questions for Carolyn's quiz. I'm going to give you a 90. That was very good. So Carolyn, this current study attempted to clarify whether and how small extracellular vesicles may mediate pathological communication between diabetic adipocytes and cardiomyocytes, exacerbating myocardial ischemia reperfusion injury. And to do this, adult male mice were fed a normal or high fat diet for 12 weeks. The small extracellular vesicles from diabetic serum, diabetic adipocytes, high glucose, high lipid-challenged, non-diabetic adipocytes were injected then, intramyocardially, distal of the site of a coronary ligation. Dr Carolyn Lam: Okay. So Greg, I would not have guessed it was about extracellular vesicles, but very interesting. What did they find? Dr Greg Hundley: Intramyocardial injection of diabetic serum small extracellular vesicles or these SEVs, in the nondiabetic heart, significantly exacerbated myocardial ischemia reperfusion injury, as evidenced by poor cardiac function recovery, larger infarct size, and greater cardiomyocyte apoptosis. And administration of small extracellular vesicles, biogenesis inhibitors, significantly mitigated the myocardial ischemia reperfusion injury in diabetic mice. And mechanistic investigations in these studies identified that MIR 130B3P is a common molecule, significantly increased in diabetic serum of small extracellular vesicles and mediated the pathological communication between the dysfunctional adipocytes and the cardiomyocytes. Therefore, if in the future, we could interfere with this molecule, that could perhaps be a novel strategy for attenuating diabetic exacerbation of myocardial ischemia reperfusion injury. Really, a clever study, I think. What else did you find in this issue of the journal? Dr Carolyn Lam: Yeah, Greg, this week's issue is packed with other papers too. For example, there's the research priorities for HFpEF by NHLBI working group summary by Dr Shah, et al. There's a research letter by Dr Kaltman on the disparities in congenital heart disease mortality based on proximity to a specialized pediatric cardiac center. There's also another research letter by Dr Irisawa, on the impact of low-flow duration on favorable neurological outcomes of extracorporeal CPR, after out-of-hospital cardiac arrest, and this is a multicenter prospective study. Dr Greg Hundley: It sounds like a lot's in the mailbag. In the couple of things that I wanted to talk about, Dr Giulia Rivasi from the University of Florence, and William White from University of Connecticut, exchange a series of letters back and forth regarding a previous publication on the effects of intensive versus standard ambulatory blood pressure control on cerebrovascular outcomes in older individuals. I have another research letter entitled, The Cardiac Cell Therapy Rejuvenates the Infarcted Rodent Heart via Direct Injection, but not by Vascular Infusions. And that is from Dr Jeffrey Molkentin from Cincinnati Children's Hospital Medical Center. Finally, though Carolyn, there's a very interesting piece from Dr Carl Bakker at the Ann and Robert H. Lurie Children's Hospital of Chicago, discussing are we now in a time, in the United States, where congenital heart surgery should be coalesced or regionalized? And that really comes on the back of a discussion of there have been several high-profile articles in the national media, reporting on US congenital heart surgery programs. And that's led to, the author describes, some closure of several centers and at least in five programs. So a great discussion on, should this be regionalized? But we've got a great feature article coming ahead and how about if we head to that. Dr Carolyn Lam: Let's go, Greg. Dr Greg Hundley: Welcome everyone, to this feature discussion where we are going to discuss the use of diagnostic ultrasound in the carotid arteries and how that pertains to selection of patients for vascular surgery. And with us today, we have Dr Jesse Columbo from the Geisel School of Medicine at Dartmouth University in Hanover, New Hampshire. We also have Dr Bob Zwolak, from the Manchester VA at the Dartmouth School of Medicine and we have our own Josh Beckman from Vanderbilt University, one of our associate editors at Circulation. And Bob, let's get started with you. Could you tell us a little bit, what was the background of this study and what hypothesis were you looking to test? Dr Robert Zwolak: It goes without saying that stroke is still a huge health problem in the United States. If there is any good news, it's that stroke incidence is falling slightly, but there are still over 100,000 deaths from stroke each year in United States and as many as 700,000 new strokes each year, and a significant proportion of those derive from atherosclerotic plaque in the carotid bifurcations. Carotid duplex ultrasound is a fantastic way to assess the presence of plaque in the carotid bifurcations because it does not use any ionizing radiation, does not require any contrast. Ultrasound is a relatively less expensive technology than CT or MR, and the study can be repeated so we can follow people over time, who are found to have significant atherosclerotic plaque in their bifurcations. The hypothesis of our study though, was that there is variation in the diagnostic thresholds used by various carotid ultrasound testing laboratories, such that it may impact the healthcare and the treatment plans of people who undergo the studies. Jesse will tell you the details, but specifically, we hypothesized that people who undergo this carotid ultrasound test may or may not be inducted into a surveillance program and intensive therapy based on the diagnostic criteria that were used by the individuals conducting their ultrasound study. And even more substantially, we hypothesized that individuals who undergo carotid endarterectomy or potentially carotid stenting, could also have their procedure influenced, whether or not they undergo surgery or stenting based on the carotid ultrasound results. It might vary from one facility to another. So it potentially could be that an individual would be inducted into ultrasound surveillance or even undergo carotid surgery, depending on the vascular laboratory in which they were tested. Dr Greg Hundley: Jesse, could you tell us a little bit, what was your study population and how did you design this to address the hypothesis that Bob just stated? Dr Jesse Columbo: Sure. A review of the published literature really shows a variability in that ultrasound criteria that's used for diagnosing carotid stenosis. And so our first objective was to see if we could obtain as many in-use criteria as possible. Our first step was to partner with the Intersocietal Accreditation Commission, the commission that accredits vascular labs. We partnered with them and obtained a 25% random sample of ultrasound criteria in use across the US. And so that kind of gave us the starting point for the criteria upon which to look at. We then wanted to apply those to a couple of different groups. As Dr Zwolak mentioned, there's really two primary breakpoints here. One, you either have mild stenosis, where you get medical therapy, but no further surveillance, or moderate stenosis, at which point you then are dedicated to long-term surveillance per the AAJ recommendations, or then, the break point between moderate and severe stenosis where surgery is considered. What we wanted to do is examine the impact of moderate and severe stenosis thresholds. For the severe stenosis thresholds, we use the Vascular Quality Initiative Registry, which collects information on patients who underwent carotid endarterectomy. When we studied patients specifically that we thought the percent stenosis would be the major deciding factor in who got surgery, those are the asymptomatic stenosis and we applied the range of severe stenosis criteria from the IAC to those patients. We then wanted to study other individuals who might be committed to long-term surveillance based on the criteria used. And so for that, we used participants in the Cardiovascular Health Study, which had their induction into the study, had baseline data on carotid stenosis collected. And so that kind of formed our basis of the study, applying the criteria to those two different groups of individuals. Dr Greg Hundley: And so how many subjects did you have in the two cohorts? And then tell us what were your study results? Dr Jesse Columbo: Sure. Once we narrowed down that patients in the vascular quality initiative to those who underwent surgery for asymptomatic carotid stenosis, we had about 28,000 patients. And then when we examined the Cardiovascular Health Study, we had about 4,800 or 5,000 patients in that group. What we found was pretty interesting. If you look at individuals who underwent surgery, and you take the carotid threshold criteria and apply it to them, and if you say, "Well, we're going to take criteria in the fifth percentile versus criteria in the 95th percentile," what you'll find is that 10% of patients who got surgery, fall between that range. And what that means is that there are patients, approximately 10% of patients, who are undergoing surgery that may not have been offered surgery if they had gone to a different institution, which we thought a pretty important finding. The second part was studying patients who maybe committed to long-term surveillance. And if we took centers that were in the fifth percentile versus those in the 95th percentile for their carotid stenosis thresholds, we found a twofold difference in the number of patients that would be committed to long-term surveillance. And remember, this is the difference between getting aspirin and a statin and medical therapy, but no longer surveillance and getting carotid ultrasound every six months to a year for a long period of time. That twofold difference really could have a meaningful impact on patients. Dr Greg H…

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Circulation March 17, 2020 Issue Mar 16, 2020

Show notes

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. Dr Greg Hundley: I'm Dr Greg Hundley from the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, this issue features a very important, but rather somber subject and it talks about suicide attempts among LVAD recipients and the real-life data from the Assist-ICD study. Now we have to get to that and it's a very interesting discussion, but first, let's discuss a couple of papers and I'll start. Now, we know that extracorporeal cardiopulmonary resuscitation using extracorporeal membrane oxygenation or ECMO, for hemodynamic support has been shown to enhance survival for patients with refractory VF or VT out of hospital cardiac arrest. However, what are the effects of prolonged CPR on development of metabolic derangements and neurologically favorable survival in these patients? Well, this was examined by Dr Bartos from University of Minnesota School of Medicine and colleagues who retrospectively evaluated survival in 160 consecutive adults with refractory VF/VT out of hospital cardiac arrest, treated with extracorporeal cardiopulmonary resuscitation, and compared these with 654 adults who had received standard CPR in the amiodarone arm of the ALPS trial. They found that extracorporeal CPR was associated with improved neurologically favorable survival compared to standard CPR at all CPR durations less than 60 minutes. However, CPR duration remained a critical determinant of survival with a 25% increase in mortality with every 10 minutes of CPR beyond 30 minutes. The progressive metabolic derangement which developed during prolonged CPR was associated with reduced neurologically favorable survival. Dr Greg Hundley: This mirrors an article that we had maybe about a month ago. What are the clinical implications of this particular study? Dr Carolyn Lam: Well, healthcare systems utilizing extracorporeal CPR for out of hospital cardiac arrest should optimize pre-hospital and in-hospital processes to minimize time to CPR. Further research is needed to identify strategies to increase CPR efficiency, improve profusion, and decrease the metabolic demands such that the progressive metabolic derangement associated with prolonged CPR can be delayed. This is discussed in an editorial by Dr Sonneville and Schmidt. Dr Greg Hundley: Very nice, Carolyn. Well, my next article is from Roxana Mehran from the Icahn School of Medicine at Mount Sinai. It's really getting at the issue of high-risk implantation of inter-coronary stents and balancing where is that risk. Is it from bleeding or a complication from the procedure? In this study, they had a total of 10,502 patients and they were included from four registries. 3,507 were identified as having high bleeding risk. The authors aimed to evaluate the long-term adverse events in the high bleeding risk patients undergoing PCI with cobalt chromium, everolimus-eluting stent implantation. Dr Carolyn Lam: Ah, Greg. Awesome. I'm a fan of Dr Mehran and looks like I'm going to be a fan of this study. What did they find? Dr Greg Hundley: Well, Carolyn, I love just thinking about coated stents. How about that? Interestingly, those at high bleeding risk had more comorbidities. They had higher lesion complexity and a higher risk of four-year mortality. In fact, four times that of those without those risk factors. The risk of mortality was increased after coronary thrombotic events and after major bleeding. Thus, rather than just being evaluated as a subset of patients in whom the risk of bleeding takes precedence, high bleeding risk patients must be considered a vulnerable population in whom both ischemic as well as bleeding events have a significant impact on their mortality. Dr Carolyn Lam: Nice, Greg, and you said all of that without repeating everolimus. Dr Greg Hundley: Coated, remember, coated stents. Dr Carolyn Lam: These tongue twisters, but hey, my next paper provides novel insights into mechanisms underlying diastolic stiffness in cardiomyocytes and the myocardium. This is from Dr Prosser from Perelman School of Medicine in Philadelphia and colleagues, who interrogated the role of the microtubule network in the diastolic mechanics of human cardiomyocytes and myocardium. They found that stable detyrosinated microtubules contributed viscous forces during diastolic stretch that increased cardiomyocyte stiffness, particularly in patients with heart failure. Depolymerizing microtubules reduced myocardial stiffness over the range of strains and strain rates associated with early rapid filling in tissue from patients with diastolic dysfunction. Dr Greg Hundley: Now, how are we going to take this to patients? Are there any translational insights? Dr Carolyn Lam: Microtubule deep polymerization using colchicine. Colchicine, the stuff we use for gout, this reduced myocardial viscoelasticity with an effect that decreased with increasing strain. Post-hoc subgroup analysis revealed that myocardium from patients with heart failure reduced ejection fraction were more fibrotic and elastic than myocardium from patients with heart failure preserved ejection fraction, which were relatively more viscous. Now, colchicine reduced viscoelasticity in both HFpEF and HFrEF myocardium, but may confer greater benefit in conditions with limited myocardial fibrosis including HFpEF. How's that for translational? Dr Greg Hundley: Oh, very nice, Carolyn. My next paper comes from Dr Lior Zangi from Mount Sinai School of Medicine. Carolyn, in this study, the authors performed transcriptomics sphingolipid and protein analyses to evaluate sphingolipid metabolism and signaling after myocardial infarction. They investigated the effect of altering sphingolipid metabolism through a loss of chemical inhibitors or gain modified MRNA and modified RNA of acid ceramidase function post hypoxia or MI. Dr Carolyn Lam: Whoa, so what did they find? Dr Greg Hundley: Well, Carolyn, translationally, the authors found that transiently altering sphingolipid metabolism through acid ceramidase over expression is sufficient and necessary to induce cardio-protection after myocardial infarction. Carolyn, these results highlight a new therapeutic potential of acid ceramidase modified messenger RNA in ischemic heart disease. The basic science is just phenomenal in our journal. Dr Carolyn Lam: It is, and I loved the way you explained that one, Greg, thanks. Now, there's lots of stuff also in the journal. There's an On My Mind by Dr Ray entitled "LDL Cholesterol Lowering Strategies and Population Health: Time to move to accumulative exposure model." We also have a research letter by Dr Chen describing a novel mouse knock-in strategy utilizing a biotin ligase-based system called biotin identification 2, to identify the cardiac diet proteome in vivo. Well, very interesting stuff, especially in terms of this particular novel strategy. Dr Greg Hundley: You know, Carolyn, this week the mailbox is just full, so I've got a research letter emphasizing trends in anti-arrhythmic drug use among US patients between 2004 and 2016 and it's from Dr David Frankel from the Hospital of the University of Pennsylvania. I've also got a letter to the editor regarding the association between the use of primary prevention implantable cardio defibrillators in mortality in patients with heart failure, a prospective propensity matched analysis from the Swedish Heart Failure Registry, and the corresponding author is Professor Laszlo Littman from atrium health at the Carolinas Medical Center in Charlotte, North Carolina. There is also a response to this letter from Dr Gianluigi Savarese from Karolinska Institute. Then finally I have a new another EKG challenge, Carolyn, from Dr Miguel Arias. It's a case of new onset, recurrent syncope triggered by fever. Can you get it right from just looking at the EKG? Well, Carolyn, should we head on to our feature discussion, which this week has a very somber tone? Dr Carolyn Lam: Let's go. Left ventricular assist devices or LVADs are really becoming established therapy for end stage heart failure. Now, we who manage such patients realize there are numerous complications and have seen patients who suffer things like anxiety and depression. Interestingly, until today, there was very little data regarding the suicide risk in this population. I am so pleased to welcome the authors of a very unique and important research letter and they are Vincent Galand as well as Erwan Flécher, both from Ren University Hospital in France, and of course Mark Drazner, our associate editor from UT Southwestern. Vincent, could you start us off by telling us what made you do this important study and what did you find? Dr Vincent Galand: As you know, in the entire population where a lot of tests have thromboses or infection or ventricular arrhythmias, but there is a lack of data about the clarity of life for the secret distress or suicide in this population. I think it's very important to have information about the population. At the beginning is the Assist-ICD study is a study focused on arrhythmias in this population, but we recorded data about suicide in this population. What the objective of this study was to analyze the incidents of suicide in this population and to see if there is some predictor of suicides in this population. Dr Carolyn Lam: What did you find? Dr Vincent Galand: We find that in centers without LVAD nurse coordinator, the incidents of suicide, was higher. It was not significant, but it was a very big trend. Additionally, we found that patient implanted in destination therapy was a bigger risk of suicide compared to patient granted bridge transportation or bridge to recovery. I think there is two factors of suicide. The first one is a lack of LVAD nurse coordinator and the second one is the implementation and destination therapy. Dr Carolyn Lam: Yeah, and the really cool thing is that that first factor is something that I suppose can be addressed in future efforts. Mark, could I just ask you to put these findings and this research that are into context for circulation to publish quite a specialty, if you may, topic, why is this so important? Dr Mark Drazner: DT vans are really a rapidly emerging therapy for patients with advanced heart failure, with almost exponential growth. As these profound technologies are emerging on the scene, it's important, first, to consider all the ramifications for our patients. I think anyone could imagine having an LVAD implant and how that might have profound influence on your life in totality and the impact on the psychological aspects. While there's been previous studies, there seems to be much avoidance in us really fully understanding the total impact. There have been previous case reports of suicide, but not anything to this magnitude where a systematic series with an estimate of the frequency of as high as 2%, which may not sound high, but, compared to the general population, is increased. We view this as an important look at a critical topic. It's the beginning, there needs to be, as you said, it's a research writer on a case series, but it's a cautionary tale and really is pointing the way for us to proceed with further investigation as potentially important complication related to that. That's essentially why the editorial board found this interesting. Dr Carolyn Lam: Indeed. Could you just remind us how big this study was? Because this is really big for an LVAD study. Dr Erwan Flécher: We collected data from 19 university centers in France over 10 years period and we collected a lot of that especially in the fields of arrhythmia. As Vincent said, we thought it was interesting to take the entire picture, so we collected data about quality of life and how do they live and if they had a lot of risk of suicide, if not, and that's how we succeeded to lead this study. In France, what is important also for you to know is that we do implant a different population of patients than in the US. We do implants in bad patients, in very, very sick patients. Most of them are currently in cardiogenic shock or already under temporary support, ECMO support, IMPELLA support, so it may impact also our results. That's an interesting point to say and the overall thing is that our paper demonstrated, I think, that we need to take care of these patients not only about the device, not only about the anticoagulation, but also, I mean again, the entire picture. The social part, the quality of life, the way they do live is very important. Probably they should be proposed for psychological follow-up also, or any kind of support for the family. This is important in order to decrease the risk of suicide, in my opinion. Dr Carolyn Lam: I liked those take-home messages that are very practical, and you kind of read my mind about that question of generalizability. Mark, did you have any reflection on that? The generalizability to the US population? Dr Mark Drazner: Yeah, that's an important point. I was struck in the paper that 80% of the patients who committed suicide were followed at centers without LVAD coordinators. That number seems high compared to what we're used to seeing. It would be intriguing how widespread that is, where patients who are getting implanted don't have access to a VAD coordinator in your country. Dr Erwan Flécher: Well, that's an important point also. It is different in France. I mean, we just created...That coordinator did not exist a few years ago in France and I know you are used to work with VAD coordinator in the US, in the UK, even in Netherlands and Germany, but in France it was not like that and all patients were only followed by cardiologist or cardiac surgeons and a few centers started few years ago, five, eight years ago to have a VAD coordinator nurse program. We do believe it is very, very important. That's also plea for a better organization of care in our country. Dr Mark Drazner: Yeah, that's a thinking point. I didn't realize that that was not widespread practice and relatively new implementation. It'll be interesting to see if the rates subsequently fall with that change in practice. Can I ask, let me follow up in terms of your previous comment. It sounds like a lot of these patients were acute presentations and I wonder also whether they may not have had the full time to grasp exactly what they were getting into, for example. I think we've all been there. Someone went into cardiogenic shock, ends up crashing and burning and has to go for a durable VAD. A very different complex in someone who has consolidation has been followed in the center for a while, has a chance to come to understand what all that really is. You think that is a major factor in this experience? Dr Vincent Galand: We think that patients who are granted in case of emergency; it's a bigger risk of surgical distress afterwards the implantation. In fact, that they cannot many information before the implantation, information about the worth life after the LVAD implantation. Of course if they don't the information, they can't be prepared for life after surgery. I think it's a bigger risk, yeah. Dr Erwan Flécher: That's why maybe in your country or maybe elsewhere, I don't know, maybe the findings would have been different. That's, that's an option we should consider, also. In France, as we told you, we do implants. Most of our patients are implanted in emergency. They're already in ICU. Most of them are already under mechanical ventilation, so they just wake up and they learned that they have been implanted. Not all of them, but mos…

Full show notes at the publisher

Circulation March 10, 2020 Issue Mar 09, 2020

Show notes

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.

Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, the feature article today is really interesting. It's evaluating the evolution of cardiovascular disease associated adverse events in developing countries and It's really fascinating looking at differences between Russia, China, India, and Brazil, but more to come. Don't want to spoil all that. How about we get started with a cup of coffee and discussing some of the articles in the Journal.

Dr Carolyn Lam: You bet, Greg. Well, I want to start off with this paper that provides really novel insights into the pathogenesis of hypertrophic cardiomyopathy.

Dr Greg Hundley: Carolyn, you're one of the cardiomyopathy experts. Can you give us a little background before we get started?

Dr Carolyn Lam: Not sure about expert, but I can sure give you a background. So. Hypertrophic cardiomyopathy remember, is caused by pathogenic variants in the sarcomere protein genes, and that evokes hypercontractility, poor relaxation, and increased energy consumption by the heart and increases the patient's risk for arrhythmias and heart failure. Recent studies show that the pathogenic missense variants in myosin are clustered in residues that participate in dynamic confirmational states of the sarcomere proteins.

In today's paper from co-corresponding authors Dr Seidman and Toepfer from Harvard Medical School, authors hypothesized that these confirmations were essential to adapt contractile output for energy conservation and that pathophysiology of hypertrophic cardiomyopathy resulted from destabilization of these confirmations.

So they assayed myosin ATP binding to define the proportions of myosin in two confirmational states called SRX or DRX. This was done in healthy rodent and human hearts at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic hypertrophic cardiomyopathy variants.

They found that hypertrophic cardiomyopathy mutations that disrupted the physiologic balance of SRX and DRX altered cardiomyocyte contraction, relaxation and metabolism, and conveyed increased risk for heart failure and atrial fibrillation. In fact, a small molecule could restore the physiologic balance of SRX and DRX and improve functional energetic and cellular abnormalities that occurred in hypertrophic cardiomyopathy.

Dr Greg Hundley: Very interesting, Carolyn. Well, let me tell you about my paper. It's called The OUTSMART Heart Failure. It's a randomized controlled trial of routine versus selective use of cardiovascular magnetic resonance for patients with non-ischemic heart failure. And it's from Dr David Ian Paterson at the University of Alberta.

This is a study from Canada randomizing 500 patients with suspected non-ischemic heart failure to either having a cardiac MRI as the first imaging study or have an echo, and then based on the echo, order an MRI if the physician so indicates. It was an older version of MRIs, so it's a SUNY assessment of function, including the EF, and then delayed enhancement, a technique that again has been available for the past 20 years and incorporates gadolinium contrast.

Dr Carolyn Lam: Greg, this is so unfair. I'm an echo person, you're an MRI person, but you get to tell us the results and inject your thoughts.

Dr Greg Hundley: No bias. So, Clinical outcomes, Carolyn, you'll be very appreciative, were similar for the two groups of subjects, although the heart failure etiology was more frequently derived in those that received an MRI, whether you're randomized to an MRI first or if you had an echo and they said, "Oh, go get an MRI." The patients with specific heart failure etiologies from imaging had worse outcomes, whereas the heart failure etiologies defined clinically did not.

So, if you didn't take the imaging into account, it didn't discriminate. Importantly, the authors note that more modern techniques, involving mapping with or without contrast, were not employed. It's an older form of the MRI imaging, but the results would suggest that physician decisions regarding the potential use of MRI are important. Bringing us in to decide when to get it is a good idea based on these results.

Dr Carolyn Lam: That was very balanced. Thank you, Greg. But I've got a question for you now. What do you think of coconut oil? Do you take it?

Dr Greg Hundley: Well, I love coconut cake. Does that count?

Dr Carolyn Lam: Well, I have to tell you, I cannot even begin to name the number of people, it's friends and relatives and patients, who take coconut oil because they believe it's good for them. They literally spoon it into their mouths. The truth is coconut oil has been accorded much attention in the popular media as a potential beneficial food product. In fact, a survey in 2016 found that 72% of Americans viewed coconut oil as a healthy food. This represents a remarkable success in marketing by coconut oil and related industries calling coconut oil a natural healthful product despite its known action to increase LDL cholesterol. Of course, we know that, that's an established cause of atherosclerosis and cardiovascular events.

This paper in our journal really deserves attention. It's from corresponding author Dr Rob van Dam from Saw Swee Hock School of Public Health and the National University of Singapore. He and his colleagues conducted a systematic review of the effect of coconut oil consumption on blood lipids and other cardiovascular risk factors compared with other cooking oils using data from clinical trials. In a meta-analysis of 16 trials, they found that coconut oil consumption significantly increased LDL cholesterol concentrations as compared with non-vegetable oils. Although coconut oil consumption also increased HDL cholesterol concentrations, we need to remember that efforts to reduce cardiovascular risk by increasing HDL, have not really been successful in the past.

Anyway, there was no evidence of benefits of coconut oil over non-tropical vegetable oils for adiposity or glycemic or inflammatory markers. Now, this is discussed in an editorial by Dr Frank Sacks at Harvard T.H. Chan School of Public Health and it's entitled: "Coconut Oil and Heart Health. Fact or Fiction?"

Dr Greg Hundley: Very nice, Carolyn. Well, I guess I can't use my coconut cake to lower my LDL. How about we get on to what else is in the journal? You want to go first?

Dr Carolyn Lam: Yeah. We have an important white paper by Dr Sharma on the impact of regulatory guidance on evaluating cardiovascular risk of new glucose lowering therapies, to treat type two diabetes. It talks about lessons learned and future directions. All of this was occurring in February 2018 when a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of findings of the completed CV outcome trials. Very, very important read. We also have a research letter from Dr Wanken entitled, "Characterization of Endovascular Abdominal Aortic Aneurysm Repair Surveillance in the Vascular Quality Initiative." You got to read about that.

Dr Greg Hundley: Well, Paul Ridker writes a very nice perspective piece. Will all atherosclerosis patients soon be treated with combination lipid lowering and inflammatory inhibitors? Very interesting read. In a separate article, there's a nice ECG challenge from Dr Andrei Margulescu, An Irregular Tachycardia that's not Responsive to Medical Treatment: What is the Diagnosis? A great read for those in training.

Got a couple letters to tell you about. One is the research letter on filamin-C and it's essential for heart function from Professor Ju Chen University of California, San Diego. Then, there's a letter to the editor regarding the article, Stroke Risk as a Function of Atrial Fibrillation Duration in CHA2DS2-VASc Scores from Dr Ming-Wu Xia from Hefei Affiliated Hospital and Anhui Medical University. Then there's a response letter from Rod Passman from the Feinberg School of Medicine at Northwestern University. Well, Carolyn, how about we go to learn about the evolution of cardiovascular events and how they're evolving in Russia, China, India, and Brazil.

Dr Carolyn Lam: Super excited about this one. Let's go, Greg. Our feature paper today focuses on cardiovascular disease burden in the BRICS, and that stands for Brazil, Russia, India, China, and South Africa, B. R. I. C. S. Which is a grouping of upper and lower middle-income countries constituting almost half the world's population and contributing almost a third of the world's GDP. A really, really important paper here. I'm so pleased to have with us the corresponding author of this paper, Dr Zhiyong Zou from Peking University School of Public Health.

Dr Jo, can you please start by telling us a little bit about how you did this study? I thought the methods were amazing.

Dr Zhiyong Zou: There was little study on cardiovascular disease in breaks. So most of the studies have focused just fatality across year, and then reported change in different age groups. However, this fails to distinguish cohort from period effects. So our study aims to examine the time change and also the relative contribution of period and cohort facts.

Dr Carolyn Lam: Wow. So that's big and an acute area. So could you tell us a little bit more about how you did this? Like the databases and then some of the very interesting methodology such as net drift, age curves, period, relative effects. Could you maybe describe those?

Dr Zhiyong Zou: The data was derived from global burden disease 2017 which was as estimate by the university of Washington. This data was estimate for the whole population in each country from many original data sources. Our study used a new method, age period, cohort model.

We can use this model to estimate first cohort from period effects so we can compare different post cohort population and the different period population. They have different effects. And also, we can estimate the net drift, net drift is the overall annual percentage change. It is different from other study. Just to calculate the average percentage change. It is different. It was adjusted for period effects.

Dr Carolyn Lam: Audience, I really have to refer you to the figures of this paper. They're beautiful and that really... Pictures say a thousand words, but Dr Zou, could you now tell us what were the key findings?

Dr Zhiyong Zou: First, although there have been reductions in the breaks of the CVD mortality, they have lagged behind North American by over 15%. Yes, it is very decreased slowly but there is a notable exception of Brazil and the second, there was striking difference between countries. Russia consistently has the highest CVD mortality and Brazil have the lowest. Brazil and China have had continuing vitality improvements since 1992 but there has been little decry in India for middle age Indian males. CVD mortality has increased.

The last one is China has a high rate of out of hospital ischemia heart disease test reflecting poor pre-hospital care. Only 11% of the out of hospital desks received a basic cardiopulmonary citation. And the yes in China, this situation is very serious.

Dr Carolyn Lam: So really fascinating results. And maybe I could just add that you observed over a 25-year period from 1992 to 2016 the general picture is at least there's a decline in these areas, but definitely not as much as that observed during the same time in North America. But I absolutely agree that the striking country differences, so you know, maybe we should start with something positive. Dr Zou, what lessons do you think we could learn from Brazil's strikingly exceptional example?

Dr Zhiyong Zou: Brazil stands out for successful epidemiological transition. Yes, they with a rapid reduction. There are two important factors: The first one is Brazil investment in health with a decrease in smoking from 13.5% in 1999 to 17% in 2009 it decreased by 15%. Another factor is Brazil reform of primary health care focus on the family health program and the prevention and the care for the management of SADs.

Dr Carolyn Lam: I like that. From this paper we could get very, very important public health messages that may inform countries on how this burden can be tackled better like that. Good example of Brazil, but now maybe the tougher topic of in China, what do you think is the reason for the continuing problem with ischemic heart disease

Dr Zhiyong Zou: In China? The real mortality of ischemia heart disease increased very quickly, around 13.5% Increase. Compare that with other countries or declined. So in China with that, there were about 300 million more smokers in China. It was the biggest number in the world? Yes. So it's a big challenge for the government to control the smoking rate. And also, we mentioned that only 11% of the outside hospital Does received a cardiopulmonary citation.

Dr Carolyn Lam: Yeah. And so the point about the low CPR rates may point to more systematic issues in a primary care and public setting, isn't it? And it must be so difficult in a place as huge as China with such diversity in rural communities versus urban and so on. So very important points. I mean, do you have any insights for the issues that are seen in, for example, South Africa, Russia and India?

Dr Zhiyong Zou: We don't have data from the other countries.

Dr Carolyn Lam: Sure. One postulation I suppose thinking about things could be just very rapid transition from the era of infectious disease, communicable diseases to noncommunicable diseases. But you know, the diversity even among those is really, really astounding.

And I think everyone really just has to pick up your paper and have a good read. So could I ask, what are some of the take home messages and next steps that you may have in further research?

Dr Zhiyong Zou: The take home message is, Brazil's success suggest that the prevention policies can both reduce the risk for younger both cohorts and also, the greater risk for all age groups indicating greater progress in achieving CVD health is possible in rapid three in merging economics, which provide example for China and for India. And also a failure to investigate CVD prevention in countries undergoing rapid economic change will exert huge human and economic costs. So that's the take home message.

Dr Carolyn Lam: And those are great, great summaries. And do you have personal plans for further research in this area?

Dr Zhiyong Zou: Yes. In future, we will forecast on the risk factors because in this paper we find many priority age groups in different countries like example, in China those aged over 15 years old, is the prime priority age groups. But in India, 35-60 years old is the most priority age group because in these people, they are most of the productive age, but the mortality increased very quickly.

Dr Carolyn Lam: Yeah, a very good point. And investigating those risk factors would be so informative. Well, thank you so much, Dr Zou for sharing your incredible work with us. We're so proud to be publishing this important work.

Thank you, audience, for joining us today. You've been listening to Circulation on the Run. Please tune in again next week.

Dr Greg Hundley: This program is copyright, the American Heart Association 2020.

Circulation March 03, 2020 Issue Mar 02, 2020

Show notes

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. Dr Greg Hundley: And I'm Dr Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. You know that problem we have with the development of calcification of the aortic valve, the aorta, etcetera with hemodialysis? Well, our feature is going to talk about the results of a randomized phase 2B study to address this. But first, how about if you get us started with a couple of your papers? Dr Carolyn Lam: In fact, it is a couple of papers and they're both related to hypertension. So in the first one, we know that exercise is associated with a lower incidence of hypertension, but what's the association of excessive levels of exercise in the incidence of hypertension? This question was examined by Dr Andersen from Uppsala University Hospital and colleagues, who compared the incidence of hypertension among almost 207,000 participants in a long-distance cross-country skiing event and more than 505,500 persons randomly sampled from the general population who are matched to the skiers on age, sex, and place of residence. Dr Greg Hundley: I love skiing! I want to be in the match group. Tell me, now, how long was this distance that they had to cover? Dr Carolyn Lam: Ah ha. Now the long distance event was really long. It was the Vasaloppet. I hope I pronounced that right, but it's a 45 to 90 kilometer skiing race. So participation, I'm sure you want to hear this, participation was associated with a 41% lower incidence of hypertension over the next eight years, compared to non-participation. And the better the performance in terms of percent of winning time, the lower the incidence of hypertension. If the observed associations are causal, it really adds to the list of beneficial effects of high, or even very high physical fitness. I can see you smiling, Greg. Dr Greg Hundley: This is your confirmation that the AHA wants to send us to Norway to do one of these recordings. Dr Carolyn Lam: Well, this next paper asked the question, what is the association of cumulated blood pressure exposure from young adulthood to midlife with gait and cognitive function in midlife. This is from Dr Mahinrad from Northwestern University Feinberg School of Medicine and colleagues who included 191 participants from the coronary artery risk development in young adults' study, which is a community-based cohort of young individuals followed over 30 years. Cumulated blood pressure was calculated as the area under the curve for baseline up to year 30 exam and gait and cognition were assessed at the year 30 exam. Cerebral white matter hyperintensity was available at year 30 in a subset of participants who underwent MRI. Dr Greg Hundley: I heard that MRI word. So what did they find Carolyn? Dr Carolyn Lam: They found cumulative exposure to higher blood pressures from young adulthood to midlife, even at levels below the clinical definition of hypertension, was associated with worse gait and worse cognitive function in midlife. The impact of cumulative levels of blood pressure exposure was independent of other vascular risk factors during a follow-up period of over 30 years, and the higher burden of midlife cerebral white matter hyperintensity on MRI, Greg, moderated the association of cumulated blood pressure exposure with gait but not with cognitive function. Dr Greg Hundley: You've got me convinced we now have to go to Norway. But what did the authors think were the clinical implications of their study? Dr Carolyn Lam: Well, here it is. The deleterious effect of elevated blood pressure on brain structure and function may begin during early adulthood and this really emphasizes the need for all primordial, if you may, prevention of high blood pressure. But also reconsidering individual levels of blood pressure for the diagnosis of hypertension. Furthermore, gait may be an earlier measure of hypertensive brain injury than cognition. Now these issues are discussed an editorial by Angela Jefferson from Vanderbilt University Medical Center. Dr Greg Hundley: Very nice, Carolyn. Well, I'm going to take another sort of twist on hypertension. My paper is from Dr Thomas Thum from the Hanover Medical School and is really looking at the relationship between cardiac fibrosis and diastolic dysfunction. So the study sought to identify anti-fibrotic drug candidates by functional screening of 480 chemically diverse natural compounds found in human cardiac fibroblasts. Dr Carolyn Lam: Ooh, interesting. And what did they find? Dr Greg Hundley: What they found is using multiple in vitro fibrosis assays and stringent selection algorithms, the authors identified the steroid bufalin, also seen in Chinese toad venom, and the alkaloid lycorine, from the Amaryllidaceae species, to be effective anti-fibrotic molecules, both in vitro and in vivo, leading to improvement in diastolic function in two hypertension dependent rodent models of cardiac fibrosis. In addition, administration of these agents at effective doses did not change plasma damage markers, nor the morphology of the kidney and liver. And therefore, it's kind of an early first toxicological safety study. Dr Carolyn Lam: Fascinating. Not just in the findings and the methods, and who knew we'd be talking about Chinese toad venom on this podcast, Greg? Okay. But let me tell you about what's more in this issue. So, there is a research letter by Dr Djoussé, and it is entitled Supplementation with Vitamin D and/or Omega-3 Fatty Acids and the Incidence of Heart Failure Hospitalization. And this one is a letter from the VITAL-Heart Failure ancillary study of the parent VITAL trial. I'm sure I've got everyone's attention. (You) Got to read that letter. The next is an On My Mind, by Dr Joe Hill, and is entitled, very intriguingly, Can HFpEF and HFrEF Co-exist? Basically accumulating evidence has revealed that the pathophysiologic mechanisms driving HFrEF and HFpEF are distinct, but this On My Mind paper asks can they coexist? Is it possible to identify subjects who harbor pathophysiological elements of both syndromes simultaneously, and if so, we may find that targeting specific pathways is beneficial and in depth characterization of specific subsets of patients might help overcome the limitations of an ejection fraction driven approach. Dr Greg Hundley: Very interesting, Carolyn. I've got some letters from the mailbox, and the first letter is regarding SGLT2 inhibitors in cardiac hypertrophy and the corresponding author is Professor Kazushi Tsuda from Kansai University of Health Sciences. Another letter, from the corresponding author Dr Renato Lopes from Duke University Medical Center in Durham, evaluates stent thrombosis in patients with atrial fibrillation undergoing coronary stenting from the AUGUSTUS trial. And our own Tracy Hampton provides an update on cardiology news features. And John Warner, from UT Southwestern, the prior American Heart Association president, discusses his journey through healthcare reform. And then finally, our own Sarah O'Brian provides highlights from other journals in the Circulation family related to high points in cardiovascular disease. Well, Carolyn, how about on to dialysis and calcification? Dr Carolyn Lam: Can't wait. Let's go. Our feature discussion today, we will be focusing on patients with end-stage kidney disease. And we know that in these patients, the high cardiovascular morbidity and mortality could partially be due to extensive cardiovascular calcification. Well, our feature paper today is the first double blind placebo-controlled phase 2B trial that tests intravenous myo-inositol hexaphosphate, a novel strategy to inhibit the formation and growth of hydroxyapatite and therefore reduce calcification in these patients. I won't tell you more. I'll leave that to the corresponding author, Professor Paolo Raggi, from University of Alberta, and I'm also so pleased to have with us our editor for digital strategies and associate editor Dr Amit Khera from UT Southwestern. So Paolo, please tell us about SNF472 and your very novel trial. Prof Paolo Raggi: As you correctly stated, patients with end stage renal disease have phenomenally high morbidity and mortality, particularly cardiovascular, and they also manifest extreme calcification on the cardiovascular system. Both the valves and the vessels are very heavily calcified. There's a very clear impression throughout the literature that calcification contributes, no doubt, to the high morbidity mortality with these patients. SNF472 is a derivative of a natural product that is only present in nature in sub molecular quantities and essentially is administered intravenously and the mechanism of action is quite simple. It keeps calcium and phosphorous molecules separate. In other words, it doesn't allow crystallization of calcium and phosphate into what we call hydroxyapatite, or amorphous calcium crystals. This, hopefully, was developed, this product was developed, to inhibit the final step of calcification. Everything comes down, no matter what the promoting event is, to crystallization of calcium and phosphorus. Therefore, if we were able to stop the final event, hopefully you will be able to inhibit further calcification, and that's what we tested in this particular article, in this particular study. Dr Carolyn Lam: Oh Paolo, I just love the way you described that. Very, very crystal clear, if you don't mind the pun. But could you please let us know, so a phase 2B trial, does that mean a surrogate outcome, duration of treatment, number of patients? How about telling us a little bit about the trial? Prof Paolo Raggi: So, the trial involved recruiting three different groups of patients. One would be treated with placebo and two other cohorts would be treated with either 300 milligrams of SNF472 three times a week or 600 milligrams of SNF472 three times a week. The product is injected intravenously into the dialysis line. Therefore, the patients do not have to remember to take a pill or inject themselves. Actually, it's perfect, if you will, compliance because all they have to do is come to their dialysis session and they receive it during dialysis. The study therefore, it was a relatively small study, but enough to prove our point. Three groups were recruited, about 90 patients each, and the two treatment arms at 300 milligrams and the 600 milligrams, were combined as a single group for the purpose of reporting the primary results. The follow up was at one year, so these patients were submitted to CT scanning of the chest without contrast for measurement of calcification only at baseline and then again at 52 weeks. In the intention to treat group, patients were included if they had a baseline scan and at least one follow-up scan at some point during the study. These are very sick patients and sometimes are referred for transplant. Sometimes they withdraw from studies. So, we asked everybody to have a second scan if they needed or wanted to withdraw before the 12 month mark was reached. That's for the intention to treat analysis. And then we need some confirmatory analysis on patients who actually did have the baseline in an actual 12 months scan and received the entire year treatment with these two drugs, with a drug or placebo. Dr Carolyn Lam: That's great and please tell us the results. Prof Paolo Raggi: The results were, in our minds, very exciting. And let me first say, that in all the literature that looked at what is the average progression of calcification in the general population, it's anywhere between 10 to 15% per year. For the person with calcium in the coronary arteries, there's an expected progression about 10 to 15%. All the publications in patients with renal failure and undergoing dialysis, show the progression of anywhere between 25 and 35%, so these people are not only more calcified, these patients also progressing very fast. In the particular trial that we reported in Circulation, we demonstrated on average, a progression of 20% in the group receiving placebo and about 11% in the group receiving SNF472. So, there was about a 45% slowing of progression in the treated group compared to the placebo group. Interestingly enough, we saw a slower progression unusual in the placebo group. As of today, many more treatments are available to patients with end stage renal disease that were not available when the original studies that I mentioned earlier were conducted. So, the 25 to 35% progression that we saw 15 years ago, it's now slowed, you notice, to a 20% progression in these patients, but SNF472 was even more effective at further slowing that progression. Dr Carolyn Lam: Well, congratulations first and foremost on a very successful and really striking and novel results. Well, Amit there's so much to discuss I don't even know where to start. But first, maybe can I bring you in by saying, so what, is Circulation now publishing renal papers? Dr Amit Khera: The answer is absolutely yes. So first I want to congratulate Dr Raggi on a fantastic paper. This was a concomitant late breaking science at the American Heart Association Sessions; so, we always try to think of timely and exciting topics and appreciate working so closely with this group to bring this across the finish line. At Circulation, one thing we've been working on is something called Bridging Disciplines, where purposefully we appreciate the heart is not in isolation and not in a box by itself, but within a larger system, a body system. So, we really enjoy these types of papers that cross disciplines and there's an outstanding editorial by Susan Hedayati, from UT Southwestern who's a nephrologist, who weighed in here as well. So we certainly really value these types of papers in Circulation. Prof Paolo Raggi: I have to say, working with Circulation was amazing. You know, you get a great job and so fast. It was an incredible, actually. Dr Amit Khera: Obviously, the results speak for themselves that the study was positive, and we certainly see this diminishing the vascular classification and certainly you've been, for decades now, an expert in vascular calcification and coronary imaging. And you know, the question that always comes up is, what are the implications here? Now, on one side, especially with the coronaries, you think this would be favorable, you get less obstructive disease, perhaps less ischemic heart disease. But there's always been this debate if calcium's a good or bad thing in terms of plaque stabilization, so what are your thoughts on what ends up being the clinical ramifications of this down the road? Prof Paolo Raggi: Well of course, as we clearly stated in the paper, this has to be followed by some sort of clinical outcome study. So, it is only speculating at this point as to what the benefit might be. But more specifically about your question, I think that there is a misinterpretation of what calcification means in general. And honestly, I would prefer not to have calcification in my cardiovascular system if I had the choice. Many believe, and it's possibly true to a degree, that calcification comes in to repair the plaque and there's some sort of repair mechanism, but we have shown very clearly that the greater the calcification burden, the higher the probability of cardiovascular morbidity mortality. And therefore, it is not benign to have cardiovascular calcification in general. In the case of the patients with end stage renal disease, calcification is not limited to the atherosclerotic plaque. It extends to the thickness of the entire vessel wall and it's…

Full show notes at the publisher

Circulation February 25, 2020 Issue Feb 24, 2020

Show notes

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. Dr Greg Hundley: And I'm Dr Greg Hundley, director of the Pauley Heart Center at BCU Health in Richmond, Virginia. Dr Carolyn Lam: So Greg, guess what? We are going to be discussing predicting the benefit of evolocumab therapy in patients with atherosclerotic disease using a genetic risk score. That's our featured paper this week coming from the results of the FOURIER trial. I bet you can't wait to discuss it, but I'm not going to let us until we talk about some of the papers in today's issue. Do you have one? Dr Greg Hundley: Yes, Carolyn, but first I'm going to get a cup of coffee because there's a lot of data in this one. This study is from the ODYSSEY trial and it involves alirocumab and it's from Dr Charles Paulding. Remember Carolyn, the ODYSSEY trial was a randomized double-blind placebo-controlled trial comparing alirocumab, a PCSK9 inhibitor or placebo in 18,924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. And the primary endpoint of this trial comprise death from coronary artery disease, non-fatal MI, ischemic stroke, or unstable angina requiring hospitalization. Now Carolyn, this is a sub-study and it was performed an A genome wide polygenic risk score for coronary artery disease comprising 6,579,025 genetic variants. And they were evaluated in 11,953 patients with available DNA samples. Analysis of the MACE risks, all those outcomes together, was performed in placebo treated patients while treatment benefit analysis was performed across all the patients. Dr Carolyn Lam: Ooh, so what did they find? Dr Greg Hundley: Well, Carolyn, both the absolute and relative reduction of MACE by alirocumab compared to placebo was greater in high versus low PRS patients. Those genetic, polygenetic risk scores combined in the patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6% and 1.5% respectively, and relative risk reduction in the alirocumab of 37% in the high PRS group versus 13% in the low PRS group. And so Carolyn, these results suggest the possibility of an independent tool for risk stratification using sort of precision medicine by selecting those using these genetic constructs, who may be more likely to benefit from this form of therapy. Dr Carolyn Lam: Wow Greg, that is really interesting. I genuinely think that our world is moving towards precision medicine and this really, really speaks to remember that feature paper also talking about genetic risk scores, but from the FOURIER trial. But before we get to that, I've got a basic science paper. Now this one provides insights into the mechanisms underlying age related hypertension. And it's from Dr Ying Yu and colleagues from Tianjin Medical University who hypothesize that since proinflammatory cytokines increase in T lymphocytes with aging and prostaglandin D2 suppresses T helper 1 cytokines through the D-prostanoid receptor 1, that this axis in T cells may play a role in age related hypertension. Dr Greg Hundley: Ah, Carolyn. What did they find in this study? Dr Carolyn Lam: Prostaglandin D2 biosynthesis and D-prostanoid receptor 1 expression, were both markedly decline in CD4 positive T cells from older humans and aged mice. D-prostanoid receptor 1 depletion in these CD4 positive T cells, exaggerated age dependent blood pressure elevation in mice by increasing tumor necrosis factor alpha and interferon gamma secretion. Whereas its over expression showed the opposite effect and its activation suppressed TH1 cytokines. These results really indicate that D-prostanoid receptor 1 and its downstream pathway may serve as an attractive immuno-therapeutic target for age dependent hypertension. Dr Greg Hundley: Oh wow. Very insightful Carolyn. Well, I've got a basic science paper to go over and it's from professor Kinya Otsu from Kings College London. This study addresses the mechanism of ongoing inflammation within the hearts of patients with cardiomyopathy. The study involves the assessment of Regnase-1 and RNAs involved in the degradation of a set of pro inflammatory cytokine messenger RNAs in immune cells. And the study involves the role of Regnase-1 in non-immune cells such as cardiomyocytes. Dr Carolyn Lam: Wow. Dr Greg Hundley: The degradation of cytokine messenger RNA by Regnase-1 and cardiomyocytes plays an important role in restraining sterile information in failing heart. Once the inflammatory cascade gets going, this is that constant inflammation that's ongoing. In addition, the Regnase-1 mediated pathway might be a therapeutic target to treat patients with heart failure as adeno-associated virus 9 mediated cardiomyocyte targeted gene delivery of Regnase-1 or administration of anti-IL-6 receptor antibody, attenuated the development cardiomyopathy induced by severe pressure overload in wild type mice. Dr Carolyn Lam: Wow, that's really interesting. I find this whole field of inflammation in heart failure of course, of key interest, but I'm going to next tell you about the results of the FUEL trial, which is the Fontan Udenafil Exercise Longitudinal trial. Dr Greg Hundley: Tell us about the Fontan operation. Dr Carolyn Lam: Aha, I thought you may ask, Greg. Well, the Fontan operation to remind us all, really creates a total cavopulmonary connection and a circulation in which the importance of pulmonary vascular resistance is therefore magnified. Over time, the circulation needs to deterioration of cardiovascular efficiency associated with a decline in exercise performance. This FUEL trial and reported this time by David Goldberg and colleagues from the Children's Hospital of Philadelphia was a phase 3 clinical trial, which randomized 400 patients with Fontan physiology from 30 sites in North America and the Republic of Korea. The participants were randomly assigned to Udenafil at 87.5 milligrams twice daily or placebo. And the primary outcome was the between group difference in change in oxygen consumption with peak exercise. Dr Greg Hundley: Hmmm, very large important trial it seems like Carolyn. What did they find? Dr Carolyn Lam: Treatment with Udenafil did not result in a significant increase in peak oxygen consumption, which was the primary outcome, but did result in improvements in measures of exercise performance at the anaerobic threshold, which was a secondary outcome. Udenafil was well tolerated with side effects limited to those previously known to be associated with phosphodiesterase type 5 inhibitors. These results and future perspectives are discussed an editorial called FUELing the Search for Medical Therapies in Late Fontan Failure, by Doctors Gewillig and De Bruaene. Dr Greg Hundley: Very nice, Carolyn. Now how about the rest of the journal? Dr Carolyn Lam: Oh well I want to tell you about this in-depth review by Dr Rosenkranz and it's entitled, Systemic Consequences of Pulmonary Hypertension and Right-Sided Heart Failure. Very intriguingly, talking about non-cardiac features, as well as cardiac, of right heart failure, a real, real must read with beautiful figures. In the cardiovascular case series we discuss a case of left ventricular non-compaction and cardiogenic shock by Dr Shenoy. There are also two research letters I want to tell you about one by Dr Gillinov on the accuracy of the Apple watch for detection of atrial fibrillation. And this time looking at the Apple watch series 4, which interestingly employs electrodes to generate a single lead ECG and provides two mechanisms for rhythm assessment. Won't tell you more. You got to pick up this beautiful letter. The next is by Dr Mazer on the effect of empagliflozin on erythropoietin levels IN stores and red blood cell morphology in patients with type II diabetes and coronary artery disease. And this really provides evidence to suggest that SGLT 2 inhibition with empagliflozin may stimulate erythropoiesis via an early increase in erythropoietin production in people with diabetes. Dr Greg Hundley: You know Carolyn, we just keep hearing more about EMPA and DAPA and they are just going to really pave the way I think for a whole new class of agents that we're going to be using frequently. I've got a couple letters in the mailbox and one is by Sugimoto and Taniguchi regarding the article, Internal Versus External Electrical Cardioversion of Atrial Arrhythmia in Patients with Implantable Cardio Defibrillators, a randomized clinical trial. And then also there's another research letter by Dr Hiroshi Sugimoto from Kobe Red Cross Hospital with a response by Jakob Lüker from University of Cologne. What a great issue. How about we proceed to that feature article? Dr Carolyn Lam: You bet. Can a genetic risk score identify individuals who will derive greater benefit from PC SK9 inhibition? Well guess what? We're going to find out now in our feature discussion. So pleased to have with us the first and the corresponding authors of our feature paper, Dr Nicholas Marston and Dr Christian Ruff, both from the TIMI study group in Brigham and Women's Hospital and Harvard Medical School and also to have our lovely associate editor, Dr Svati Shah from Duke University in Durham, North Carolina. Welcome everyone. Nick, could I get you started with telling us about this exciting analysis that you did from the FOURIER trial? Dr Nicholas Marston: The FOURIER trial was a 27,000 patient cardiovascular outcomes trial that studied the PC SK9 inhibitor, evolocumab and it demonstrated a significant reduction in major adverse cardiovascular events in patients who had established atherosclerotic disease. And in the study, there was a 15% relative risk reduction and a 2% absolute risk reduction, which earned it a class 2 recommendation for very high-risk patients with atherosclerosis in the recent cholesterol management guidelines. And what we've done in previous lipid trials is we studied the interactions between genetic risk and treatment benefit. For example, in 2015 we showed that patients with high genetic risk, those in the top 20% of genetic risk, had the greatest benefit from statin therapy in terms of both absolute and relative risk reductions. And so now we have the opportunity with evolocumab and data from the FOURIER trial to ask the same question of PC SK9 inhibitor. That is, could a genetic risk score identify patients who will drive a greater treatment benefit and we hypothesize that like statins, there would in fact be a significant interaction between genetic risk and therapeutic benefit. Dr Carolyn Lam: That's so cool Nick. But could I ask, the question always comes, is it nature versus nurture? And so I really love the way that you dealt with the clinical risk factors as well. Could you maybe walk us through that and then tell us the results? Dr Nicholas Marston: Yes, absolutely. We for this study, kind of had two objectives. One was to look at risk prediction and then the other look at treatment benefit and using a genetic risk score for both. However, we wanted to go further than just use the genetic risk score. We wanted to incorporate clinical risk factors since that's how we would do it as physicians in the clinic. We would have not just genetic risk data in front of us but also clinical data. And so when we were grading a patient's risk using genetic risk, we also factored in if they had multiple clinical risk factors. And what we found by combining both genetic and clinical risk was that there was a significant gradient of risk across these risk categories. That is patients who were without high genetic risk and without multiple clinical risk factors actually had no benefit from evolocumab over the 2.2-year follow-up period. However, those without high genetic risk, but who did have multiple clinical risk factors, derived an intermediate benefit. About a 13% relative risk reduction and 1.4% absolute risk reduction. And then it was the high genetic risk group, independent of whether or not they had multiple clinical risk factors that had the largest benefit from evolocumab with a relative risk reduction of 31%, absolute risk reduction of 4% and the number needed to treat of 25. And that's actually a twofold greater benefit than was seen in the overall FOURIER trial population. Dr Carolyn Lam: That's really stunning results. Now I know Svati's going to have questions for us, so maybe I should invite you Svati, just put these results into context and let the audience know what we were thinking as editors when we saw this brilliant paper. Dr Svati Shah: Yeah, thanks Carolyn. And I think Nick has done a fantastic job of describing the exciting results from this paper and just kind of taking a step back to help the audience understand what we're talking about when we're talking about genetics. For decades, we've been trying to figure out the genetics of heart disease and we're not talking about the genetics of things that are really rare like long QT syndrome, but the genetics of just common complex heart diseases. And amongst the scientific community, we've tried all different ways of sort of analyzing these data and so I want to make sure that everybody who's listening understands the novelty of really looking at these polygenic risk scores. Where we have now come to understand that it's not a single gene, it's not even two genes, that it's multiple variants and multiple genes and when they're combined, that's when you really have the power to understand how it might be useful in terms of how we take care of patients. Really important with how Nick and Christian have laid out this really nice paper as well as their prior work in statins, is that not only did they show that these polygenic risk scores are associated with cardiovascular outcomes or even different amongst whether you get treated with the drug or whether you don't, but really importantly they're getting it clinical utility, not only with regards to showing that they compare it to a clinical risk score, but really showing that if you use these polygenic risk scores, you can identify patients who may derive the greatest benefit from PC SK9 inhibitors. And importantly in their paper, they show that if you have low polygenic risk score and low clinical risk score, you may not derive benefit from PC SK9 inhibitors. With all the caveats that this is a secondary prevention population, so I really applaud Christian and Nick and his team for the nice work that was done. Dr Carolyn Lam: Oh, couldn't agree more, Svati. You know what I was very struck with too, because some people go, I may have a genetic risk. Maybe I could undo it or somehow overcome it with my clinical risk factors. And that's why I really appreciated that they showed that it was additive, and genetics still matter even if you have risk factors and vice versa. That was really cool. Christian, could I ask you to maybe describe a bit, what kind of genetic risk score this was and maybe perhaps point out some of the limitations therefore of what you studied. Dr Christian Ruff: As Svati mentioned, this is really a quickly evolving field. We now have the ability to either genotype or sequence all of the variation that makes us different from one another. Our susceptibility to disease as well as our potential benefit for treatment. We had for this study, looked at several different risk scores. The one we focused on was a coronary artery disease genetic risk score that had 27 different variants that had been shown to predict having a cardiac event, both in primary and secondary populations. And we hav…

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Circulation February 18, 2020 Issue Feb 17, 2020

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Dr Biykem Bozkurt: I am Biykem Bozkurt, Professor of Medicine from Baylor College of Medicine, Senior Associate Editor for Circulation and today, I'm joined with Sana Al-Khatib, Professor of Medicine from Duke University, Senior Associate Editor of Circulation, for the podcast for the fourth annual Go Red for Women issue for Circulation. As all our listeners are aware, cardiovascular disease is a leading cause of death among women, but we have significant gaps in our awareness and treatments, and with a recognition of these disparities for cardiovascular care in women, AHA has launched a Go Red for Women campaign back in 2004. We have made great strides, and despite the improvement in awareness, significant gaps persist and adverse trends are emerging for cardiovascular disease in women. With such recognition, in 2017, Circulation launched the annual Go Red for Women issue, dedicated to cover transformative science, exciting new treatment strategies, recent epidemiological trends, and with an intent to close the gaps and eliminate the disparities for cardiovascular care in women. This is the fourth Go Red for Women issue and we have an exciting portfolio that we'd like to share with our readers and listeners. In this issue, we have quite a few important papers. The first two that we would like to start with are going over the epidemiologic trends. Sana, do you want to walk us through the two papers that we have on myocardial infarction and sudden cardiac death? Dr Sana Al-Khatib: I would love to start with the paper on sudden cardiac death, which is very fitting. That's what I focus most of my work on. This particular paper actually looked at sudden cardiac death as the first manifestation of heart disease in women, and it was focused on the Oregon sudden unexpected death study, the timeframe for which was between 2004 and 2016 and what they really wanted to do is to assess sex specific trends in sudden cardiac death incidence. And so they focused on out of hospital, sudden cardiac death cases among adults during that time period. And they divided that 12-year period from February 2004 to January 2016 into three four-year intervals, 2004 to 2007, 2008 to 2011 and 2012 to 2015. And they really looked at these trends among women and men and they found that there were 2,938 sudden cardiac deaths, 37% of who were women. And they found an interesting U-shaped pattern of risk of sudden cardiac death with Anader in 2011. An increase in the years that followed 2011 so regarding that rebound, the rates really increased in 2013 and 2015. And when they specifically looked at women, they found that the rates of sudden cardiac death declined by 30% between the first and second four year time period and increased by 27% between the second and third period. Interestingly, the subsets with sudden cardiac death as the first manifestation of heart disease, accounted for 58% of the total rebound in sudden cardiac death incidence from period two to three but there was no change in the incidence over time for sudden cardiac death occurring among people with preexisting heart disease. For men actually sudden cardiac death also declined from the first to the second period, but not as much as in women and also increased between the second and third periods. Again, not as much as we saw in women. Subsets of sudden cardiac death occurring in the setting of identifiable heart disease was responsible for 55% of the rebound in overall sudden cardiac deaths incidence. Certainly some significant differences between men and women. Very exciting findings. Then if we actually turn our attention to the second study looking at sex specific trends in acute myocardial infarction, this particular analysis, Biykem, was done within an integrated healthcare network between 2000 and 2014 and they picked the Kaiser Permanente Southern California network. They were able to identify 45,000 plus acute MI hospitalizations between 2000 and 2014 and they found that age and sex standardized incident rates of AMI declined from 2000 to 2014. And they found that a decline for women was actually more so than in men. And in fact for men it was pretty much stable. And they found that the incidence of hospitalized MI had declined, however, declines are slowing among women compared with men in recent years. That's actually identified some unmet care needs among women that hopefully can meet people and investigators to tailor their approaches to try to close those gaps and disparities in care. With that, let me actually turn it back to you to potentially talk about to cardiovascular risk assessments in women. Dr Biykem Bozkurt: With the recognition of the disparities and the recent emerging trends of adverse outcomes, especially in younger women, there has been a focused attention in how to assess risk, cardiovascular risk in women. There is a very comprehensive review by Salim Virani and colleagues who's addressing the cardiovascular risk assessment for women. As our listeners will recall in 2018, ACC/AHA cholesterol professional guidelines specified risk enhancing factors such as premature menopause or preeclampsia for women. And if present, in borderline or intermediate risk patients, would elevate the 10 year risk to a higher category. But now with a recognition of many more risk factors, Virani and colleagues are proposing a more comprehensive cardiovascular risk assessment for women. And these include the risk factors that are not only identified in the 2018 ACC/AHA cholesterol guidelines, but additional such as gestational hypertension and diabetes or adverse pregnancy outcomes such as preterm delivery, small birth for gestational age or placental abruption or infarct or premature menarche or premature menopause, primary ovarian failure or pregnancy loss and additionally inflammatory disorders such as lupus, rheumatoid arthritis, psoriasis and history of cancer and cancer related therapies. And they formulate this in a nice and well tabulated fashion. And all these risk factors are summarized table one which I think most of our listeners and readers will refer to. And they also come up with a nice approach. What shall we do? And how shall we detect that risk? First recommendation they have is that we should obtain a comprehensive obstetric and gynecological history from all women. And if these risk factors are present, then we should then screen for other traditional risk factors early and frequently and then treat for modifiable risk factors such as hypertension, hyperlipidemia, diabetes, metabolic syndrome, and also implement aggressive lifestyle modification with strategies such as management of blood pressure control, reduction of blood sugars, remaining active eating, healthy, losing weight, and not smoking. Which is summarized as life's simple seven which is an AHA initiative that summarizes healthy lifestyle as life's simple seven. And very complimentary to Virani's review paper, we had another wonderful paper that is titled Life's Simple Seven and health by Jacqueline Kulinski who reminds us that not only these seven factors but breastfeeding for postpartum mothers is an important approach to reduce cardiovascular risk. Breastfeeding is not only beneficial for the newborn infants but for the mother as it's been associated with reduction in risk of myocardial infarction, stroke, cardiovascular disease hospitalization rates, future development of diabetes, hypertension, and even mortality. And this paper elaborates on potential mechanisms such as increases in metabolic expenditure, enhancement of insulin sensitivity, reduction in cholesterol, greater mobilization of fat stores and reversal of elevated triglycerides and cholesterol that's seen during pregnancy. It also emphasizes the importance of recognition and education of women because currently only about 25% of women are exclusively breastfeeding at six months and US has one of the lowest breastfeeding rates among industrialized countries. And we do have disparities according to race and income and black infants and infants living in rural areas in Southeast USA are less likely to be breastfed. And there is definitely increased recognition for importance and but it's also important to be able to accommodate and facilitate breastfeeding for mothers. Currently the paper emphasize that all 50 states now have laws allowing women to be able to breastfeed in public or private locations. But again, there definitely is a necessity for increased awareness and education. On that end, there is also a great paper covering the news release announcing the partnership between American Heart Association and American College of Gynecology and Obstetricians in promoting risk identification and reduction of cardiovascular disease in women through collaboration between obstetricians and gynecologists. In 2018, AHA and American College of Gynecology issued a call for action for both specialists to team up and increase screening for cardiovascular disease by obstetricians and provide education and appropriate referrals. And I think this initiative is going to increase the opportunities for young women whose primary care provider solely could be an obstetrician, who potentially will get screened for cardiovascular disease and if they have these risk factors, will potentially be able to be offered lifestyle modification, message and intervention strategies. These, I think, three very complimentary papers are enhancing our recognition for the new risk profile that needs to entail getting a comprehensive obstetric and gynecological history in all women. And in the event we recognize either of these risk factors including the traditional risk factors or obstetric and gynecological risk factors such as pregnancy related complications or preeclampsia or other additional special risk factors such as autoimmune disorders and cancer, then we will need to heighten our awareness for lifestyle modification, risk management, and earlier treatment and closer monitoring. That brings us to another important risk profile, which is cancer for women. And Sana, I know we do have two great papers related to cancer topic. If you could elaborate on those. Dr Sana Al-Khatib: I'm really excited about these papers. As you pointed out, Biykem, that cardio oncology is a field that is really expanding and so it was really very gratifying to get these two papers. The first paper had to do with a comparison between aromatase inhibitors and Tamoxifen in women with breast cancer in terms of their association with the risk of cardiovascular outcome. And this particular study was done in the United Kingdom and they studied women though with newly diagnosed breast cancer initiating hormonal therapy, either with everyone at aromatase inhibitors or Tamoxifen between 1998 and 2016. And the study outcomes that they were interested in included myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality. And they actually had a sizable patient population with 23,000 plus patients included in this analysis of whom close to 18,000 initiated treatment with either an aromatase inhibitor or Tamoxifen. And they found that the use of aromatase inhibitors was associated with a significantly increased risk of heart failure and cardiovascular mortality compared with Tamoxifen and that aromatase inhibitors seemed to have a trend towards increased risk of myocardial infarction, ischemic stroke. Although those differences were not statistically significant. They actually concluded that aromatase inhibitors were associated with an increased risk of heart failure and cardiovascular mortality compared with Tamoxifen and that there were trends toward increased risks also of MI and ischemic stroke. And so they really want clinicians and patients to be aware of these findings when they are trying to make decisions about treatment for breast cancer. We have another really interesting study, Biykem, that was actually a randomized control trial that studied the effect of exercise therapy dosing schedule on impaired cardiorespiratory fitness in patients with primary breast cancer. And so this randomized trial enrolled 174 post-menopausal patients who were randomly allocated to one of two supervised exercise training interventions, delivered either using a standard linear test or nonlinear test. And they had a control group of just stretching. They did some stretching. And they did the trial over at periods of 16 consecutive weeks and the primary endpoint was change in the VO2 level, PCO2 level from baseline to post intervention. They had a couple of other secondary endpoints and their results were interesting. They found no serious adverse events during the trial, but they actually found that 40% of patients in both exercise dosing regimens were classified as responders. And they concluded that short term exercise training independent of dosing schedule was associated with modest improvements in cardiorespiratory fitness in patients previously treated for early stage breast cancer. Really interesting, a smaller study, not really looking at hard endpoints yet. It's still important because I believe that it is going to form the basis for more studies and more research in this important field, Biykem. With this, I'd like to turn it over to you to talk about elevated body mass index in young women. Dr Biykem Bozkurt: And this is another fascinating study, a large study from Sweden. It involved more than 1.3 million young women. Average age was 27. It was a national prospective cohort. The recruitment was between 1982 and 2014. What they did was they measured the baseline of weight of women in early pregnancy in the first trimester, actually the first antenatal visit before they could gain any weight related to the pregnancy. With their BMI measurement at baseline, then they followed these patients for approximately 30 years and associated this baseline BMI with future developments or dilated cardiomyopathy or any cardiomyopathy. They looked at that dilated cardiomyopathies, hypertrophic cardiomyopathies, these other cardiomyopathies such as alcoholic cardiomyopathy and others. Interestingly, elevated body mass was associated with future development of dilated cardiomyopathy. A very similar finding was reported in former studies for adolescent men, but we didn't have this finding for young women. This study provides evidence that elevated BMI, even if it is only in the overweight range, is associated with future development of dilated cardiomyopathy. In the past we had numerous studies demonstrating overweight or obesity status being associated with future development of clinical heart failure, clinical symptoms of heart failure, but this is one of the largest scale population based cohorts demonstrating the association with dilated cardiomyopathy. And interestingly, these women at baseline did not have the usual other confounders or comorbidities associated with future development of cardiomyopathy. The risk of diabetes and hypertension was less than 1% at baseline. Very interestingly, BMI by itself, independent of all these other variables was associated with future risk. And of course the higher the BMI was, the higher the risk was. The highest risk was for those with morbid obesity or BMI over 35 and in those patients the risk was increased by about five fold. Sana, we talked about the disparities for women. Where are we with women participation in cardiovascular trials? And how do we looked globally overall regarding the disparity of cardiovascular diseases in woman? Dr Sana Al-Khatib: These are really important questions, Biykem. Let me first start with a study that will be in the Go Red for Women issue on women's participation in cardiovascular clinical trials. They looked at that. Between 2010 and 2017, which is a very important topic as you know, Biykem. And…

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Circulation February 11, 2020 Issue Feb 10, 2020

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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 Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article this week relates to an international multi-center evidence-based reappraisal of genes reported to cause congenital long QT syndrome. But, before we get to that, how about if we grab a cup of coffee and start on our other papers? Do you have one you'd like to discuss? Dr Carolyn Lam: Yes. My favorite part of the week. So this first paper really asks the question, "What's the association between HDL functional characteristics, as opposed to HDL cholesterol levels, and acute coronary syndrome?" The paper comes from Dr Hernáez from IDIBAPS in Barcelona, Spain and colleagues who conducted a case control study nested within the PREDIMED cohort. Originally a randomized trial where participants followed a Mediterranean or low-fat diet. Cases of incident acute coronary syndrome were individually matched one is to two to controls by sex, age, intervention group, body mass index, and follow-up time. The authors measure it the following functional characteristics, which were HDL cholesterol concentration, cholesterol efflux capacity, antioxidant ability, phospholipase A2 activity and sphingosine-1-phosphate, apolipoproteins A1 and A4, serum amyloid A and complement 3 protein. Dr Greg Hundley: Wow Carolyn, a detailed analysis. What did they find? Dr Carolyn Lam: They found that low values of cholesterol efflux capacity, and levels of sphingosine-1-phosphate and apolipoprotein A1 in HDL or all associated with a higher risk of acute coronary syndrome in high cardiovascular risk individuals, irrespective of HDL cholesterol levels and other cardiovascular risk factors. Low cholesterol efflux capacity values and sphingo-1-phosphate levels were particularly associated with an increased risk of myocardial infarction, whereas HDL antioxidant or anti-inflammatory capacity was inversely related to unstable angina. Now this is significant because it's the first longitudinal study to comprehensively examine the association of several HDL function related biomarkers with incident acute coronary syndrome beyond HDL cholesterol levels in a high-risk cardiovascular risk population. Greg Hundley: Very nice. Carolyn. It sounds like function over just the levels is important. Dr Carolyn Lam: Exactly, you summarized it well. Well Greg, I've got another paper and I want to pick your brain first. Is it your impression that type 2 myocardial infarction, the type that occurs due to acute imbalance in myocardial oxygen supply versus demand in the absence of atherothrombosis, do you think that this type of MI is on the rise? It seems more and more common in my country. Dr Greg Hundley: Do we want to say it's on the rise? Certainly by measuring all these high sensitivity troponins, et cetera, we're finding, I think, more evidence of type 2 MI. So, all in all, yeah it probably is on the rise, but likely related to some of our measurement techniques. Dr Carolyn Lam: Oh, you are so smart, Greg. Because this paper that I'm about to tell you about really addresses some of these issues and it's from corresponding author Dr Gulati from Mayo Clinic in Rochester, Minnesota. And they really start by acknowledging that despite being frequently encountered in clinical practice, the population base incidents and trends of type 2 myocardial infarction is unknown and long-term outcomes are incompletely characterized. So they prospectively recruited 5,640 residents of Olmsted County, Minnesota who experienced an event associated with cardiac troponin T greater than 99th percentile of a normal reference population, which is greater than or equal to 0.01 nanograms per milliliter. And this was between 2003 and 2012, so very careful to talk about which Troponin T assay exactly to the point you discussed earlier, Greg. The events were retrospectively classified into type 1 versus type 2 MI using the universal definition. Dr Greg Hundley: So Carolyn, what did they find? Dr Carolyn Lam: They found that there was an evolution in the types of MI occurring in the community over a decade with the incidence of type 2 MI now being similar to type 1 MI. Adjusted long-term mortality following type 2 MI is markedly higher than after type 1 MI and that's driven by early and non-cardiovascular deaths. Mortality of type 2 MI is associated with a provoking factor and is more favorable when the principle provoking mechanism was an arrhythmia compared with postoperative status, hypotension, anemia or hypoxia. And these findings really underscore the healthcare burden of type 2 MI and provide benchmarks for clinical trial design. Dr Greg Hundley: Very nice, Carolyn. Well, my paper comes from type 5 long QT syndromes and an analysis. And it's from Dr Jason Roberts from Western University. Through an international, multi-center collaboration, improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in long QT 5 was sought across 22 genetic arrhythmia clinics and four registries from nine countries that included 229 subjects with autosomal dominant long QT five. So there were 229 of those subjects. And then 19 individuals with the recessive type 2 Jervell and Lang-Nielsen syndrome. The authors compared the effects of clinical and genetic predictors on a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter defibrillators shocks, aborted cardiac arrest, and sudden cardiac death. Dr Carolyn Lam: Wow. What did they find? Dr Greg Hundley: Well, several things, Carolyn. First, rare loss of function KCNE1 variants are weakly penetrant and do not manifest with a long QT syndrome phenotype in a majority of individuals. That's a little bit of a surprise. Second, QT prolongation and arrhythmic risk associated with type 2 Jervell and Lang-Nielsen syndrome is mild in comparison with the more malignant phenotype observed for type 1 Jervell and Lang-Nielsen syndrome. And then number three, all individuals possessing a rare loss of function KCNE1 variant should be counseled to avoid QT prolonging medications and should undergo a meticulous clinical evaluation to screen for long QTS phenotype. And then finally, Carolyn, the last finding, in the absence of a long QTS phenotype, more intensive measures, such as beta blockade and exercise restriction, may not be merited. Dr Carolyn Lam: Oh, very interesting. Well, I've got one more original paper and in this, authors describe a new cellular mechanism linking ischemia-reperfusion injury to the development of donor specific antibody, a pathologic feature of chronic antibody-mediated rejection, which mediates late graph loss. This paper is from corresponding author Dr Jane Witt from Yale University School of Medicine and colleagues who use humanized models and patient specimens to show that ischemia-reperfusion injury promoted elaboration of interleukin 18 from endothelial cells to selectively expand alloreactive interleukin 18 receptor 1 positive T peripheral helper cells in allograph tissues and this promoted donor specific antibody formation. Dr Greg Hundley: Carolyn, here's the famous question. What does that mean clinically for us? Dr Carolyn Lam: Aha, I'm prepared. Therapies targeted against endothelial cell derived factors like interleukin 18 may therefore block late complications of ischemia-reperfusion injury. Dr Greg Hundley: Very nice. Sounds like more research to come. Well, how about other articles in the issue? Dr Carolyn Lam: Well, I'd love to talk about a white paper from Dr Al-Khatib, and it's about the research needs and priorities for catheter ablation of atrial fibrillation and this is a report from the National Heart, Lung, and Blood Institute Virtual Workshop. Dr Greg Hundley: Well, I've got another arrhythmia paper, so this is from Professor Michael Ackerman at the Mayo Clinic and its minor long QT gene disease associations by coupling the genome aggregation database. It's a harmonized database of 140,000 or more exomes and genome derived in part from population-based sequencing projects, with phenotypic insights gleaned from a large long QT syndrome registry to reassess the strength of these minor long QT syndrome gene disease associations. Next, Carolyn, in an on my mind piece, Professor Gerd Heusch from University of Essen Medical School discusses, how can the many positive preclinical and clinical proof of concept studies on reduced infarct size by ischemic conditioning interventions and cardioprotective drugs be reconciled with the mostly neutral results in regard to clinical outcomes. The author discusses the important differences between animal models that have been used a lot in this ischemia reperfusion and infarct size reduction science, and then the clinical scenarios of STEMI in humans as well as the many aspects of coronary reperfusion. How is that affecting the myocytes? How is that affecting the microcirculation, et cetera, that must be addressed? And then finally Carolyn, there is a series of letters, one from Professor Oliver Weingärtner from Universitätsklinikum Jena and another from Professor Yasuyoshi Ouchi from Toranomon Hospital. They're exchanging letters debating the utility of lipid lowering with Ezetimibe in individuals over the age of 75 years. Dr Carolyn Lam: Very nice, Greg. Thanks so much. Shall we now move to our future discussion. Dr Greg Hundley: You bet. Well, welcome everyone. This is our feature discussion and today we're going to hear more about long QT syndrome. We have Dr Michael Gollob from University of Toronto and our own associate editor, Dr Sami Viskin from Tel Aviv Medical Center. Good morning. Good afternoon, gentlemen. Before we get started with a discussion of some of the study findings and results, Michael, could you tell us a little bit about why you performed the study and what were some of the hypotheses you wanted to test? Dr Michael Gollob: As you know, long QT syndrome is probably the most recognized channelopathy associated with sudden cardiac death in young individuals and adults. And at the present time, there are 17 genes available for clinical genetic testing in cases of suspected long QT syndrome. We simply ask the question, "Is there sufficient scientific evidence to support that each of these genes are single gene causes of long QT syndrome based on our contemporary knowledge of genetics and the human genome? Dr Greg Hundley: Great, Michael. So, can you tell us a little bit about your study population? How did you go about this and what was your study design? Dr Michael Gollob: We designed a methods approach that would assure that any conclusions that were made from our working group were not based on the opinions of one or two individuals. We wanted to ensure that this was a consensus conclusion with multiple experts in the field including genomic scientists, genetic counselors, inherited arrhythmia experts, and researchers in the field. We created three independent teams of genetic experts to curate the genetic evidence reported in the medical literature for each of these 17 reported causes of long QT syndrome. This was essentially an evidence-based approach using a pre-specified evidence-based matrix or scoring system depending on the level of evidence, genetic primarily, in the reported literature for each gene. Each of these curation teams worked independently of each other and they were blinded to each other's work and they were tasked with concluding whether a gene, based on the medical literature and the resource methodologies, had sufficient evidence for disease causation. Their classifications would be one of disputed evidence, limited evidence, moderate evidence, strong or definitive evidence for claims towards disease causation. Remarkably, independently, all of these teams reached the same conclusion. In the end, their summary data was reviewed by a clinical domain expert panel with individuals with expertise, particularly in long QT syndrome and other channelopathies. So in total 19 individuals reviewed all of the literature and the data presented and came to unanimous conclusions for each gene. Dr Greg Hundley: Out of the 17, were there some that were more important than others or was it uniformly all 17 were relevant? Dr Michael Gollob: Well, I think the most relevant conclusions of our study are that nine of these genes, more than half of these genes, were felt not to have sufficient evidence to support their causation as a single gene cause for typical long QT syndrome. So nine genes that are currently tested by clinical genetic testing providers do not have enough evidence to support their testing in patients with suspected long QT. And to us, that is the most relevant observation because testing genes that do not have sufficient evidence for disease causation poses a significant risk to patient harm and family harm. We concluded that only three genes had very definitive evidence for causation of long QT syndrome. Those three genes were KCNQ1, KCNH2, and SCN5A. There were another four genes that were concluded to have strong or definitive evidence for unusual presentations of long QT syndrome. And by that, I mean presentations that typically occur in the neonatal period and are associated with heart block seizures or developmental delay or in the case of one of these genes, Triadin, an autosomal recessive form of the disease. Dr Greg Hundley: So helping us perhaps what types of genes to screen for when we have someone with this condition or suspected. So Sami, can you help us put this into perspective? How does this study help us in management of this clinical situation. Dr Sami Viskin: In Circulation, we immediately recognize the importance of the manuscript, the importance of the study because unfortunately, there are too many physicians all over who will accept the results of genetic testing essentially like gospel. Now it's in the DNA, it's in the genes, so whatever you find must be true. And too often, clinical decisions on treatment including ICD implantation have been undertaken based on results of genetic testing's; thus are wrongly interpreted. So we recognize immediately the importance of this paper. We already had a different study by Dr Gollob and his associates. Again, reassessing the role of genes in Brugada syndrome. So we were familiar with this type of analysis. We recognize the importance and we moved ahead to accept this paper, it went fairly easily, I think only one revision. At the same time, we were getting additional paper by other groups. So in the same issue, we have two more papers, one from Jason Roberts with the International Long QT Registry of long QT 5, reaching similar conclusions that this is a gene with very limited penetrants and another study by the Mayo clinic also showing that many of the genes who are not the major genes are overrepresented in the healthy population. So we put all these three papers together with a very nice editorial by Chris Semsarian in the same issue. So everything is put in the right perspective of how we should be looking at all the genes of these disease in a different way. Dr Greg Hundley: So as a clinician quickly, how can I use this information in the issue, perhaps this paper and all three, in management of patients with either suspected or long QT syndrome? Dr Michael Gollob: First off, I would emphasize that the diagnosis of long QT syndrome or any genetic base disease for that matter, should be based on clinical phenoty…

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Circulation February 04, 2020 Issue Feb 03, 2020

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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 Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, this issue is full of super interesting papers, many of which were presented as late-breaking presentations at the American Heart Association, like the feature paper that sacubitril/valsartan across the spectrum of ejection fraction in heart failure, where this was really analyzed across the landmark PARADIGM and PARAGON trials. I'm sure everyone's looking forward to hearing about it, but before we talk about that, I want to share some more very interesting results from a very important trial, the REDUCE-IT trial. So, as some background, some trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. And this was the reason that there was a pre-specified subgroup analysis of the REDUCE-IT trial, which really is the reduction of cardiovascular events with icosapent ethyl-intervention trial, and this analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States. So, Greg, do you remember what the REDUCE-IT trial was about? Dr Greg Hundley: Well, Carolyn, I think REDUCE-IT randomized 8,179 statin-treated patients with triglycerides between 135 and 500 milligrams per deciliter and LDL cholesterol levels between 40 and 100 milligrams per deciliter and a history of atherosclerosis or diabetes to Icosapent Ethyl, four grams per day or placebo. And the primary endpoint, I believe, was cardiovascular death, nonfatal myocardial infarction, non-fatal stroke, coronary revascularization or hospitalization for unstable angina. Hah! Dr Carolyn Lam: Wow, Greg, you pass that quiz, like maybe you had a cheat sheet answer. Dr Greg Hundley: All right, Carolyn, tell us now what did REDUCE-IT USA find? Dr Carolyn Lam: This was from a corresponding author, Dr Deepak Bhatt, from Brigham and Women's Hospital Heart and Vascular Center, and his colleagues and they found that in the United States Icosapent Ethyl at four grams a day produced large and significant reductions in multiple ischemic endpoints including cardiovascular death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina. Furthermore, REDUCE-IT US demonstrated that Icosapent Ethyl provided a statistically significant 30% relative risk reduction and a 2.6% absolute risk reduction in all-cause mortality. The risk benefit profile of Icosapent Ethyl was highly favorable with an overall safety and tolerability profile virtually identical to placebo. Dr Greg Hundley: Wow, Carolyn. So, this does have important implications for us in the US, very nice. Thank you for that lovely quiz. So, Carolyn, I'm going to switch now and talk about a paper from Roddy Walsh from Amsterdam in the Netherlands. In this study, the investigators defined the frequency of rare variation in 2,538 patients with dilated cardiomyopathy across protein-coding regions of 56 commonly tested genes and compared this to both 912 confirmed healthy controls and a reference population of 60,706 individuals to identify clinically interpretable genes robustly associated with dominant monogenetic dilated cardiomyopathy. Dr Carolyn Lam: Wow, wow. That's a huge study. So what did they find? Dr Greg Hundley: Okay, Carolyn. So overall rare variants in 12 genes potentially explain 17% of cases in the outpatient clinical cohort representing a broad range of adult patients with dilated cardiomyopathy and 26% of cases in the diagnostic referral cohort enriched in familial and early onset dilated cardiomyopathy. And so, practically speaking, by analyzing two dilated cardiomyopathy cohorts with distinctive patient profiles, the authors were able to comprehensively evaluate the genetic basis of dilated cardiomyopathy and identify variant classes that were particularly associated with early-onset disease. By restricting analyses to validated and interpretable genes and variant classes, the authors hoped in this study to increase the accuracy and reduce the uncertainty associated with genetic testing in dilated cardiomyopathy. Dr Carolyn Lam: Very nice, very practical information. Well, my next paper is, I have to admit a super favorite topic of mine, and that is sex differences in heart failure. Now as a reminder to everybody, women represent over half of patients with heart failure with heart failure preserved ejection fraction, and there are multiple effective drug and device therapies for HFrEF, or heart failure reduced ejection fraction, but none approved for HFpEF. Thus, there is a greater so-called failure therapeutic deficit in women compared to men. So, does the recently presented PARAGON trial provide answers? Dr Greg Hundley: Ah, Carolyn, you were involved in the PARAGON trial. Maybe tell us a little bit about that first to help us get oriented. Dr Carolyn Lam: I would love to. So PARAGON compared sacubitril/valsartan with valsartan in patients with HFpEF. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes, and the trial overall narrowly missed this primary outcome. However, an intriguing result in PARAGON was a significant sex-by-treatment interaction. And this was explored further in the current pre-specified subgroup analysis of outcomes by sex, which was reported by John McMurray from University of Glasgow and his colleagues. Dr Greg Hundley: Ah, so I'm interested. What was this interaction? Dr Carolyn Lam: Ah, so here is how the interaction work. Now, remember this was multi-variably adjusted significant in a pre-specified large subgroup of PARAGON. And what we found was that as compared with valsartan, sacubitril/valsartan seem to reduce the risk of heart failure hospitalization more in women than in men. Now, while the possible sex-related modification of this effect of treatment has potential explanations, the current study really cannot provide a definitive mechanistic basis for this finding. Dr Greg Hundley: Very interesting. So, perhaps then, in heart failure preserved ejection fraction, sacubitril/valsartan could be very helpful in women. Dr Carolyn Lam: Yes, and perhaps especially those with each ejection fraction in the lower ejection fraction range. And that is coming up in our future discussions, so let's not preempt it. You got another paper, Greg? Dr Greg Hundley: Absolutely, Carolyn. My next paper is from Professor Irene Lang at the Medical University of Vienna, and it's related to microvascular disease and chronic thromboembolic pulmonary hypertension and hemodynamic phenotyping and histomorphometric assessments. So, Carolyn, pulmonary endarterectomy is the gold standard for treatment of patients with operable chronic thromboembolic pulmonary hypertension. However, persistent pulmonary hypertension after PEA or endarterectomy remains a major determinant of poor prognosis. Dr Carolyn Lam: Ah, so are there any possible solutions to this? Dr Greg Hundley: Well, Carolyn, today it is thought that a concomitant small vessel arteriography in addition to major pulmonary artery obstruction may play an important role in the development of persistent pulmonary hypertension and survival after pulmonary endarterectomy. One of the greatest unmet needs in the current preoperative evaluation is to assess the presence severity of small vessel arteriopathy. Dr Carolyn Lam: Huh, that makes a lot of sense. So what did the authors do? What they find? Dr Greg Hundley: Okay. Well, Carolyn, they had 90 patients with 49 of them receiving lung wedge biopsies for validation. So, in analyses incorporating receiver operating characteristic curves, pulmonary vascular resistance measures and larger arterial upstream resistance beds predicted persistent pulmonary hypertension after pulmonary endarterectomy, and certain values identified patients with poor prognosis after endarterectomy. Therefore, perhaps this form of analysis could be helpful in establishing prognosis in these patients and perhaps suitability for future interventions. Dr Carolyn Lam: Wow, very interesting. Well, we were saying this issue's full of very important papers, and that also includes research letters. There's a research letter by Dr Cannon talking about evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease according to baseline HbA1c, including those with an HbA1c less than 7%. And these are very interesting results from the CREDENCE trial that was also presented at the American Heart Association. There's a research letter by Dr Jackevicius on the population impact of generic valsartan recall in Ontario, Canada, that really highlights the potential burden and risks associated with recalls of chronic oral medications used by large populations. And in Cardiology News, Bridget Kuehn talked about cardiovascular risk biomarkers, high-sensitivity cardiac troponin T and NT-proBNP and talked about how these two biomarkers may help clinicians stratify which patients may benefit the most from therapies for hypertension or diabetes. And this was according to a pair of studies presented, again, at the American Heart Association. Dr Greg Hundley: Well, Carolyn, that's quite a nice review. I've got just a couple more papers to discuss. There's a perspective piece from Dr Ben Levine and colleagues from UT Southwestern that discusses whether a simple physical exam and maneuvers could actually supplant tilt-table testing. He provides arguments as to whether we should continue with tilt-table testing given the high rate of false positives. And then lastly, from the Mailbag, Dr Shuyang Zhang from Peking Union Medical College Hospital and the Chinese Academy of Medical Sciences provides a letter to the editors regarding a prior publication on the clinical applicability of the awareness of androgen-deprivation therapy's effects on ventricular repolarization. And Dr Joe-Eli Salem from Vanderbilt University provides his response. Well, Carolyn, how about onto that feature? Dr Carolyn Lam: Let's go. Our feature discussion today is all about left ventricular ejection fraction. Ah, that measure we both love and hate in the world of heart failure, I think. And this paper is truly remarkable, in my opinion. It is the look at the effect of sacubitril/valsartan across the spectrum of left ventricular ejection fraction in the PARADIGM and PARAGON trials. And I'm just so pleased to have none other than the first and corresponding author, Dr Scott Solomon, from Brigham and Women's Hospital and Harvard Medical School, as well as our Senior Associate Editor, Dr Biykem Bozkurt, from Baylor College of Medicine as well. Scott, could you start by telling us about this analysis and why the opportunity to do such a special analysis in this paper? Dr Scott Solomon: This was a really fantastic opportunity because, as you know, we did these two trials, PARADIGM and PARAGON, not at the same time but essentially in series. PARADIGM was a trial of patients with heart failure reduced ejection fraction, so ejection fraction of 40%, and PARAGON was a study of patients with heart failure with preserved ejection fraction. And the interesting thing is that, with the exception of ejection fraction, the criteria for enrolling patients in these trial was virtually the same. In other words, we enrolled patients with signs and symptoms of heart failure, some elevation in natriuretic peptides, and we followed them. So it's really an extraordinary dataset of 13,195 patients in whom we can look at heart failure across that full spectrum of ejection fraction. We haven't been able to do this really since the CHARM study, which enrolled about 8,000 patients across the spectrum of ejection fraction. And it gave us an opportunity to look at a number of things including the effect of sacubitril/valsartan across that full spectrum of ejection fraction. Dr Carolyn Lam: Great. And, Scott, you want to tell us what you found? Dr Scott Solomon: When we pooled 13,195 patients, and by the way, this was a pre-specified analysis that we had decided to do prior to unblinding PARAGON. We see that if we put them all together, all these patients together, and just treat them as one group, we see that for every endpoint that we looked at, whether heart failure, hospitalization and cardiovascular death, cardiovascular death, all-cause mortality, whether we look at the time to first event endpoints or the total number of heart failure hospitalizations, we see a significant benefit in patients receiving sacubitril/valsartan compared to patients receiving either enalapril in the PARADIGM study or valsartan in the PARAGON study. Now, what we also saw though, and this is probably most important, is that there appears to be an attenuation of the treatment effect as ejection fraction rises. Now we know that patients with higher ejection fractions tend to have a lower frequency of these events such as heart failure, hospitalization and cardiovascular death. But we also see here that as ejection fraction goes up that the benefit of sacubitril/valsartan appears to wane, especially when you get over about 60, an ejection fraction of about 60%. We've looked at this in categorical ways and also looking at a continuous spline analysis throughout the entire spectrum. Dr Carolyn Lam: Yeah, I love that, and I just need to point every listener right now to figures 3 and 4 of your paper. I have a feeling we're going to be seeing these figures in a lot of talks and cited everywhere. Biykem, could I bring you in on this? What are the implications of something like this? Dr Biykem Bozkurt: The interesting findings from the pooled data are, first, support of what we had seen in PARADIGM, meaning the lower the EF, the more the benefit or the higher the benefits. And as we had seen in PARAGON, which did not show an improvement in the combined endpoint with treatment with sacubitril/valsartan in patients with heart failure with preserved ejection fraction. In the pooled analysis as the EF got higher, there didn't seem to be any benefit, but the interesting, perhaps group of patients that the pooled analysis allowed us to have a deeper dive into was heart failure with mid-range EF. And we can crudely perhaps define this as ejection fraction between 40 and 50%. And by certain analyses, which again this is in the post-hoc and also in a continuous analysis and a specific analysis and a cubic spline analysis, it appeared that the benefit extended into those individuals with mid-range ejection fraction. Again, we need to keep several points in consideration. One is ejection fraction can vary over time and is not a very precise measurement. There's definitely inter-reader as well as intra-reader variability and is not a good mayor of contractile performance. And we tend to actually have a significant amount of a specific infiltrative cardiomyopathies in that EF range, which tend to be excluded from usual clinical trials. And with that caveat, having kept this in mind, it's also important to recognize from cohorts and population-based studies, about 10 to 20% of our patients currently reside in that have HeFmrEF or heart failure with mid-range EF status. And thus the findings are intriguing, hypothesis generating and also encouraging that we may see perhaps benefits with RAS antagonism in individuals that do have LV systolic dysfunction. And probably, if this is persistent and a clear reflection of a phenotype that reflects itself as reduced eje…

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Circulation January 28, 2020 Issue Jan 27, 2020

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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 Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: I'm Dr Greg Hundley, also Associate Editor, the Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Say, Greg, you know the feature paper this week talks about the perennially hot topic now and that is transcatheter aortic valve replacement or TAVR or TAVI. It's actually data from the France TAVI Registry comparing balloon expandable versus self-expanding transcatheter aortic valve replacement. I'm sure you want to hear more about it, but first I'm going to tell you about another paper in the same issue, this time also comparing a balloon expandable versus a self-expanding transcatheter aortic valve implantation, but data from a nationwide analysis and from corresponding author Dr Fauchier from Centre Hospitalier Universitaire Trousseau. He and his colleagues basically did a head to head comparison of the two competing transcatheter aortic valve replacement technologies that have been published but have not really been followed for long-term clinical outcomes. This was comparing balloon expandable versus self-expanding technology. They collected information from more than 31,000 consecutive patients treated with Tavern in France between 2014 and 2018 and based this on the French administrative hospital discharge database. They did propensity score matching, which was used for the analysis of outcomes according to the Sapien 3 balloon expandable versus the Evolut R self-expanding TAVR technology and studied this as nationwide level in France. Dr Greg Hundley: Wow. Carolyn, 31,000 patients. That's a really large study. What did they find? Dr Carolyn Lam: They basically found that balloon expandable TAVR was associated with lower mortality rehospitalization heart failure and pacemaker implantation compared with the self-expanding TAVR. Now, that's of course a pretty big finding and this is discussed along with the feature paper that we're going to hear about in an editorial by Drs. Abdel-Wahab and Thiele from Heart Center Leipzig. I want to tell you about another paper before I let you tell you about yours, okay? Dr Greg Hundley: Sounds great, Carolyn. Dr Carolyn Lam: Greg, what is your clinical impression of Impella use in the United States among patients undergoing PCI? Do you think it's increasing or decreasing over time? As a reminder, Impella was approved for mechanical circulatory support in 2008, so from then, what do you think? Dr Greg Hundley: You know, Carolyn, I really think it's increasing, especially used more frequently rather than an intra-aortic balloon pump. How about you? What's going on in your area of the world? Dr Carolyn Lam: My impression too, but you know, you're lucky because we now have data looking at the trends in Impella use, but in the United States, and this comes from the corresponding author, Dr Amit Amin from Washington University School of Medicine and colleagues who describe clinical outcomes and costs across U.S. hospitals in PCI patients treated with mechanical circulatory support, which is either the Impella or the intra-aortic balloon pump. They found that among more than 48,300 real world patients undergoing PCI with mechanical circulatory support at 432 hospitals between 2004 and 2016 in the Premier Healthcare Database, Impella use was indeed found to be rapidly increasing with marked variability across hospitals and not only its use, but also in its associated adverse outcomes. When analyzed by time periods or at the level of the hospitals or at the level of the patients, Impella use was associated with higher rates of adverse events and higher hospital costs. Dr Greg Hundley: You know, I wasn't thinking about the higher rate of adverse events. You wonder sometimes, are we using a technology in a sicker group of patients? Did this study shine any light on that? Dr Carolyn Lam: Those are great, great thoughts. The authors concluded that the variability in Impella use, the variability in its associated outcomes, and the association of Impella use with higher adverse events and costs really, really underscore the need for better defining of the appropriate use of mechanical circulatory devices and that was what you indicated as well, Greg, and what we need there is adequately powered randomized clinical trials and prospective real world evidence, which we don't quite have yet. Until then, perhaps a more measured approach is needed in clinical practice that balances risks versus benefits in complex patients undergoing PCI who require mechanical circulatory support. Dr Greg Hundley: That's going to be really needed, I think in this era, especially with the results from this study. Well, Carolyn, I'm going to switch over to the world of basic science and the first study I'm going to talk about is from Dr Richard Lee from Harvard University and it's a very interesting study. Just as some background, current differentiation protocols to produce cardiomyocytes from human induced pluripotent stem cells are capable of generating highly pure cardiomyocyte populations, but these cardiomyocytes remain immature and they really more closely resemble the fetal state. As a result, they have a lower maximum contractile force, slower upstroke velocity, and immature mitochondrial function compared to adult cardiomyocytes. Also, they're prone to ventricular arrhythmias. During development, cardiomyocytes undergo a shift from a proliferative state in the fetus to a more mature but quiescent state after birth. The mechanistic target of Rapamycin mTOR signaling pathway plays a key role in nutrient sensing and growth, and Dr Lee and colleagues hypothesized that transient inhibition of the mTOR signaling pathway could lead cardiomyocytes to a quiescent state and enhance cardiomyocyte maturation. Dr Carolyn Lam: Wow Greg, I really love the way you explained that. That's so interesting. What did they find? Dr Greg Hundley: Among human induced pluripotent stem cell lines, transient treatment with Torin 1, an inhibitor of the mTOR pathway, shifted cells to a quiescent state and enhanced their cardiomyocyte maturity. Also, the investigative team suggests that further testing will be necessary to evaluate whether delivery of Torin 1 treated cardiomyocytes could reduce the risk of ventricular arrhythmias in newly differentiated myocytes derived from pluripotent stem cells. Really an important advance in this whole area of developing mature cardiomyocytes from our own pluripotent stem cells. Well, Carolyn, my second basic science paper comes from Dr Calum MacRae from Brigham And Women's Hospital, also at the Harvard Medical School. Carolyn, this study used both highly purified human pluripotent stem cell derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells with human MYL4 mutations in a zebrafish MYL4 knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations associated with definitive genetic causes of atrial fibrillation. Dr Carolyn Lam: Oh, that's really interesting. Is this new genetic predispositions that they discovered? Dr Greg Hundley: I think the answer's yes. They found there was evidence of increased retinoic acid signaling in both human pluripotent stem cell derived cardiomyocytes and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins and loss of intracellular NAD and NADH, and thereby established a mechanistic link between the transcriptional, metabolic, and electrical pathways previously implicated in the atrial fibrillation substrate of MYL4. In the future, these data could lead to novel therapies for some patients with atrial fibrillation. Dr Carolyn Lam: Wow. That really is fascinating, Greg. Well, let me round up by telling you about some of the other things in the issue. There is a research letter by Dr Parish on the effects of Omega-3 fatty acid supplements on arrhythmias and here, these authors reported more comprehensively on atrial fibrillation and other arrhythmias using additional data extracted from linked electronic health records in the ASCEND trial, remember, which was 1 gram of Omega-3 fatty acid supplementation daily in people with diabetes but without known atherosclerotic cardiovascular disease. Dr Greg Hundley: Oh wow. That's fantastic, Carolyn. I've got a couple other really interesting articles in the issue. First there's an In Depth review from Dr Yvan Devaux from Luxembourg Institute of Health, and he discusses regulatory RNAs in heart failure. In a perspective piece, Dr Alejandro Lucia from Universidad European de Madrid discusses the role of aerobic and resistance training as a therapy in addition to prescribed medications in patients with resistant hypertension. Really interesting. Then finally, Dr Ify Mordi from University of Dundee examines metformin use and clinical outcomes among patients with diabetes, with or without heart failure, kidney dysfunction observations from the SAVOR-TIMI 53 trial in which Dr Bergmark and colleagues found that metformin use was associated with a reduction in all-cause mortality and cardiovascular death, but not due to myocardial infarction or stroke, particularly in patients without a prior history of heart failure. What could the mechanism be, if not related to presumed atherosclerosis? Dr Mordi and colleagues proposed possibilities, and Dr Brian Bergmark from the TIMI study group and the cardiovascular division of Brigham and Women's hospital at Harvard Medical School and colleagues, they write a very nice response. It's really interesting listening to how could metformin reduce events but not related to atherosclerosis? How about onto our feature article? Dr Carolyn Lam: You bet. Dr Amit Khera: This is Amit Khera, digital strategies editor for Circulation from UT Southwestern Medical Center joined by my colleague, Dr Dharam Kumbhani who's also an associated editor at Circulation and we're pleased to have Dr Eric Van Belle, Professor Van Belle, from Lille University Hospital to discuss the featured article today, "Transcatheter Aortic Valve Replacement Propensity Match Comparison From the France TAVI Registry." Welcome to you both. Dr Van Belle, I'm going to start with you and we always like to hear a little bit. Perhaps you can tell us some of the background, what led up to this investigation, what led to your group pursuing this manuscript? Dr Eric Van Belle: Nowadays, the TAVI procedure, the TAVR procedure, is becoming very prominent kind of way of treating patients without stenosis, and basically we have two different type of devices that are available to treat the patients. Once series is based on the balloon expandable concept and the other one on the self-expandable concept. These two type of devices are considered to be used primarily in every kind of patient. Theoretically, we can use any of these two devices, any kind of patient, if we follow the recommendation of the manufacturer and I'll just say that that'd been done. These two devices are being validated against surgery, so basically, we could potentially use any kind of them. In today, there is no direct and there was no direct comparison between the two different kinds of concept, although they are very different. Again, the device is different. The way we implant the device is different. The major question that we had behind was to say, okay, what is the outcome? If it's a mean patient get one of the devices or can we expect or should we expect a different outcome? That was the main question behind it. Dr Amit Khera: Okay, so essentially there's two valves, they're both being used fairly regularly and without any kind of direct comparisons. Tell us a little bit about the study design and what you found in this project. Dr Eric Van Belle: For methodology, we used what is called a French study registry, basically nationwide registry with almost all patients treated in France included, and we used it as a database of patients between 2013 and 2015 with an overall group of 12,000 patients treated with either of these two kinds of devices. This is one of the aspect of this registry. The other very important aspect of this registry, and that's the mortality data survival that was obtained in all the patients in 2008 through 2016, so we have a set of 12,000 patients. It was a cool kind of device with complete mortality data by April 2016 so basically, this is the main methodological aspect. On top of this, we did the best to do some matching on the older clinical variables and all the matching valuables that we had to create pairs of patients that could be matched to one to one. We had, at the end, a group of almost 4,000 patients. Dr Amit Khera: Okay and tell us a little bit about some of your main findings of this study. Dr Eric Van Belle: The two main findings were those differences between the two groups of patients, that is a patient treated with self-expandable devices at a higher risk of valvular regurgitation. This was mainly a confirmation because this finding was already reported previously in previous studies trying to compare the two devices, but what was more striking was the difference in mortality. It was a difference mostly in hospital mortality but also in mortality after two years. That was significant with an absolute difference in mortality around 3% by two years. Dr Amit Khera: Well, obviously important, as you mentioned that paravalvular leak had been seen before and this now a long-term mortality difference. Certainly an important finding and one of the main findings of your study. One of the concerns about comparative effectiveness research, essentially you're using observational data such as this is that there still could be residual confounding. There still may be patient characteristics or decisions made by interventionalists that aren't fully accounted for. How did you all really try to account for some of these components, this residual confounding to try to get the best answer that you could? Dr Eric Van Belle: That's going to be a major comment, and everything you can do, every best way to try to control for this, there is no better answer than to do a randomized study, and probably we'll discuss on this. Let's see, indeed, we try to do our best to minimize as much as we could, all these potential confounders, so we did it in a different way, indeed. The first way to do it was to adjust all the potential differences among group but what was very also interesting to remind is that, when you look at the 25 clinical and imaging variables and creating the aortic annulus diameter that was incorporated in the matching, that actually 21 of the 25 variables were already there. We were balanced between the two groups, existing that indeed most of the case, the operators, we are not so much directing or at least if there was selecting it was not captured but all of these valuables because again, out of 25, the correction needed to do the matching was only affecting 4 variables, mainly. Those variables were already pretty well-matched between the two populations. The other way we did it was to look at what is called falsification endpoint, that it is endpoints that are supposed to be unrelated to the devices to verify that indeed, we have not selected a population that will have issues that are not related to the device itself. We look at, let's say, mortality by infection, mortality by cancer, to verify that, indeed, this kind of event where it did wel…

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Circulation January 21, 2020 Issue Jan 20, 2020

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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 Carolyn Lam, Associate Editor from National Heart Center at Duke National University of Singapore. Dr. Greg Hundley: And I'm Greg Hundley, Associate Editor, Director of the Pauley Heart Center in Richmond, Virginia. Dr. Carolyn Lam: Greg, it is so good to be back. I just love doing these podcasts with you and what more when we get to feature a paper like the one that we have this week. It's all about high sensitivity, cardiac troponin and the universal definition of myocardial infarction, one of these evergreen topics that we truly need to understand better. But before we go onto that, I want to share my first paper. It's a preclinical paper and it provides an important breakthrough discovery that could protect the heart against progressive left ventricular systolic dysfunction following injury. Want to hear about it? Dr. Greg Hundley: Absolutely. Dr. Carolyn Lam: Okay. It's from course wanting authors, Drs Sabourin and Benitah from INSERM University, Paris, as well as Doctors Foster and Beech from University of Leeds. Dr. Carolyn Lam: Now, whereas store operated calcium entry has recently gained attention in cardiac pathophysiology, the role of the prototypic store operated channel known as Orai1 remains elusive. So these authors used a novel genetically modified mouse that specifically disrupts the Orai1 channel in cardiomyocytes and showed that functional inhibition of Orai1 preserved alterations of calcium homeostasis, fibrosis and systolic function without affecting hypertrophy. A novel in vivo small molecule Orai1 channel inhibitor, in fact, markedly improve left ventricular systolic function and calcium handling after pressure overload without causing adverse effects. Dr. Greg Hundley: Tell me, how does this help me as a clinician? Dr. Carolyn Lam: All right, you always ask the tough questions. Well, these results really suggest that Orai1 inhibition has the potential for favorable hemodynamic value in the protection of the heart from maladaptive hypotrophy, and therefore might represent a new way to provide inotropic support to help relieve systolic dysfunction. Dr. Greg Hundley: Very good. Well Carolyn, my first paper is from Dr Peter Kudenchuk from University of Washington Medical Center and this study evaluates the overall survivor after out of hospital cardiac arrest from shock refractory ventricular fibrillation or pulseless ventricular tachycardia related to the route of accessory drug administration. So to accomplish this, the investigators had 2,358 individuals that had received Amiodarone, lidocaine or placebo study drugs and randomized to an IV route. Dr. Greg Hundley: And then they also included 661 patients that received the same medications, but they were randomized to an intraosseous route. Dr. Carolyn Lam: So what were the results, Greg? Dr. Greg Hundley: Well, Carolyn, while no significant effect modification by drug administration route was observed point estimates for the effects of both drugs, both the lidocaine and the Amiodarone, compared to placebo were greater for the IV, as opposed to the intraosseous route and that was across all outcomes. And they had significant increases in survival to hospital admission and discharge and favored improved neurological outcomes with the IV administration. Dr. Greg Hundley: Unfortunately, however, the study was underpowered to examine for an interaction between the route of vascular access and drug effectiveness and thus additional studies are needed to determine whether Amiodarone in lidocaine may be lifesaving drugs in patients with shock refractory out of hospital cardiac arrest when given IV, but not necessarily intraosseous. Dr. Carolyn Lam: Very interesting. Well, my next paper is really focused on HIV infection and asks the question, is HIV infection associated with abnormal cardiac repolarization that may contribute to a greater risk for sudden arrhythmic death? Well, corresponding author Wendy Post, our very own from Johns Hopkins University School of Medicine and her colleagues studied 1,123 men, 589 of whom were HIV positive and they were from the multicenter AIDS cohort study and they were studied using the ZioXT ambulatory ECG patch. Dr. Greg Hundley: Wow. Carolyn, this study sounds like it's the largest study of QT variability in HIV today. Dr. Greg Hundley: Is that right? And what did the authors find? Dr. Carolyn Lam: Yeah, it's right. It's huge. And basically they found that HIV positive men had greater beat to beat variability in the QT interval compared to HIV negative men, especially in the setting of HIV viremia and heightened inflammation. Dr. Carolyn Lam: Among HIV positive men, a higher QT interval variability suggests ventricular repolarization lability which could increase susceptibility to arrhythmias. However, lower heart rate variability also may signal a component of autonomic dysfunction. Dr. Greg Hundley: Ah, Carolyn. My next paper goes back to the world of basic science and it's from Dr. Chen Yan from University of Rochester. And in this study, Dr. Yon and colleagues examine the role of cyclic nucleotide phosphodiesterase in isolated adult mouse cardiomyocytes and fibroblasts as well as in preclinical mouse models of hypertrophy and/or heart failure. And they found that phosphodiesterase 10A expression is significantly induced in mouse and human failing hearts. Dr. Greg Hundley: It directly promotes cardiomyocyte hypertrophic growth as well as cardio fiber-blast activation, proliferation, migration and extracellular matrix production. In addition, phosphodiesterase 10A deficiency, so not as much of it, ameliorates cardiac hypertrophy fibrosis and/or dysfunction in different preclinical mouse cardiac disease models. And finally inhibiting phosphodiesterase 10A activity with a compound labeled T P 10 effectively antagonizes the pathological cardiac remodeling in LVH. Dr. Carolyn Lam: Huh, that's interesting Greg. And now I'll ask you, so what are the clinical implications? Dr. Greg Hundley: Well, phosphodiesterase 10A inhibitors have been evaluated in phase two clinical trials for treatment of schizophrenia, suggesting that these agents are safe, druggable, if you will, targets. And therefore the results with TP 10 suggests a potential therapeutic effect of targeting phosphodiesterase 10A on antagonizing the development of pathological cardiac remodeling. Perhaps as suggested by Dr. Ezekowitz last week, this could represent another new agent in the treatment of the adverse effects of heart failure syndromes, more pharmacological agents coming to treat heart failure. Dr. Carolyn Lam: Wow. That is interesting. But okay, let's talk about what else is in this issue. So let me tell you about an online mine by Dr. Kalra and it's called the Cardiovascular Science India Tour. And what this talks about is a multi-pronged initiative bringing together professionals and diverse expertise to allow better understanding of the issues driving the ever-rising cardiovascular disease burden in South Asia. Dr. Greg Hundley: Oh, very good. And from the mailbag, I've got a research letter, Carolyn from Dr. Julian Luetkens from the University of Bond, who investigates a surrogate of frailty by examining the fat fraction within skeletal muscle at the L three L four level. So it's from an axial CT that's acquired at the time of CT scanning for TAVR pre-evaluation and uses the fat muscle fraction to forecast TAVR outcomes. Well. Carolyn, that's a great wrap up. How about we get onto our feature article? Dr. Carolyn Lam: You bet. Dr. Amit Khera: Hi, this is Amit Khera. I am digital strategies editor for circulation and today with our featured podcast we have Dr. Andrew Chapman from the university of Edinburgh, UK who is the first author of a study entitled high sensitivity cardiac proponent and the universal definition of myocardial infarction. Welcome Dr. Chapman. Thanks for joining us. Dr. Andrew Chapman: Good morning. It's a pleasure. Thank you. Dr. Amit Khera: This is obviously a very interesting study and timely and on the backs of the prior work that your group has published. Maybe we can start by you telling us a little bit about the impetus, the background which led to this work. Dr. Andrew Chapman: We've been using high sensitivity cardiac troponin in Europe now for some years, and the way that we diagnose myocardial infarction has, of course changed. We now recognize that myocardial infarction can occur in the context of an occluded coronary artery, be that a STEMI or an NSTEMI, also known as a type one myocardial infarction. Dr. Andrew Chapman: But increasingly with the use of more sensitive cardiac troponin, we're recognizing myocardial infarction can occur in other conditions. So for example, after arrhythmia or after severe infection with hypoxia. So the real rationale and background for this study is trying to understand better the different subtypes of myocardial infarction. As proposed in the universal definition. Dr. Andrew Chapman: And we were in quite a unique position to evaluate this as, when we implemented high sensitivity cardiac troponin testing in Scotland as part of a randomized controlled trial. We did so across different hospitals and two of our major cities, Edinburgh and Glasgow, and the trial which formed the basis for this study was called the high States trial and we enrolled 48,000 patients of who we initially used a contemporary sensitive cardiac troponin on an IRC and we then implemented a high sensitivity cardiac troponin IRC. Dr. Andrew Chapman: And that allowed us to evaluate what impact implementing this high sensitivity test hard firstly on the prevalence of different subtypes in myocardial infarction, but also on the investigations and the treatments received. And finally of course the clinical outcomes of these patients. Dr. Amit Khera: So obviously at a really sizable study and good forethought on your group to implement this as this step wedge type study design. As you pointed out, the goal here was to understand the different subgroups of myocardial infarction, the prevalence and implications. Tell us a little bit about what you found in this study. Dr. Andrew Chapman: As I mentioned, we had over 48,000 consecutive patients and that was the real benefit of this step wedge design is that rather than recruiting patients between say nine and five where we had research nurses available, we enrolled all consecutive patients. So we think this is quite a representative population for our area. So of those patients, we found around 10,000 had elevation in the high sensitivity cardiac troponin concentration, and we adjudicated these diagnoses in parallel. So two independent clinicians look through every case, all the clinical information. And we had a consensus from a third when there was disagreement. So in short we found that around half of all elevations in cardiac troponin in this study were to take one myocardial infarction, that is that the blocked artery phenotype and the type two myocardial infarctions or an acute or chronic myocardial injury and myocardial injury being elevation and cardiac troponin, either acute with a rise or fall or chronic with a stable concentration with no evidence of myocardial ischemia and occurred in the other 50% of patients. Dr. Andrew Chapman: So looking between the phases of the study, we found introducing high sensitivity troponin disproportionately increased the diagnosis of Type II MI or acute or chronic myocardial injury. So there's just an 11% increase in the diagnosis of Type I MI, and I think again that's highlighting that these more sensitive tests are finding myocardial damage in areas that previously it might not have been recognized. Dr. Andrew Chapman: So moving forward from that, we evaluated the primary outcome of the trial, which was future myocardial infarction or cardiovascular death by subgroup. And we also evaluated unimportant non-cardiovascular death. If I may for just 30 seconds, I'll just discuss why this is important. Dr. Andrew Chapman: So evaluating future cardiovascular events is very important and in different subgroups of myocardial infarction. However, we know patients with Type II MI and acute or chronic myocardial injury are different. So they tend to be older, they're more commonly female, they have more comorbidities, they're on more medications to start with. Dr. Andrew Chapman: And these patients are ar increased risk of a competing events to cardiovascular death or a myocardial infarction. And that is that these patients can go on and die, will primarily from their primary illness, be an infection or a pulmonary embolism or what have you. But also they are at increased risk of death from other non-cardiovascular causes. Dr. Andrew Chapman: So in this study we were able to evaluate future cardiovascular risks using quite advanced competing risks modeling. And I was very grateful for the input of a number of experts and we managed to find that actually, Type I myocardial infarction patients with occlusion or partial occlusion of the coronary artery were at the highest risk of cardiovascular events going forward. Dr. Andrew Chapman: But interestingly, even despite the vast excess in non-cardiovascular death, patients with Type II MI, and acute or chronic injury also had quite a high cardiovascular risk over three folds out of patients without myocardial injury. And we noticed that these patients did not stand to receive increases in investigations or treatments for coronary heart disease and we speculate and we hypothesize that actually in a proportion of these patients there is some clinical coronary artery disease which has manifested itself during this physiological stress test of an alternative illness. We wonder and we hope that moving forward this might be an opportunity for better targeting it in an investigation and perhaps even improving clinical outcomes. Dr. Amit Khera: Well, you just shared a ton of important findings there and I'm going to unpackage a few of them. I guess the first is this sort of type I versus type II MI, and I think one of the fears with implementing these high sensitivity troponin would be perhaps an explosion in these type II MIs. And I think, if you look, although you mentioned proportionally, the absolute numbers of increase in type I and type II MI was relatively small so it didn't seem we had this explosion that I think people had feared was implementation. Dr. Andrew Chapman: Yes, that's a fair point. And also need to bear in mind this is a population of patients from Scotland and our high sensitivity troponin testing is quite selective. You would find differences in the impact of high sensitivity if you're testing practices were different and I know there's prior work from the United States showing that less selective testing or to put it in a different way, testing troponin in more patients. Perhaps some of them may not have symptoms of chest pain or symptoms suggestive of myocardial infarction, is likely to change the prevalence of these different groups and you are likely to pick up more secondary injury or type II MI, but I think we don't need to panic. There's no need for alarm. I don't think there is going to be an explosion in recognition of these patients. If you check a temperature, you'll find a fever, but provided we're sensible and who we're testing, then I don't think practice needs to change dramatically. Dr. Amit Khera: That was a great way to say it. Unfortunately, we're always looking for fevers in the U.S. So as you pointed out, the prevalence increase may increase a bit, but definitely reassuring from what you're finding in your p…

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