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This week's episode features special Guest Host Mercedes Carnethon, as she interviews author Sung-Min Cho and Associate Editor Marc Ruel as they discuss the article "Cerebrovascular Events in Patients with Centrifugal-Flow Left Ventricular Assist Devices: A Propensity Score Matched Analysis from the Intermacs Registry." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. 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, this week's feature, we're going to look at centrifugal flow, left ventricular assist devices and cerebrovascular events. But before we get to the feature, how about we grab a cup of coffee and jump into some of the other articles in the issue? And maybe how about I go first? Dr. Carolyn Lam: All right. I got my coffee. Dr. Greg Hundley: So my first paper comes from Professor Dali Luo from Capital Medical University. And it's pertaining to calsequestrin-1. So calsequestrin-1, and calsequestrin-2 isoforms buffer calcium and regulate its release from the sarcoplasmic reticulum of skeletal and cardiac muscle. Human inherited diseases associated with mutations of calsequestrin-1 or 2 include malignant hyperthermia and environmental heat stroke and catecholamingergic polymorphic ventricular tachycardia. However, patients with hypothermia, environmental heat stroke events often suffer from an arrhythmia for which the underlying mechanism remains unknown. Dr. Carolyn Lam: Wow. Okay. And what did the current paper do and find? Dr. Greg Hundley: Great, Carolyn. So what the authors found, calsequestrin-1, the skeletal isoform of it is indeed expressed in cardiomyocyte sarcoplasmic reticulum for mirroring in human hearts, mostly presenting as a polymeric form and interacting with the ryanodine 2 receptor in ventricles. Second, calsequestrin-1 deficiency cause sinus tachycardia in basal conditions. And this is a novel finding which may be associated with sinus beat regulation and ventricular arrhythmia as an independent arrhythmogenesis if a high concentration of volatile anesthetics are used. Next, these volatile anesthetics and heating to 41 degrees C can directly induce calsequestrin-1 oligomerization, thereby causing enhancement of diastolic calcium leak and premature calcium transience through a reduced regulatory effect of calsequestrin-1 on ryanodine 2 activity. And so Carolyn, this novel mechanism underlying the arrhythmia occurring in patients with malignant hypothermia or environmental heatstroke episodes may provide different strategies for heart disorders as an independent profile in these syndromes. And finally, the finding of calsequestrin-1 confirmational change induced by triggers in those with malignant hyperthermia and environmental heatstroke could lead to novel therapeutic approaches to prevent these types of episodes. And that may also very, very useful in treatment of heatstroke.   Dr. Carolyn Lam: Wow. Thanks Greg. Well, moving from this preclinical world to a very common clinical question of the diagnosis of acute myocardial infarction. Now we know that in patients presenting to the emergency department with symptoms suggestive of an MI, the European Society of Cardiology zero and one hour algorithm is recommended by current ESC NSTEMI guidelines with a class one recommendation. Now, what this does is it combines a very high safety for early rule-out and high accuracy for rule-in allowing a definite triage of about 70 to 75% of patients using the zero in one hour sample. Dr. Carolyn Lam: However, what is the most appropriate management of the 25 to 30% of patients who remain in the gray observed zone? So this is the question that the current paper addresses. Now to answer this, we also need some more background that a single center pilot study previously of patients in the observed zone had derived a cutoff of seven nanograms per liter for a zero and three hour high sensitivity cardiac troponin T change to identify patients also eligible for early rule-out or rule-in of NSTEMI. So the current study that we're talking about in today's issue from Dr. Christian Mueller from Cardiovascular Research Institute in Basil, Switzerland, and colleagues, really aimed to externally validate that previously proposed seven nanogram per liter change cutoff, and if necessary derive and internally as well as externally validate some new criteria for these patients in the observed zone of the ESC zero in one hour algorithm. Dr. Greg Hundley: Wow, Carolyn, so we're learning a lot about cutoff values and also algorithms here with high sensitivity cardiac troponin T. So what did they find here? Very interested to hear. Dr. Carolyn Lam: So in two large prospective multicenter diagnostic studies, they found that the proposed zero and three hour high sensitivity cardiac troponin T change of seven nanogram criteria, unfortunately provided suboptimal safety for ruling out NSTEMI in patients remaining in the observed zone of the ESC zero and one hour algorithm. So this had a sensitivity of only 33% and missed 80 patients with NSTEMI. So they derived their own novel criteria based on zero and three hour samples. And these novel criteria combined a three hour high sensitivity cardiac troponin T concentration of less than 15 nanograms per liter and a zero and three hour absolute change cutoff of four nanograms per liter. Dr. Carolyn Lam: And that combination provided a high safety for ruling out NSTEMI in these patients in the observed zone and with a sensitivity of 99% missing only one patient with NSTEMI. Another further thing they found was at a zero and three hour cardiac troponin T absolute change of greater or equal to six nanograms per liter triage, 63 patients, or 11% towards rule-in thus resulting in a specificity of 98%. So in summary, this novel criteria based on zero and three hour sample seemed to balance safety and efficacy well for the further decision making in patients who are remaining in the observed zone after the zero and one hour cardiac troponin T algorithm. Internal validation of these novel criteria and external validation in an independent international cohort showed robustness of performance metrics and further strengthen its possible clinical use.   Dr. Greg Hundley: Very nice, Carolyn. Lots of data there, and hopefully very important clarification on both the zones as well as the cutoff values for using cardiac troponin T. Well, Carolyn, my next paper again comes from the preclinical science world and it's from Dr. Anne Eichmann at Yale University School of Medicine, and it pertains to activin receptor-like kinase 1. And we're going to call that ALK1.   Dr. Greg Hundley: Kinase 1 and we're going to call that ALK1. And it's an endothelial transmenbrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. And loss of function mutations of the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasias, a devastating disorder that leads to arteriovenous malformations. Dr. Carolyn Lam: Oh, okay. And what did the authors find? Dr. Greg Hundley: Dr. Carolyn Lam, ALK1 mutants displayed defective polarization against the direction of blood flow in capillary and venous endothelium as well as increased integran VEGF receptor 2 mediated P13K activation of YAP/TAZ signaling. Dr Carolyn Lam: Okay, Greg, that was super summarized but what are the clinical implications? Dr. Greg Hundley: Carolyn, pharmacological integrin inhibition using cilengitide or ATN-161, or YAP/TAZ inhibition using verteporfin, prevented AVM malformation in ALK1 mutant mice. And therefore for this study, the authors revealed that integrin and YAP/TAZ were novel affectors of ALK1 signaling in AVM pathogenesis that might be targeted for AVM treatment in patients with hemorrhagic telangiectasias. Dr. Carolyn Lam: Thank you, Greg. Well, let's review what else is in today's issue. There's an exchange of letters between Doctors Amadio and Valentine on cell-free DNA to detect heart allograph acute rejection. There's an AHA Update paper by Dr. Churchwell on preemption, a threat to building healthy, equitable communities. There's a Research Letter by Dr. Merkler on the association between cervical artery dissection and aortic dissection. Dr. Greg Hundley: And Carolyn, I've got a paper from Professor Daniels regarding the Clinical Implications of Basic Research getting inside the engine, the myosin modulation of hypertrophic cardiomyopathy and systolic heart failure. And then finally, there's an In Depth piece from Dr. Viskin entitled, “Polymorphic Ventricular Tachycardia: The Terminology, mechanism, diagnosis and Emergency Therapy.”   Dr. Carolyn Lam: Nice. Well, let's go on to our feature discussion. Can't wait. Dr. Greg Hundley: You bet.   Dr. Mercedes Carnethon: Welcome to this episode of Circulation on the Run, our podcast where we have an opportunity to talk with the authors of some of the top articles within our journal for a given week. And we've chosen today to focus on a set of articles, one of which is led by Dr. Sung-Min Cho from the Johns Hopkins University. And I'm really excited to have you with us today, Dr. Cho and joining us as well as the associate editor, Dr. Marc Ruel who handled the paper. And my name is Mercedes Carnethon from the Northwestern University's Feinberg School of Medicine. I guess without further ado, welcome to you both and we'll just jump right into it. Dr. Mercedes Carnethon: Dr. Cho, I'd love to hear a little bit more about your paper today. What made you choose to pursue this particular topic and what really inspired you? Dr. Sung-Min Cho: Thank you so much for the invitation and opportunity to talk today. During my training as a neuro person, I'm a neurointensivist by training and neurologist. I noticed that we are getting a lot of consults for LVAD associated strokes. When I took a closer look at the ENDURANCE trial, very showed really 29.7% stroke rate at two years and a few years later, we had this MOMENTUM 3 trial, which showed HeartMate 3 device had 10% stroke rate at two years. And we realized that a stroke is a major issue in this population and I wanted to study the incidence respecters and outcome of this strokes in LVAD population. However, despite the many observational studies in the past, we were really interested in looking at device specific stroke risk for current continuous flow LVADs and we wanted to look at the device specific risk and prevalence of these patients balancing co-morbidities each cohort. And that's why we conducted this study. Dr. Mercedes Carnethon: Great, well Sung-Min, it's not often that as an epidemiologist and cardiovascular epidemiologist that I actually get to talk with neurointensivists and get their insights on the importance of their work. Can you tell me a little bit about what you found and whether it surprised you? Dr. Sung-Min Cho: Population, we used the Intermacs registry database. This is well established database as all cardiologists and cardiothoracic surgeons know, and we defined a neurologic adverse event as stroke plus TIA, transient ischemic attack. We used a propensity score matching analysis to assess the association of HVAD with stroke risk, to balance for pre-implant risk factors. And basically after performing propensity score matching, we found that hazard of stroke was higher for patients with HVAD device compared to HeartMate 3. We kind of expected this based on the randomized control trials in the past but there was no head to head comparison between these two cohorts. This study really confirmed our suspicion that HeartMate 3 actually had lower hazard of a stroke compared to HeartMate 3. Dr. Mercedes Carnethon: Well, thank you so much. It's a really great explanation. And for those who haven't had a chance to dig into the issue yet, I really encourage you to read the piece. I found it to be very instructive. And I'm interested as well, Mark in your take about what excited you about this piece. Dr. Marc Ruel: Well, thank you very much Mercedes and Sung-Min it's really a pleasure to have you with us today. As you know, this has been a very impactful paper and you were very kind to share with us the study around your idea as to why you wanted to evaluate this question but even more than your idea and what led to the completion of the paper are the implications of your paper. And I think it would be great if you shared with us a little bit, what has been the path that your paper has led to and including amongst others, very likely a decision by the Medtronic to pull the HVAD out of market. It's interesting that your data, to my knowledge, correct me if I'm wrong, were presented first at the annual meeting of the Society of Thoracic Surgeons in January, 2021. And again, I want to reiterate that Circulation's very thankful that you chose to send your paper to our journal and we feel that it will give it full justice, like many other journals of would have had but we're really excited to have received your paper and give it the fullest consideration. Dr. Marc Ruel: Can you tell us a little bit about the implications and for lack of a better word, the storm that your paper has created in the field and your take on it? Dr. Sung-Min Cho: Right. That's a great question. Thank you for that. Like I said, as a neurologist, we see these patients after complication, patients having stroke and then we see these patients and we always wanted, cardiologists and cardiothoracic surgeons and neurologists, we always wondered which device carried more risk for stroke and TIA. And really our group actually worked on many papers in the past looking at single institutional data and also systematic review meta-analysis looking at this topic, but really HeartMate 3 came along a couple years ago, more recent device so we didn't have a lot of data. Dr. Sung-Min Cho: So intermex registry really helped since we didn't have a lot of data. So, INTERMACS Registry really provided opportunity for us to look at this specific question, really balancing those two chords to look at the risk of stroke in this HeartMate 3 and HVAD. And when we did that two years ago, we submitted a proposal to INTERMACS, and Dr. Kirklin from UAB, he really helped us to look at this data closely with his statistical team. And we had really a thorough statistical method to perform a propensity matching analysis. And we finally finished the analysis and presented in annual STS meeting in January, and it did really trigger a lot of attention to a lot of academic institutions and people who are practicing LVAD, and after that, when we finally submitted this paper to Circulation, we had to have a lot of discussion in between FDA and the Medtronic and discussing this implication of this paper. When it was finally published in Circulation, we are happy that there's a lot of attention and we made it through. Dr. Marc Ruel: Well, thank you, Dr. Cho, and maybe for the listener of this podcast, I would like to reiterate some of the salient points of your paper essentially, and correct me if I'm wrong, over 6,200 patients were included, about roughly 3,000 patients per group comparing the HeartMate 3 versus the HVAD. Dr. Marc Ruel: Now, as you alluded to the HVAD is the more ancient device, if you will. So there's a slightly longer follow-up, around 12 months on median, versus nine months with the HeartMate 3. And there's adjustment that has been made for this. And I think to me, really the key finding is that in the early acute phase around implantation, there is no real difference with regards to the risk adjusted incidents of neuro adverse events. However, once you pass the early implantation acute phase, in the chronic stable phase, there starts being really a signal that is detrimental to the performance of the HVAD versus the HeartMate 3. And I think your hazard ratio, correct me if I'm wrong, it's around 5.7 for neuro adverse events. Dr. Marc Ruel: So this is a very compelling hazard ratio, even coming out of an observational study with all the careful attention that you provided to adjust for residual confounding, et cetera. Dr. Marc Ruel: So obviously this is a very strong finding, but I would like you to perhaps comment on this, the patients are not the same. There's some indication that the HVAD patients may have been a little sicker, more RV dysfunction, more tricuspid regurgitation, higher INTERMACS-1 incidents more often on ECMO prior to an implant. What are your thoughts about this? Dr. Marc Ruel: Obviously, you've been very careful and the reader will note in the paper that many attempts have been made to account for those. But please give us your take around that 5.7 hazard ratio for neuro adverse event that you found. Dr. Sung-Min Cho: Right? In fact, we were really being careful adjusting those compounders. So we did a propensity matching has a primary analysis, but as you pointed out, as a secondary analysis, we wanted to look at multi-variable logistic regression analysis, looking at multi-hazard analytics. And when we did the secondary analysis, as you said, in the beginning early hazard period, the risk was similar, as time went on in the constant hazard period, the hazard ratio was 5.7 for HVAD compared to HeartMate 3, which gives a much higher risk of stroke and TIA for those patients with HVAD compared to HeartMate 3. Dr. Sung-Min Cho: So, that was really convincing to us. Confirming the findings from propensity matching analysis, showing that same findings were consistent throughout the different analysis. As we pointed out, HVAD patients actually were sicker, they had more ECMO, and they had more ventilation requirement or sicker patients INTERMACS level. Those are all carefully balanced in both propensity matching analysis and also multi-hazard analytics. And both of these analysis consistently showed that HVAD carried more risk of TIA and stroke compared to patients with HeartMate 3. Dr. Mercedes Carnethon: Thank you so much Sung-Min. You know what excites me as I think about choosing articles for journal clubs, when we're working with our trainees, the propensity matched approach and comparing it directly with what you're getting from multi-variable regression really provides an excellent methodological strategy to be able to generate results from these real world studies where it's not a randomized trial of who received which device, but we're able to yield practical conclusions that are actionable based on these findings when we have these well done analyses. And Marc alluded earlier to the actions that were taken in response to the findings from your study. Can you expand on those just a little bit more? Sung-Min Cho: Of course. So I guess, I don't know the real backstory, what was going on behind the scene, but I know for sure that STS leadership and INTERMACS leadership, they had a lot of discussion with the company who made HVAD device and also FDA, and I know that this study, the results of this study contributed to the decision they made back in June, pulling up HVAD device from the market. Sung-Min Cho: So I'm glad that this study could contribute to the science and hopefully this will help the patients in the future for device selection. So yeah. Dr. Marc Ruel: Sung-Min, I think it's fair to say that your study is probably, if not the most impactful in the field of ventricular assist devices, and I probably would personally think that it is, if not the single most impactful, certainly one of the two or three that are the most impactful. So congratulations to you and your team. Dr. Marc Ruel: If you still have a minute or two, I had a couple of more secondary questions? Dr. Marc Ruel In your analysis I noted that in the early acute phase, there are some protective predictors, such as performing the LVAD implant by sternotomy, which essentially results in about half of the neuro adverse events that you would otherwise observe. So I was a little intrigued by that. And high volume centers had about 1.8 hazard ratio. I suspect that's probably reflective of baseline risk and more acute illness in those patients coming. But if you have a chance, I'd love to hear your thoughts around this? Dr. Sung-Min Cho: Yeah, that's exactly what we thought actually is, initially we thought, hypothesized that surgical volume, the center volume will be associated with lower risk of stroke, but it was the other way around. But as you said, probably higher volume centers were getting sicker patients, so that's the association probably we were getting in the analysis. And we wanted to adjust for surgical techniques, sternotomy versus thoracotomy, and even after adjusting for that, HVAD remained a significant hazard per stroke, which showed in the table two and three, I think in the manuscript. Dr. Sung-Min Cho: And if I may, I want to say these couple of things. In the raw number, in the 6.4% of patients actually had TIA and strokes, neurological adverse events in HeartMate 3, at one year based on our study. And the risk goes up with a longer follow-up time of course. Moment3 trials had two-year follow-up, about 10% had stroke. And this is still, after HVAD is taken off the market, still there's a significant risk for stroke in these patients and based on autopsy and MRI studies although there is a very small studies--MRI studies, although they're a very small series, studies looking at MRI'd brains after explantation of LVAD. And it shows actually more than 95% of patients have cerebral micro bleeds, which is a marker for small vessel disease in the brain. I think this is an important issue, and although we show that one device had a lower risk of stroke, still question remains, are these patients have a high risk of stroke? And there is a need for improving biomedical engineering aspect, and I'm sure cardiologists and cardiothoracic surgeons know much better than I do regarding hemo-compatibility, especially for stroke. Dr. Sung-Min Cho: There is also a dire need for early detection and intervention for these events to improve the outcome for these patients, because once you have a stroke, the outcome is devastating, right? So I think there needs to be better medical management, neuroprotective agent, as well as neuro- monitoring methods, maybe biomarkers to predict stroke or TIA to come so we can intervene and prevent these really devastating complications. Dr. Marc Ruel: Mercedes, if I'm so allowed, I do have one final comment and question. Dr. Mercedes Carnethon: Most definitely. This has been delightful, so yes. Dr. Marc Ruel: Wonderful. So, first, Sung-Min, I want to thank you for working with us. We at Circulation were interested in your paper. You may recall you and I spoke on the phone offline when the decision to revise was made, and we went carefully over what the editors were anticipating would make your paper even better. And you were very responsive. You and your co-author's team were tremendous. And I think the paper that we have before us is absolutely very, very insightful and very important. And obviously tremendously impactful. So I want to thank you again for that. Dr. Marc Ruel: And my question is probably the very difficult question which is in everybody's mind at this point and I would like your take as a neurointensivist. You have someone who you have to care for who has a well-functioning HVAD, two years post implant. What would you recommend in terms of optimization for the prevention of neural adverse events? I realize we don't have all the information, but you are one of the few experts in the world who can probably provide us with a very valid take on this very difficult question. Dr. Sung-Min Cho: Yeah, it is indeed a difficult question. And that's what I am, including me a lot of neurointensivists, they are very interested in this topic. I think really, as I alluded before, only detection is really important, but it's really tough because either patients, they cannot get MRI. There's no way to know who's going to have stroke or not.   Dr. Sung-Min Cho: We know that a bacteremia is a huge risk factor for these patients. Whenever they have device infection, dry valve infection, bacteremia, their stroke risk goes up quite a bit. We have a lot of data on that. So we can carefully monitor these patients, follow these patients. There is some data that, within six days from infection, their stroke risk goes quite high up for these patients. Dr. Sung-Min Cho: But really, neuro-monitoring and biomarker study, there's so little data on this, but patients who are sick like this, not just LVAD patients but ECMO patients or ICU patients, are close neurologic monitoring and some markers to predict occurrence of a stroke or vascular event. I think that's something we really need to study and look into. Dr. Sung-Min Cho: Of course, we have a lot of biomarkers we can pick up from the brain, brain injury markers that we can study, and that has not been done in this space. And there are a lot of opportunities, I think, to look at that. And there's some signal based on Cleveland Clinic data that Randall Starling actually looked into, use of PDE5 inhibitor in this patient population, some protection against the ischemic stroke, and I think that's something also we should look into for neuroprotective agent. Dr. Mercedes Carnethon: Thank you so much! This has been such a delightful discussion this morning with Sung-Min Cho, the lead author of the study and the Associate Editor, Marc Ruel who handled it. Dr. Mercedes Carnethon: I really appreciate your attention. I hope the listeners enjoyed this episode of Circulation on the Run. Please join us again next time. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

This week's episode features author Shih-Chuan Chou and editorialist Alexander Sandhu discuss the article "Impact of High-Deductible Health Plans on Emergency Department Patients With Nonspecific Chest Pain and Their Subsequent Care." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We are your co-hosts, 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. Dr. Carolyn Lam: Greg, I am so excited about today's feature discussion that's going to be about high deductible health plans and their impact on emergency department patients with chest pain and their subsequent care. Now, I can tell you as coming from outside of US, I learned so much from this discussion so everybody's going to want to hear it. But before we go there, let's discuss the other papers in today's issue. Greg, do you have a paper? Dr. Greg Hundley: You bet. Thanks Carolyn. So my paper is going to really evaluate a very interesting question about the role of measuring lipoproteins and their subfractions in patients, not with coronary disease, but peripheral arterial disease. And it comes to us from Dr. Scott Damrauer from the University of Pennsylvania School of Medicine. So Carolyn lipoprotein related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, just like we said. Largely based on their role in progression of coronary artery disease, but the relative contributions of these lipoproteins to those with peripheral arterial disease really haven't been as well defined. So these authors leveraged a large scale genetic association data to investigate the effects of circulating lipoprotein related traits on peripheral arterial disease risk. Dr. Carolyn Lam: Interesting. So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So ApoB was prioritized as the major lipoprotein fraction usually or almost causally responsible for both peripheral and coronary artery disease risk. Extra small VLDL particle concentration, we'll call that excess VLDLP was identified as the most likely subfraction associated with peripheral arterial disease risk while large LDL particle concentration was most likely the sub fraction associated with coronary artery disease risk. And genes associated with excess VLDLP and large LDL particle concentration included canonical ApoB pathway components although gene specific effects were quite variable. And then finally Carolyn, lipoprotein A was associated with increased risk of peripheral arterial disease, independent of Apo protein B. So therefore Carolyn, I think the take home message from this study is that ApoB lowering drug targets and ApoB containing lipoprotein subfractions had really diverse associations with atherosclerotic cardiovascular disease and distinct subfraction associated genes suggested that possible differences in the role of these lipoproteins really are involved in the pathogenesis of peripheral arterial as opposed to coronary arterial disease.   Dr. Carolyn Lam: Wow. Thanks Greg. Hey, it struck me that we haven't had a quiz in a long time. Okay, but we're not going to do it now. Don't choke because this one's kind of tough. I don't think I could even answer it. What is phospholamban? Dr. Greg Hundley: Well, let me guess. I remember having this, I think. Let's just... Carolyn I do not know what phospholamban is. Dr. Carolyn Lam: Let me just tell us all. Phospholamban is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in phosphate lanvin is associated with dilated cardiomyopathy and a high prevalence of ventricular arrhythmias. But how this deletion causes dilated cardiomyopathy is still poorly understood. And there are no disease specific therapies. And hence today's paper, which comes from Dr. Karakikes and colleagues from Stanford university school of medicine. What they did is they employed human induced pluripotent stem cells and CRISPR Cas9 gene editing technologies to create an in vitro model of dilated cardiomyopathy associated with this phosphate lanvin 14 deletion mutation. Single cell RNA sequencing revealed the activation of an unfolded protein response pathway, which was also evident by significant up-regulation of marker genes in the hearts of patients with the deletion. Pharmacological and molecular modulation of this unfolded protein response pathways suggest a compensatory role in this type of dilated cardiomyopathy. Augmentation of the unfolded protein response by the small molecule BIP protein inducer X Millia rated contractile dysfunction. Dr. Greg Hundley: So Carolyn, tell me what are the clinical implications? Dr. Carolyn Lam: Well, these findings suggest a mechanistic link between proteostasis and the phospholamban 14 deletion induce pathophysiology that could be exploited to develop a therapeutic strategy for this kind of cardiomyopathy. The study also highlights how human induced pluripotent stem cells and cardiomyocyte modeling could be combined with small molecule testing as a paradigm for studying genotype, phenotype associations in heart disease. Dr. Greg Hundley: Very nice Carolyn. Well, my next paper comes to us also from the world of preclinical science. And it's from Dr. Philip Marsden from the University of Toronto. And Carolyn endothelial nitric oxide synthase or eNOS is an endothelial cell specific gene predominantly expressed in medium to large size arteries where endothelial cells experience athero-protective laminar flow with high shear stress. Now disturbed flow with lower average shear stress decreases eNOS transcription, which leads to the development of atherosclerosis especially at bifurcations and in the curvatures of arteries. So the prototypical arterial endothelial cell gene contains two distinct flow responsive SIS DNA elements in the promoter. The shear stress response element and the Kruppel-like factor or KLF element. Previous in vitro studies suggested there're positive regulatory functions on flow induce transcription of the endothelial genes, including eNOS. However, the in-vivo function of these SIS DNA elements remains unknown. Dr. Carolyn Lam: Wow. So what did these investigators do, Greg? Dr. Greg Hundley: Right. So Carolyn the authors report for the first time that the shear stress response element and the KLF elements are critical flow sensors necessary for a transcriptionally permissive hypo methylated eNOS promoter in endothelial cells under chronic shear stress in vivo. Moreover endothelial nitric oxide synthase expression is regulated by flow dependent epigenetic mechanisms, which offers novel mechanistic insight on eNOS gene regulation in atherogenesis. Dr. Carolyn Lam: Nice. Thanks Greg. Well, let's go through what else is in this week's issue. In a cardiovascular case series, Dr. Ribeiro discusses the Platypnea-Orthodeoxia Syndrome, a case of persistent hypoxemia in an elderly patient. In ECG challenge, Dr. Challenge shows a case of diffuse St. Segment elevation with idiopathic malignant ventricular arrhythmias. There's an exchange of letters between doctors Wang and Sattler regarding the article cross priming dendritic cells exacerbate immunopathology after ischemic tissue damage in the heart. And there's an On My Mind article by Dr. Mullasari Sankardas on of occlusions, inclusions and exclusions time to reclassify infarctions. So interesting. Dr. Greg Hundley: Very nice, Carolyn. So I've got a couple of things in the mail bag. There is from Professor Kunfu a Research Letter entitled PTP MT-1 is required for embryonic cardio lipid biosynthesis to regulate mitochondrial morphogenesis and heart development. And then finally our own Bridget Kuhn has a cardiology news entitled vegan diets that are culturally aligned with traditional soul food gained popularity among black individuals. Well Carolyn, I can't wait to get to your feature discussion today. Dr. Carolyn Lam: Me too. Today's feature paper is about the impact of high deductible health plans on emergency department patients with non-specific chest pain and their subsequent care. I'm so pleased to have with us the first author Dr. Andrew Chou from Brigham and Women's hospital, as well as the editorialist Dr. Alexander Sandhu from Stanford university. Welcome gentlemen, please tell us about your current study. Dr. Andrew Chou: Yeah, so I think the reason we did this study was really obviously aware of the context, but also me working as an emergency decision. So anybody in the ED will now that, there's all kinds of versions of chest discomfort that comes through the ED and they always are worried about heart attack. And we do this testing kind of day in day out, it gets kind of inundated. So a lot of people have put thought into what we should do in the emergency room. We should get ECG, we should care cardiac enzymes when we're worried about it. But what really quite remains uncertain is really what to do afterwards. We get this patient, we test them, we didn't really find heart attacks, but there's a lot of uncertainty about what to do after. Do we do stress test, do we hospitalize them to get the stress test or other testing. Dr. Andrew Chou: As a result, there's a lot of variation in care. And I think partly because of that, they're kind of the shared decision making came out of that. As a part of the solution was to involve patient via, Hey, here are your risks. Let's talk about whether or not this would make sense for you to stay, get testing among other decisions. But what's always interesting to me is that even though we have this push towards having patients have kind of needing to make these decisions because of money, we don't really talk about costs and even their sort of sense of pride about, oh, we don't want to talk about costs. We just want to be the best medical treatment for you, but cost is such a reality for the patients. So, that's kind of the motivation behind getting this study done. So the way we wanted to test it was to set it up as closely as possible to run my trial but knowing that it's not really possible in the real world to do something like that. Dr. Andrew Chou: So we had to be pretty selective about who we include as a study population. So the first thing we did was we took essentially a large national insurer and their claims database. We look at only the people who enrolled in insurance products through their employer. So employers in the US can choose what type of plan they want to offer patients. And we only chose employers that offer only one type of insurance at a time within each year of a plan. So what we did is we chose people who had essentially two years of enrollment. And in the first year, they all have to have loaded up full plans. Dr. Andrew Chou: Meaning deductibles are less than $500. It's still a lot of money, but it's less compared to... The second year either they still have low deductible plan or the experimental group is going to be a group of people who employer only offer high deductible plan, which we define as having deductible greater than $1,000. So that sort of set up a control and experimental group with a similar baseline and then a different followup period of a year. And then we also did additional matching by employer characteristics and their own, the member characteristics to kind of make them as close as possible in terms of compabilities, age, as well as employer size, which we find to be a really big factor. Because large employers tend to have lower deductibles because they can risk care a lot better among their employees where a small employers like companies with five, 10 employees tend to have high deductible plans. So we use that population to compare essentially what happens after a certain company switch to kind of calculate the effect of the high deductible plan. Dr. Carolyn Lam: Great. Very novel design. But could you please tell us your results? Dr. Andrew Chou: Yeah, so we found is that once the employees from the companies that switch, there were less ED visits that ended up with a diagnosis of chest pain. This is important to bring in also the nuance here, which is that these are ED visits that effectively are not have been seen and test it. And they don't have a severe diagnosis like a heart attack or other significant cardiac issues that were found at least during the initial ED stay. And that decreased, which sort of makes the question whether or not these decreased visits or either where they just another chest visit without really other diagnoses or are they visits that actually have diagnosis. The other thing we found was also that there's a decrease in admissions from these ED visits actually. And majority of it, even though when we did our study, we actually were looking at admissions through the 30 days after these ED visits. Dr. Andrew Chou: But we found that the majority of difference is actually the admissions directly from these initial ED visits with time is just horrible. Two more things we found was that the amount of testing that was done after the ED visits, or not really consistently decreased because of high deductible, some tests really didn't have a difference and some more invasive and expensive tests did have some differences. But if you account for the decrease in the chest pain ED visits, then they're not really that notable. But the last finding, which perhaps is the most interesting of which is that there seems to be an increase in heart attack diagnosis and admissions after these visits for chest pain and our statistics for the entire study population actually wasn't significant. But we decided to look at the subgroup patients from poor communities who presumably have lower income and found that the same findings in this group was actually statistically consistent and so we felt comfortable reporting that. So I think that was probably the most interesting finding from our study. Dr. Carolyn Lam: Right. Thanks Andrew. Alex, I have to bring you in here. I really love the editorial love that you said to go or not to go as the title. But could you put these findings in context, please? Dr. Alexander Sandhu: Yes. Happy to and thank you for having me. I think studies like this study by Andrew and colleagues are incredibly important as we make health policy decisions that have large impacts on clinical decision-making for both patients and clinicians. It's important that we study them to understand how they impact patient decision-making clinical outcomes and costs, because obviously that can have important ramifications for future design at the end detecting unintended consequences. I think this study adds to a large body of work done by Andrew and his colleagues, really helping us to understand the implications of high deductible health plans on patient decision-making and subsequent outcomes. This is an incredibly important topic because of the proliferation of high deductible health plans over time and then potentially since the advent of the Affordable Care Act with fixed premiums leading to more and more cost sharing for patients. And it's really critical that we understand how that cost sharing impacts patients. Dr. Alexander Sandhu: And I think that chest pain is a wonderful test because chest pain can be something very serious. It's almost universal that when patients have acute onset chest pain, that a clinician asks them to go to the emergency department for further evaluation. However, we also have a large body of evidence that suggests that the large majority of chest pain episodes are not serious and don't end up needing additional treatment. So it's an area that I think both you could imagine decreased utilization once you applied cost sharing to patients. But what were you very much worried about the unintended consequences of people not going to the emergency department, if it's a serious condition. I think this was a well-designed quasi experimental analysis to look at the lower risk, but majority of episodes of chest pain where they're non-specific and not resulting in acute coronary syndrome and to try to demonstrate it that the high deductible health plans do lead to reductions in those episodes. Dr. Alexander Sandhu: I think as Andrew said, one of the most fascinating findings was this increase in acute MI's it was consistently significant amongst the low-income patients, but was not related to patients that were discharged because of potentially the effects of the high deductible and then came back in with acute MI's but were actually acute MI's during the initial admission. I was wondering if Andrew could maybe both explain that nuance a little bit more, which you get into the discussion of that paper, and then also walk us through maybe some thoughts that you and your study team had for causes for that potential finding. Dr. Andrew Chou: Yeah, absolutely. Thanks for raising that. So I think going into it initially, our hypothesis was really that, but when we first saw it, our initial thought was that, oh, maybe perhaps after they're discharged, they're supposed to get testing and patients or then follow up with their doctors. So they have increased poor outcomes. And so after that thought, that's when we did the kind of subgroup analysis looking at just patients who were discharged versus those who were admitted when they were diagnosed with chest pain at their initial ED visits. And exactly what we found is that the difference is really among people who were admitted initially, which is surprising to us. So I think what that signals to us is that our initial thought was not correct in the sense that this is not really a result of lack of followup or didn't intend to the testing that they were scheduled or didn't go see their doctor afterwards. But really like patients who are showing up in the ED already are more prone to perhaps having a heart attack. Dr. Andrew Chou: And so it really points to which is what you mentioned at your program, which we totally agree as well, that more upstream factors is affecting this. Could it be that they don't tend to take their medications as they should, or they didn't go to their doctors for checkups as they should, or they could have had earlier identification of heart problems if they have more perhaps milder symptoms beforehand until before the ED visits that could have presented certain things. So, that's hard to say. I do think that there is a... One of my mentors in this paper, Dr. Wareham, who has done a ton of work in the space of high deductible plan with kind of chronic disease management, they have definitely shown a lot of differences when patients have higher cost sharing. They'd certainly defer a lot of carriers, especially in diabetics have more complications and it might be a similar scenario here that which would make the most sense and fits the best with our findings here. Dr. Carolyn Lam: So that's a great question Alex and great insight Andrew. I think at this point, I need to ask you both. So what overall do you think is the clinical implication or there'd be any practical next step that you think should follow from this? Maybe I'll let Andrew start and then Alex finish? Dr. Andrew Chou: Sure. Thank you. I think there's kind of... I think two aspects to this one is really broader policy changes. I think if anything, it's quite uncertain whether or not the reduction in ED visits for chest pain is something detrimental. It's unsure whether or not the reduce admission is detrimental. But what is certain is that especially in lower income population certainly feels the higher out-of-pocket costs a lot more. And if there is an unintended consequence, it will certainly be magnified in this population. And in fact, I think a couple of past studies who having compared really high income versus low income population has found that really, high income patients tend to do okay and they're able to pick and choose appropriately of type of care they need. Whereas low-income patients tend to have really unanticipated changes. So, really trying to minimize the impact for low-income patients is going to be important policy direction. Dr. Andrew Chou: And there are a number of ways of doing it. I think there certainly is an increasing trend for companies to fund the health savings account, which is actually a tax deferred almost like investment accounts or certain fund to help them offset some of their healthcare out-of-pocket costs. But the other aspect of it, which I think is all a bit harder to push for is really for employers and insurance to just keeping their account patient's income when they're kind of pushing forward products for a high deductible plan. So low-income patients should just not have quite as big of a deductible as the high income earners do. But a different aspect it's really clinically for clinicians. It's tough because I think insurance put this forward because they want to influence patient decisions before they even see the clinician. But after they decide to come visit clinician, I think the clinician should be aware of the financial reality for the patient when making these decisions. Dr. Andrew Chou: But it's really hard for me to think about whether or not this is going to be a good thing for the patient or not. And one of the biggest concerns for really my colleagues in the department is really whether or not if we are really talking poor patients out of certain care by reviewing their financial reality with them and by through that are we essentially discriminating against other patients. So that's really a big unknown. I think that's definitely an area that we should definitely heavily invest in research because we're just pushing forward with price discussion for care to encourage price discussion at the clinic here without really knowing what's going to happen. Dr. Carolyn Lam: Yeah. Wow. Alex? Dr. Alexander Sandhu: Yeah, I definitely agree with Andrew. I think if we want to make decisions based on cost and we want patients to make those decisions and we as clinicians, obviously should be helping them. We need more transparency around costs, current deductible status, and that has to be available at the point of care so it actually can be integrated in decision-making. But I think that's likely not enough. I mean, even for clinicians, it's hard to determine how clinically necessary it is to get emergency evaluation before you see the patient when you get a phone call. So I think, if it's hard for clinicians with all of our years of experience, it's hard to understand how we can really expect that from our patients. Dr. Alexander Sandhu: I wholly agree with Andrew that I think a critical step is it's going to be important to reduce the risk of cost sharing for low-income patients with a number of potential interventions to do that, which I think are the real policy implications here. And then more generally, I think we should make sure that deductibles aren't discouraging utilization of high value cost effective intervention. There are currently safeguards in the Affordable Care Act about that. But I think we need to think about those closely and probably expand that so we don't see high deductible health plans leading to lower stat rates or worse diabetes prevention. Dr. Carolyn Lam: Wow. Words of wisdom. I just cannot thank you both enough for publishing such a beautiful paper, important findings, as well as just a very lovely editorial in Circulation. Thank you. Learned a lot. I'm sure the audience did too. Please remember you're listening to Circulation on the Run. Please tune in again next week with Greg and I. Dr. Greg Hundley: This program is copyright of the American heart association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American heart association. For more visit ahajournals.org.  

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This week's episode features author Aaron Baggish and Associate Editor & Editorialist Satyam "Tom" Sarma as they discuss the article "SARS-CoV-2 Cardiac Involvement in Young Competitive Athletes." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts ... 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 from VCU health in Richmond, Virginia. Dr. Carolyn Lam: Greg, this feature discussion is just so relevant to our current times. It talks about SARS-CoV-2 cardiac involvement in young competitive athletes. Oh, one that I'm sure we're all dying to get to. Very important. But first, let's tell you what's in this week's issue. Greg, you want to go first? Dr. Greg Hundley: You bet, Carolyn. I'm going to grab a cup of coffee, and we're going to dive into the world of preclinical science. Our first paper comes to us from Professor Naftali Kaminski from Yale University. Carolyn, these investigators reprocessed human control single-cell RNA-sequencing, or scRNA sequence data from six datasets to provide a reference atlas of human lung endothelial cells to facilitate a better understanding of the phenotypic diversity and composition of cells comprising the lung endothelium. Also, the signaling network between different lung cell types was studied. Dr. Carolyn Lam: Wow. Okay. So what did they find, Greg? Dr. Greg Hundley: Six lung single-cell RNA-sequencing datasets were reanalyzed and annotated to identify over 15,000 vascular endothelial cells from 73 individuals. Beyond the broad cellular categories of lymphatic, capillary, arterial and venous endothelial cells, the co-authors found two previously indistinguishable populations. Pulmonary venous endothelial cells, called COL15A1neg localized to the lung parenchyma and systemic venous endothelial cells, COL1581positive localized to the airways and visceral pleura. Dr. Greg Hundley: Now, among capillary endothelium cells, the authors confirmed their subclassification into recently discovered aerocytes characterized by EDNRB, SOSTDC1, and TBXX2 and general capillary endothelial cells. The authors confirmed that all six endothelial cell types, including the systemic venous endothelial cells and aerocytes, are present in mice and identified endothelial marker genes conserved in both humans and mice. Dr. Greg Hundley: So Carolyn, I'm going to take a question I bet you're getting ready to ask. What are the clinical implications of this research? Well, mainly that understanding the lung endothelial diversity is crucially important to identify new therapeutic approaches for vascular diseases such as pulmonary hypertension. Dr. Carolyn Lam: Wow. That was interesting, Greg. Thank you. I've got another one from basic science world as well, and this one talks about the initial functional characterization of an exercise-induced cardiac physiological hypertrophy associated novel long non-coding RNA or LncRNA. Dr. Greg Hundley: Okay, Carolyn. Quick quiz. Can you remind us what these long-coding RNAs are? Dr. Carolyn Lam: Ha. Sure. So long non-coding RNAs or LncRNA refers to RNAs that are longer than 200 nucleotides and lack the potential to encode proteins, but have still been closely related to the occurrence and development of many diseases. Dr. Carolyn Lam: The current paper comes from co-corresponding authors, Dr. Li from the First Affiliated Hospital of Nanjing Medical University and Dr. Xiao from Shanghai University. They identified a LncRNA in the heart named cardiac physiological hypertrophy associated regulator, or CPhar. This was increased following exercise training and was necessary for exercise-induced cardiac growth. In neonatal mouse cardiomyocytes, over expression of this LncRNA induced an increase in these cardiomyocytes' size and expression of proliferation markers while inhibition of the LncRNA reduced these neonatal mouse cardiomyocytes' size and the expression of proliferative markers. Over expression of the LncRNA led to a reduction in oxygen glucose deprivation reperfusion-induced cardiomyocyte apoptosis, while LncRNA knockdown aggravated the apoptosis. Dr. Carolyn Lam: In vivo over expression of that LncRNA prevented myocardial ischemia reperfusion injury and improved cardiac function. So mechanistically though, the transcription factor, ATF7, acted as the functional downstream effector of this cardiac physiological hypertrophy associated regulator, the LncRNA. Dr. Carolyn Lam: Now Greg, following your example, I'm going to ask what are the clinical implications and tell you. So these results provide new insights into the regulation of exercise-induced cardiac physiological growth, demonstrating the cardioprotective role of this LncRNA known as cardiac physiological hypertrophy associated regulator in the heart. It also expanded our knowledge and understanding of the functions and fundamental mechanisms of LncRNAs in general. Dr. Greg Hundley: Wow, Carolyn. Beautifully described. Well, my next paper comes to us from the world of clinical science and really it's kind of something that's going to get into spending. It comes to us from Dr. Brandon Bellows from Columbia University. Dr. Greg Hundley: So Carolyn, spending on cardiovascular disease and cardiovascular risk factors, in total cardiovascular spending, accounts for a significant portion of overall US healthcare spending. The author's objective was to describe US adult cardiovascular spending patterns in 2016 and changes from 1996 to 2016, and look at the factors associated with these changes over time. Dr. Carolyn Lam: Wow. Okay. So were the authors are viewing time-dependent changes in cardiovascular spending. Is that it? What did they find? Dr. Greg Hundley: Absolutely Carolyn. So a bunch of data. Just kind of some interesting facts here. So let's work through them. Adult cardiovascular spending increased from 212 billion in 1996 to 320 billion in 2016, a period when the US population increased by over 52 million people and the median age increased from 33 to 36.9 years. Dr. Greg Hundley: Next, over this period, public insurance was responsible for the majority of cardiovascular spending at 54% followed by private insurance at 37% and out-of-pocket spending at 9%. Dr. Greg Hundley: Next, health services for ischemic heart disease at about 80 billion and hypertension, 71 billion, led to the most spending in 2016. Dr. Greg Hundley: Next, increased spending between 1996 and 2016 was primarily driven by treatment of hypertension, hyperlipidemia, and atrial fibrillation flutter on which spending rose by $42 billion, $18 billion and $16 billion respectively. Increasing service price and intensity alone were associated with 51% or 88 billion, and cardiovascular spending increased from 1996 through 2016. Whereas, changes in disease prevalence was associated with a 37% or $36 billion spending reduction over the same period after taking into account population growth and population aging. Dr. Greg Hundley: So in summary, Carolyn, US adult cardiovascular spending increased by about $100 billion from 1996 to 2016. Maybe policies tailored to control service price and intensity and preferentially reimburse higher quality care, perhaps that could help counteract future spending increases due to population aging and growth. Dr. Carolyn Lam: Oh, wow. Those are staggering numbers. Thanks Greg. Now let's go through what else is in this week's issue. There's an exchange of letters between doctors Mehmood and Houser regarding the article, Cardiac Remodeling During Pregnancy with Metabolic Syndrome: A Prologue of Pathological Remodeling. There's an ECG challenge by Dr. Real on an unusual call from the urology ward. There's also a Research Letter from Dr. Molkentin on cardiac cell therapy failing to rejuvenate the chronically scarred rodent heart. And finally a Special Report by Dr. Althouse on Recommendations for Statistical Reporting in Cardiovascular Medicine: A Special Report from the American Heart Association. Dr. Greg Hundley: Great, Carolyn, and I've got a Perspective piece entitled, Intravenous Iron Therapy in Heart Failure with Reduced Ejection Fraction: Tackling the Deficiency. It's from Professor Ardehali. Dr. Greg Hundley: Well, Carolyn, how about we get on to that feature discussion and learn more about SARS-CoV-2 in young competitive athletes. Dr. Carolyn Lam: Ooh, let's go. In our current COVID-19 pandemic a huge question is, does cardiac involvement in athletes with COVID-19 preclude their further participation in sports? What is their involvement after they've recovered from COVID-19? Guess what? Today's feature discussion is really hitting the spot with this question. So pleased to have with us the corresponding author of the feature paper, Dr. Aaron Baggish from Massachusetts General Hospital, as well as Dr. Satyam Sarma also known as Tom Sarma, our dear Associate Editor from UT Southwestern, who is also an editorialist for today's paper. So welcome Aaron and Tom. Aaron, could you start us off by describing your study and what you found? Dr. Aaron Baggish: Sure. So just very briefly, some historical context. As everyone is quite aware, when we first started seeing COVID-19 in the hospital, there was a lot of concern about what the virus did to the hearts in people that were sick enough to be hospitalized. Those of us in the sports cardiology community were quite concerned that when young athletes that developed COVID-19 infection got sick and then returned to sport, that we'd be seeing the adverse events associated with cardiac involvement. So that was the impetus to start the ORCCA Registry, which was really an opportunity to try to capture the large-scale experience with collegiate athletes returning to sport after COVID-19 infection. Indeed, with roughly 19,000 student athletes across 42 universities, there were approximately 3,000 that developed COVID-19 infection and then went through some form of cardiac screening prior to return to play. The registry was really about telling that story of what we found and what we think the implications are. Dr. Carolyn Lam: Aaron, I mean, first of all, more than 19,000 athletes recruited in just ... What was it? September 1st to December 31, 2020? How did you accomplish this amazing registry so quickly? That's amazing. Dr. Aaron Baggish: I need to acknowledge the fact that this was an incredible team effort. I was joined and continue to be joined in this by my co-PIs, Dr. Jon Drezner and Kim Harmon, who are sports medicine physicians out of the Seattle area, and the combination of cardiology, expertise and sports medicine expertise really able to pull in many of the large universities and colleges around the country, including most of the Power Five schools to participate in this registry. Dr. Aaron Baggish: In short order, team physicians from all these schools understood the importance of this work and agreed to partner with us to work very hard to enroll their student athletes and to provide us with the information we needed. Dr. Carolyn Lam: Incredible. But with the foresight, congratulations, this in and of itself is amazing. Now, could you please tell us what you found? Dr. Aaron Baggish: Sure. So we found that indeed, as we expected, that these student athletes were undergoing a fair bit of cardiac testing prior to being allowed to return to sport, and that there was variability in terms of what type of testing they were getting. The majority of schools were following what at that point were the recommendations, which were do, what we call the cardiac triad testing, which includes an echocardiogram, a high-sensitivity troponin, and an ECG and to use that information to either clear athletes or send them through further clinically indicated tests. A small number of early adopters had decided to do mandatory cardiac MRIs. So within that, we were able to understand what the prevalence, if you will, of cardiac involvement in these COVID-19 student athletes looked like, and it varied as a function of what type of tests people were doing. Dr. Carolyn Lam: And? Give us a sneak peek. Dr. Aaron Baggish: As people would expect, the more sensitive tests you do, the more abnormalities you detect. So among the schools that were using a mandatory cardiac MRI approach, there was a 3% prevalence, if you will, of either definitive, probable or possible COVID-19 cardiac involvement. When schools were following the triad testing first followed by clinically indicated CMR that prevalence was much less. It was approximately 0.5 or 0.6%. So I would emphasize that on the whole, regardless of which test was being used, that the involvement was at a much lower rate than we expected based on what we saw early in the hospitalized patient experience. So I think it's a very good news story. Dr. Carolyn Lam: Indeed. That's exactly, I think the title almost of Tom's editorial. Tom, could I bring you in here, please? Could you give us the context of this and then tell us what as editors we thought of the paper when it kind of reached out doors at Circulation? Dr. Satyam “Tom” Sarma: Sure. No, this was, I actually remember almost exactly when I was asked to handle this paper from an editorial standpoint. Joe texted me, Joe, our editor-in-chief texted me ... I think, the night, actually it was a Friday night I think ... That we had a really important paper, would you be able to take care of it on an expedited basis? I said, "Of course." So took a look at it over the weekend, and it's one of those papers when you're reading it, you almost wish you had a time machine because you realize if we had known this information eight, nine, 10, 11 months ago, it would have totally changed how we handle the pandemic from an athlete and young person standpoint. So from that aspect, I thought this is obviously a very high impact paper. Dr. Satyam “Tom” Sarma: Which then led me to the second challenge is finding the right reviewers for this paper because obviously this is a very controversial topic. We wanted to make sure we had the best reviewers we can get. The challenge, unfortunately, was that a lot of my usual go-to reviewers were actually members of the ORCCA Registry. So there were some issues with conflict of interest there, and so from a reviewer standpoint, I looked to sort of leaders in the field who had done something similar. The first thing that came to mind was really how the field has handled ECG screenings for our young athletes. I think there's, again, a perspective there that I think is very similar to how do you handle patients or young athletes with COVID and then how do you emphasize shared decision making? So from that standpoint, I had a narrow list of experts in shared decision making in sports cardiology, and really leaned on them to help guide us through the process because this is a complex paper. Dr. Satyam “Tom” Sarma: I think their feedback was instrumental in really helping to kind of distill the message, to kind of phrase things in a way that allowed the message to be easily digested by both the lay media, but more importantly, by sports trainers and athletic directors around the country. From that standpoint we really work hard and again, really thank you to Aaron and Jonathan on this manuscript because they worked so hard with our reviewers. They were incredibly responsive to almost every review comment. From that standpoint, I think the end result was amazing to really see it in final format. Dr. Carolyn Lam: I love that behind-the-scenes look. Thank you so much, Tom. What is the strong clinical implication of this? If you have questions for Aaron, please go ahead. Dr. Satyam “Tom” Sarma: Sure. No, I think the biggest thing for us as editors and sort of from the public health impact was, as Aaron mentioned, some schools have unlimited resources to really throw as much money as they can at the problem or what they think is the best approach to the problem. Again, when you have unlimited resources, you can get the "best tests." I think, unfortunately not every school in this country, both from a collegiate or high school level, has a capacity and more importantly, around the world. That's a really important limiting factor. Dr. Satyam “Tom” Sarma: Is there a way to distill the algorithm in a way that's both safe for the athletes, but more importantly is feasible for most schools? For us, that was the most important public health message was really to get that out there. The second of course, was that thinking back to last summer, just how many COVID myocarditis papers we handled in Circulation. Looking back with the again, in the heat of the battle, things are always challenging, but just to sort of see how the pendulum shifted in such a 180 degree sort of manner. So that also I think was important to get out there as well. Dr. Carolyn Lam: Yeah. And exactly why this paper is so important. So thank you once again for publishing it with Circulation. Tom though ... Okay. I mean, not to underestimate the MRI findings and so on. I think you had a question for Aaron in relation to that? Dr. Satyam “Tom” Sarma: I do. One of the challenges, again, being on the myocardial side is that we're not always experts in the papers we're assigned, and it's obviously been an incredible learning process. For me, I was hoping to pick your brain a little bit about the MRIs and sort of how you think the field will evolve from a sports cardiology standpoint. Especially as scanners get more powerful, as scanners get more sensitive, the challenges I think the field's going to have is really detecting the tiniest fleck of an abnormality. Dr. Satyam “Tom” Sarma: I think the context here is really the recent paper out of the Big 10 where they MRI'd, I believe, everyone in that registry ... I want to say it was over 2,000 athletes. Just out of curiosity, how was that handled, again, amongst your co-authors in deciding how best to present the MRI data? I like how you use the probabilistic language of it's either definite, probable or possible. How do you see that sort of progressing in terms of is that something practical that can be used by sports trainers and sports medicine staff to help restratify your athletes or athletes? Dr. Aaron Baggish: Tom, there's so much packed into that question. Let me try to unpack it piece by piece. So first off in our registry, there were a few schools that were early adopters in mandatory CMR screening, and so we wanted to very much responsibly report that. Again, there was about a 3% prevalence of something being abnormal with the myocardium based on the scans. We also realized that not all abnormalities were created equal, and that's why we did come up with that definitive, possible, probable nomenclature to really capture the fact that there were a few people that looked like they had overt myocarditis. But the vast majority had non-specific findings that those of us as clinicians pre-COVID would not have considered myocarditis. Dr. Aaron Baggish: The issue with MRI is a complicated one. The way I like to think about this as, as you mentioned earlier, is to go back to the historical experience we had with ECG screening in which doing that before we understood how to use it as a screening tool caused more problems than it solved. Dr. Aaron Baggish: It was really back in the mid-2000s when the Italians published their first ECG screening paper that the Americans got interested in it. What we learned is that if you used ECG, and this applies to MR too, without having good normative data, without understanding the cost implications, without having the experts prepared to interpret the test and deal with the downstream findings, that you're just not ready for prime time. Dr. Aaron Baggish: While I think the use of MRI as a screening technique during COVID was done with the best of intentions, I think the Big 10 paper, which is a very important dataset in this discussion, highlighted why MRI is just simply not a useful screening tool right now. If you look across their schools, they had tremendously variable rates of cardiac involvement, which is not a function of pathobiology. This virus is not different in Virginia than it is in Tennessee than it is in Wisconsin. It's just simply that people are using the tool in different ways and coming up with different findings. What we're now seeing clinically is that all these MRIs are finding a lot of stuff that either we don't want to care about or we don't want to know, and we're stuck dealing with it. So a challenge ahead of us, for sure. Dr. Satyam “Tom” Sarma: No, I think that's a really important point, Aaron. I think looking back even from a clinical standpoint in those, didn't not necessarily look at athletes, I think what you bring up is really important. The cognitive bias. Find something abnormal. I do wonder if you could talk a little bit about ... One of the other concerns we had behind the scenes was if you know an athlete, if you're an MRI reader and you know an athlete or the scan in front of you says 19-year-old athlete with COVID, can you talk a little bit about the cognitive biases that kind of go into sort of assuming either the worst case scenario, especially with athletes, because again, these are young, robust, healthy people who may or may not be on TV or in a very public format. How do you handle that as a sports cardiology in general, just kind of overcoming the cognitive bias, both from a public policy standpoint, but also from a lay public standpoint? Dr. Aaron Baggish: Yeah. So I think bias is such an interesting word to me because bias has a negative connotation, but bias actually also has some positive attributes associated with it. Bias really pushes people to be, in this situation, to be conservative and to try to do what they think is best. Dr. Aaron Baggish: But what I think it boils down to is going back to a very simple tenet and that's understanding the pre-test probability of disease. So when we interpret imaging data or exercise testing data, it always goes back to the question of why did this person get the test done in the first hand and what is our pre-test probability of finding something wrong? I think what we've learned through the COVID pandemic is that just simply having COVID does not equate with a high pre-test probability of having myocarditis in this young population. That it's really the kids that present, and these are the rare few and far between, that present with clinical findings that any doctor would think of as being consistent with myocarditis, where the scan is really helpful. The vast majority of time it's just simply not that case. Dr. Satyam “Tom” Sarma: No, I agree. I think that's always the challenge as well, too clinically as well too, with the diagnostic creep of you get one test that's kind of abnormal and the next thing you know, you're doing a cardiac biopsy and trying to figure out how you got to where you got to. Dr. Satyam “Tom” Sarma: I wanted to circle back to Carolyn's comment. I guess obviously COVID kind of really was the dominant health story over the last 12 to 14 months. Has there been a similar rash, in other words, I'm thinking back to H5N1 or some other pandemics in the past, was there a similar concern historically from the sports cardiology community with those viral outbreaks? Dr. Aaron Baggish: No. Not to my knowledge, and that's simply because there wasn't as much of an experience with hospitalized patients in the US in those prior pandemics. Again, our concern in sports cardiology world really stemmed from a very different population than the one we deal with on a daily basis. I think we learned that, although we thought that was a well-intending way to approach it, that it turned out to be an overreaction. Dr. Aaron Baggish: Before we end, I want to return to Tom's comments about the process and just share with the listeners what a satisfying process this was as an author. Having been through the peer review process, many hundreds of times with different journals, I don't remember one that was as satisfying nor one that led to as high quality of paper based on the feedback we got from the reviewers. So very much appreciative. Dr. Aaron Baggish: I also want to acknowledge the American Heart Association that has become a long-term partner in this effort. As we move out of the pandemic, the ORCCA Registry will be pivoting to really capture what happens to young athletes that are diagnosed with genetic and congenital forms of heart disease. We're very appreciative that the AHA has agreed to partner with us on this. Dr. Carolyn Lam: Aw, my goodness. Thank you so much, Aaron and Tom, for this incredible discussion. I really want to end with, if I may Tom, citing your editorial. I love the way you ended it by saying, "As Nelson Mandela said, 'Sports has the power to change the world. It has the power to inspire. It has the power to unite people in a way that little else does.'" We got seriously scared with COVID-19, but this paper is just so important in providing some reassurance that there has not been a single case of cardiac complication to date, documented to be clearly related to COVID-19 in this population. It's a real testament to the hard work that you've put in. So thank you. Thank you very much for this paper. For all the effort. Thank you both for being here to discuss this. Dr. Carolyn Lam: Well, audience, you've been listening to Circulation on the Run. Thanks for joining us today, and don't forget to join us again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

This week is a Double Feature Circulation on the Run. Please join author Patrick Serruys, editorialist Shamir Mehta, and Associate Editor Emmanouil Brilakis as they discuss their article "Ten-Year All-Cause Death According to Completeness of Revascularization in Patients with Three-Vessel Disease or Left Main Coronary Artery Disease: Insights from the SYNTAX Extended Survival Study" and editorial "Achieving complete revascularization for multi-vessel coronary artery disease." Then, please join author G. Michael Felker, and Associate Editor Mark Link as they discuss the Research Letter "Implantable-Cardioverter-Defibrillator Eligibility after Initiation of Sacubitril/valsartan in Chronic Heart Failure: Insights from PROVE-HF." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, 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. Dr. Carolyn Lam: So guess what, Greg, we have another double feature this week. First, we need to talk about completeness of revascularization in patients with three-vessel disease or left main coronary artery disease. Always a question, and this time we've got insights from the SYNTAX Extended Survival Study. And then, the next feature talks about implantable cardioverter defibrillator eligibility after initiation of sacubitril/valsartan in heart failure, and these are insights from PROVE-HF. But before we get to that, I suggest, as I pick up my coffee, could you tell us what some of the papers you've spotted? Dr. Greg Hundley: Thanks so much, Carolyn. Sure. So I'm going to start from the world of preclinical science, and the paper comes to us from Dr. Vadim Fedorov from The Ohio State University Wexner Medical Center. Carolyn, up to 50% of the adult human sinoatrial node is composed of dense connective tissue, and cardiac diseases, including heart failure might further increase fibrosis within the sinoatrial node pacemaker complex, leading to impaired automaticity and conduction of electrical activity to the atrium. However, unlike the role of cardiac fibroblasts in pathological fibrotic remodeling and tissue repair, nothing is known about fibroblasts that maintain the inheritantly fibrotic sinoatrial node environment. Dr. Carolyn Lam: That's true. So what did these authors do? Dr. Greg Hundley: Right, Carolyn. So these authors found that increased sinoatrial node-specific fibrosis, with presence of myofibroblasts and CILP-1, and periostin-positive interstitial fibrosis only in heart failure versus non-heart failure human hearts. And comprehensive proteo-transcriptomic profiles of sinoatrial node fibroblasts identified up-regulation of genes and proteins promoting stiffer sinoatrial node extracellular matrix in heart failure hearts. Dr. Greg Hundley: And next, fibroblast specific profiles generated by the team's proteo-transcriptomic analyses of the human sinoatrial node provided a comprehensive framework for future studies to investigate the role of sinoatrial node-specific fibrosis in cardiac rhythm regulation and arrhythmias. So really very interesting preclinical science, Carolyn. Dr. Carolyn Lam: Yeah. Makes me think of arrhythmias and heart failure very differently, too. Thanks Greg. Well, for my next paper, we know that dietary high salt is bad for us. It's associated with mortality and morbidity. Serum sodium can accumulate at sites of inflammation and affect the function of both innate and adaptive immune cells. But how do changes in extracellular sodium actually affect mononuclear phagocytes? Dr. Greg Hundley: Ah. Carolyn, this is really an interesting question, but how would you even set this up or go about investigating this? Dr. Carolyn Lam: Ah, good question, Greg, and these investigators are really smart. So first, let me tell you about the co-corresponding authors, Dr. Kempa from Berlin Institute of Medical Systems Biology at Max Delbrück Center for Molecular Medicine in the Helmholtz Association, and Dr. Müller from the Experimental and Clinical Research Center in Berlin, Germany. Now, guess what they did? They used sea horse technology, pulsed stable isotope-resolved metabolomics and enzyme activity assays to characterize the central carbon metabolism and mitochondrial function of human and murine mononuclear phagocytes under high salt, in vitro. Dr. Carolyn Lam: And what they found was a disturbance of mitochondrial respiration as the initial step by which high salt mechanistically influenced immune cell function. While these functional changes may help to resolve bacterial infections, a shift towards pro-inflammation could accelerate inflammatory cardiovascular disease. A further potential implication is that mitochondrial functional analysis in monocytes and other immune cells upon a high-salt challenge, could serve as a test for salt sensitivity of immune cells in future. Dr. Greg Hundley: Oh wow, Carolyn. We don't often think about salt sensitivity in immune cells. Really informative research. Well, my next paper comes to us from the world of clinical science, and it's from Professor Derek Chew, from the school of medicine, at Flinders University, the Department of Cardiovascular Medicine at Flinders Medical Center. Dr. Greg Hundley: Carolyn, this paper reports results from a multicenter prospective, patient-level, randomized comparison of care informed by unmasked zero to one-hour, high-sensitivity troponin-T protocol, reported as less than five nanograms per liter versus standard-practice, masked high-sensitivity, cardiac troponin T-testing, reported at a value of less than 29 nanograms per liter, assessed at zero to three hours, and followed participants for 12 months. Participants included were those presenting to metropolitan emergency departments with suspected acute coronary syndromes, without ECG evidence of coronary ischemia. And the primary endpoint was timed to all-cause death or myocardial infarction. Dr. Carolyn Lam: Interesting experiment there. So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So, while the use of the zero to one-hour, high-sensitivity, cardiac troponin T-protocol expedited discharge of patients presenting to the emergency department, with a low-event rate at 30 days, an increase in death or myocardial infarction was observed at one year in those with unmasked, high-sensitivity, cardiac troponin T-concentrations. Next, among those with intermediate cardiac troponin concentrations, where care was informed by zero to one-hour unmasked, high-sensitivity, cardiac troponin T-protocols, increases in revascularization and reductions in noninvasive cardiac investigation were observed. Dr. Greg Hundley: So these changes in practice that result from the use of rapid-discharge protocols, may be potentially associated with an increase in all-cause death or MI, by 12 months among those low-level troponin elevations. So in summary, Carolyn, this research found that unmasked, high-sensitivity, cardiac troponin T-reporting, deployed within a zero to one hour protocol, did not reduce ischemic events over a 12-month followup, and changes in practice associated with the implementation of this protocol may be associated with an increase in death in MI among those with newly-identified troponin elevations. Dr. Carolyn Lam: Wow, that's very, very interesting and clinically important. Thanks, Greg. Well, let's do a little bit of a tour around what else is available in this week's issue, shall we? I want to talk about a Special Report that I was so privileged to contribute to and was led by Dr. Gemma Figtree. And it's a Call to Action for new global approaches to cardiovascular disease drug solutions. There's also a Research Letter by Dr. Solomon on the prognostic value of natriuretic peptides and cardiac troponins in COVID-19. Dr. Greg Hundley: Great, Carolyn. So I'm going to tell you about an exchange of letters between Professors Correia and Chaitman regarding a prior published article, entitled “Myocardial Infarction in the ISCHEMIA Trial: Impact of Different Definitions on Incidence, Prognosis, and Treatment Comparisons.” Also, there's a very nice Case Series from Professor Shapira entitled, “In the Heart of the Ancient Silk Road: Fever of Unknown Origin, Right Ventricular Mass, and Systemic Vasculitis. And then, finally, Dr. de Boer has a very nice On My Mind piece From Studying Heart Disease and Cancer Simultaneously to Reverse Cardio Oncology. Dr. Carolyn Lam: So interesting. Well, let's get onto our double feature, Greg. Dr. Greg Hundley: Absolutely. Well, listeners, we are here for our first feature discussion today and we have with us really, an very interesting panel. First, Dr. Patrick Serruys from National University-Ireland, Galway, Dr. Shamir Mehta from McMaster University in Ontario, and our own associate editor, Dr. Manos Brilakis, from Minneapolis Heart Institute. Welcome gentlemen. Patrick, we're going to start with you. Could you describe for us the hypothesis that you wanted to test. Dr. Patrick Serruys: Yeah. The hypothesis was that if the surgeon and the interventional cardiologist doesn't achieve a complete revascularization, there will be a penalty. The penalty is we look at the all-cause mortality because that's really a unbiased assessment. Dr. Greg Hundley: And then, tell us the design of your study for us. Dr. Patrick Serruys: So SYNTAXES, which is the extension of the SYNTAX study up to 10 years, had 1,800 patient, and then basically, we took a threshold of eight. If you have a residual SYNTAX for more than eight, you have an incomplete revascularization. We stratify for less than four, four to eight, and above eight. And clearly, the group above eight has a bad outcome, not only with PCI, but also with surgery. The score is a little bit more difficult to establish in surgery, because you don't have an angiography immediately after the procedure. Dr. Patrick Serruys: And then as I said, if you do a complete revascularization by PCI, and that's basically a residual SYNTAX score of zero, then you have an outcome which is comparable to the surgical outcome. What is interesting, if you have above eight, you have to think twice and maybe refer that patient to surgery. It's difficult to anticipate, but of course, bifurcation, total chronic occlusion, small vessel, is the three major reason to have a residual SYNTAX score. Dr. Greg Hundley: Very good. So Shamir, could you help us put these results in context with other studies that have been performed in this sphere of research? Dr. Shamir Mehta: Yeah, sure. I would be happy to. So the SYNTAX study was unique in that they were able to look at the degree of revascularization, and the key finding that PCI was comparable to CABG surgery in terms of outcomes, when complete revascularization was able to be achieved, is a very intriguing finding. In cases where PCI was not able to achieve complete revascularization, it was clear superiority of CABG surgery. And so the question is in this study, this comparison, which is a non-randomized comparison, whether or not there's any type of external validity for these findings. Dr. Shamir Mehta: And, in fact there is. It's a timely publication, because recently we had the 4,000-patient multinational COMPLETE trial, which looked at the issue of complete revascularization versus incomplete revascularization in patients with STEMI, and found that complete revascularization with multi-vessel PCI, in appropriately-chosen patients, reduced hard clinical outcomes, including the composite of cardiac mortality and/or current myocardial infarction. And it reduces it quite substantially, by about 26%, and it's a highly-significant benefit. Dr. Shamir Mehta: I think the caveats to this finding are important, though. Because in the COMPLETE trial, patients were not eligible for recruitment, unless the interventional cardiologists felt that all of the lesions were amenable to PCI. So complete revascularization had to be achieved in the trial. And in fact, over 90% of patients in the trial were able to achieve complete revascularization. So that's absolutely key, and that brings up the importance of having a heart team in evaluating these patients. Dr. Shamir Mehta: The second point is that the SYNTAX score, Patrick had referred to was relatively low in the trial, it was only 4.6. Meaning that the lesions that were attempted were relatively straightforward, meaning that there was a high probability of achieving complete revascularization. So again, I think we're starting to see from the randomized trials and from the observational studies, the types of patients that may be suitable for PCI versus suitable for CABG surgery. Dr. Greg Hundley: Very nice. Well, Manos, Shamir, what an outstanding description in helping us put this paper in context with other research in this space. Manos, I know you see a number of papers come across your desk. Also, for you, what attracted you to this particular study? Dr. Emmanouil (Manos) Brilakis: Yeah, thank you, Greg. And again, congratulations to Patrick for a phenomenal study. I think the main strength of this analysis is the clinical relevance. I think everyone is still debating this question, is complete revascularization the goal in every patient? And all of the data, as mentioned already, have several limitations. Nevertheless, they move us a little bit closer to understanding better on whom complete revascularization should be used. Dr. Emmanouil (Manos) Brilakis: So the clinical relevance is one key. I think this paper does set the stage well for a randomized trial. End of the day, we are still not hundred percent sure if COMPLETE is the best for everyone, because COMPLETE counts as a risk, and the risk is going to be higher in those patients who have more complex anatomy. But that study will give us the definitive answer about which is the best way to go for each individual base. Dr. Greg Hundley: Very nice, Manos. So that's a great segue. So I'll turn to both Shamir and Patrick, and ask them also, as well, what do you think is the next study to be performed in this particular space? Shamir, you first and then we'll finish with Patrick. Dr. Shamir Mehta: Well, I think the concept of complete revascularization has now essentially been proven in multiple trials. And don't forget, if you go back several decades, really the first proof was in the context of CABG surgery. So really, this should be the goal in patients with multi-vessel disease. The next large randomized trial that is going to be starting very soon is the COMPLETE 2 trial where we are actually looking at the lesions physiologically to see whether or not we need to revascularize lesions that are physiologically significant versus anatomically severe. Dr. Shamir Mehta: This is an important question because what it does is it has the potential to reduce the number of lesions that we perform PCI in, by about 50%. We are also looking at plaque composition in that trial with optical coherence tomography. A very, very large number of patients will be receiving that. So that will be trying to target PCI to the actual pathophysiology of the disease, by targeting unstable plaques to perform PCI on. I think this is the whole next era of coronary intervention, where we are now beginning to target our therapies to the actual pathophysiology of the disease, which is a very, very exciting idea. Dr. Greg Hundley: And Patrick, do you have anything to add? Dr. Patrick Serruys: Yeah. I think, that obviously, you have to convert the anatomical SYNTAX Score in a functional SYNTAX Score. You could do that with the pressure wire and hyperemia of diastolic resting gradient. You can also do that by QFR or FFR CT. So we are going in that direction since a few years. The second point is that we have been working on machine learning that, at some point, the segmentation of the coronary segment, the assessment of the narrowing is done. And then, the next step that we are doing right now to is to convert that to the multi-slice CT scan. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Patrick Serruys, from National University-Ireland, Galway, Dr. Shamir Mehta from McMaster university in Ontario, and our own associate editor, Dr. Manos Brilakis, from Minneapolis Heart Institute, really bringing to us this paper that, in patients with complex coronary artery disease, incomplete revascularization can be common after PCI. And the degree of incompleteness can be associated with 10-year mortality. And therefore, if it's unlikely that complete or nearly complete revascularization can be achieved with PCI in patient with three-vessel disease, maybe we should be considering coronary artery bypass grafting. Dr. Greg Hundley: Well, again, let's get on now to that second feature discussion. Well, listeners, we are now here for our second feature discussion today, and we have with us Dr. Michael Felker from Duke University, and our own associate editor, Dr. Mark Link, from UT Southwestern. Welcome, gentlemen. And Mike, we'll start with you. Tell us a little bit about the background pertaining to your study and what hypothesis did you want to address? Dr. G. Michael Felker: Great. Thanks, Greg. So I think everybody's very familiar with the concept of favorable ventricular remodeling in patients with heart failure, that we know is something that happens when we treat our patients with guideline-directed medical therapy, like beta blockers, ACE inhibitors, MRAs. Interestingly, with the introduction of sacubitril/valsartan and the landmark PARADIGM trial, we had a drug where we had clearly a major outcome benefit, but we actually had very little understanding about whether that was mediated by remodeling. Dr. G. Michael Felker: And those questions led us to design the PROVE trial, which was a single-arm trial of 794 patients, looking at whether or not patients with heart failure and reduced ejection fraction who met the FDA label for sacubitril/valsartan, the initiation of that therapy will be associated with favorable changes in ventricular structure and function, as well as favorable changes in natriuretic peptide. The current paper's really trying to put those results in a clinical context around some of the things that we make clinical decisions about, in taking care of heart failure patients in this case, whether and when patients qualify for a primary prevention ICD. Dr. Greg Hundley: Fantastic, Mike. And so you've told us a little bit about the study design, and did you have exactly the same number of patients, or what was the study population for this sort of substudy, if you will? Dr. G. Michael Felker: Yeah. So in PROVE, we enrolled people who had chronic heart failure in the EF, less than 40%, because that's the FDA label for sacubitril/valsartan. In this analysis, because we were interested in patients who qualified for ICD therapy, we limited our analysis to those who an EF plus or equal to 35%. Because, as you all know, the guideline for primary prevention ICD is people who have a EF less or equal to 35% after at least three months of optimized heart failure therapy. Dr. G. Michael Felker: And so, one of our questions was in some patients start on sacubitril/valsartan, what happens to their ventricle and how many patients might favorably remodel? This is, obviously, a question that comes up a lot clinically as more and more we're switching people from ACE inhibitors, or ARBs, to sacubitril/valsartan in line with the recommendation that's 1A from the AHA guidelines. Dr. Greg Hundley: Fantastic. ell, we're all listeners waiting to hear your results, Mike. This is very exciting. So what did you find? Dr. G. Michael Felker: I think our results were quite interesting. I mean, for one thing, the patients that were enrolled PROVE were incredibly well-treated at baseline, and they had had heart failure for quite some time, and a average median time of over six years. So this is not patients who are just recently diagnosed. A lot of these are people that you might think, clinically, we're unlikely to go on and have much favorable ventricular modeling, but that's not what we found. We actually found that after the initiation of sacubitril/valsartan, after six months, on average, we had a five point increase in injection faction. Dr. G. Michael Felker: And by 12 months, on average, that was almost 10 points. So quite a bit of favorable remodeling, even in these patients you might think were less likely to do that. And we put that in the context of ICD decision-making. By six months, 32% of the patients who would initially have been eligible based on the guidelines for primary prevention ICD, no longer met those criteria because their EF had risen to greater than 35, and by 12 months, it was up to 62% of those patients. So as we're thinking about decision-making around ICDs, I think these data have some pretty obvious direct clinical relevance to decisions we now make in the care of our patients. Dr. Greg Hundley: Really interesting. So Mark, I know you get several papers coming across your desk, and as associate editor, boy, I think I can see why this paper was attractive to you. Tell us a little bit, how do we put these results from this study into the context of how we decide whether a patient should receive an ICD? Dr. Mark Link: Yeah. The current guidelines are to wait three months after guideline-directed medical therapy, and then repeat the ECHO and see if they still qualify. I think what this study shows us is that patients can continue to improve after three months, and that improvement is somewhat continuous, actually. Because at six months, the improvement in EF was five percent, and at 12 months, it was 10%. So I think that's what this shows, the context is, if you have a patient who has a low EF and they are improving, but still haven't quite made it to 35, let's say when they went from 25 to 30 in three months, I'd probably hold off and wait another three months and repeat the ECHO again. Dr. Greg Hundley: Excellent. Well, Mike, Mark, I'm going to ask you question. And we'll start with you Mike, and then go to Mark. What study would you perform next in this space? Mike, you first. Dr. G. Michael Felker: So, I think it's important to recognize some of the limitations of any study you do, including this one. So this was not a randomized trial. PROVE was a single-arm trial, there wasn't a control group. And the question about the ICD per se was not pre-specified. It was really a post-hoc analysis. So as is often the case, I think these are intriguing and highly-suggestive results, but I think there's clearly an opportunity to confirm them in perspective studies designed to answer this specific question. Dr. G. Michael Felker: So you could imagine a trial where patients who are starting on sacubitril/valsartan who don't have ICDs, get randomized to waiting three months or waiting six months, or 12 months or whatever the interval would be. So I think these are intriguing, and that there definitely opportunities to develop confirmatory results. Dr. Greg Hundley: Excellent. Mark, do you have anything to add to that? Dr. Mark Link: I think the big thing we would really like to know are predictors, predictors of response and predictors of non-response. And that would take a larger trial perspective, and that would be very, very valuable. Because if you could have a predictor of a non-responder, they would get an ICD earlier, and predictors of responders, you might wait a while. Dr. Greg Hundley: Very nice. Well, listeners, we get rate studies here in circulation, and you'll find this one as a research letter, highlighting that in the substudy of the PROVE heart failure study, that in patients with an EF less than or equal to 35%, the introduction of sacubitril/valsartan improved EF to greater than 35%, at 62% of subjects at 12 months. Really an interesting finding, and perhaps further randomized clinical trials as suggested by both Mike and Mark here, are maybe warranted in the future. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to A, thank Dr. Mike Felker and also our associate editor, Mark Link, and wish you, as listeners, a great week, and we will catch you next week On the Run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

Shout out to Greg Lewis (@glewisecom_) for suggesting…and requesting and requesting and requesting…the 7.62x25 as one of our 10-Minute Talks. This bottlenecked pistol cartridge is flat-out cool-as-heck. Tune in to hear Ryan Muckenhirn enlighten us on this unique, ahead-of-its-time, blast from the past!...Thanks Greg!

[As heard on WGAN 2021-06-02-wgan. The following is an automated transcript.] Craig Peterson: [00:00:00] Good morning, everybody. Craig Peterson here. Thanks for joining me this morning. I was talking more about this Commonwealth of independent states. In case you're not aware of it, these are the countries that were part of the Soviet Union. Now not all of them are in it, but the majority of them are. And why are the hackers going out of their way to avoid hacking? [00:00:25] It might be a red herring, frankly, but it also might be because there could be some severe penalties for them and how you can use that in order to help save you from getting hacked. So all of that here this morning, as well as a little bit more about the meatpacking plant that had to close down here throughout. [00:00:49] North America. So here we go with Mr. Matt, Gagnan [00:00:54] Matt Gagnon: [00:00:54] 7:36 on WGAN morning news. A good time to talk to Craig Peterson, our tech guru, who joins us at this time every Wednesday. Of course, you also hear him on Saturdays at one. When he talks about all these topics and more in more depth, Craig, how are you this morning? [00:01:12] Craig Peterson: [00:01:12] Oh, WGAN is always a good time. Not just when I'm on, I'd do a little something extra, [00:01:17] Matt Gagnon: [00:01:17] a little something extra. Thanks so much for joining us here. Of course, for that little something extra right now, Craig Peterson, I do have to ask you first about. Meat hacking. I've been plugging it all morning here. [00:01:30] Obviously, we had the oil pipeline hack. Now we have beef plants forced to shut down because of a cyber attack here. So these cyber attacks are happening with increased frequency. And are a problem. Tell me, sir, what's happening here and what it means for us? [00:01:45]Craig Peterson: [00:01:45] We have a whole crew of people internationally. [00:01:49] Some are in Russia, some are in China. Of course, we've talked about North Korea and others before who are trying to make money. And the way they can make money is by going after targets that are particularly rich that have the money to pay the ransom. And that's why they're going after these guys. It's like Sutton. Why did he Rob banks, supposedly? Because that's where the money was. And in this case, that's really what they're doing, Matt. [00:02:20] Matt Gagnon: [00:02:20] It certainly is where the money is, and they're happening with, it seems like greater frequency or at the very least greater visibility because they're going after big stuff here. [00:02:28]Do you expect this to continue? I know that there's been some talk hereafter the pipeline attack that we're going to reinforce our infrastructure and make sure things like this don't happen again. Any truth to that. [00:02:37]Craig Peterson: [00:02:37] Yeah, there is there, there's a number of things that are going on right now to try and tighten things up. [00:02:43] But I've got to say this JBS, which is the company that was attacked here, this meatpacking company, that basically a quarter of all of our beef and a fifth of all of our poultry is packed to there. They responded pretty darn well. They didn't, obviously, keep the hackers out, but nothing is a hundred percent. [00:03:05] They immediately did something thing that solar winds took a not soldier cringe, but were a colonial pipeline, took a little bit longer to do. And that is, they shutting me down very quickly. Yeah. They started to look, see what was going on. They immediately brought in a team of people. This is what they do. [00:03:25] They help bring companies back from a ransomware attack. They brought in a lot of people, so they could start restoring all of the systems. It looks like from backups and then starts turning things back on one at a time. I imagine they'll tighten up some of their security operations, which we. All need to do, which goes right into your question of are we going to do more? [00:03:49] Is there more we can do? And the answer to that is absolute. Yes. Every one of us, that most of the time the bad guys are using what is called zero-day attacks initially, which means there is a vulnerability in something very often in Microsoft windows or in a firewall. And the bad guys know about it, but it hasn't been patched yet. [00:04:15] But I got to tell ya that is only really used against these very big operators where there's a whole lot of money involved. Most of the time, we're getting hacked. Because we haven't patched. Now I know how painful it could be the patch. Okay. Especially when we're talking about Microsoft, you can apply their patches and then brick to your machine. [00:04:38] In other words, turn your machine into something that's almost useless, and it's going to take you days to recover. So people are weighing that back and forth. Is it worth, potentially knocking myself off the air for a day or two or three? Because the patch was bad from Microsoft or from another vendor, or should I do the patch and take the risk of it not working very well or may be causing harm and then going further, I blame Microsoft budget. [00:05:09] You blame [00:05:09] Matt Gagnon: [00:05:09] Microsoft for a lot of things. [00:05:11] Craig Peterson: [00:05:11] Greg terrible company. They really are. They're the things they've done to the industry, but the reason I'm blaming Microsoft here is, are you kidding me? They're sitting on billions of dollars in cash, and they released patches for their buggy software. Okay. I get that. [00:05:27] Everybody releases patches, and the patches break systems. So people don't trust it anymore. So that's how I'm looking at it. Here. I read an article this morning from the New York times, and they were looking at this hack from a again, probably, maybe Russia, maybe China. And they're quoting, they're saying. [00:05:50] President Biden says it's from Russia reading between the lines. Microsoft said their hack, which was the major part of the whole SolarWind attack was actually from China and the Biden administration went quiet on this, but it's hard to say we know Russia has been hacking a lot. We know China's been hacking a lot of little China's more behind the scenes. [00:06:12] We don't really know where they come from, but Matt, we can do something about it. Keep your software up to date. If you can, don't use windows and switch over to a Mac, their patches work, and they have for years and be more security conscious. So [00:06:30] Matt Gagnon: [00:06:30] speaking of Russian hackers, Craig, I do have to ask you whether or not there is something we can do a one weird trick, if you will. [00:06:37] One of those eternal click baity items area, right? If there is one weird trick to stop these Russian hackers right there, out there, how do you do it? [00:06:46] Craig Peterson: [00:06:46] This is the coolest thing ever. It's absolutely true. This comes from Brian Krebs and a few other people out there right now. There is something you can do right now. [00:06:56] It only take you 10 minutes, maybe 15, and we're here. Here's what it is. We know that the Russian hackers are not. Attacking former Soviet territories. And the reason from that it, for that is if they are hacking from Russian territory and they hack a Russian company or another one of these companies that are part of the Commonwealth of independent state, which is again the former Soviet union for the most part if they hack a Russian company, they, and they get caught, they get to go to a Russian prison, which doesn't sound like much fun to me. [00:07:35] And so what they've done is they've built into almost all of this soft, where a kill switch. We're talking about ransomware software, hacker software. If you install a virtual. Russian keyboard on your computer, just like a, you may have a Spanish keyboard or a French keyboard on your computer, install, a Russian or one of a few other languages keyboard on your computer. [00:08:01] You don't have to use it. You don't have to type in rush and you don't have to learn Cyrillic. None of that when the software starts to run in your computer, almost all of it. The first thing it does is says, is there a Russian keyboard? And if the answer's yes, it's short circuits at shelf, and this is what we're thinking. [00:08:21] And I think this is right. This is the way the Russian hackers are avoiding attacking Russian or Russian Commonwealth states is Commonwealth of independent states. It's a way they're stopping the inadvertent hack of a nation of a company that might end them up in Siberia because they still do have some fun stuff going on up there. [00:08:43]Matt Gagnon: [00:08:43] Greg Peterson, our tech guru joins us at this time every week to go over the world of technology. Thanks Greg, as always good luck on Saturday. And we'll talk to you next week, sir. Hey, you're [00:08:52] Craig Peterson: [00:08:52] welcome. And I'm going to put instructions on how to do this in this week's newsletter. So make sure you're signed up@craigpeterson.com and we'll talk a little bit more about it as well on Saturday.

In this week’s podcast, articles “The Cardiac Late Sodium Channel Current is a Molecular Target for the Sodium-Glucose Co-Transporter 2 Inhibitor Empagliflozin” by Light et al (www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.053350) and “Metabolic effects of empagliflozin in heart failure: A randomized, double-blind, and placebo-controlled trial (Empire HF Metabolic) by Jensen et al (www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.053463) are discussed. Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts, 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, Dr. Carolyn Lam: Greg, it's double feature day. And guess what? Both papers that we're going to talk about are regarding the SGLT2 inhibitors, and really look at the mechanism of action of these amazing compounds, from both a pre-clinical and clinic point of view. That's all I want to say, because we've got to tune in, a very interesting discussion coming right up. Dr. Carolyn Lam: But first I'd like to ask you a question. What do you think is the association between health-related quality of life and mortality in heart failure around the world? Dr. Greg Hundley: Well, Carolyn, I would think that, actually, they might be linked. Dr. Carolyn Lam: That's a really clever answer. Thanks Greg. Well, the authors are actually going to tell you with this next paper. It's from Dr. Salim Yusuf from Population Health Research Institute and McMaster University in Hamilton, Canada, and colleagues, who looked at the global congestive heart failure, or GCHF study, which is the largest study that has systematically examined health-related quality of life, measured by the Kansas City Cardiomyopathy Questionnaire, which is the largest study that has systematically examined health-related quality of life and its association with outcomes in heart failure, across eight major geographic regions, spanning five continents. Dr. Greg Hundley: Wow, Carolyn. So what did they find here? Dr. Carolyn Lam: Health-related quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire, or KCCQ, really differs considerably between geographic regions, with markedly lower quality of life related to heart failure in Africa compared to elsewhere. Health-related quality of life was also a strong predictor of death and heart failure hospitalization in all regions, irrespective of symptoms class, and with both preserved and reduced ejection fraction. Dr. Carolyn Lam: Indeed, this paper really highlighted a great need to address disparities that impact health-related quality of life in patients with heart failure in different regions of the world. Dr. Greg Hundley: Fantastic, Carolyn. Well, I have two studies to discuss, Carolyn, and they're kind of similar, so we're going to do them back to back. The first study reports the results of the Sort Out X Trial, a large scale randomized multi-center, single-blind, two-arm, non-inferiority trial, with registry based follow-up designed to evaluate the Dual Therapy Sirolimus-Eluting, and CD34 positive antibody coated combo stent or DTS versus the Sirolimus-Eluting Orsiro Stent or SES. Dr. Greg Hundley: And the study comes to us from Dr. Lars Jakobson, from Arhus University Hospital. The primary endpoint target lesion failure, or TLF was a composite of cardiac death, myocardial infarction, or target lesion revascularization within 12 months, all analyzed using intention to treat. Dr. Carolyn Lam: All right, Greg. So the DTS compared to the SES, what did they find? Dr. Greg Hundley: Thanks, Carolyn. So the DTS did not confirm non-inferiority to the SES stent for target lesion failure at 12 months. The SES was superior to the DTS, mainly because the DTS was associated with an increased risk of target lesion revascularization. However, rates of death, cardiac death, and myocardial infarction at 12 months did not differ significantly between the two stent groups. Dr. Greg Hundley: Now Carolyn, in this same issue, we have another study evaluating endothelial function and implantation of intercoronary stents. And this second study comes to us from Professor Alexandra Lansky, from the Yale University School of Medicine and Yale Cardiovascular Research Group. And Carolyn, the study evaluated whether implantation of an intercoronary stent that facilitated endothelialization after the four to six weeks smooth muscle anti-proliferative effects post-stent implantation would be non-inferior to traditional drug-eluting stents. Dr. Carolyn Lam: Okay, another interesting study. And so, how did they do that? What did they find? Dr. Greg Hundley: Yeah, so Carolyn, a total of 1,629 patients were randomly assigned in a two to one fashion to the supreme DES stent, so 1,086 patients, or the DPDES stent, which was 543 patients. And there were no significant differences in rates of device success, clinically driven, target lesion revascularization, or stent thrombosis at 12 months. Dr. Greg Hundley: And the safety composite of cardiovascular death and target vessel revascularization or myocardial infarction was 3.5 versus 4.6% with the supreme DES stent compared to the DPDES stent. But target revascularization for this new stent was two and a half fold higher. Dr. Greg Hundley: So Carolyn looking at these two papers, what have we learned? So first, the Jakobsen, et al, tested whether the stainless steel COMBO Sirolimus-Eluting Stent coated luminally with CD34 positive antibody could theoretically capture endothelial progenitor cells and regrow endothelium. Dr. Greg Hundley: And the investigators observed that this stent had higher, not lower or equivalent, target lesion revascularization relative to the current generation Cobalt-Chrome Stent that only eluted sirolimus. Dr. Greg Hundley: In the second study, Lansky and associates examined an approach which was touted as enhancing endothelial recovery, where the early erosion of material and release of drug was thought to allow earlier endothelial recovery enhancing vascular response. Non-inferiority of the rapid release was demonstrated, but rather than hints of superiority, there were signs of inferiority. Hereto, target lesion revascularization was problematic and was two and a half fold higher. Dr. Greg Hundley: And so, Carolyn, there's a wonderful editorial from Professor Elazer Edelman from the Massachusetts Institute of Technology entitled, “Karnovsky's Dictum that Endothelium is Good Looking and Smart,” where Dr. Edelman emphasizes that while some endothelial cells may have been present after deployment of these devices, perhaps a fully constituted functioning endothelium may not have been achieved. Dr. Greg Hundley: And as we know, it is a fully functioning endothelium with nitric oxide release, buried platelet adhesion that is most protective. It is a really provocative read that reflects on previous thoughts from Morris Karnovsky, who suggests preservation of endothelial function is optimized by minimizing injury to it. And so, Carolyn, these combined articles really highlight the current state of new developments within interventional cardiology to thwart re-stenosis and highly recommend them to our readers. Dr. Carolyn Lam: Wow, thank you, Greg. That was amazing. But you know what, so's this next paper, because it really provides novel insights into that enigma of the role that the epicardium plays in the pathogenesis of arrhythmogenic cardiomyopathy. Dr. Carolyn Lam: Now, to delineate the contributions of the epicardium to the pathogenesis of arrhythmogenic cardiomyopathy, doctors Marian from University of Texas Health Science Center at Houston, Texas and colleagues performed a series of elegant mouse experiments using conditional deletion of the gene encoding desmoplakin in the epicardial cells of mice. Mutations in genes and coding desmosome proteins, including desmoplakin are known to be major causes of arrhythmogenic cardiomyopathy. Dr. Greg Hundley: Wow, Carolyn, very interesting. So what did they find here? Dr. Carolyn Lam: Epicardial derived cardiac fibroblasts and epithelial cells expressed paracrine factors, including TGF-β1 and fibroblasts growth factors, which mediated epithelial mesenchymal transition and contributed to the pathogenesis of myocardial fibrosis, apoptosis, arrhythmias, and cardiac dysfunction in a mouse model of arrhythmogenic cardiomyopathy. These findings really uncover contributions of the epicardial derived cells to the pathogenesis of arrhythmogenic cardiomyopathy. Dr. Carolyn Lam: Greg, there's a whole lot of other interesting stuff in today's series, as well. There's an exchange of letters among doctors Mehmood, doctors Moayedi and Dr. Birks regarding the article “Prospective Multicenter Study of Myocardial Recovery Using Left Ventricular Assist Device.” There's an ECG challenge by Dr. Ezekowitz on a silent arrhythmia. How would you treat this patient? Go quiz yourself. Dr. Carolyn Lam: There is an AHA Update by Dr. Churchwell on how federal policy changes can advance the AHAs mission to achieve health equity. And finally, a Perspective by Dr. Talbert on rheumatic fever and the American Heart Association, The Nearly 100 hundred-Year War. Well, that wraps it up for the summaries. Let's go to the double feature, shall we? Dr. Greg Hundley: You bet. Dr. Carolyn Lam: Wow, today's feature discussion is really all about SGLT2 inhibitors, and that question that we're still asking, how do they work? And today, we are discussing two papers, very interestingly, looking at it from different aspects, one from a preclinical lens, finding a very novel target for SGLT2 inhibitors, and the other from a clinical lens, and really looking at the metabolic effects of the SGLT2 inhibitors in a way you've not seen before. Dr. Carolyn Lam: I'm very pleased to have with us the authors of these very exciting papers. We have Dr. Jesper Jensen from Herlev and Gentofte University Hospital in Denmark. We have Dr. Peter Light from University of Alberta, in Canada, and we have our associate editors, Dr. Thomas Eschenhagen from University Medical Center, Hamburg, and Dr. Justin Ezekowitz from University Alberta. Dr. Carolyn Lam: So, welcome gentlemen, thank you so much for joining us today. I suggest, let's start from the mice before we go to the men, and Peter, if you don't mind by starting us in, please tell us about this novel target you found, why you looked at it, how you found it, what it means. Dr. Peter Light: Hi, Carolyn, yeah, happy to discuss that. So, we all know that through numerous clinical trials, there's a very unexpected and exciting cardioprotective effect against heart failure with the SGLT2 inhibitors. And we decided to investigate some of the molecular mechanisms, which may underlie that protection. And in looking at the literature previously, and from my own lab's work, we're very interested in control of electrical excitability and ionic homeostasis in cells. Dr. Peter Light: So we investigated a known target or a known iron channel, which is involved in the etiology of heart failure as well as cardiac arrhythmias. And that would be the cardiac sodium channel. So, we investigated the effects specifically on a component of the cardiac sodium channel called the late sodium current, which is only induced in disease states, and they could be that during heart failure or ischemia, or can actually be in congenital conditions such as Long QT Syndrome Three, which involves certain mutations in this sodium channel. Dr. Peter Light: So we basically investigate the effects of empagliflozin, dapagliflozin and canagliflozin, in several different models of a sodium channel dysfunction, including mice with heart failure. And really what we've found is that this class of drug, and this is a class effect, it's not specific to just one of these SGLT2 inhibitors, what we found, they are very good inhibitors of this late current of the sodium channel. And in fact, they don't even affect the peak current at all. Dr. Peter Light: And when we did this and we analyzed the data, we found the IC 50s were in the low micromolar or even sub micromolar range for these drugs, which is exciting. And we extended those studies into cardiac myocytes and looked at calcium handling in those cardiac myocytes and saw that we get a very nice reduction in abnormal calcium handling in cardiac myocytes. Dr. Peter Light: We also used in silico molecular docking of these drugs to the cryo-EM structure of the NaV1.5, which is the cardiac sodium channel and identified that these drugs bind to a known region of that channel, which also binds the local anesthetics or anti-arrhythmic drug, Lidocaine, as well as the anti-anginal drug, Ranolazine. Dr. Peter Light: And finally, we showed that these drugs also reduce inflammation through the NLRP3 inflammasome in an isolated beating heart model. So collectively, we provide evidence that the late component of the sodium channel is a really important, or maybe a really important target for the molecular actions of this drug, and may underlie those observations received from the clinical trials relating both to heart failure, as well as sudden cardiac death. Dr. Carolyn Lam: Thomas, could you put this in context for us? Dr. Thomas Eschenhagen: Thanks, Carolyn. I mean, we immediately liked the story because as you said, and Peter as well, these drugs have amazing effects and every clinical paper and indeed some new ones, but it's really unclear how they do that. And what is, besides the established target, the SGL2 in the kidney, what could be the reason for all of this or some of this?   Dr. Thomas Eschenhagen: And then, of course, other examples proposed, like the sodium hydrogen exchanger, but this story didn't go so far. So we saw now this data from Peter showing that, and this is, of course, for a pharmacologist, just like me, very important, it's very potent binding. It's not a binding which happens in a millimolar or high micromolar, but as Peter said in low micromolar range. So that makes it a very realistic effect, for example, much more potent than ranolazine. Dr. Thomas Eschenhagen: And, of course, now the question is, to which extent could this, now I would say, establish the effect on the late sodium current, explain some of the findings which came out of the clinical studies, and actually, a question I would have to Peter, now that I think most of you know, the late sodium current is a reason for the increased sodium for LQT3 syndrome, very rare. Dr. Thomas Eschenhagen: But, of course it would be tempting to say, okay, maybe that would be a very good drug, particularly for people with LQT3. Did you think about that, Peter? Is it something on your list, mexiletine has been tried. Dr. Peter Light: Yeah, so I think that it's a certainly intriguing possibility. In fact, in our study, we did test out several different Long QT3 mutations and saw a reduction in the late component as also sodium channel. It's tempting to speculate that, indeed, these could actually be a rather effective anti-arrhythmic drug in patients with these LQT3 mutations or specific ones. I would love to be able to test that in at least some of the genetic mouse models of Long QT3 and to see whether this concept holds water or not. Dr. Carolyn Lam: Wow, this is incredible. SGLT2 inhibitors from anti-diabetic to now anti failure, and now anti-arrhythmic drugs? That's just amazing. Thank you, Peter. We should move on to this next paper, and this one all the way on the other spectrum, a clinical paper called Empire Heart Failure, Empire Heart Failure Metabolic, actually. Jesper, could you tell us about your trial and what you found? Dr. Jesper Jensen: Sure, thanks for the invitation to take part in the podcast, first of all. I'll tell you a little bit, we designed this study to try to get behind mechanisms, so the clinical benefits of the SGLT2 inhibitors in order to try to make a clinical outcome trial. But as you know, the DAPA-HF and the EMPEROR-Reduced were competed very fast, demonstrating the clinical benefits in HFrEF patients. Dr. Jesper Jensen: So, the data of our study provides some detailed mechanistic insights to these findings. And from the literature, we know that SGLT2 inhibitors improve glucose metabolism in patients with diabetes, and these changes might not be surprising in the diabetes population, but moreover, alterations in glucose metabolism may not be the main mechanism for the early occurring clinical benefits. Dr. Jesper Jensen: However, we know that many of our heart failure patients without diabetes are insulin resistant as a metabolic feature of the heart failure, and the insulin resistance is associated with an increased risk of developing future diabetes, which in turn reduces the long-term survival and quality of life. So, the targeting insulin resistance in HFrEF patients is, therefore, of clinical relevance to our patients. Dr. Jesper Jensen: So, the population of the Empire HF Metabolic consisted of patients with chronic HFrEF, with or without type two diabetes, who are on a stable guideline directed heart failure therapy, and have also indicated on anti-diabetic therapy. And we randomized patients to receive empagliflozin 10 milligrams once daily, or matching placebo as an-add on for 12 weeks. Dr. Jesper Jensen: And this was a modest sized randomized control trial, including 120 patients. A very large proportion of patients received guideline directed heart failure therapy, and they generally consisted of the best one third of atypical HFrEF population, and only 10% had concomitant history of type two diabetes. Dr. Jesper Jensen: We then, at baseline and after 12 weeks, we formed an oral glucose tolerance test to assess the hepatic and a peripheral insulin sensitivity and performed a whole body DXA scan to investigate alterations in body composition. We know that patients lose weight when they get an SGLT2 inhibitor with and without diabetes, but we don't know what it consists of in a HFrEF population. Dr. Carolyn Lam: Tell us what you found after 12 weeks. Dr. Jesper Jensen: Yeah, so a large proportion, actually half of the patients without a history of diabetes, had a new onset diabetes, or impact glucose tolerance at baseline. So even though few have no diabetes, this population were at very high risk of developing future diabetes. And the main finding was that empagliflozin improved insulin sensitivity. So the hepatic insulin sensitivity was improved by 13% and the peripheral insulin resistance was improved by 20% compared to placebo. Dr. Jesper Jensen: And moreover, both fasting and postprandial glucose were significantly reduced. And regarding the body composition, patients in a mean lost at 1.2 kilos, or 2.6 pounds, which mainly consisted of a loss in lean mass and no significant changes were observed in fatness, and this is from the DXA scan. Dr. Carolyn Lam: Hmm. Justin, could you shed some light on what the editors thought about this, and there's lots of questions still, huh? Dr. Justin Ezekowitz: Yeah, absolutely, Carolyn, and thanks Jesper for sharing this paper with Circulation. Thanks for summarizing it so well. I think the questions that come up and the reason why we liked it so much was we're all trying to understand mechanism of how these medications work so profoundly for our patients. Dr. Justin Ezekowitz: Now, in this predominantly non-diabetic population, the fact that the liver and the peripheral insulin sensitivity improves, how does that bear out for the fact that there is no fat loss in the early stages, yet that's all been linked to later improved exercise capacity and increased fat loss later on in life. Dr. Justin Ezekowitz: So, do you think those two are going to be linked if you went to say from 12 weeks beyond the 52 or two years down the road? Dr. Jesper Jensen: Yes, that is what we've seen from diabetes populations, at least. So you could imagine that the same would be the case also in the HFrEF primarily non-diabetic population, but again, we don't know. But early loss is the mass loss. Dr. Justin Ezekowitz: So Jesper, when you think about the peripheral insulin sensitivity improvement, is that largely indicating mostly muscle based insulin sensitivity improvement, and that would indicate that the muscles, perhaps, are functioning better in the short term with just a simple change in therapy. Dr. Jesper Jensen: Yeah, that could be a way to put it. I would agree upon that. Dr. Justin Ezekowitz: So thanks, Jesper, I think that may indicate the quality of life improvement that we may be seeing in the functional status there, Carolyn. Dr. Carolyn Lam: Yeah, but as you said, Justin, there just seems so many other questions. To Jesper, I want to know, what further might you want to do to find out what's happening with this? The loss of lean mass surprised me, frankly. I thought it would have been fat mass. So, what are you doing to look at that? And then to Peter, I want to go the other direction. What are you planning next that might bring this closer to humans and a clinical study? So maybe I'll ask Jesper to go first. Dr. Jesper Jensen: So, I definitely agree with you, Carolyn. We would also have to put our money on the fat from the beginning, before the study. So with respect to the weight loss, then a loss in lean mass is not preferable if it represents muscle. So however, the weight loss works to mediate the observed change in insulin resistance. And additionally, a significant loss in muscle would result in reduced insulin sensitivity. And we observed the opposite. Therefore, the observed loss in lean mass may be speculated to represent water and pointing towards the early diuretic effect SGLT2 inhibitors. So, the DXA scan is good at looking at body composition, but it has difficulties in separating lean mass from whether it's muscle or water, but combined with the findings on the insulin resistance, we speculate that the lean mass loss is more. Dr. Carolyn Lam: Thank you. And Peter, could you very quickly tell us what are next steps, in your view? Dr. Peter Light: Yeah, obviously we were studying mouse model of heart failure. We'd like to make a more of a translational step in the next experiments we do by studying human tissues. So getting access to ventricular tissue from ex-planted hearts, human hearts, too, and then measure electrical activity as well as some calcium imaging. Dr. Peter Light: Looking at some of these Long QT3 animal models would be another thing that we're going to do. And also start looking at to see whether we can get access to any electrophysiological data from electronic medical records to start looking for DCGs and measuring QT interval, for example, would be another nice step to that. Dr. Peter Light: And then, more of a drug development side of things, we are actively synthesizing new derivatives of these drugs and seeing whether we can enhance the cardio-protective effects on the late sodium current, but actually remove the ability to inhibit SGLT2. So we would no longer have a glucose-lowering drug, but we'd have a cardioprotective drug. So, it's all very exciting work going on right now. Dr. Carolyn Lam: You've been listening to Circulation on the Run. From Greg and I, don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

This week, please join author Uwe Tietge and Associate Editor Anand Rohatgi as they discuss the article "High-Density Lipoprotein Anti-Inflammatory Capacity and Incident Cardiovascular Events" (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.050808) Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. We're your co-hosts, 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, we've got a very interesting feature this week. It involves another paper in the line of the story of HDL, and looking at HDL and future cardiovascular events. But before we get to that, how about we grab a cup of coffee and jump in and review the other articles and the issue? And Carolyn, this week, maybe I'll go first. Dr. Carolyn Lam: Go, I've got my coffee. Dr. Greg Hundley: Very good. So Carolyn, this paper comes to us from Dr. Huso Hakala, from the University of Turku at Turku University Hospital, and the study pertains to cognition and cardiovascular disease. So Carolyn, as you know, cardiovascular risk factors such as high blood pressure, adverse serum lipids, and elevated body mass index, and midlife may harm cognitive performance. So importantly, perhaps the presence of cardiovascular risk factors since childhood, Carolyn, may impact cognition later in life. So these authors studied the associations of the cardiovascular risk factors from childhood to midlife, their accumulation and midlife cognitive performance. They gathered their data beginning in 1980 from a population-based cohort of 3,596 children who are aged three to 18 years that were repeatedly followed up for 31 years, and they assess blood pressure, serum lipids, body mass index, all in the follow-ups. Dr. Carolyn Lam: Wow. So accumulating risk, I suppose, Greg. So what did they find? Dr. Greg Hundley: Great. Carolyn, glad you asked. So consistently high systolic blood pressure or serum total cholesterol associated with worse midlife episodic memory and associated learning, compared to situations when blood pressure or cholesterol values were low. Obesity since childhood associated with worse visual processing and sustained attention compared to individuals or children that had normal weight. And an inverse trend association was observed for the cardiovascular risk factor accumulation with episodic memory and associated learning with visual processing and sustained attention and with reaction and movement time. So the take home Carolyn, is that, maybe we should be launching preventative strategies against some of these cardiovascular risk factors beginning in childhood, because perhaps they could benefit primordial promotion of cognitive health for those later in adulthood, maybe like you and me. Dr. Carolyn Lam: Oh, wow. Thinking back on my blood pressure, cholesterol and weight, I suppose, since childhood, yikes. Well, the next paper Greg is an important analysis from DAPA-HF. Now as a reminder in the DAPA-HF trial, the sodium glucose co-transporter two inhibitor dapagliflozin was shown to reduce the risk of cardiovascular death and a first episode of worsening heart failure, in patients with heart failure with reduced ejection fraction or HFpEF. In the current paper from Drs. Jhund and colleagues from University of Glasgow, they described the efficacy of dapagliflozin on the predefined secondary end point of total heart failure hospitalizations. That's the first and recurrent heart failure hospitalization and cardiovascular death. And this is so important because we know that patients with HFrEF are known to experience multiple episodes of heart failure during the course of the disease. Dr. Greg Hundley: So Carolyn, what did they find? Dr. Carolyn Lam: Well, they did this analysis by two methods in the first, which was the Lin, Wei, Ying and Yang or LWYY model the rate ratio for the effect dapagliflozin on recurrent heart failure, hospitalizations or cardiovascular death was 0.75. Dr. Carolyn Lam: And the second method, a joint frailty model, the rate ratio for total heart failure hospitalizations was 0.71 while for cardiovascular death, the hazard ratio was 0.81. The factors associated with more hospitalizations were, being a men, having a higher heart rate, NT-proBNP, New York Heart Association class type 2 diabetes, and a longer duration of heart failure with less hospitalization in those with higher systolic blood pressure and higher ejection fraction. So in summary, dapagliflozin in reduced the risk of total heart failure, hospitalizations and cardiovascular death. In fact, if you compare it to the time to first analysis, you can see that, that actually underestimated the benefit of dapagliflozin in HFpEF. Dr. Greg Hundley: Very nice Carolyn, well, my next paper comes to us from the world of basic science. And so Carolyn, neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species production that induces DNA damage. These cellular changes contribute to cardiomyocytes cell cycle exit and loss of the capacity for cardiac regeneration. Now the mechanisms that regulate this metabolic switch and the increase in reactive oxygen species production have been relatively unexplored. Dr. Carolyn Lam: Okay, Greg. So what did this current paper find? Dr. Greg Hundley: Right, Carolyn, so Dr. Ahmed Mahmoud from University of Wisconsin-Madison, they found that malonate, a competitive inhibitor of succinate dehydrogenase, promotes adult cardiomyocyte proliferation, revascularization of the infarct zone and myocardial regeneration following infarction. They also found that SDH inhibition by malonate is consistent with a metabolic shift from oxidative phosphorylation to glucose metabolism in the adult heart. So Carolyn, the clinical implications include the observation that transient inhibition of SDH may represent an important metabolic target to promote adult heart regeneration, following myocardial infarction. Dr. Carolyn Lam: Cool. Thanks Greg. Well, I've got another basic science paper. Let me try to tell you about la ribonucleoprotein domain family member seven. And I'm going to call that LARP7. Again, it's la ribonucleoprotein domain family members seven. Now LARP7 is a master regulator that governs the DNA damage response. The authors today, Dr. Zhang, from Xin Hua Hospital and Shanghai Jiao Tong University and colleagues aim to study its role in heart failure, pathogenesis by assessing LARP7 expression in human heart failure and in non-human primate and mouse heart failure models. Dr. Greg Hundley: Great, Carolyn. So what did they find? Dr. Carolyn Lam: LARP7 was essential for mitochondrial biogenesis energy production and cardiac function by modulating silent mating type information regulation to homolog-1, which is cert one, cert one homeostasis and activity. Now, reduction in LARP7 and diseased hearts due to activation of ataxia-telangiectasia mutated protein pathway contributed to the heart failure pathogenesis and conversely restoring LARP7 in the injured heart conferred myocardial protection. So in some, these results identified that this LARP pathway is a target or rather is a potential target for therapeutic intervention in heart failure. Dr. Greg Hundley: Great, Carolyn. One of the things I love about our journal is really the translational basic science that really could have future implications for how we manage patients with cardiovascular disease. So I, to follow, have another basic science article, and it comes to us from Dr. Florian Weinberger from the University Medical Center in Hamburg-Eppendorf. So Carolyn, human engineered heart tissue transplantation represents a potential regenerative strategy for our heart failure patients and has been successful in preclinical models. Clinical application requires upscaling, adaptation to good manufacturing practices and determination of the effective dose. So these authors performed studies in which cardiomyocytes were differentiated from three different human induced pluripotent STEM cell lines, including one reprogrammed under these GMP conditions. Protocols for human induced pluripotent STEM cell expansion, cardiomyocyte differentiation and engineered heart tissue generation were adapted to substances available in good manufacturing process quality. Engineered heart tissue geometry was modified and repair efficacy was evaluated at three doses in a cryo-injury Guinea pig model, human scale patches were epicardialy transplanted onto healthy hearts in pigs to assess the technical feasibility of this entire process. Dr. Carolyn Lam: Wow. And what did they find? Dr. Greg Hundley: Right, Carolyn? I mean, this is just so exciting, the practicality of how you implement some of these new strategies that we work on in the lab. So Carolyn, they found that human engineered heart tissue patch transplantation resulted in a partial re-muscularization of the injured heart and improved left ventricular function in a dose dependent manner in a Guinea pig injury model and human scale patches were successfully transplanted in pigs in a proof of principle study. So an exciting new front for engineered cardiac tissue transplantation. I mean, this is a really exciting article. Dr. Carolyn Lam: Wow, well, indeed. Thanks, Greg. Well, other than those wonderful papers in today's issue, we have an exchange of letters between Drs. Morgan and Lopes regarding initial invasive versus conservative management of stable ischemic heart disease patients with a history of heart failure of left ventricular dysfunction and that's insights from the ischemia trial. Tracy Hampton does her wonderful review from the literature and it covers new research published in nature medicine, which indicates the impact of a Mediterranean diet on cardio-metabolic disease risks, which may be affected by an individual's gut microbes and goes all the way to network correcting therapeutic candidate for heart valve disease, which was published in science and even a newly discovered genetic arrhythmia syndrome, which was described in science translational medicine. That's a perspective piece by Dr. Kuwabara on the Japanese national plan for promotion of measures against cerebral vascular and cardiovascular disease. Dr. Greg Hundley: Great, Carolyn. Well, you've heard of mission accomplished. Well, Dr. Brooke has an On My Mind piece entitled mission unaccomplished, the optimal hyper, any hypertensive therapy. And then finally, Dr. Glembotski has a Research Letter entitled optimizing AAV9 for studies of cardiac chamber specific gene regulation. Well, Carolyn, what a great issue and integrating all the wonderful world of basic science in a translational fashion. Now, how about we get on and move toward our feature discussion? Dr. Carolyn Lam: Yep. HDL, here we come. Dr. Greg Hundley: Well, listeners, we are onto our feature discussion today and we're very excited to have with us today, professor Uwe Tietge from Stockholm, Sweden, and our own associate editor Anand Rohatgi from UT Southwestern. Welcome gentlemen. And Uwe, could you describe for us the hypothesis that you wanted to test and tell us a little bit about your study design? Dr. Uwe Tietge Okay. So thank you very much for inviting me and for having the opportunity to discuss this article with you today. So we've been for a long time interested in HDL function, and we have developed an HDL anti-inflammatory see, and we have tested it in some cross-sectional studies. And we have seen in this cross-sectional work, for example, in the acute mi or diabetes, are associated with significant reductions in HDL anti-inflammatory function. So we felt that the next important step would be to study this prospectively in the general population. So this is why we made use of the prevent cohort, which is a prospective general population study with white participants from Groningen, which is a city in the North of the Netherlands. Prevent stands for prevention of menial and stage disease, and prevent has a total number of participants of 8,592. Dr. Uwe Tietge So we first excluded all that had already experienced mi intrusion. And then we took all subjects, was the first cardiovascular disease events during follow up and matched controls for sex, age, smoking, and importantly also for HDL cholesterol levels. And we felt that such a design would allow us to truly identify changes in HDL function, independent of HDL cholesterol levels. So then finally we ended up with 340 match case control pairs. Dr. Greg Hundley: Uwe, sounds like a very interesting hypothesis. So what was your methodology and how did you perform your analysis? And then also describe for us, what did you find? Dr. Uwe Tietge The key method that we used was our essay determining the atrial anti-inflammatory capacity and the main outcome measured was incident cardiovascular disease. And in our case, that was deaths from cardiovascular disease, hospitalization from mi, PDCA, ischemic heart disease, or CABG. We did not have stroke in our study. So with respect to HDL function, we isolate HDL by means of PEG precipitation. And this is an established method that is widely used in larger cohort studies. We then take a primary industry that cells, humans, and we pre incubate them for 30 minutes with the individual engineer preparations. Then the agents removed and TNF alpha is added for another five hours. And after these five hours, we isolate RNA and determine BK1 and mRNA levels by quantitative real time PCR. Then we calculate the results relative to the [inaudible 00:16:09] or without the edit HDL. So when the empties data, we use statistical analysis to determine the perspective association in, based on HDL anti-inflammatory function and the outcome measure incident CVD. Dr. Uwe Tietge So to summarize the main findings of the study. So first of all, the anti inflammatory activity of HDL baselines intrusion in this study was significantly higher in controls than in cases. Next, the HDL anti-inflammatory activity was not correlated with any other CBD related biomarkers. Importantly also know it was HDL cholesterol at 8.1, but also not, for example, with triglycerides, or isolated CRP, and also not with [inaudible 00:16:58] capacity, which is another function metric of HDL. Dr. Uwe Tietge The further finding was that in conditional logistic regression analysis, we found that baseline HDL anti-inflammatory activity was significantly associated with future CV events, even in a fully adjusted model. Then finally, when we were adding this function of HDL to the premium, this form, or when we were replacing anti-inflammatory capacity in the score that improved risk prediction and interestingly adding cholesterol reflux and other HDL function, as said before, resulted in a further improvement. Dr. Uwe Tietge So the general conclusion was that of the HDL functional measures in the case of our actual study, this is the HDL anti-inflammatory activity has the potential to provide clinic information independent of conventional use biomark. Dr. Greg Hundley: Very nice who made. So we always think of HDL is the good cholesterol. And sounds like you're describing a whole nother process by which HDL could be beneficial. Well, Anand turning to you now. I know you see many papers come across your desk. What drew your attention to this particular manuscript and how does this new HDL anti-inflammatory capacity or activity impact the remaining science that we have that focuses on other beneficial effects of HDL? Dr. Anand Rohatgi: Thank you, Greg. And I would like to first start by thanking Dr. Tika to submitting his article to circulation and thinking about us for his studies. I will say when this came across my desk, I became extremely excited as HDL function is an area that is near and dear to my heart as well. And Dr. Tika is an international expert in this area. So we are quite excited. The reason why this really picked our attention at circulation is that this was really the first and large demonstration that this novel marker on anti-inflammatory capacity was linked to the incidents of cardiovascular events, so that it wasn't just the range and people who already had disease, but at baseline, in people who are otherwise healthy, it could predict those who would go on to be at higher risk of atherosclerotic events. So in this case, what we saw was a truly unique and novel cardiovascular marker. Dr. Anand Rohatgi: It was a significant translational study working in effort on the part of Dr. Tika and his research team to be able to do this, and so many participants, this is not an easy undertaking. So to be able to do this and show the results that they were able to show is really remarkable, which is really why it elevated to our interest at circulation. A couple of things in terms of the implications in science are that when they recorded this study, they intriguinly we found that there were really no other stablished risk factors, cholesterol levels, or other markers that are associated with this novel anti-inflammatory capacity, it really wasn't associated with high sensitivity CRP, a global marker of inflammation. And it wasn't associated with the only other HDL function that had been shown to be linked to cardiovascular events, cholesterol influx. Dr. Anand Rohatgi: So really what we have here is a truly novel marker that stands on its own. And it's not confounded by the usual things of obesity or other cardiovascular risk factors, and is clearly imparting different information than a global marker, like CRP. I'll extend that these observations to one or two concepts, when it comes to inflammation, there are a couple of things to think about. One is the timing of the inflammatory cascade. A lot of markers are studied at the time where people are in an acute disease state and pro-inflammatory already, and so that can actually have an effect itself on the markers. In this case, by self-report, the participants did not have any acute illness. And so the relationship we see here between anti-inflammatory capacity and cardiovascular events is presumably in the context of a healthy, low inflammatory state. So I think that's important. The other thing that's important, I think for our audience to know is that the inflammation can have tissue specific effects. Dr. Anand Rohatgi: So when you think of global markers like CRP or interleukin 6, those are flagged systemic levels of inflammation in your body, and they are also predictive. But when it comes to atherosclerosis, we think about specific tissue types, the endothelium, macrophages, dipocytes. And in this case, what this marker represents is specific activity at the level of the endothelium, which is a key player in the atherosclerotic process. So it really gives us new and novel insights into that process. And it highlights the potential to find maybe therapeutic targets that can be more precise in targeting the atherosclerotic process and improving outcomes. So those were some of the main things that we saw that were exciting. Dr. Greg Hundley: Very nice. Uwe, as an international expert. What do you see as the next study that needs to be performed that will perhaps use this new market? Dr. Uwe Tietge I think what we need here first would be validation in another cohort and ideally a cohort that involves different ethnicities because our participants were predominantly white. So in terms of generalization, I think this is the next step that we would need. In terms of making this essay applicable to clinical settings in the daily routine, so to speak, we need to simplify it. And this is another issue that we are currently working on, trying to have an easier essay that gives us quicker readouts and ideally, maybe not using primary industry, but something that is better standardizable. And I mean, when you think about next steps, then also identification of a certain biomarker, comes to mind. So something that would reflect the dimension, the activity component of the age that reflects its functioning. And can be used in daily routine and is applicable. It lies to take all the types of essays. Dr. Greg Hundley: Very good. Anand, do you have anything to add to that? Dr. Anand Rohatgi: Well, I agree completely. I think when you always see a novel marker, you want replication and validation, and I think extending this to other nonwhite cohorts is important. The prevent cohort with 70% men, and also add average out there were probably higher than contemporary populations, at least in the United States. So it'd be nice to see an extension of these observations and cohorts that reflect that diversity. Interestingly, cholesterol wheat blocks the other HDL functions that's been associated with events is not linked through vascular events, it's mostly linked to coronary events. So it would be really interesting to find out how the anti-inflammatory capacity relates to events related to other vascular beds outside of the coronary tree. And then I guess a question that I had for professor Tika is, do you think there might be certain groups of people either by disease or demographic that this might be more powerful formative? Or do you think you would have the same kind of information across the board? Dr. Uwe Tietge Yeah, that's a relevant question of course. When we divided our population by participant level characteristics, we saw that there are sex differences. So the predictive capacity seems to be a bit better in females are significantly better than females, which is in male. And also in participants with lower BMI, with ahigher BMI. And the third parameter was in participants with was lower for this one was higher this month. So yes, I expect that some parameters can play a role here and it would be very wise to explore these connections. Dr. Greg Hundley: Very good. Well listeners, what an excellent discussion. And we want to thank Dr. Uwe Tika and his team from Stockholm, Sweden, and also our associate editor, Dr. Anand Rohatgi for bringing to us this new research regarding this marker of anti-inflammatory capacity involving HDL, that demonstrates an inverse association with cardiovascular events. Dr. Greg Hundley: On behalf of both Carolyn and myself. We want to wish you a great week and we will catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association, for more visit ahajournals.org.  

For this week's Feature Discussion, please join authors Igor Klem, Pasquale Santangeli, Mark N.A. Estes III, and Associate Editor Victoria Delgado as they discuss, in a panel forum, the articles: " The Relationship of LVEF and Myocardial Scar to Long-Term Mortality Risk and Mode of Death in Patients with Non-Ischemic Cardiomyopathy," "Prognostic Value of Non-Ischemic Ring-Like Left Ventricular Scar in Patients with Apparently Idiopathic Non-Sustained Ventricular Arrhythmias," and "Cardiac Magnetic Resonance Imaging in Nonischemic Cardiomyopathy: Prediction Without Prevention of Sudden Death." Dr. Carolyn Lam: Welcome to Circulation on the run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. 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 in Richmond, Virginia. Well Carolyn, this week we've got another sort of double feature with a forum and our focus is going to be on myocardial scar that's observed with late gadolinium enhancement during cardiovascular magnetic resonance and the two author groups we'll be discussing the impact of that scar on the development of ventricular arrhythmias. But before we get to that, how about we grab a cup of coffee and jump into the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I certainly would. Although I have to say, can't wait for the double feature. I love those, and this is right up your alley too. All right. But first, the first paper I want to talk about provides new randomized trial information regarding the benefits of catheter ablation in atrial fibrillation in patients who also have heart failure. Now, this is a sub-study of the CABANA trial. Dr. Greg Hundley: So Carolyn, remind us a little bit about the CABANA trial first. Dr. Carolyn Lam: I thought you might ask. Well, CABANA randomized 2,204 patients with atrial fibrillation who were 65 years or older or less than 65 with one or more risk factors for stroke at, it was huge at 126 sites, and they were randomized to ablation with pulmonary vein isolation or drug therapy. Now of these, 35% of 778 patients had New York Heart Association Class II or higher at baseline, and really formed the subject of the current paper. Although this sub-study was not specifically designed to evaluate patients with heart failure with preserved ejection fraction, about 91% of the patients with a clinical diagnosis of heart failure participating in CABANA for whom such data on injection fraction were available, really had an ejection fraction of above 40% and fully 79% had an ejection fraction above 50%. So excitingly, this is really majority talking about, have HFpEF. Now, what did they find well in patients with New York heart Association Class II or III heart failure at trial entry, most of whom did not have a reduced ejection fraction. Dr. Carolyn Lam: There was substantial clinical outcome benefits with the ablation over drug therapy with a 36% relative reduction in the primary composite endpoint of death, disabling stroke, serious bleeding or cardiac arrest. Benefits were evident for both all-cause mortality and atrial fibrillation reduction. However, the effects on heart failure hospitalization were small and not significant. Authors also caution that these results should not be viewed as practice changing until they are reproduced in a confirmatory trial of ablation in the same population. And this is beautifully discussed in an editorial by Lynda Rosenfeld and Alan Enriquez from Yale University School of Medicine. Dr. Greg Hundley: Oh, wow. Thanks Carolyn. Well, my first paper comes from the world of basic science and it's from Professor Thomas Braun, from the Max Planck Institute for Heart and Lung Research. So Carolyn, vascular smooth muscle cells show a remarkable phenotypic plasticity allowing acquisition of contractile or synthetic states, but critical information is missing about the physiological signals that promote formation and maintenance of contractile vascular smooth muscle cells in vivo. So BMP-9 and BMP-10 are known to regulate endothelial quiescence after secretion from the liver and right atrium. And these investigators are studied the role of BMP-9 and 10 for controlling formation of contract, all vascular smooth muscle cells. Dr. Carolyn Lam: Greg, talking about vascular smooth muscle cells always reminds me of their role in pulmonary hypertension, am I right? Dr. Greg Hundley: Yes, Carolyn. So these investigators found that in mouse models, BMP-9 and BMP-10 act directly on vascular smooth muscle cells for induction and maintenance of their contractile state, and surprisingly the effects of BMP-9 and 10 in vascular smooth muscle cells are mediated by different combinations of BMP type 1 receptors in a vessel bed specific manner. And therefore, just as you suggest, Carolyn, these results may offer new opportunities to manipulate blood pressure in the pulmonary circulation. Dr. Carolyn Lam: Thank you, Greg. Well, my next paper provides the first proof of principle of gene therapy for complete correction of Type 1 Long QT syndrome. Dr. Greg Hundley: Ah, so tell us a little bit about Type 1 Long QT syndrome, Carolyn. Dr. Carolyn Lam: Okay. Well Type 1 long QT syndrome is caused by loss of function variants in the KCNQ1 and coded potassium channel alpha sub-unit. And that is essential for cardiac repolarization providing the slow delayed rectifier current. Now no current therapies target the molecular cause of this Type 1 long QT syndrome. Well, this study from Dr. Michael Ackerman colleagues from Mayo Clinic Rochester really established a novel dual component suppression and replacement KCNQ1 gene therapy approach for Type 1 long QT syndrome. And it's the type that contains the KCNQ1 short hairpin RNA to suppress endogenous expression and a codeine altered short hairpin RNA immune copy of this KCNQ1 for gene replacement. Dr. Carolyn Lam: So this very novel approach rescued the prolonged action potential duration in inducible pluripotent STEM cell cardiomyocytes derived from four patients with unique Type 1 Long QT syndrome, causative, KCNQ1 variants. So it's super cool. Just go have a look. Dr. Greg Hundley: Well, thanks Carolyn. Dr. Carolyn Lam: I want to also tell you about other things in the mail bag. We have ECG Challenge by Dr. Dai on “Severe Arrhythmia Caused by a Chinese Herbal Liqueur. What's the Diagnosis?” I'm not going to tell you. You have to go see. We have Dr. Karen Sliwa writing a beautiful Joint Opinion paper from the World Heart Federation and American College of Cardiology, American Heart Association, and European Society of Cardiology on "Taking a Stand Against Air Pollution, the Impact on Cardiovascular Disease." Dr. Greg Hundley: Well, thanks Carolyn. So I've got a couple other articles. First Professor Yacoub has a global rounds describing and working towards meeting the challenges of improving cardiovascular health in Egypt. Those are really interesting features to learn about cardiovascular care worldwide. Next there's an In Depth article by Professor Thum entitled, "Therapeutic and Diagnostic Translation of Extracellular Vesicles in Cardiovascular Diseases, Roadmap to the Clinic." And then finally, a Research Letter from Dr. Bottá entitled, "Risk of Coronary Artery Disease Conferred by Low Density Lipoprotein Cholesterol Depends on Apologetic Background." Well, Carolyn, what a great issue and how about now we proceed on to that double feature? Dr. Carolyn Lam: Oh, I can't wait. Thanks Greg. Dr. Greg Hundley: Well, listeners, we are here for a really exciting feature discussion today that's going to focus on imaging, in particular magnetic, resonance imaging, and some new findings in that era and how those findings may pertain to ventricular dysrhythmias. With us today, we have Dr. Igor Klem from Duke University who will be discussing a paper, Dr. Pasquale Santangeli from University of Pennsylvania, our own associate editor, Dr. Victoria Delgado from Leiden and an editorialist, Dr. Mark Estes from UPMC in Pittsburgh. Welcome to all of you. Well, Igor, we're going to start with you. Could you tell us what was the hypothesis for your study and what was your study population in study design? Dr. Igor Klem: Yes. Good morning, Greg and thanks for the invitation. We wanted to know if you have a patient who you diagnosed with non ischemic cardiomyopathy based on clinical grounds and you refer him for a cardiac MRI study with contrast, what is the additional information that you get from the MRI study? And so we wanted to compare, and that's primarily related to the findings on scar imaging with late gadolinium enhancement. And we wanted to compare that to one of the most robust clinical parameters in cardiology, which is left ventricular ejection fraction, and in particular using a cutoff of 35%, which somehow in our clinical management has sort of as established as a break point for many clinical decisions. Dr. Igor Klem: And so we created a registry among three centers of patients who undergo a cardiac MRI study, where we found an LVEF of less than 50% and we followed them for a number of outcomes. One is all caused death. And then we wanted to separate a little bit the events into those who have cardiac mortality to look at a little epidemiology because in those patients, we have two major adverse events: one as heart failure related mortality. One is arrhythmia related mortality. Dr. Greg Hundley: And how many subjects did you include? Dr. Igor Klem: We included about a thousand patients from three centers and coming to the major findings of our study, we found that both left ventricular ejection fraction, as we know, is a robust marker of all cause mortality and cardiac death. And so it was the presence of myocardial scar on cardiac MRI. But the major difference was in relation to the arrhythmic events. We founded left ventricular ejection fraction in particular, when we use the 35% cutoff actually had very little predictive power to inform us who is at risk of arrhythmic events. In contrast, there was a very strong and robust relationship or multiple statistical methods to stratify patients who are at risk for sudden cardiac death, appropriate ICD shock, as well as arrhythmic cardiac death. Dr. Greg Hundley: Very good. Well, Pasquale understand you also performed a research study utilizing cardiovascular magnetic resonance. Could you describe for us your hypothesis as well as what was your population and your study design? Dr. Pasquale Santangeli: Thank you, Greg. And of course, thanks to the editor for the interest in our paper. I need to thank also the first call authors Daniele Muser and Gaetano Nucifora for putting together a registry of 70 institutions throughout the U.S., Europe, and Japan and the our hypothesis came from a clinical need. We do know that patients with idiopathic ventricular re we ask, which includes not sustain a weakness like PVCs or non-sustained VT. Very few of them, but there is a group of them that have a higher risk of ending malignant and up comes in terms of your ethnic events over follow-up. And prior studies have shown that by doing an MRI and showings and the detecting scar related announcement, there is an increase with how we make events of a follow-up. However, if you do look at those studies late, an answer's been reported in up to 70% of these patients, which you never view is a highly practical way of re-stratifying these patients, because you have a risk factor that is present 70% of those, then it's hard to use it for clinical decision-making. Dr. Pasquale Santangeli: So in this registry, which you put it again at 686 patients with panel data idiopathic, not sustained ventricular arrhythmias, which were defined by a normal WBC gene status, a normal echocardiogram and a normal stress test. We looked at whether there is a specific pattern of late announcement. So how basically I believe lands, and it looks on the MRI, they may predict better or outcomes over follow-up. And again, we use a composite and Pauline the full cost mortality, but associated cardiac arrest due to ventricular fibrillation or a hemodynamically unstable BP, or in a subgroup of patients that underwent ICD therapy. We also looked at, I approve SED shocks. Dr. Pasquale Santangeli: The groups were divided in three different categories. The first one, which is a larger group of 85% of patients and no late announcement. The second group, the one with late announcement, which represents the remaining 50% of 15% of patients, we divided it into a ring light pattern, which was defined as that word says, as a ring like distribution of the lead announcement in the mid-market segments, which involves a three consecutive continuous segments in a short axis view. It looks like really at least half the ring or three-quarters of the ring. Dr. Pasquale Santangeli: And the other group is the one that had the leader announcement without a ring light pattern. And it's interesting that the third and the latest announcement was not that similar between the ring light and the one without ring light late announcement. What we did find though for our follow-up the patient with a ring light pattern, a significantly higher rate of the primary composite endpoint, which happened in the median follow-up about 61 months so it was quite long. And the composite outcome occurred in 50% of patients in the ring light group versus 19% in the no ring light a positive announcement group and a 0.3%. So really, really rare in patients. So then concluded that of course, late announcement does provide some information in general, particularly the type of announcement that increases the risk significantly. Probably although this has to be confirmed prospective fashion patient with a ring light pattern may benefit from other forms of interventions, including potentially defibrillator therapy in a prophylactic fashion. Dr. Greg Hundley: Very nice. So now listeners, we're going to turn to our associate editor. One of the imaging experts here at Circulation, Dr. Victoria Delgado. Victoria, you see a lot of papers come across your desk and as an imaging expert, what attracted you to these two papers? And what do you think are their significance? Dr. Victoria Delgado: Thank you, Greg. I think that these two papers are important because right now, if we follow the clinical guidelines, we decide implantation. For example, of an ICD based on the ejection fraction, and we see that in many patients based on ejection fraction, they may not benefit ever from an ICD because they don't have arrhythmias. What other patients who do not meet the criteria often injection fraction below 35%. They may have still arrhythmias. So the article by Igor highlights the relevance of the amount of burden of late government Huntsman with CMR, in patients with non ischemic cardiomyopathy, which are sometimes very challenging patients on how to decide when we implant an ICD or not. We need sometimes to base the decision on genetics. Dr. Victoria Delgado: If we have an on the other hand, the paper of Pasquale, these were patients with normal echocardiogram. So what patient, having arrhythmias where we don't see on echocardiogram, that is the first imaging technique that we usually use to evaluate these patients. We don't see anything, but CMR can give us more information in terms of structural abnormalities and particularly not only the burden of scar, but also the pattern of the scar. And we have seen in other studies that for example, not only for ICD implantation, but for ventricular tachycardia ablation. The characteristics of that scar and some areas where these are short of panel that can be targeted for that ventricular tachycardia ablation can lead to much more precise treatment if you want of these patients. Dr. Greg Hundley: Thank you, Victoria. So it sounds like listeners we're hearing late gadolinium enhancement, regardless of EF could be forecasting, future arrhythmic events. And then also the pattern of late gadolinium enhancement, where contiguous segments in a ring-like fashion may also offer additional prognostic information. Well, now we're going to turn to our editorialists and as you know, listeners at Circulation, we'll bring in an editorialist to really help put things together and uniquely here today, we have Dr. Mark Estes, who is really not an imager per se, but like many of us uses the information from imaging to make clinical decisions. Mark, how do you see this late gadolinium enhancement as perhaps a new consideration for placement of devices? Dr. N.A. Mark Estes: Greg, that's one of the key questions. There's no doubt, not only based on these two studies, which extend our prior information about LGE and patients with valid and non ischemic cardiomyopathies that scar burden is important in predicting not only total mortality, but arrhythmic events. All of the criteria that were used in the original ICD studies, which include the definite, the Skuid half Danish and made it our it trials use only ejection fraction and functional status, no imaging. These are legacy trials. Now, many of them, a decade or more older. And the treatment of advanced heart failure has progressed to the point that the total mortality is dramatically lower than it was at the time of these studies. In some instances down to 4 or 5% per year. The studies are important in that they identify a subgroup of patients with low ejection fractions, less than 35%, who might qualify for ICDs, who are unlikely to benefit. Dr. N.A. Mark Estes: They also identify a group of patients with preserved ejection fraction greater than 35%, less than 50 in whom the risk of sudden death may be substantial. And it extends prior observations about patchy, mid Meyer, cardio wall fibrosis, subendocardial, subepicardial and important ways. But the key issue here, and it was alluded to with Pasquale's comments about prospective validation, is that when one has a risk stratifier and identifies a high risk population that has to be linked to an unequivocal therapy, it improves survival. And we don't have that link quite yet. Dr. N.A. Mark Estes: Prospective randomized trials are unlikely to be done in the low ejection fraction because they would probably be considered unethical. Given the trials that have shown the benefit you can't randomize to defibrillator versus an implantable loop recorders. I think the future really lies in risk stratification for people with preserved ejection fractions greater than 35%, less than 50 using LG in that patient population. Currently, I think the best information we can give to clinicians is to stick with the AHA guidelines, which is PF less than 35% with dilated, nonischemic class II symptoms who have had optimal medical therapy for at least three months using perhaps in that patient population LGE for shared decision-making in patients about the magnitude of the risk. And I think that's as far as we can go pending future studies, and there is one which we can discuss later on the CMR study at just that preserved ejection fraction LGE randomizing to defibrillator versus ILR. Dr. Greg Hundley: Thank you, Mark. So listeners just really quickly, let's go back to each of our experts and ask them, you know, in 20 seconds, Igor, Pasquale, Victoria, and Mark, what's the next study that needs to be performed in this space? Igor, we'll start with you. Dr. Igor Klem: Well, number one, following on Mark's comment on the less than 35% population, I think that it's unlikely that they're randomized clinical trial is ethical in this population, but we may consider a wealth of registry data by now that shows that there is a subgroup of patients who have a lower risk or lower benefit from an ICD. I think in the preserved ejection fraction above 35%, maybe up to 45%, 50%. That's an interesting study that's coming up. Maybe there's more trials that can provide us that robust information that we need today in order to change the guidelines to risk stratify, not based on the LVF, but on the presence of scar or maybe subgroups of scar. Dr. Greg Hundley: Pasquale? Dr. Pasquale Santangeli: Yes. So I think of course, one of the major studies is the one already alluded by this, which is a prospective study that links as specific therapy like ICD or even additional risk factors like we've been using program's stimulation some of these patients to further risk for the five to see what they can benefit. Dr. Pasquale Santangeli: Based another one that I think is important for the study that we did is a mechanistic more study to understand why the ring light pattern was there, as opposed to other patterns. We do believe we think that some of these patients may have an initial form of lb dominant arrhythmogenic paramount. There wasn't really a detective before and ran. Now, if we actually extending our study and have a registry to try to screen also the family members or patients with ring light pattern to understand whether there is a familiar component to it, because really we do not see this type of pattern that commonly and it'd been associated with lb dominant. Magnetic kind of alpha in some others, small studies. Dr. Pasquale Santangeli: So that's the other part to dig in a little bit more into the field type for these patients to understand why one pattern versus another happens and whether that gets main to, to explain why there's a higher risk in one population versus another. Dr. Greg Hundley: Victoria. Dr. Victoria Delgado: Yeah. Following what has been said. I think that from the imaging point of view, we are always criticizing in a way that we increase the burden or the cost of healthcare. But I think that these studies or any randomized study where MRI or echo is used in order to design a therapy and show the value of using that imaging technique to optimize the health care costs is important. So I will not add much on which sort of populations, but probably patients within non ischemic cardiomyopathy with preserved ejection fraction that do not fulfill the recent scores, for example, in hypertrophic cardiomyopathy to be implanted with an ICD. But probably if we see a lot of scar on a AGE where specific patterns that can help to decide which are the patients that have benefited from an ICD implantation, for example. Dr. Greg Hundley: Thank you. And finally Mark. Dr. N.A. Mark Estes: But I think all the major points have been hit here. And unfortunately we have a bit of a dilemma. And that dilemma is that these legacy trials for ICDs, which selected based on low ejection fraction and functional class II were done at a time when contemporary heart failure treatment was not as good as it currently is pharmacologically. And it's been reflected with a lower total mortality. When the mortality in this patient population gets down to the 4 and 5% per year, it's unlikely that any intervention for prevention of sudden death is going to impact on that total mortality. Dr. N.A. Mark Estes: So I do think that the registries hold a lot of promise, giving us insights into the subgroup of patients that previously would have been selected for defibrillators who may not have as much benefit or who may benefit the most. And I think that they will play an important part in perhaps refining the risk stratification with greater sensitivity and specificity in the patient population, less than 35%. I think the CMR guide trial is going to be a critical trial and looking at ICDs in the patient population between 35 and 50%, but we need to be mindful of one thing. And that in the Danish trial, they get a sub study looking at about 240 patients using LGE. And they found that ICD in patients with LGE that was positive, did not make a difference in survival or total mortality. So again, we need to get the data. I think the best clinical practice has come out of the best clinical evidence. You'll clearly be limitations to what we can do, but I think in the future, we'll have much better data to make these judgment calls. Dr. Greg Hundley: Very good. Well listeners, we want to thank our panelists, Dr. Igor Clem, Pasquale, Santangeli, Victoria Delgado, and Dr. Mark Estes for this wonderful discussion related to magnetic resonance imaging, late gadolinium enhancement, and how it may be useful in identifying those at risk for future arrhythmic events. On behalf of both Carolyn and myself, want to wish you a great week and we will catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021.  

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, 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 and director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature involves interleukin-6 and a phenome-wide association study. So we have a lot to look forward to, but before we do that, how about we grab a cup of coffee and jump into the other articles in this issue? I could start first because I've got to tell you about some results from the ODYSSEY outcomes trial. And Carolyn, this comes to us from Professor Gregory Schwartz at the University of Colorado School of Medicine. Well, Carolyn, this study pertains to LDL lowering. As you know, recent international guidelines have lowered the recommended target levels of LDL cholesterol for patients at very high risk for major cardiovascular events or MACE. Dr. Greg Hundley: However, uncertainty persists as to whether additional benefit results from achieving LDL-c levels below some of these conventional targets. Now inferences from prior analyses are limited because patients who achieve lower versus higher LDL-c on lipid lowering therapy differ in other characteristics prognostic for MACE, and because few achieved very, very low LDL-c levels. So to overcome these limitations, these authors performed a propensity score matching analysis of the ODYSSEY outcomes trial, which compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome receiving intensive or maximum tolerated statin treatment. Dr. Carolyn Lam: Sensible question, and what did they find? Dr. Greg Hundley: Well, Carolyn, the main finding of the study was that after accounting for differences in baseline characteristics and adherence, patients treated with alirocumab who achieved LDL-c levels less than 25 milligrams per deciliter did not appear to derive further reduction in the risk of MACE compared to those who achieved LDL-c levels of say 25 to 50 milligrams per deciliter. So, Carolyn, the take-home message is that recent international guidelines have lowered LDL-c goals for patients at very high risk for MACE to levels less than 55 milligrams per deciliter, and in some cases, maybe less than 40 milligrams per deciliter. However, any potential benefit of achieving LDL-c levels significantly below these goals to those very low, less than 25 really remains uncertain. Dr. Carolyn Lam: Very interesting. Thanks Greg. Well, my paper is about the HOST-REDUCE-POLYTECH-ACS trial. Got your attention? All right. I'll tell you what it is. It's an investigator-initiated, randomized, open-label, adjudicator-blinded, multicenter, non-inferiority trial, which compared the efficacy and safety of durable polymer versus biodegradable polymer, drug-eluting stents. And these investigators led by Kyung Woo Park from Seoul National University Hospital looked at 3,413 patients with acute coronary syndrome. At 12 months, the primary endpoint of patient oriented composite outcome, which was a composite of all-cause death, nonfatal myocardial infarction, and any repeat revascularization, occurred in 5.2% of the durable polymer group and 6.4% of the biodegradable polymer group. And so that met the non-inferiority P value of less than 0.01. the key secondary end points of device oriented composite outcome, which is a composite of cardiac death, target vessel MI, or target lesion revascularization occurred less frequency in the durable polymer versus biodegradable polymer groups, and this was mostly due to a reduction in target lesion revascularization. The spontaneous nonfatal MI and stent thrombosis rates were very low with no significant difference between the groups. Dr. Greg Hundley: Well, Carolyn, you know one of my favorite questions, so what's the take-home message here? Dr. Carolyn Lam: In patients with acute coronary syndrome receiving PCI durable polymer drug-eluting stents were non-inferior to biodegradable polymer drug alluding sense with regards to patient-oriented composite outcome at 12 months. I think that's the significant take-home message, and it's accompanied by an editorial where all this is discussed, and this editorial is by Doctors Byrne and Hanratty from Dublin. Dr. Greg Hundley: Very nice, Carolyn. Well, Carolyn, I am going to turn to the world of basic science and discuss phospho-lamin phosphorylation and how that may regulate vascular tone, blood pressure, and hypertension in both mice and men. And it comes to us from Dr. Michael Shattuck from King's College, London. So Carolyn, it's long been recognized that smooth muscle Na,K-ATPase modulates vascular tone and blood pressure. However, the role of its accessory protein phospho-lamin has not been characterized. So Carolyn, the aim of this study was to test the hypothesis that phospho-lamin phosphorylation regulates vascular tone in vitro, and this mechanism plays an important role in the modulation of vascular function and blood pressure in experimental models, both in vivo and in man. Dr. Carolyn Lam: Okay. So what did they find? Dr. Greg Hundley: Carolyn, these authors found that in aging wild type mice, phospho-lamin was hypo-phosphorylated, and this correlated with the development of aging induced essential hypertension. In human subjects, they identified a non-synonymous coding variant, a single nucleotide polymorphism RS-61753924, which causes the substitution of R-70 C and phospho-lamin. The R-70 C mutation prevented phospho-lamin phosphorylation at searing 68. This variance rare Alleo was associated with increased blood pressure in middle-aged men. So Carolyn, taking together these translational animal and human studies demonstrate the importance of phospho-lamin phosphorylation in the regulation of vascular tone and blood pressure and suggest a novel mechanism for aging-induced essential hypertension. Dr. Carolyn Lam: Interesting. And I suppose opening the door to translationally preventing this hypertension. Very interesting. Well from the next paper we switch to cardiac troponins, and you know these are the cornerstone of diagnosing acute myocardial infarction. But have you ever wondered, what is the duration of ischemia necessary to induce a measurable release of the cardiac troponins, or the very early release kinetics of cardiac troponins following an ischemic event? Well, this study is the first to report the early release kinetics of cardiac troponin concentrations, following different durations of experimental coronary balloon occlusion in humans. Dr. Greg Hundley: Ah, Carolyn. So how did they do this? Dr. Carolyn Lam: So 34 patients with N geographically normal coronary arteries were randomized into four groups with different durations of induced myocardial ischemia from zero to 30, 60, 90 seconds. Ischemia was induced by inflating a balloon in the left anterior descending artery between the first and second diagonal branch. Blood was collected prior to balloon inflation and every 15 minutes for the first three hours and every 30 minutes for the next three hours. Cool, huh? Dr. Greg Hundley: Yeah. So did any of the patients suffer complications? Dr. Carolyn Lam: So the first thing to report is none of the patients had any complications, but what they found, and this was from authors, Dr. Iverson from Copenhagen, Denmark and colleagues. This is what they found increased cardiac troponin concentrations were detected by all three high sensitivity assays, be they high sensitivity troponin T by the Roche assay, high sensitivity troponin I by the Siemens essay, or high sensitivity troponin I by the Abbot essay. All assays detected a cardiac troponin increase after only 30 seconds of ischemia. High sensitivity troponin I by Siemens rose faster and reached a higher peak. Copeptin levels did not significantly change. So these interesting findings are accompanied by an editorial by Christopher deFilippi and Nicholas Mills discussing how the findings challenged some of our assumptions and may help shape future care pathways and the classification of ACS. Dr. Greg Hundley: Carolyn, so more in the evolution of high sensitivity troponins. Well, I'm going to shift to my last article of the day, and it focuses on eccentric remodeling and ischemic cardiomyopathy, and comes to us from Professor Konstantinos Drosatos at the Lewis Katz School of Medicine at Temple University. So Carolyn, these authors have shown that cardiomyocyte Krüppel-like factor or (KLF)-5 regulates cardiac fatty acid oxidation, and as heart failure has been associated with altered fatty acid oxidation, they now investigated the role of cardiomyocyte (KLF)-5 in lipid metabolism and the pathophysiology of ischemic heart failure. Dr. Carolyn Lam: Wow, Greg. What did they show? Dr. Greg Hundley: Well, Carolyn, they found that (KLF)-5 is induced during the development of ischemic heart failure in humans and mice and stimulates ceramide biosynthesis. Genetic or pharmacological inhibition of (KLF)-5 in mice with myocardial infarction prevents ceramide accumulation, alleviates eccentric remodeling, and increases left ventricular ejection fraction. Thus, the authors suggest that (KLF)-5 may emerge as a novel therapeutic target for the treatment of ischemic heart failure. Well, Carolyn, we've got some other articles in the issue, and I'm just going to tell you quickly about an in-depth article entitled, “Cardiovascular Disease and Chronic Kidney Disease: Pathophysiological Insights and Therapeutic Options” that come to us From Dr. Marx, and then I'm going to turn it over to you. Dr. Carolyn Lam: Yes, we've got an exchange of letters between Doctors Grace and Mital regarding the article, “A Validated Model for A Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy.” There's an ECG challenge by Dr. Peng on an irregular complex tachycardia. And there's this very interesting on-my-mind paper by Dr. Skolnik simply entitled, Gratitude. And I just have to tell you a bit about it, and I'm quoting from it now, “…having two surgeries for a large aortic aneurysm and aortic regurgitation, I am also left with an overwhelming sense of gratitude for living in the age in which I'm living. While some focus on what is wrong in the world, at least for today, my focus is on what is right.” Now, please read that paper. It's just such a beautiful piece. And, finally, there's a perspective piece by Dr. Sandhu entitled, “The Affordability of Guideline-Directed Medical Therapy, Cost Sharing, and How Cost Sharing is a Critical Barrier to Therapy Adoption.” Well, looks like it's a wrap. Greg, let's get on to our feature discussion, shall we? Dr. Greg Hundley: You bet. Well, listeners, we are now coming to our feature discussion today, and we're very fortunate to have with us today, Dr. Martin Dichgans and Dr. Marios Georgakis both from Munich, Germany. And we also have Dr. Svati Shah from Duke University, one of our associate editors. Welcome to you all. And I'll start with you Martin, could you explain to us a little bit of the background behind this study and what was the hypothesis that you wanted to test? Dr. Martin Dichgans: Yes, of course. We are interested in stroke, and more broadly, in cardiovascular disease, and inflammatory cytokines and inflammatory mechanisms in general play a major role in cardiovascular disease and particularly in arthrosclerosis, which connects a cardiac disease and stroke and also multiple other disorders. So that was our starting point. And we previously noted the importance of specific inflammatory cytokines in stroke, which is all primary area of research. We then quickly became aware of the central position of IL-6, which is downstream of IL-1β in the inflammatory cascade, and recognized not only that there's a lot of data on IL-6 in cardiovascular disease already, but that IL-6 actually is implicated in multiple inflammatory conditions, including autoimmune diseases, vascular, as I mentioned, and also metabolic disorders. And we noted that IL-6 receptor inhibition is already in use in some of these disorders, particularly in the treatment of autoimmune diseases, but not yet in use in cardiovascular disease. Dr. Martin Dichgans: So we asked ourselves whether there would be any repurposing potential, and also whether there would be an opportunity to explore the safety profile in its full width using genetic data because, and this I didn't mention, we have a background in genetics, a large interest in genetics, and you might have noticed that previously there has been a wealth of genetic data coming out, both on stroke, but also on cardiovascular disease in general. So also including other phenotypes, like for instance, and it has now become possible via a methodology called Mendelian randomization to utilize these genetic data and explore causal relationships between exposures such as IL-6 levels or specific cytokines and outcomes such as ordinary-after disease or stroke, and even go one further and explore the therapeutic potential, and also the full width phenotypes that could be relevant in such a scenario. So what we did is we took advantage of large scale genetic data from the UK biobank and data on specific outcomes available in the UK biobank to dive into the questions we were interested in. Dr. Greg Hundley: Martin, that was a wonderful explanation. So could you describe, what was the aim of your study? Dr. Martin Dichgans: In brief, the aim was to use large scale genetic data to explore the repurposing potential and safety profile of IL-6 receptor inhibition in the general population. Dr. Greg Hundley: Very nice. Describe your study design. Dr. Martin Dichgans: So the study population was the UK biobank, which is a population-based sample of, in this case, 340,000 unrelated individuals. And what we did is we performed the phenome-wide association study. So we looked across all available phenotypes that are systematically encoded in the UK biobank, and which included both clinical outcomes and biomarkers, in this case about 1,400 clinical outcomes and 360 or 70 biomarkers and endophenotype of human disease in this biobank. And again, explored relationships between IL-6 receptor inhibition and the effect on these outcomes. Dr. Greg Hundley: Very nice. Well, Marios, let's turn to you. Could you describe the results? What did you find? Dr. Marios Georgakis: Yes. Hello from my side as well. So, as Martin mentioned, we explored associations between genetically down-regulated IL-6 signaling and 1,400 clinical outcomes, as well as with 360 biomarkers in another, I would say hypothesis reapproach. So, following corrections from output testing, we found significant associations with genetically down-regulated IL-6 signaling activity with 16 clinical outcomes and 17 biomarkers. As we had shown in the past, genetically down-regulated IL-6 signaling activity was associated with several cardiovascular phenotypes, specifically atherosclerotic phenotypes, primarily including coronary artery disease manifestations, but also for example, abdominal aortic. Interestingly though, we also found a significant association with a lower risk of type two diabetes, as well as with a lower glycated hemoglobin, another finding that was consistent not only in the UK biobank, but also in two cohorts that we use for validation. So in the past, there have only been data from small observational studies and small case series in patients with rheumatoid arthritis supporting these findings, but to date, no data from large clinical trials. Dr. Marios Georgakis: Furthermore, we find significant associations between genetically down-regulated IL-6 signaling and higher total cholesterol, but also higher HDL cholesterol levels, but no association with LDL cholesterol. This further supports associations of IL-6 signaling downregulation with, let's say more favorable argument among the profile. Now, why is this important? This is a very interesting finding because previous clinical trials had suggested that IL_6 receptor inhibitors might lead to increases in total cholesterol levels, which would, of course, be an undesired side effect for people who'd ever envisioned using IL-6 receptor inhibitors in the context of lowering cardiovascular risk. Dr. Marios Georgakis: Here, however, we show, and our results support, that this increases primarily the results of the effects of IL-6 signaling bar down-regulation on HDL and not LDL levels. On the negative side, and finally, we found significant associations between genetically down-regulated IL-6 signaling and the number of potential side effects, particularly strong associations with bacterial infections, such as cellulitis and urinary tract infections, which is probably also related to the identifed association with the lower risk of neutropenia. So while these are well-described side effects of IL-6 signaling and condition in the context previous clinical trials, this, we believe, disagreement with our findings adds additional confidence to, let's say, the validity phenome-wide association state. Dr. Greg Hundley: Very nice Marios. Really appreciate this exciting work. And now we want to turn to our associate editor, Doctor Svati Shah. And Svati, you have many papers come across your desk, what attracted you to this paper? And then how do you put the results that these men have presented into context with other papers in this area of investigation? Dr. Svati Shah: Yeah. Great question, Greg, and thanks for having me. I thought this paper was really important, but I want to start at a broader level, and that's why it's attracted my attention is, I think genetics can not sort of inherently appeal to the broad Circulation reader. It can feel somewhat esoteric. We do these genome-wide association studies, these whole-exome association studies, and we find new genes and we're really excited about them as people who live in the genetic epidemiology realm. But when we think about the broader circulation readership and the broader cardiology readership, how does this really relate to how I take care of patients, and what might be important for me in my cardiovascular realm? And I think this paper really highlights the power of human genetics and how we really understand things that have clinical utility. Dr. Svati Shah: And let me just expand on that really briefly. And that is, in the human genetics realm, we can look at what we call human knockouts. We're not actually doing gene editing in humans, but looking at people who have loss of function variants. They're emulating a drug for example. And we also have PheWAS, which is a phenome-wide association study, where we say, "We're just going to look at lots of different clinical things and biomarkers and try to understand things that are associated." And then finally we have Mendelian randomization, which allows us at a very statistical level to really assess causality. We know there are things that are correlated with each other, but we don't necessarily know that they're causal, and this is a statistical way for us to potentially assess causality. I say that very carefully because it's a statistical way to do that. Dr. Svati Shah: And what's really cool about this paper is they combine PheWAS and Mendelian randomization, but with a very clinically important aspect. What are the potential good side effects, the on-target things that we want to try to address with these potential drugs, like tocilizumab, and what are potential side effects of these potential drugs. And in this case, because they combined PheWAS, they're able to look across all kinds of things. So the things that we already know about, they're not looking at a drug per se, but they're emulating a drug by looking at these genetic variants to say, "Okay. Well, we're going to look across all these different clinical factors." So it's not only things that have been evaluated in these clinical trials, but even just beyond that. And then the Mendelian randomization piece allows them to be able to say, again, statistically, are these causal. So if you antagonize these receptors, does it 'cause' these downstream effects. So, that's what was really cool to me about this paper. Is it really highlights the potential for human genetics in a very short term translational clinical potential. Dr. Greg Hundley: What a wonderful explanation for our listeners here. Well, let me ask each of you, Martin, Marios, and then Svati, what do you see as the next research endeavor in this space? Martin, you first. Dr. Martin Dichgans: And I completely agree with Svati that we have to utilize genetics in order to improve our means of treating patients, and I think that's obviously our aim here. And what this study shows, and let me just briefly also confirm what you said, we were intrigued by how the genetic data reflect what we see, for instance, in clinical trials. Just to expand a little bit on that aspect, the seven genetic instruments, which consisted of seven snips, single nucleotide polymorphism, when we looked at the effects of genetic lowering in this context on upstream and downstream, known upstream and downstream biomarkers of IL-6 signaling, this really very much matched what we know from clinical trials with tocilizumab so with pharmacologically lowering IL-6 signaling. Again, giving us confidence that it's informative and we will see with genetics what we are going to expect in the future in clinical trials. Dr. Martin Dichgans: So now getting to your point here and providing an answer, what we see as the next step, we should, for instance, combine the genetic data we have here with genetic data on other approaches to see whether, and maybe Marios can be more specific about this, whether by combining two different approaches, for instance, LDL lowering and targeting residual inflammatory risk, whether we could in future clinical trial provide additional benefits to high-risk patients with a cardiovascular disease. And I think that will be a very important area. Also, I think we should extend this approach to other inflammatory cytokines that have come up in Mendelian randomization analysis to explore their potential in future clinical trials. Dr. Greg Hundley: Marios? Dr. Marios Georgakis: Yeah. So just to add a little bit on Martin's summary, I would say here that now that we have established the efficacy of anti-inflammatory approaches in lowering cardiovascular risk, both with clinical trials, but also with showing genetic and clinical evidence, I think that the next step is first to identify the proper clinical scenario where anti-inflammatory approaches targeting IL-6 signaling would be used for reducing cardiovascular risk in order to design the proper clinical trials. And secondly, as Martin mentioned, to explore whether targeting IL-6 signaling would, one, pass additive benefits on Kruppel available approaches such as lipid-lowering approaches, and second, to see whether the risk-benefit balance of anti-inflammatory targeting IL-6 signaling would be acceptable in the clinical setting. Dr. Greg Hundley: And Svati. Dr. Svati Shah: Yeah. It's hard to follow up on those comments. I'll say, since I am very interested in diabetes and insulin resistance, the cholesterol story is fantastic, but I think the fact that they see effects on, again, statistical lowering of hemoglobin A1C and type two diabetes is fascinating to me. I would take it even a little step further. I think we need clinical trials. These data are very suggestive. It sort of flips the story almost. We've seen, even in some of the clinical trials of these drugs, that there are beneficial metabolic effects with regards to glucose, although some of the data are contradictory. So flipping it and saying, we know that inflammation is complex and we know that IL-6 has pro and anti-inflammatory roles in inflammation, and we know that diabetes with regards to inflammation is very complex, but maybe these drugs potentially are useful in type one and type two diabetes. So I think we need carefully designed clinical trials, potentially, to understand the role of blocking inflammation, and in particular IL-6 signaling, in patients who have diabetes. Dr. Greg Hundley: Excellent. Well, listeners, we want to thank Dr. Martin Dichgans, and Dr. Marios Jojakas, and our own associate editor, Dr. Svati Shah for bringing us this study incorporating phenome-wide association and Mendelian randomization to identify a relationship between down-regulated IL-6 signaling with subsequent clinical cardiovascular outcomes. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2021.  

This week, join author Chintan Dave and Associate Editor Naveed Sattar as they discuss the risk of cardiovascular outcomes in Type 2 Diabetes patients following the addition of SGLT2 inhibitors versus sulfonylureas to baseline GLP-IRA therapy. TRANSCRIPT BELOW: Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts, 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. Dr. Carolyn Lam: Greg, I love today's featured paper. It's a question everybody's asking. It's about cardiovascular outcomes, potential benefits, following the addition of SGLT2T2 inhibitors versus sulfonylureas to baseline GLP-1 receptor agonist therapy. Now, okay, I'm going to keep you waiting because that was just a hook. We got to get to us summaries first. And I'm going to start. The first original paper I want to describe is an analysis of myocardial infarction from the ischemia trial. And it looks at the impact of different definitions on the incidents, prognosis and treatment comparisons. Dr. Carolyn Lam: Because I know you're going to ask, I'm going to tell us a little bit about ischemia. So in an ischemia and initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality compared with a conservative strategy in patients with stable ischemic, heart disease, and moderate to severe myocardial ischemia. The most frequent component of the composite cardiovascular end points was myocardial infarction. So in the current report from Dr. Chaitman and colleagues from St. Louis University school of medicine, the aim was to compare treatment effects on the primary and major secondary competent end points in the ischemia trial using the pre-specified primary and secondary MI definitions. Dr. Greg Hundley: So Carolyn, what were those two EBI definitions, the primary and secondary? Dr. Carolyn Lam: Right. Now, I'm going to try to simplify this. So, for procedural MI, the primary MI definition use CK-MB as the preferred biomarker, whereas the secondary definition used cardiac troponin. Dr. Greg Hundley: Great, Carolyn. So what did they find? Dr. Carolyn Lam: So procedural MI definition had an important impact on event frequency and subsequent prognosis. When the pre-specified secondary MI definition was applied, the conservative strategy had a significantly lower composite event rate for the primary and major secondary trial end points, due to an increased number of procedural MIs in the invasive strategy. Furthermore, spontaneous Type One MI events associated with increased risk of cardiovascular death were reduced with an invasive strategy, which is either PCI or CABG. Dr. Greg Hundley: Nice, Carolyn. Well, my first paper actually is a favorite topic of yours, HFpEF. And it really involves the central command and the regulation of exercise rate response. It comes to us from Dr. Ben Levine and colleagues at the University of Texas Southwestern Medical Center in Dallas. Dr. Carolyn Lam: Yay. Dr. Greg Hundley: All right, Carolyn. So chronotropic incompetence is common in HFpEF. And it's linked to impaired aerobic capacity. Whether upstream, autonomic signaling pathways are responsible for raising exercise heart rate are impaired in patients with HFpEF, That's really unknown. Dr. Carolyn Lam: Yep. It is something that we wonder. And so what did Dr. Levine find? Dr. Greg Hundley: Thanks Carolyn. So the central command, so vaguely mediated and the metabo-barrow receptor function, which is sympathetically mediated in patients with HFpEF, We're not different from healthy senior controls, despite significantly lower peak whole body exercise, heart rates. So these results, Carolyn, demonstrate key reflex autonomic pathways, regulating exercise, heart rate responsiveness are actually intact in patients with HFpEF. Great new work from Dr. Ben Levine. Dr. Carolyn Lam: And I love the way you summarized that. Thank you, Greg. Well, my next paper is the first report implicating the cross priming function of dendritic cells in immunopathology after Type Two MI. And that includes inflammation, fibrosis and functional decline. Dr. Greg Hundley: So tell us a little bit more Carolyn about these dendritic cells? Dr. Carolyn Lam: Ah-ha so I was ready for that question. So after ischemic injury to the myocardium, dendritic cells respond to cardiomyocyte necrosis present the cardiac antigen to T-cells and potentially initiate a persistent auto-immune response against the heart. So cross priming dendritic cells may have the ability to activate both CD4-positive helper and CD8-positive cytotoxic T-cells in response to necrotic cells. And may thus be crucial players in exacerbating auto-immunity targeting the heart. Dr. Carolyn Lam: So, in this study, authors led by Dr. Sattler from Imperial College, London, performed some elegant mouse experiments and showed that cross-priming dendritic cells were present in the heart and activate it after ischemic injury. Depletion of these dendritic cell cross priming function, inhibited accumulation, and activation of cytotoxic T-cells and stopped myocardial immunopathology and functional decline. So with cross-priming, these authors provided a targetable pathway to prevent activation of T-cells cyto-toxicity and persistent post Mia immunopathology exacerbating heart failure risk. Dr. Greg Hundley: Oh, beautiful. Carolyn, what a great description there. So my next paper comes to us from Dr. David Park from the New York University school of medicine. So Carolyn elevated intracardiac pressure due to heart failure, induces electrical and structural remodeling of the left atrium that begets atrial myopathy and arrhythmias. At present the underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. So the purpose of this study for these investigators was to characterize the response of the ETV1 signaling axis in the left atrium during cardiac pressure overload in humans, as well as mouse models. And explore the role of ETV1 in atrial electrical and structural remodeling. Dr. Carolyn Lam: Ah, another study involving both animal and human models. Very important subject too. So what were the results? Dr. Greg Hundley: Well, Carolyn, evidence from both the Cleveland Clinic, Biobank Human Subjects Repository and the animal science experiments revealed that ETV1 is downregulated in the left atrium during cardiac pressure overload. Thereby contributing to both the electrical and the structural remodeling that we observe in the left atrium during cardiac pressure overload. Dr. Carolyn Lam: Nice. Well, let's quickly finish up with what's in the mailbag. We've got a research letter by Dr. Randi on the lack of evidence of AEs to expression and replicative infection by SARS-CoV-2 in human endothelial cells. There's another by Dr. Stokes on the association of cigarette and electronic cigarette use patterns with levels of inflammatory and oxidative stress biomarkers among US adults. And another research letter by Dr. Hemelsoet on screening for Fabry disease in male patients with arrhythmia requiring pacemaker or ICD. Dr. Greg Hundley: Thanks Carolyn. So I've got a paper it's a cardiovascular case series from Dr. Workman that involves a case of presyncope after transcatheter aortic valve replacement. Dr. Özeke has an ECG challenge reminding us that common things occur commonly. Dr. Zaha has a Perspective entitled, "Mending Broken Hearts, a New Treatment Paradigm for Immune Checkpoint Inhibitor Induced Myocarditis." And then finally, Dr. David Goff, the director of the NHLBI has a wonderful perspective piece (Special Report). And it really addresses some results from the Bethesda conference at the National Heart Lung and Blood Institute and the American Heart Association. And it was co-sponsored the bending curve of cardiovascular disease mortality, the Bethesda plus 40 years Symposium. Dr. Greg Hundley: The report, Carolyn, summarizes the relevant research, policy, and practice opportunities discussed at the symposium, including participant led discussion that explored the challenges and barriers in promoting cardiovascular health, across lifespan. And established a potential framework for observational research interventions that would begin in early childhood. Well, Carolyn, how about now we jump forward to that feature discussion. Dr. Carolyn Lam: All right, now we can go. Dr. Greg Hundley: Well, listeners, we are to the feature discussion today. And we have with us Dr. Chintan Dave from Rutgers University in New Jersey, and our own associate editor, Dr. Naveed Sattar from Glasgow, Scotland. Welcome gentlemen. Chintan, could you explain to us some of the background information that went into the construct of your study and then what hypothesis did you want to test? Dr. Chintan Dave: So just for background, so we know that artheriscraotic cardiovascular events in heart failure typically occur in higher prevalence in patients with type two diabetes. What's been really exciting in recent years is that certain second-line therapies, namely SGLT2 inhibitors and GLP-1 receptor agonist in these large cardiovascular outcome trials have shown to reduce the incidents of cardiovascular events. So from these trials, we can infer that SGLT2 inhibitors typically reduce heart failure hospitalizations, and also have an impact on 3P-MACE, which is just the composite of cardiovascular death, non-fatal MI and non-fatal stroke hospitalizations. While GLP-1 receptor agonist tend to reduce, also have an impact on 3P-MACE, but they also have some modest benefits in heart failure hospitalizations as well. Dr. Chintan Dave: So now that we know that these agents reduce cardiovascular risk, what's not known is, whether or not, if we can use these agents together to further maximize a reduction in cardiovascular events. So in the cardiovascular outcome trials the dual use of SGLT2 two inhibitors and GLP-1 receptor agonists was rare and ranged from between 0% to 5.3%. So as a starting point, we said, "Okay, let's look at observational data to see what happens when you add SGLT2 inhibitors to patients who are already using GLP-1 receptor agonist." And we hypothesized that, given the orthogonal pharmacodynamic effects on cardiovascular risk, adding SGLT2 inhibitors to existing GLP-1 receptor therapy should further reduce cardiovascular events. Dr. Greg Hundley: Very good. And can you describe for us your study population and study design? Dr. Chintan Dave: Sure. So we used three databases in the US. Two of these databases were commercial claims data, which is typically your employer based insurance plans, which have patients between the ages of 18 and 64. And we supplemented that data with Medicare fee for service claims, which have patients over the age of 65. So within these three databases, we identified patients who have a diagnosis of type two diabetes and are already a GLP-1 receptor therapy or GLP-1RAs and initiating either SGLT2 inhibitors or sulfonylureas. Dr. Chintan Dave: And after we identified this patient population, we controlled for several pertinent variables that could be considered confounders, including socio-demographic variables, diabetes complications, and cardiovascular conditions. And we had two primary endpoints. The first primary end point of interest was a composite cardiovascular endpoint, which is defined as the composite of non-fatal MI or nonfatal stroke hospitalizations in all cause mortality. The reason we used all cause mortality instead of cost specific mortality is basically because we didn't have information on cause of death. So we have to resort to a more generic definition of mortality in the composite cardiovascular endpoint. The second primary endpoint that we used was heart failure hospitalizations. So we then in this population, estimated hazard ratios using basically a time to event framework. Dr. Greg Hundley: Okay. And what were your results? Dr. Chintan Dave: So after applying the eligibility criteria in all three databases and after doing a one-to-one propensity score matching, we had 12,500 patients who initiated SGLT2 inhibitors and 12,500 patients in the sulfonylurea groups. For the true primary end points the addition of SGLT2 inhibitors to baseline GLP-1RA therapy was associated with a 22% decrease in the incidents of composite cardiovascular end point or an adjusted hazard ratio of 0.78. And the caught 95% confidence intervals were statistically significant. For the endpoint of heart failure hospitalizations, we noted a 36% decrease in the risk of heart failure hospitalizations with the adjusted hazard ratio being 0.64. And again, that was statistically significant as well. Dr. Chintan Dave: The CCE or the Composite Cardiovascular Endpoints was driven primarily by non-statistical decreases in the risk of MI by about 25%, in all cause mortality by about 32%. But we also found no effect on stroke, which is also in line with what others have reported. The other thing we looked at was also to look at any evidence for heterogeneity in treatment effects by presence of cardiovascular diseases. And we found no statistical significant difference in that aspect. The last thing we looked at also was to look at any evidence of heterogeneity by baseline cardiovascular disease in the patient groups. And we found no evidence to that effect. Dr. Greg Hundley: Very nice. Well, Naveed help us put this study in perspective with some of the other research that I know you're familiar with related to the use of SGLT2 inhibitors and GLP-1 receptor agonists. Dr. Naveed Sattar: Yeah. Thanks Greg. So as we all know, the biggest gains in diabetes in the last few years is these two costs of the trucks SGLT2 inhibitors and GLP-1. We believe and the evidence suggests that SGLT2s, are more cardiorenal in its benefits, and GLP-1 more atherothrombotic. So the hope is that if you combine these drugs, you get additional benefits, but there are no trials that have actually tested this. So this particular paper being kind of first observational, look at adding an SGLT2 versus another drug on top of a GLP-1, tries to get at that particular question. And it provides an early hint that yes, if you add an SGLT2 on top of the GLP-1, you get additional benefits. Giving us some insight that yes, you combine these two classes of drugs, you might get additional benefit in one drug on its own. Dr. Naveed Sattar: Of course, this is not trial. Some of our readers are going to be nihilist and will not believe the data because it's not a trial, but that's fine. But it's done as well as it possibly can. This observational propensity analysis is well matched. The data have some kind of external validity in the sense that the greatest benefits or risks reductions, but for heart failure post-acquisition, which is what we would believe ratio to inhibitors. So there is some sense of validity here, but clearly colleagues, they want to know, and I actually had a patient in the clinic on Tuesday who was on a GLP-1 and actually was an SGLT2. And I wanted to add the GLP-1. And this kind of evidence provides me some evidence of confidence that yes, by adding both drugs, I might get additional benefits in that one drug on its own. Dr. Naveed Sattar: So what you're going to ask next, Craig, and I'll give my answer first. What we really need to do now is actually do the trials. And I think the trials will predominantly work, adding GLP-1 on people who are on SGLT2, because I think more people will be initially an SGLT2 because it's a oral therapy. Then we'll add GLP-1. Although we do have a new oral GLP-1 in play as well. So, that's the kind of paradigm we're in. Some hints, the combination gives you more than the single drug and I think that's really quite promising for people. Dr. Greg Hundley: Very nice. So Naveed suggesting a clinical trial to confirm some of these results. Chintan, do you have anything to add? What study do you think or what area of investigation in this field do you feel is next in line? Dr. Chintan Dave: Yeah, I mean, I would just start by saying that I agree with everything that Naveed said in the sense that this is a starting point. And that I think the key take home from this study that sort of is going to be published is basically that not only do SGLT2 inhibitors reduce the cardiovascular events in patients using GLP-1 therapy, but the fact that the magnitude of this reduction is very similar. What was noted in cardiovascular outcome trials of SGLT2 inhibitors for GLP use was very minimal. In other words, you can super impose the cardiovascular benefit profile of the SGLT2 inhibitors, which were seen in trials two patients using GLP-1 therapy. Dr. Chintan Dave: Now the converse is what needs to be done next, basically, where we need to look at what happens when you add GLP-1 receptor agonist, to SGLT2 inhibitors, as Naveed just said. And he raised a really good point in that more patients are going to be on SGLT2 inhibitors, because they want to avoid GLP-1 receptor agonist because they don't want to use injectable therapies. Of course we have oral semaglatites maybe that may mitigate these issues. But the fact that that aspect is still unknown, could potentially be really good idea for future studies. So that potentially would be a nice, good step. Dr. Greg Hundley: Excellent. Dr. Naveed Sattar: Can I see one last thing, Greg? There is a trial coming this year called AMPLITUDE‐O, which is a GLP-1 trial, which does have a fair number of people on base than SGLT2s. We might be able to get a curly hint at that ongoing trial in the next six months to a year. Dr. Greg Hundley: Excellent. Well, we want to thank both Chintan Dave from Rutgers and our own associate editor, Dr. Naveed Sattar from Glasgow, Scotland. And really presenting information from US Claims databases highlighting the addition of SGLT2 inhibitors to GLP-1 receptor agonists and finding there was an association with a further reduction of cardiovascular risk relative to the use of GLP-1 agonists alone. On behalf of both Carolyn and myself, we want to wish you a great week. And catch you next week On the Run. This program is copyright of the American Heart Association, 2021.  

One of my favorite things about doing this podcast is actually putting a voice to people I follow on social media. I always pictured Greg as Larger Than Life - you know - Ultra Ninja like. He is so down to Earth. He has so many accomplishments and we only touched a few of them. I definitely found out why so many people are so found of him. He so super cool and personable. Can't wait for you to listen!Thanks Greg!You can follow Greg:Twitter - https://twitter.com/UltraNinjaRunnrInstagram - https://www.instagram.com/ultraninjarunnr/Website - https://www.gregsisengrath.com/team-ninja-coaching----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Leave me some feedback on Twitter or Instagram. Reach out and ask questions. Share suggestions.You can follow me:https://twitter.com/MIDAGEDRUNNERhttps://www.instagram.com/midagedrunner/You can follow The Social Run Podcast:https://twitter.com/SocialRunPodhttps://www.instagram.com/thesocialrunpodcast/Share the podcast with someone. It makes all the difference!

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, 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 discussion, actually our whole issue, is going to involve the flozins, empa, dapa, et cetera, but that feature discussion will get some results from the EMPEROR-Reduced trial. Well Carolyn, how about we grab a cup of coffee and this is your area, so we're going to let you run with it today. Dr. Carolyn Lam: Man, and I can't wait to talk about this. Yes, the sodium-glucose cotransporter 2 inhibitors or SGLT2 inhibitors, are indeed now the foundational therapies for patients with heart failure with reduced ejection fraction. Initially developed to improve glucose control in patients with type II diabetes, SGLT2 inhibitors have beneficial cardiovascular and renal effects in patients with diabetes, HFrEF, chronic kidney disease. Well, today's issue contains two pre-specified subgroup analyses from DAPA-HF and EMPEROR-Reduced, both trials evaluating SGLT2 inhibitor effects on renal outcomes, as well as cardiovascular outcomes, by baseline renal function in patients with HFrEF. The first paper comes from Dr. Jhund and colleagues from the University of Glasgow and it is revolving around the DAPA-HF trial. Dr. Greg Hundley: Ah Carolyn, tell us a little bit about DAPA-HF. Dr. Carolyn Lam: Gladly. In DAPA-HF, the SGLT2 inhibitor, dapagliflozin, reduced the incidence of the primary composite outcome of cardiovascular death or worsening heart failure in patients with HFrEF, with and without diabetes and an estimated GFR of greater or equal to 30. Of more than 4,700 patients with a baseline GFR, 41% had a GFR less than 60. The effect of dapagliflozin on the primary and secondary outcomes did not differ by GFR category or examining GFR as a continuous variable. The pre-specified composite renal outcomes, which in DAPA-HF was a more than 50% sustained decline in GFR, end stage renal disease or renal death. Now this composite renal outcome was not reduced by dapagliflozin, but the rate of decline of GFR between days 14 and 720 was less with dapagliflozin. Dr. Greg Hundley: Carolyn, what's the take home message here? Dr. Carolyn Lam: Dapagliflozin slowed the rate of decline in GFR in patients with HFrEF, both in patients with and without diabetes. There was no difference in the efficacy of dapagliflozin by baseline renal function in preventing the risk of cardiovascular death or worsening heart failure. Dr. Greg Hundley: Okay, well now how about the EMPEROR-Reduced trial? Dr. Carolyn Lam: All right. Well, let me remind you first that in EMPEROR-Reduced the SGLT2 inhibitor empagliflozin also reduced cardiovascular death or heart failure hospitalization and total heart failure hospitalization and slowed the progressive decline in kidney function in patients with heart failure with reduced ejection fraction with and without diabetes. Now, more than 3,700 patients were randomized, of whom 53% had chronic kidney disease, defined as a GFR less than 60 or a urinary albumin to creatinine ratio above 300 milligrams per gram. Empagliflozin reduced the primary outcome and total heart failure hospitalizations in patients with and without chronic kidney disease. Empagliflozin also slowed the slope of GFR decline and the risk of the pre-specified composite kidney outcome, now defined as a sustained, profound decline in GFR, chronic dialysis or transplant, was reduced similarly in patients with and without chronic kidney disease. Dr. Carolyn Lam: The effect of empagliflozin on the primary composite outcome of cardiovascular death and heart failure hospitalization, as well as the key secondary outcomes of total heart failure hospitalization and GFR slope, were consistent across the broad range of baseline kidney function measured by clinically relevant GFR subgroups or by albuminuria and including patients with a GFR as low as 20. Above all, empagliflozin was well tolerated in these patients with chronic kidney disease. All of this is discussed in a beautiful editorial by doctors Carnicelli and Robert Mintz. Dr. Carolyn Lam: Now, can I tell you about yet another paper with the SGLT2 inhibitors? This time a pre-specified comparison of the effect of empagliflozin in patients with and without diabetes. Dr. Greg Hundley: Ah, great Carolyn. What did this study find? Dr. Carolyn Lam: Well, this is from Dr. Stefan Anker from Berlin and colleagues, including myself and of the more than 3,700 patients enrolled in EMPEROR-Reduced, 50% had diabetes, 34% had pre-diabetes and 16% had normal glycemia. Empagliflozin reduced the risk of the primary outcome similarly in patients with and without diabetes. Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total heart failure hospitalizations, on the decline in EGFR over time or on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with pre-diabetes or normal glycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome. Empagliflozin also did not lower HbA1c in patients with pre-diabetes or normal glycemia and was not associated therefore with an increased risk of hypoglycemia. Dr. Greg Hundley: Carolyn what's the take home message here? Dr. Carolyn Lam: Well, empagliflozin significantly improved cardiovascular and renal outcomes in patients with HFrEF, independent of baseline diabetes status and across the continuum of HbA1c. Dr. Greg Hundley: Very nice Carolyn. Well, my paper comes from professor Wai Ho Tang and it's a basic science paper. Carolyn, aberrant expression of circular RNA or CircRNA, contributes to human diseases. CircRNAs regulate gene expression by sequestering specific microRNAs. In this study, the authors investigated whether CircMAP3K5 could act as a competing endogenous microRNA-22-3p sponge and regulate neointimal hyperplasia. Dr. Carolyn Lam: Wow, that's interesting. And what were the results? Dr. Greg Hundley: Carolyn, the authors identified that CircMAP3K5 is a master regulator of TET2-mediated, vascular smooth muscle differentiation. Targeting CircMAP3K5, microRNA-22-3p and the TET2 axis, may provide a potential therapeutic strategy for diseases associated with intimal hyperplasia, including restenosis as well as atherosclerosis. Dr. Carolyn Lam: Oh, nicely summarized. Thanks Greg. Well, we've got other papers in today's issue. There's an ECG challenge by Dr. Frész on acute coronary syndrome with tall R waves and inverted T waves in the precordial leads, an ignored entity. We have an exchange of letters between Drs. Vandecasteele and Zhao regarding the article, Cardiac Over Expression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure. Dr. Greg Hundley: Thanks Carolyn. I have some Research Letters. The first Research Letter is entitled, “Cardiovascular Toxicities Associated with Loperamide: An Analysis of the World Health Organization Pharmacovigilance Database,” and the corresponding author is Dr. Pierre Ollitrault. The second Research Letter is entitled, “Incessant Pericarditis as a Risk Factor for Complicated Pericarditis and Hospital Admission,” and it comes from Professor Massimo Imazio. And then finally, there's a White Paper (Frontiers) for atrial fibrillation screening research priorities from the NHLBI workshop with the corresponding author being Dr. Emelia Benjamin from Boston University School of Medicine. Well Carolyn, how about we jump in to more SGLT2 and another feature discussion? Dr. Carolyn Lam: Yes, can't wait. Thanks Greg. Dr. Greg Hundley: Well listeners, we're now to our feature discussion and we have with us today, Dr. Milton Packer from Baylor University Heart Vascular Center in Dallas and also our own associate editor, Dr. Justin Ezekowitz from Edmonton. Milton, welcome and wanted to ask you first off, tell us a little bit about the background that got you to want to perform this study. And what hypothesis did you want to address? Dr. Milton Packer: Greg, first of all, I'm delighted to be here with you and Justin. And as everyone knows, SGLT2 inhibitors have had a remarkable track record in trials of type II diabetes, trials of chronic kidney disease and now trials of patients with heart failure and a reduced ejection fraction. And in these trials, SGLT2 inhibitors have had two important benefits. The first benefit has been a reduction in serious heart failure events, primarily a reduction in heart failure hospitalizations. And the second has been a reduction in serious adverse renal outcomes. And that has been now shown consistently in trial after trial in diverse populations. Dr. Milton Packer: Now we carried out a trial called EMPEROR-Reduced with was the trial in patients with heart failure and a reduced ejection fraction. It was a sister study, so to speak, with a very parallel trial called DAPA-HF, which was carried out with dapagliflozin. And both DAPA-HF and EMPEROR-Reduced were studies, were trials of SGLT2 inhibitors, dapagliflozin and empagliflozin in people with heart failure and a reduced ejection fraction. And they produced remarkably consistent results. And specifically a reduction in serious heart failure events and serious adverse renal events. Dr. Milton Packer: But the trial studied complimentary patient populations. We studied patients that were a bit sicker than patients in DAPA-HF. And Greg, what's really fun is that each trial designed its own case report forms so that we collected information that the investigators were really interested in and they were not necessarily the same types of information across the two trials. One of the things that was really interesting about EMPEROR-Reduced was we were really interested in these heart failure events. We wanted to understand them. We wanted to understand whether they occurred as outpatients, inpatients. If they occurred as inpatients, what kind of hospitalizations were these? Were these serious hospitalizations? Were these short term, very mild hospitalizations? This paper, the hypothesis in this paper was to take a look at what empagliflozin did in patients with heart failure and reduced ejection fraction, specifically with respect to outpatient and inpatient worsening heart failure events. Dr. Greg Hundley: Very nice. How many patients did you include? What were the characteristics of the study population? And what was the design? Dr. Milton Packer: We enrolled, randomized 3,730 patients. All patients had heart failure with a reduced ejection fraction. All were receiving all appropriate treatments for heart failure. Interestingly, 20% were receiving nephrolysin inhibitors, which is really a very high percentage, but they were also receiving inhibitors, renin-angiotensin system beta blockers, mineralocorticoid receptor antagonists and they were patients who had an average ejection fraction of about 27%, which is much lower than most heart failure trials recently. They also had meaningfully elevated levels of natriuretic peptides. These were sicker patients and they had a much higher placebo event rate. They were randomized double-blind, one to one ratio to either placebo or empagliflozin. Dose was 10 milligrams once daily. And this was added to all previously existing therapy and patients were followed for double-blind therapy for an average duration of 16 months and we recorded prospectively information on outpatient and inpatient heart failure events. Dr. Greg Hundley: Very nice. What did you find, Milton? Dr. Milton Packer: We originally reported that in this trial, there was a reduction with empagliflozin on heart failure hospitalizations and that reduction was about 30%. We wanted to know, well, what else was going on with respect to these heart failure events? And so we asked the question, well, did empagliflozin reduce urgent and emergency room visits for heart failure? Did empagliflozin change the types of hospitalizations? We recorded the use of positive inotrophic drugs, vasopressor drugs, vasodilator drugs, cardiac devices, intervention, surgical interventions. And we found out that across the entire spectrum of heart failure outcomes, there was a reduction in serious outcomes with empagliflozin and they all were around a 30% reduction in risk. They varied a little bit from about 28 to 33, but approximately all were in the same ballpark. And what was really interesting was we had a fair number of hospitalizations where patients required IV inotropic drugs, vasopressors, mechanical intervention, they were reduced by 30% with empagliflozin. Hospitalizations associated with intensive care reduced by 30% with empagliflozin. Dr. Milton Packer: And then we looked at outpatient events. Outpatient intensification of diuretics reduced by 30, 33% with empagliflozin. We looked at New York heart class. And what was really interesting was that patients treated with empagliflozin had a 20 to 40% greater likelihood of showing improvement in New York heart class and a 20 to 40% lower likelihood of showing worsening in New York heart class. And those benefits, we're seeing within 28 days after randomization. This early effect is really interesting and it's generated a lot of discussion. And so we looked at our Kaplan Meier curves for the composite of cardiovascular death, heart failure hospitalizations, urgent care, emergent care visits, and we found that the two curves separated quite early and reached statistical significance only 12 days after randomization. This is a very early effect. I want to add that this early separation of curves has been reported previously with beta blockers, with mineralocorticoid receptor antagonists, with neprilysin inhibitors and now we can add this early separation with SGLT2 inhibitors. Dr. Greg Hundley: Very nice, Milton. Well, I'd like to turn now to our associate editor, Dr. Justin Ezekowitz. and Justin you've seen a lot manuscripts come pass through your hands. What attracted you to this manuscript? And then how do you put the findings that Milton has just described in the context with the other results that we have been witness to regarding SGLT2 inhibitors? Dr. Justin Ezekowitz: Thanks Greg. And also, thanks Milton for letting us look at this remarkable manuscript as I do think the clinical implications for a manuscript like this are quite profound. The first thing that really strikes me is we often get worried about looking at a number of different end points. Within a clinical trial, we often don't want to have too many looks at the data because of the risk of finding something that is spurious, is high, but in this case, the way the data was collected and the exploration is quite valuable. We can look at any one of the combinations of clinical end points that actually have direct clinical relevance for a clinician and the patient. And this paper really explored that in a lot of data, in a lot of depth and also helped us by putting the caveats around these findings that this is exploration, but it does anchor it in the SGLT2 world, but also the heart failure world. Dr. Justin Ezekowitz: And Milton, I think one of the striking findings that you showed and it's buried in many of the great figures and tables, is that one in two patients had something happen in the next year. In the next 12 months, that patient walking into an office for a routine followup, one in two had something and the reduction was pretty remarkable across the end point. Milton, I wanted to pick your brain on this one, just to understand when you look at the intensification of diuretics, that was anything from adding another 20 milligrams of furosemide, to doubling or tripling that. Do you think these findings are pretty ubiquitous across the patients enrolled? Or do you think they're a niche finding in only some patients at the highest risk? Dr. Milton Packer: Well, we actually looked at that. We actually looked at whether baseline variables influenced the effect on intensification of diuretics and it was across the board. Well, let me just say, across the board in the patients that we studied and obviously can't make reference to people we didn't study, but we didn't find any particular subgroup that responded particularly well with respect to either a hospitalizations or diuretic intensification or New York heart class changes. But Justin, there's one thing that you just said that is so important. And that is, our patient population was characterized by their physicians, 70% as having class II heart failure. And a lot of physicians think that class II heart failure represents a stable population, clinically stable population. And as you said, one in two patients in our study during followup had worsening heart failure, either represented as an inpatient or outpatient event. A class II patient with heart failure and reduced ejection fraction, even though they're getting optimal medical therapy, is not a clinically stable patient. Dr. Greg Hundley: Very, very interesting finding. Well, just to ask each of you, maybe Milton first and then Justin next, Milton, what do you think is the next study that we need to perform in this patient population using this class of drugs? Dr. Milton Packer: We're really excited about a new phase of heart failure research with SGLT2 inhibitors, which is to look at the impact of these drugs in patients with heart failure and a preserved ejection fraction. DAPA-HF and EMPEROR-Reduced were trials of inpatients with hard failure and a reduced ejection fraction. But we really, about half patients with heart failure, have an ejection fraction of greater than 40%. We really need to understand what SGLT2 inhibitors can do for these patients. And here's the good news. And there are two large scale trials that are both nearing completion. And the first of those trials will be reporting out in about nine months from now with the next trial following about six months later. We will in the next 12 to 18 months, have two major large scale trials of these drugs in a population which is highly different and yet complimentary to the patients who have been studied to date. Dr. Greg Hundley: Justin, how about you? Dr. Justin Ezekowitz: Well, to compliment what Milton is suggesting, I think that's one area. And I think the other area is in implementation science. Now that we have four big classes or groups of drugs, is to how to start these and how to optimize these efficiently in the first month to two months or even three months so the patients can get the benefit for all these medications. And I think what we need to really study is how do we do that? Because we have the drugs but the implementation is where we're not quite there yet. If we get the implementation and testing, randomized strategies and how to do it, I think we may be able to help more patients globally than with the addition of even any new drug that may come out onto the markets soon or in the future, as that remains one of our challenging topics. Dr. Greg Hundley: Well listeners, we want to thank Dr. Milton Packer for bringing this study to us at Circulation and also our own associate editor, Dr. Justin Ezekowitz and really highlighting how the initiation of this SGLT2 inhibitor, empagliflozin, at 10 milligrams per day, in a heart failure reduced ejection fraction population with an average left ventricular ejection fraction of 27%, resulted in a 12 day, at 12 days into therapy, a separation of the development of adverse heart failure related events that was then sustained over the next 16 months. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, I want to wish everyone a great week and we will catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021.  

How far would you go to save money? The bar: "I wear the same pair of jeans everyday, Free sandwiches, homie, two stamps away; Book flight December but I leave in May, Drugs are generic but still work the same; I get logins for Netflix from my cousin Greg, Thanks Greg!... Save dat money"

One thing is for sure, you better love Dunn’s Dill Pickle potato chips because the bag is massive! As in over a pound and half of potato chips. These chips from Dunn’s, a Montreal restaurant since 1927, were sent in my man Greg. Thanks Greg! So, how’d these dill pickle potato chips stack up? Watch and find out --- Support this podcast: https://anchor.fm/inthechips/support

My boss was extremely generous and got me a cajon. Wow.

This week on SlapperCast, we talk about favorite Christmas traditions, favorite (and least favorite) Christmas songs. Thanks Greg for the question! Also: brand new Blaggards coffee mugs (https://blaggards.com/store/blaggards-coffee-mug/) are for sale for a limited time at blaggards.com Show notes Merry Christmas Everybody - Slade (https://youtu.be/BpfHSqLXePI) Nat King Cole - "The Christmas Song" (1961) (https://youtu.be/hwacxSnc4tI) Vince Guaraldi Trio - Christmas Time Is Here (Instrumental) (https://youtu.be/YvI_FNrczzQ) Art Carney - Twas The Night Before Christmas (https://youtu.be/1hz1EIpfvLY) PETER SELLERS & SPIKE MILLIGAN - 'Unchained Melody' - 1955 (https://youtu.be/wcHdzdCxLuo) Traveling Wilburys - Heading For The Light (https://youtu.be/VarURT-pH8o) My Way - Drummer Steals The Show (https://youtu.be/a9kPfelTEds) Join us in IRELAND Fall 2021 Ireland 2021 (https://blaggards.com/ireland/) — Sign up to learn more about our next Ireland tour Show dates Blaggards.com (https://blaggards.com/shows/) Facebook (https://www.facebook.com/pg/blaggards/events/) Bandsintown (https://www.bandsintown.com/a/3808) Follow us on social media YouTube (https://www.youtube.com/blaggards) Facebook (https://www.facebook.com/blaggards/) Twitter (https://twitter.com/blaggards) Instagram (https://www.instagram.com/blaggards/) Become a Patron Join Blaggards on Patreon (https://www.patreon.com/blaggards) for bonus podcast content, live tracks, rough mixes, and other exclusives. Rate us Rate and review SlapperCast on iTunes (https://itunes.apple.com/us/podcast/slappercast-a-weekly-talk-show-with-blaggards/id1452061331) Questions? If you have questions for a future Q&A episode, * leave a comment on Patreon (https://www.patreon.com/blaggards), or * tweet them to us (https://twitter.com/blaggards) with the hashtag #slappercast.

Join Andrew Wommack and special guests every weekday for our Charis Daily Live Bible Study! Interact with dynamic speakers in real-time and gain a deeper understanding of the scriptures as they answer your questions. Tune in every day to hear from different speakers as they share from God's Word. The instructors will not only include Andrew Wommack and Charis Woodland Park staff but also our stateside and international directors. You'll witness miracles happen right there, wherever you're listening!

This week on SlapperCast, Eric talks about his adventures with Percussive Arts Society... also favorite instrumentals. Thanks Greg for the question! Blaggards online store https://blaggards.com/store/ Join us in IRELAND Fall 2021 Ireland 2021 (https://blaggards.com/ireland/) — Sign up to learn more about our next Ireland tour Show dates Blaggards.com (https://blaggards.com/shows/) Facebook (https://www.facebook.com/pg/blaggards/events/) Bandsintown (https://www.bandsintown.com/a/3808) Follow us on social media YouTube (https://www.youtube.com/blaggards) Facebook (https://www.facebook.com/blaggards/) Twitter (https://twitter.com/blaggards) Instagram (https://www.instagram.com/blaggards/) Become a Patron Join Blaggards on Patreon (https://www.patreon.com/blaggards) for bonus podcast content, live tracks, rough mixes, and other exclusives. Rate us Rate and review SlapperCast on iTunes (https://itunes.apple.com/us/podcast/slappercast-a-weekly-talk-show-with-blaggards/id1452061331) Questions? If you have questions for a future Q&A episode, * leave a comment on Patreon (https://www.patreon.com/blaggards), or * tweet them to us (https://twitter.com/blaggards) with the hashtag #slappercast.

Film-Maker who is Making a Difference This is definitely one of my all-time favorite conversations on The Journey. I encourage you to listen to this raw and informative conversation about Greg’s film projects from hip-hop music videos, the Space Needle in Seattle to the film project with high school students about the issues they struggle with. We went everywhere during this conversation from film to racial tension to empathy to mental illness and all the stereotypes. Loved this conversation. Thanks Greg.

Today’s episode discusses the paper “Randomized Comparison of the Polymer-Free Biolimus-Coated Biofreedom Stent With the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Orsiro Stent in an All-Comers Population Treated With Percutaneous Coronary Intervention: The SORT OUT IX Trial”   Dr Carolyn Lam and Dr Greg Hundley also discuss the following: “Incidence, Microbiology, and Outcomes in Patients Hospitalized With Infective Endocarditis” by Shah et al. “Reducing Hypermuscularization of the Transitional Segment Between Arterioles and Capillaries Protects Against Spontaneous Intracerebral Hemorrhage” by Joutel et al. TRANSCRIPT 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 Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn our feature article this week, we're going to dive into evaluating stent efficacy and looking at biodegradable stents and polymer free stents, and I can't wait to get to that feature. But before we do that, how about we get to other articles in our journal today? Would you like to start? Dr Carolyn Lam: You bet, Greg. So this paper describes temporal changes in the incidence, microbiology and outcomes of infective endocarditis and the impact of changes in national antibiotic prophylaxis guidelines on incident infective endocarditis in Scotland. Dr Anoop Shah from University Center for Cardiovascular Science at University of Edinburgh, and colleagues used a Scotland wide individual level linkage approach to identify all patients hospitalized with infective endocarditis from 1990 to 2014, and linked their records in national microbiology, prescribing and morbidity and mortality datasets. Dr Greg Hundley: Interesting, Carolyn. So what did they find in this study? Dr Carolyn Lam: The crude incidence rate of infective endocarditis hospitalizations increased from 1990 to 1995 but has remained relatively static thereafter with both short and long-term adjusted case fatality rates showing a steady decrease over the last 25 years. However, the incidence rate has doubled in the elderly. Importantly, there was no change in crude incidence following the 2008 change in antibiotic prophylaxis guidelines. The majority of patients with endocarditis in their cohort did not have positive blood cultures. However, in those that did have positive microbiology, staphylococcus and enterococcus conferred the highest risk for all-cause mortality. Dr Greg Hundley: Ah, very interesting. More in the world of endocarditis. Well, Carolyn, my paper is also interesting and it involves both mouse and human experiments to identify the etiology of deep intercranial hemorrhagic stroke. Now I'm not going to quiz you this week because I think you're going to want to quiz me in anticipation of some of these exciting study results. A little bit of background. First of all, the study comes from Dr Anne Joutel from INSERM and it has been thought that smooth muscle cell degeneration at the site of arterial wall rupture may be sufficient to cause hemorrhage. However, deep intracranial hemorrhages are rare in some aggressive small vessel diseases that are characterized by significant arterial smooth muscle cell degeneration. Therefore, the authors hypothesized that a second cellular defect may be required for the occurrence of intercranial hemorrhage. So to address this hypothesis, the author studied a genetic model of spontaneous deep intercranial hemorrhage in mice, and analyzed cerebral retinal micro vessels, performing genetic rescue experiments, vascular reactivity analysis, and computational modeling. And in the human experiments, they examined post-mortem brain tissues from patients that had sporadic deep intercranial hemorrhage. Dr Carolyn Lam: Wow, that's a lot of work from mice to men. Well, let's start with the mice. So what did they find there, Greg? Dr Greg Hundley: Right, Carolyn. So the authors identified in the normal cerebral retinal vasculature, a novel segment between arterials and capillaries herein called the transitional segment, and that is covered by neural cells distinct from smooth muscle cells and parasites. In Col4a1 mutant mice, this transitional segment was hyper muscularized with a hyperplasia of neural cells expressing more contractile proteins, whereas the upstream arterial exhibited a loss of smooth muscle cells. Moreover, the hyper muscularization of the retinal transitional zone increased its contractility in tone and raised the intravascular pressure in the upstream feeding arterial. Dr Carolyn Lam: Wow, masterful explaining, Greg. Okay. What about in the humans? Dr Greg Hundley: Well, the author similarly found that hyper muscularization of the transitional segment and focal arterial or smooth muscle cell loss in brain tissues from patients were observed in those with sporadic deep intercranial hemorrhage. Dr Carolyn Lam: Okay, so put it together for us, Greg. Dr Greg Hundley: Right. So the results suggest that hyper muscularization of this transitional segment is involved in the incurrence of intracranial hemorrhage in these studied mice, and this hyper muscularization in this zone raises the intravascular pressure in the upstream feeding arterial and promotes its rupture at the site of smooth muscle cell loss. The human data corroborate these findings indicating that these two mutually reinforcing vascular defects may represent a general mechanism of deep intercranial hemorrhage. Really interesting results. Dr Carolyn Lam: Not just interesting, but very, very nicely summarized. Thanks Greg. Well, other very interesting papers in today's issue include a research letter by Dr Tiantian Li et al, entitled Associations Between Short Term Exposure to Fine Particulate Matter and Cardiovascular Disease Hospital Admissions After Index Myocardial Infarction. A case crossover study from Beijing, China. There's also a white paper from Dr Milton Packer on the role of deranged energy deprivation signaling in the pathogenesis of cardiac and renal disease in states of perceived nutrient over abundance. This beautiful white paper presents a mechanistic framework that may explain the findings of large scale randomized trials of SGLT-2 inhibitors and the close association of ketogenesis and erythrocytosis with the cardio protective and renal protective benefits of these drugs. Interesting. There's also a series of papers on COVID-19, including an online white paper by Dr Franz Messerli on COVID-19 and renin-angiotensin blockers, current evidence and recommendations. A perspective paper by Dr Michael Givertz on the challenges in heart transplantation in the era of COVID-19. Another online paper by Dr Harsimran Singh entitled New York City innocence lost, cardiology in the COVID-19 pandemic. Dr Greg Hundley: Wow, Carolyn, this issue is just truly full of a lot of articles in addition to our original research. So I have an exchange of letters to the editor between Richard Sutton and Dr Ben Levine regarding Dr Levine's previously published tilt table manuscript. Next, Dr James Byrd from the University of Michigan offers a perspective on pausing clinical research during the COVID-19 pandemic. Dr Comilla Sasson from the American Heart Association heads a very large group of authors to provide a very nice piece on guidance for life support during the COVID-19 pandemic. Next, Professor Guilo Stefanini from Humanitas University has a research letter regarding ST elevation myocardial infarction in patients with COVID-19, both the clinical and the angiographic outcomes. And then finally, another ECG challenge from Dr Adrian Baranchuk entitled an ominous ECG sign in critical care. Well, Carolyn, what a great issue, and let's get on to that feature discussion to learn a little bit more about bio resorbable intercoronary stents. Dr Carolyn Lam: Great. Let's go, Greg. Dr Greg Hundley: Well, listeners, We're here for our feature discussion. And today we have Professor Lisette Jensen from Denmark and Dr Dharam Kumbhani from Dallas, Texas, one of our own associate editors. Lisette, could you tell us a little bit about the background for your study of intercoronary stenting and what was the hypothesis that you wanted to address? Prof Lisette Jensen: The overall background or aim for this program is that we want to have a quality control of what we put into the patients, what stent we put in, and also we wanted to do as much research as possible, and we want to do it if it's possible on a low budget. For the present study, the Sort Out IX, before we did the study, we knew that the Bio Freedom stent was doing very well with a short time of dual antiplatelet therapy in patients with high bleeding risk. At the same time, we knew that the Orsiro stent was doing very well in all common populations, we used it in Sort out VII also. We wanted to see how the Bio Freedom stent, the one you could use with a short time of dual antiplatelet therapy, how it was compared to a gold standard stent. In this study, we did not shorten the treatment time with dual antiplatelet therapy, but we followed the guidelines with six months for patients with stable angina, and 12 months for patients with acute coronary syndrome. Dr Greg Hundley: Can you just remind our listeners, what's the difference between the Bio Freedom stent and then Orsiro stent? Prof Lisette Jensen: There's several differences. The strut thickness of the two stents differs. The Orsiro stent is an ultra-thin stent strut and the Bio Freedom stent is 120 microns. Also, the Bio Freedom stent is free of a polymer, compared to the Orsiro stent where the polymer is biodegradable and is degraded in one to two years. And also the drug is sirolimus in the Orsiro stent and it is released within three months compared to the Bio Freedom stent where most of the drug biolimus is released within one month. Dr Greg Hundley: So the Bio Freedom is a stainless-steel drug coated stent, and the Orsiro stent is a biodegradable stent. So can you tell us what was the study design, and then the study population? Prof Lisette Jensen: It was a randomized trial and we enrolled 3,151 patients. They were randomized one to one, two to two stent groups, and we followed the patients. The primary endpoint was after one year, and this is what we're going to publish now in the journal, and we plan to do up to five years follow-up in the patients. Dr Greg Hundley: And what outcomes were you looking for? Prof Lisette Jensen: The primary endpoint was MACE, and that was a composite endpoint of cardiac deaths, target lesion revascularization, and myocardial infarction, not clearly related to any other segment that the index listed. Dr Greg Hundley: So 3,151 patients, so a very large study. Can you tell us a little bit about your study outcomes? Prof Lisette Jensen: The outcome was the primary end point after one year was, we saw MACE rate in the Bio Freedom treated patients was 5.0% compared to 3.7% in the Orsiro group. And the study was designed as a non-inferiority study, so with these numbers, Bio Freedom stent did not meet the criteria for non-inferiority.   Dr Greg Hundley: And were there any particular patient populations or subgroups where you saw differences in performance from one stent versus the other? Prof Lisette Jensen: We looked into several predefined subgroups, which are also in the paper as figure three where we did a force plot, and in all the pre-specified subgroups, including indication for PCI, acute coronary syndrome or stable angina, young patients, old patients, diabetic, non-diabetic, gender, we did not see any significant difference. Dr Greg Hundley: Well, Dharam, I'd like to switch over to you a little bit. Can you help us put this study in perspective to the other world's literature related to intercoronary stenting? Dr Dharam Kumbhani: You know, one of the biggest advantages of the way they enroll patients is they tend to be a lot more inclusive than many of the other trials that are done. So typically isn't all common population. So, now and again, I think it was an important trial because as she just outlined, it compares the Bio Freedom stent, which is a polymer free stent to a biodegradable stent. And this was really the first comparison of this Bio Freedom stent with a more contemporary stent that is used in clinical practice. There have been a couple of other trials like the industry three and industry two trial which have compared it with bare metal stents. We know that this stent has a better performance than that, but when you compare it with, especially the thin struts or Orsiro, the latest in this class of DES, it is the thinnest strut, one of the thinnest strut stents that is in the market. The strut thickness, we know it really correlates quite well in stent restenosis. I think this really helps move the field forward in terms of having data available for this comparison, and it suggests that perhaps in this kind of pragmatic design, that this Bio Freedom stent did not necessarily in the timeframe that they studied, meet the criteria for non-inferiority compared with the Orsiro stent. So I think there's still valuable insight. The stent is not yet approved in the US. None of the Bio Freedom stents are available in the US. This is CE Mark, but not available in the US. So I think this does add to the overall body of literature for this group of stents. Dr Greg Hundley: I would like to ask you both, perhaps one at a time. Lisette, you first. What do you see is the next research study that needs to be performed in this field? Lisette. Prof Lisette Jensen: Can I just give one more comment to what Dharam mentioned with the restenosis, because that was actually what we saw in the Sort Out IX. We had a higher rate of the target lesion revascularization rate in the Bio Freedom stent group, so the efficacy was less. It could be because of the bigger stent struts, pushing us in a direction where we should use stents with thinner stent struts. And also we saw that the safety did not differ as we saw the equal number of stent thrombosis within one year. I think what we should do next is maybe we should continue to work on the thin stent struts, and then also for the patients, the bleeding matters a lot. So it should be better to reduce the bleeding time to develop devices where we can reduce the treatment time for dual antiplatelet therapy. Dr Greg Hundley: Very good. Dharam, your thoughts? Dr Dharam Kumbhani: I would definitely agree. I think one of the most appealing aspects of this group of stents, because they don't have polymer, the ability to shorten the duration of antiplatelet therapy. And over the last couple of years, we've seen an incredible change in how we think about dual antiplatelet therapy and a number of trials have really challenged that dogma. So I really think that a stent like this, I think it will be very interesting to study this in patients who are either high bleeding risk. This does perform better than bare metal stents, we know that. So conceivably we can get away with a much shorter duration of dual antiplatelet therapy, or just a lower duration of dual antiplatelet therapy in general. So I would think that that would be one of the next areas of research in a randomized fashion for this group of stents. Dr Greg Hundley: Well, listeners, we've had a wonderful conversation here with Professor Lisette Jensen from Denmark and Dr Dharam Kumbhani from Dallas, Texas, related to some new evolutionary thoughts in intercoronary stenting. For all our listeners out there on behalf of Carolyn and myself, we wish you a great week and look forward to speaking with you next week. This program is copyright of the American Heart Association 2020.  

This week Ash and Avi got to go to the Royal Opera House to meet with Director Greg Eldridge and get chatty all about directing... Thanks Greg for coming on the podcast! Greg's links: Website : https://www.greg-eldridge.com Facebook: https://www.facebook.com/directorgregeldridge Twitter: https://twitter.com/Geldridg_ AA Opera Links @AAOperaPod aaoperapod@gmail.com Instagram:http://bit.ly/2YuK7UE Facebook: http://bit.ly/2LQGSVC Twitter: http://bit.ly/2ks38sW Rossini's Dish - https://en.wikipedia.org/wiki/Tournedos_Rossini

Ep.015 - Episode Notes: Dr. J. Gregory Gillum was interviewed on November 22, 2109. He is a Ky native, keynote speaker, author, and acclaimed entrepreneur business coach. Greg is CEO of the humanfusion group of companies. As the lead executive coach and trainer, he specializes in leadership development applications, business performance coaching, emotional intelligence, and guiding transformational change in individuals and organizations. A frequent keynote speaker in the areas of human performance and potential, Greg spent six years on the faculty of the Medical College of Virginia, and eight years in marketing and senior management with GlaxoSmithKline. He earned his doctorate from the University of Kentucky and his professional coaching credentials from the Coaches Training Institute in San Rafael California. He lives with his wife and two children on a farm in the rolling hills of Central Kentucky. Greg is kind enough to share his time and expertise in our classrooms with his friend Dr. Faridah Awang, professor of Corporate Communication and Technology here in the EKU School of Business. Thanks Greg!Find out more at https://business5q.pinecast.co

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage passes 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 Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature article really starts to look at micro-circulatory dysfunction and abnormal coronary perfusion during exercise that can be associated with myocardial ischemia. I hear you're anxious to hear about it, but why don't we go to your article first. Dr Carolyn Lam: Here we go. This first paper I'd like to tell you about reports a novel cardiac kinase as a potential regulator in heart failure. Dr Greg Hundley: Now remind me, Carolyn, I got to take me back a little bit. What are cardiac kinases? Dr Carolyn Lam: Ah, I thought you would ask. Cardiac kinases are known to play a critical role in the development of heart failure and represent potential trackable therapeutic targets. Now to identify novel cardiac kinases involved in heart failure, the corresponding authors, Dr Hind Lal from University of Alabama at Birmingham and colleagues, employed an integrated transcriptomics and bioinformatics analysis and identified homeodomain-interacting protein kinase 2 or HIP kinase 2, as a novel candidate kinase. Now this is the first study to define the role of HIP kinase 2 in cardiac biology. In essence, they performed a series of mouse experiments that showed that cardiac HIP kinase 2 expression is elevated in adults compared to embryonal and neonatal stage of mouse experiments, but down regulated in failing hearts. Deletion of HIP kinase 2 in the cardiomyocytes led to decreased cardiac function in adulthood. The cardiac effect of HIP kinase 2 correlated to its gene expression level and impaired ERK signaling was discovered as the main driver of HIP kinase 2 deficient phenotype by enhancing apoptosis. Taken together these findings really suggest that cardiomyocyte HIP kinase 2 is required to maintain novel cardiac function via ERK signaling. Dr Greg Hundley: All right, Carolyn, my favorite question, what does this mean for us clinically? Dr Carolyn Lam: Two points, first since HIP kinase 2 is protective in cardiomyocytes, gene therapy using HIP kinase 2 could be a potential therapeutic method of heart failure treatment in future. Secondly, because inhibition of HIP kinase 2 has been proposed as a therapeutic approach for certain cancers and for renal fibrosis, these results suggest that caution needs to be taken for the potential cardiotoxicity of HIP kinase 2 inhibition in the adult heart. Interesting. Dr Greg Hundley: Yeah. Very nice. Well, I'm going to switch gears a little bit Carolyn and talk about ablation for atrial fibrillation. And the corresponding author of this paper is Jason Andrade from Vancouver General Hospital. In his study, they randomly assigned 346 patients with drug-refractory paroxysmal atrial fibrillation to A, contact force guided RF ablation, B, four-minute cryoballoon ablation or C, two-minute cryoballoon ablation and they followed the patients for 12 months. Now the primary outcome was time to first documented recurrence of symptomatic or asymptomatic atrial tachyarrhythmias, whether that be AFib, aflutter, atrial tachycardia, between days 91 and 365 after the ablation or a repeat ablation procedure at any time. And the secondary endpoints included freedom from symptomatic arrhythmia and AF burden. Dr Carolyn Lam: Interesting clinical question. What did the results show? Dr Greg Hundley: One-year freedom from atrial tachyarrhythmia defined by continuous rhythm monitoring, was 54, 52 and 52% with each of those therapies respectively. One-year freedom from symptomatic tachyarrhythmia defined by continuous monitoring was 79, 78 and 73% with those therapies respectively. No difference statistically in either. Dr Carolyn Lam: Right. No significant difference in those outcomes but what about AF burden or side effects? Dr Greg Hundley: Right, Carolyn. Well, compared to the pre-ablation monitoring period, AF burden was reduced by a median of 99%, 99.9% and 98.4% in each of the three therapies. No significant difference. And serious adverse events occurred in two patients in the CF-RF group, in six patients in Cryo with four minutes and in seven patients with Cryo in two minutes. Again, no significant difference between those groups. Dr Carolyn Lam: Greg, were there any significant difference in these techniques? Dr Greg Hundley: Well, Carolyn, that contact force RF group at a significantly longer procedure duration but a significantly shorter fluoroscopy exposure. And the P was 0.001 versus the cryoballoon group. In summary, in this multicenter, randomized, single blinded trial, contact force RF ablation, and two different regimens of cryoballoon ablation, resulted in no difference in one-year efficacy, which was 53% by time to first recurrence, but 98% burden reduction as assessed by continuous cardiac rhythm monitoring. A new study in patients with ablations looking at these new techniques and for many reasons they're very similar. Dr Carolyn Lam: Very interesting. My next paper also has to do with atrial fibrillation. Now we know that numerous skills exist for classification of major bleeding events in patients with atrial fibrillation who are anticoagulated. Now there are limited data comparing the most commonly used bleeding scales within a single at-risk cohort of patients with atrial fibrillation. And so Dr Bergmark from the TIMI study group and colleagues analyzed bleeding outcomes according to the ISTH, TIMI GUSTO and BARC bleeding scales in the ENGAGE AF-TIMI 48 trial of edoxaban versus warfarin. And they found that among patients with atrial fibrillation at risk for stroke, there was an approximately four-fold difference in the frequency of the most severe bleeding events across these commonly used bleeding scales. Further, the relative safety of edoxaban as compared with warfarin tended to increase with greater severity of bleeding. Dr Greg Hundley: Interesting Carolyn. Tell me, what's the take home message from this study? Dr Carolyn Lam: This analysis reminds us that the currently available and commonly used bleeding scales differ in important ways. The analysis shows us that one size does not fit all and that the most appropriate bleeding scale really depends on the clinical setting and the intervention being investigated. For patients particularly concerned about bleeding, these results should provide additional reassurance about the safety of the DOX. Finally, this analysis also illustrates how the differential effect of edoxaban compared to warfarin on bleeding, impacts the assessment of net clinical benefit. Now this is discussed in an editorial by John Alexander and Adam Nelson who highlight that one of the most interesting findings was the statistically significant and graded amplification of edoxaban safety compared to warfarin with more severe bleeding. Greg, perhaps now's a good time, tell us what else is in this issue of the journal? Dr Greg Hundley: Happy to do so. Ben Freedman from the University of Sydney discusses in a white paper concurrent thoughts from the AF, another atrial fibrillation paper, AF screen international collaboration, which summarizes existing evidence and knowledge gaps on searching for an AFib post-stroke using ECG monitoring. And Carolyn, our own James de Lemos suggests in an on my mind piece that subdividing type two MI into different based on etiology could lead to improved forecasting of events. In a perspective article, Tommy Wang from Vanderbilt revisits the polypill and discusses why we need population-based approaches in the precision medicine era. Dr Carolyn Lam: Wow. Super interesting. And how about letters? What's in the mailbox? Dr Greg Hundley: Oh gosh, Carolyn. It's really full this week. There are multiple letters ranging from science, to responses, to prior inquiries. It is really interesting to read these responses and the authors going back and forth and having that open discussion for us. And so Brody Slostad first has his own research letter that reviews unicuspid aortic valves, the demographics, comorbidities, and echocardiographic features and long-term outcomes. Darren Casteel from UC San Diego discusses blood pressure lowering by the antioxidant resveratrol is counterintuitively mediated by oxidation of the cyclic GMP dependent protein kinase. And there's a nice response by Dr Joseph Burgoyne from Kings College London. Finally, there's a letter by Daxin Wang and his associates from Yangzhou University regarding the article targeting filament A reduces macrophage activity in atherosclerosis and there's a corresponding response from Levent Akyürek event accurate from the Institute of Biomedicine. Great mailbox this week, Carolyn. How about now we go on to our feature discussion? Dr Carolyn Lam: Oh boy, I can't wait. Thanks Greg. How does coronary microvascular dysfunction relate to exercise physiology or inducible myocardial ischemia? Well, we are going to be talking all about that in the next few minutes and that's because our feature paper this week is the first study to really directly assess coronary blood flow during exercise in patients with microvascular dysfunction. And to compare these changes with high resolution perfusion imaging. We're really pleased to have with us the first and corresponding author, Dr Divaka Perera from Kings College London, as well as our associate editor Dharam Kumbhani from UT Southwestern. Welcome gentlemen and Divaka. Could you start by telling us what makes your study unique? What did you do? What did you find? Dr Divaka Perera: As you said, microvascular dysfunction is being recognized as quite a common cause of angina. In fact, about 40% of patients who present to the Cath lab for a diagnosis of angina are found to have nonobstructive coronary artery disease, and a significant proportion of these are thought to have microvascular dysfunction. The definition of microvascular dysfunction has been based on demonstration of impaired coronary flow reserve, but what we haven't known is whether the Cath lab measurements that are made actually correlate with exercise maladaptation. Bearing in mind that these patients experience symptoms during exercise and whether there's actually demonstrable ischemia in these patients who don't have obstructed coronary artery disease. Our study's unique in that we were able to measure directly exercise physiology during cardiac catheterization and we were able to stratify patients upfront on the basis of their coronary flow reserve and then in a blinded fashion assess whether these patients who did or didn't have augmentation of flow reserve had ischemia. Dr Carolyn Lam: Divaka, could you give us a detailed picture of what that meant? These patients were sitting with catheters and then riding bikes or give us a picture of what you did. Dr Divaka Perera: Right. This is a setup we've been working on for the last 10 years or so to make sure that we have a reproducible and safe protocol that can be carried out in a Cath lab. A patient who was referred for diagnostic angiography, this may have been the first investigation they were having, or they may have had some form of noninvasive testing beforehand. These patients would undergo angiography via the right radial artery with their arm extended out to the side. And then during angiography when the time was right to assess this condition, they would carry out supine bicycle exercise. And that was a bike that was mounted onto the Cath lab table. During all of this, we would measure intracoronary pressure and flow velocity using this combo tipped wire which could give us distal coronary pressure and Doppler flow velocity and we were able to do this throughout the condition of exercise. Dr Carolyn Lam: That's cool, but then how did the MRI come in then? Dr Divaka Perera: Right. The MRI was actually done at a different visit and in that situation, we only carried out vasodilator testing. We also do exercise patients in the MR scanner, but we haven't included any of those data in this current paper. Patients would have two visits at least as part of this research protocol. Dr Carolyn Lam: Maybe now with that background, tell us what you found. Dr Divaka Perera: The first and most important finding was that patients are classified in the Cath lab on the basis of a coronary flow reserve below 2.5. The flow reserve threshold of 2.5, actually have demonstrable ischemia on a stress profusion myocardial magnetic resonance imaging scan. 82% of patients in the MVD group, the microvascular dysfunction group had inducible ischemia compared to just 22% of controls. This was mirrored by quantitative myocardial profusion reserve data as well, where the ability to augment overall myocardial blood flow was significantly diminished in patients with MVD. And perhaps most interestingly, their exercise pathophysiology was dramatically different to that of controls. In the healthy heart, the heart actually becomes more efficient during exercise. We were able to quantify the proportion of accelerating and decelerating waves by carrying out a technique called wave intensity analysis on the data I've just described, on the physiology data that I've just described. And by doing that we were able to quantify the proportion of accelerating waves to decelerating wave energy. In the healthy heart, as we exercise the proportion of accelerating wave energy increases and we've termed that profusion efficiency. Now in stark contrast when you have MVD, the heart actually becomes less efficient and the profusion efficiency decreases. This is a normal finding and really told us that cath lab measurement based on the response to vasodilators seems to identify a population who have maladaptation during exercise and demonstrable ischemia on scanning. Dr Carolyn Lam: Wow. Dharam, could I now ask you to help frame these results in the context of what's known or not known about microvascular disease? Dr Dharam Kumbhani: I want to congratulate the Divaka and his group. I think this is very interesting analysis. It's really a new paradigm about what is now understood to be more and more of a common issue. It seems like a lot of work, even for the patient population that was enrolled. And I think done in an incredibly thoughtful way. Having said that, I guess what I'd like to understand as a card carrying interventionalist myself, I imagine that some of this may be perhaps in need of validation. And so do you think that this study and in some of the two distinct phenotypes that you describe that this will need to be demonstrated in other labs and other situations? Dr Divaka Perera: Absolutely. I think we have demonstrated is a proof of concept that we can assess these patients in the Cath lab and then shown that firstly, the measurement of CFR and the classification of patients on the basis of CFR does identify a group with distinct pathophysiology, but that that doesn't tell the whole story because your CFR can be diminished for one of two broad reasons. That there's an abnormality of resting flow or an abnormality of hyperemic or flow at maximum stress. Now, the traditional paradigm of microvascular dysfunction has been that these patients will all have, or the majority will have, diminution of stress flow. Or that they might have an inability to reduce their microvascular resistance during stress. What we have found in contrast is that actually two thirds of patients who have impaired flow reserve have impaired flow reserve because of an abnormality of rest perfusion. One third only conform to that traditional paradigm, and this, as you've rightly pointed out, is something that's going to need further investigation. It's very exciting and it might mean that we have a basis on which to try different therapies, for instance. That those therapies might be pathophysiologically stratified, but it needs a lot of work and I'm sure you won't be surprised to know that we've already embarked on that next stage of work to validate and take this forward. Dr Dharam Kumbhani: Let's say you were able to validate this paradigm and you indeed are able to stratify patients with microvascular disease. What you have defined as a functional and a structural endotype. Do you believe that if this were validated and established further from a diagnostic standpoint in labs across other places, what kind of diagnostic testing do you imagine that this would require? Dr Divaka Perera: At the most basic level Dharam, I think we need to get interventional cardiologists and any cardiologist doing diagnostic angiography to realize that the finding of unobstructed coronary artery disease isn't the final answer. It actually begins a whole chapter of investigation and if we can at least get people to think about doing a physiology study in a way analogous to what's happened when we find equivocal amounts of coronary artery disease that you'd reach for a pressure wire and do a functional test. If we can introduce that paradigm once we find normal or unobstructed coronary arteries in a patient with classical symptoms, that would be step number one. The next step will be that we'll have across the board a harmonized means of classifying these patients and by looking at microvascular resistance as well as coronary flow reserve, we might be able to identify endotypes that behave differently and need different forms of therapy. Once we've got that in place, then we have a basis to carry out large registries and large trials in a systematic fashion. Dr Dharam Kumbhani: Let me just clarify that. You don't envision that let's say this all gets validated. Do you envision that labs that do CFR measurements would then in addition need to have the ability to do exercise testing as well? Dr Divaka Perera: No, I don't think so. I think exercise testing requires a really carefully evolved set up and it's not practical to unleash this onto world at large. But it generates hypotheses and examines concepts which can then be translated. I think routine use of microvascular function testing will rely on response to vasodilators and these will be endothelium independent techniques such as an adenosine and possibly as a second stratum, endothelium dependent methods as well. Perhaps using graded acetylcholine infusions. But it would be vasodilator testing in the Cath lab rather than exercise. Dr Dharam Kumbhani: Got it. Dr Carolyn Lam: Fascinating. Wait, Divaka, just to be sure that the audience got this. You talked about the two endotypes, a structural and functional and the structural one is the one that has a low flow to begin with. The functional is the one that the hyperemic flow is the one that's mainly impaired. Is that correct? Just checking. Dr Divaka Perera: Let me just clarify. Those patients that we've termed to have functional MVD have elevated resting flow, but actually essentially normal flow at stress. In contrast, those who have structural MVD have essentially normal resting flow but have an inability to augment their peak flow. The net result appears to be the same in the sense that they all have demonstrable ischemia on noninvasive testing, but the mechanisms are different and therefore the therapies that we direct towards these patients may also need to be different. Dr Carolyn Lam: Very nicely put. Thank you. And if the audience, you still didn't get that, pick up the paper and read it. But say, one last question because you kind of teased us just now and said, actually we are going on with next steps and so on. What are the next steps? Maybe from you and then Dharam. Dr Divaka Perera: I think the next step is to assess whether this sort of stratification allows us to treat patients more efficiently. To deliver subtype stratified therapy. And we need to assess this with reference to meaningful clinical outcomes, so quality of life, exercise-based indices, et cetera, before we get onto looking at large numbers and then looking at cardiovascular outcome data. Dr Carolyn Lam: Great. And Dharam, maybe I'll let you have the closing words. Dr Dharam Kumbhani: We're understanding a lot more about what is always been an enigma for clinicians as far as having patients who present with very typical symptoms, either stable or unstable symptoms and have no coronary artery disease. I want to congratulate the authors on really trying to dig deeper into this and helping us with this very difficult patient population. Dr Carolyn Lam: Thank you, Dharam. Thank you Divaka. And thank you listeners for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week. This program is copyright American Heart Association 2019.  

Episode 18: We switched up gears tonight and decided to discuss tequila. We sampled Sean Diddy Combs tequila DeLeon, and many other diffierent types and brands. We gave our opinion on what we thought about all of them. Since we are bourbon drinkers, we wanted to tell you how we felt about tequila vs. bourban. We also had a special guest Greg, who is a tequila "expert". Thanks Greg for helping us out with this one.

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 Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, we are going to have a great discussion coming right up regarding intensive versus standard ambulatory blood pressure control and its effects on cerebrovascular outcomes in older people. It's the INFINITY trial, but that's all I'm going to tell you for now because I want to hear all about your picks for this week's journal first. Dr Greg Hundley: Absolutely Carolyn and I can't wait to hear about that discussion regarding hypertension. My first paper though is about titin and it comes from Dr Charles Murry from the University of Washington. The giant sarcomere protein titin is important in both heart health and disease as mutations in the gene encoding for titin are the leading cause of familial dilated cardiomyopathy. The uneven distribution of these mutations within titin motivated the authors of this article to seek a more complete understanding of this gene and the isoform it encodes in cardiomyocyte sarcomere formation and function. Dr Carolyn Lam: Cool. What did these investigators find? Dr Greg Hundley: Using genetically engineered human induced pluripotent stem cell derived cardiomyocytes, the authors experimentally confirmed that the gene encoding for the giant sarcomere protein titin includes an internal promoter and start site. This internal start site encodes for the isoform Cronos, which the authors demonstrate support some sarcomere formation in these human induced pluripotent stem cell derived cardiomyocytes. Dr Carolyn Lam: Oh, nicely summarized. What are the clinical implications Greg? Dr Greg Hundley: Well, Carolyn identification that Cronos titin, a previously unstudied form of titin is necessary for normal human cardiomyocyte function could be contributing to some of these titinopathies that are relevant for some patients with dilated cardiomyopathy. Dr Carolyn Lam: Cool. Mine has to do with heart failure as well and presents new results regarding heart failure and heart failure related outcomes from the EXSCEL trial. Dr Greg Hundley: Carolyn, what was the EXSCEL trial? What did it find? Dr Carolyn Lam: Ah, so as a reminder, EXSCEL was the largest glucagon-like peptide-1 receptor agonist or GLP-1 receptor agonist trial reported to date where once weekly, exenatide had a neutral effect on hospitalization for heart failure with no differential treatment effect on major adverse cardiovascular events or MACE, by baseline heart failure status. However, the question remains, what about exenatide's effects on secondary endpoints based on the heart failure status? This is from Dr Rob Mentz and colleagues from Duke Clinical Research Institute who aim to explore the effects of exenatide on secondary outcomes in patients with and without baseline heart failure and test the effects of exenatide on recurrent heart failure hospitalization events. Now they found that out of more than 14,750 EXSCEL participants, 16% had heart failure at baseline and when stratified by the presence or absence of baseline heart failure, there was no observed reduction in all cause death with exenatide in patients with baseline heart failure. While the risk of mortality was reduced with exenatide in the no heart failure group. And that was a significant interaction P value of 0.031. Similar results were observed for the combined outcome of all cause death or heart failure hospitalizations. Now regarding recurrent heart failure hospitalizations, 450 patients experienced at least one hospitalization for heart failure, but there were 713 hospitalization heart failure events in total. The effect estimate that included the recurrent events was separately, statistically significant while the primary analysis based on just first events was not. In conclusion in EXSCEL, the use of exenatide in patients with or without heart failure was well tolerated, but the benefits of exenatide on reduction in all cause death and first heart failure hospitalization were attenuated in patients with baseline heart failure. Now this is accompanied by a great editorial by Bruce Neil and Claire Arnett who caution against using post talk subgroup analysis, but the interaction of exenatide tout with baseline heart failure, it's interesting, although should be treated with caution until confirmed by findings from another trial. Dr Greg Hundley: Very nice Carolyn, especially a nice issue regarding heart failure and I'm going to steer a little bit away from that and talk about atrial fibrillation duration and CHA2DS2-VASc scores. Putting those two together and this article comes from Rod Passman from Northwestern University. Studies of patients with cardiovascular implantable electronic devices show a relationship between atrial fibrillation duration and stroke risk though the interaction with a CHA2DS2-VASc score is poorly defined. The objective of their study was to evaluate rates of stroke and systemic embolism in those patients with cardiovascular implantable electronic devices as a function of both the CHA2DS2-VASc2 score and A-fib duration. Dr Carolyn Lam: Interesting. What did the authors do? Dr Greg Hundley: They had 21,768 non-anticoagulated cardiovascular implanted electronic device patients from the Optum electronic health record, de-identified database from 2007 to 2017 and they link those to the Medtronic CareLink TM database of CIEDs capable of continuous AF monitoring. Now the age averaged about 69 years and 63% were men and they found that increasing a fib duration, and of course increasing CHA2DS2-VASc2 score were both significantly associated with annualized risk of stroke and systemic embolism. These rates were low however, in those individuals with CHA2DS2-VASc2 scores of zero to one, regardless of the device detected a fib duration. Dr Carolyn Lam: Ah. Were there any particular threshold values that seemed important? Dr Greg Hundley: Great question, Carolyn. Yes, the stroke risk crossed an actionable threshold defined as greater than 1% per year in those with CHA2DS2-VASc2 score patients of two or more with greater than 23 and a half hours of a fib or those patients with CHA2DS2-VASc2 scores of three or four with greater than six minutes of a fib duration or finally in those individuals with CHA2DS2-VASc2 scores greater than five even if they had no atrial fibrillation. Dr Carolyn Lam: Wow. Very nice clinically relevant conclusions here. Thanks Greg. I'm going to tell you what else is in this issue. There's also a research letter by Dr Rosenmeier entitled, “Aerobic Exercise Induces Cardiac Fat Loss and Alters Cardiac Muscle Mass Through an Interleukin 6 Receptor Dependent Mechanism.” And this is a cardiac analysis of a double blind randomized controlled trial in abdominal obese humans. We have an on my mind paper by Dr Delbridge entitled “HFpEF, It's Time to Explore the Role of Genetic Heterogeneity in Conferring Phenotypic Variability.” And this discusses among other things, the role of induced pluripotent stem cells and functional studies of bioengineered HFpEF patient derived cardiac micro tissues that could potentially enable several important questions to be answered for the first time. There's an ECG challenge as well by Dr Naru Kanya, and it's really interesting. It's a hiccup artifact. If you haven't heard about that, you should take a look. And finally cardiology news by Dr Kuhn and it's entitled, “Nourishing Native American Communities by Increasing Access to Traditional Food.” A very interesting paper right there. Dr Greg Hundley: Carolyn, I have a few papers. Robert Gerszten provides a perspective piece regarding emerging affinity reagents for high throughput proteomics, sort of an emerging field, everyone doing proteomic studies, we have to pay a special attention to the reagents that are being used. And then Andrew DeFilippis from University of Louisville as well as Johns Hopkins reviews important concepts related to the definition of MI. Dr Carolyn Lam: Is this pertaining to that fourth universal definition of MI? Dr Greg Hundley: Yes, Carolyn. Absolutely. And basically in this white paper, the authors review the epidemiology, risk factor associations and diagnostic tools that may assist in differentiating between non-ischemic myocardial injury, type 1 MI and type 2 MI. And then finally from Suowen Xu from the University of Rochester, there's a letter discussing the CCN family of matricellular proteins CCN 1, CCN 2 and CCN 3, that are mechano-sensitive proteins that are differentially regulated by sheer stress, the frictional force exerted by blood flow in our vessels. Well Carolyn, that's a great issue. How about we move on to our feature article? Dr Carolyn Lam: Let's go Greg. For our feature discussion today we are talking about intensive versus standard ambulatory blood pressure control and that effect on cerebral vascular outcomes in older people or the INFINITY trial. Very, very important stuff and I'm so pleased to be with the corresponding author, Dr William White from Calhoun Cardiology Center in University of Connecticut School of Medicine. Dr White, thank you so much for being here. Could you maybe set up already the background of what you were thinking when you started this trial? Especially given the results that we know from SPRINT and SPRINT mind. Could you perhaps comment on how this INFINITY trial is different? Dr William White: We started work in this area about 15 years ago and we initially were interested in interactions among vascular risk factors including ambulatory blood pressure, lipids and other sort of thrombotic factors and so forth with the development of small vessel disease in the brain that led to these fairly classic images on MRI called white matter hyperintensity lesions. And we learned from a prospective cohort study that we started about 15 years ago, that there was a very strong relationship between ambulatory blood pressure and the development and progression of these white matter hyperintensity lesions on MRI, but not very nice relationship with the clinical blood pressures measured in the standard office practice. We decided to pursue a clinical trial, a randomized clinical trial in which we would evaluate different levels of ambulatory blood pressure versus the development of the small vessel disease as imaged by MRI, but very importantly we also wanted to link it to functional outcomes because this was in older people, typically in their late seventies, eighties and even nineties in which cognitive impairment begins to develop. There's problem with mobility, bladder function and things of that nature. And since our funder was always the National Institute of Aging of the NIH, there's a great deal of interest in more than just the vascular risk factors and even the cerebral vascular disease that we would detect on the MRI. That was the background of why the study got developed the way it did. Dr Carolyn Lam: That's so interesting. You've already pointed out ways that this was very different from SPRINT OR SPRINT MIND in looking at ambulatory instead of clinic blood pressure and I suppose in the population you selected, out of curiosity, you mentioned that your prior work showed a relationship between white matter hyperintensity on MRI and perhaps future dementia. In which direction? And is there any basis to suspect low, too low blood pressure may also be bad in these older people who already have microvascular brain disease? Dr William White: Absolutely. Very important point. When we look at our prospective cohort which was about a 100 older people, we followed for four years without any intervention. This was just a mixture of normal tensive and hypertensive individuals. Some on meds, some not on meds. But we did show that when you got too low or if you stay too low during those four years with a systolic blood pressure of under 115 on a 24-hour blood pressure monitor, it seemed like there was an almost like U shaped relationship with progression of white matter disease. Below 115 there was more accrual of white matter disease. Above 150 there was a systolic blood pressure, there was also a greater accrual, but in between about 125 and 145 we weren't really sure if there was going to be a difference. And that there was the target is that everybody's talking about for clinical measurement, so we decided to pursue that in this study to determine if we could figure out whether or not there was a sweet spot for the desk blood pressure without getting into trouble with hypotensive symptoms. Dr Carolyn Lam: Nice. Thank you for drawing that up so nicely. Now I get it that you chose the targets that you did, which just for everyone, just a reminder, it was a 24 hour mean systolic blood pressure by ambulatory blood pressure control and the two targets were 130 millimeters mercury and less versus 145 millimeters mercury and less. With that, could you please tell us the results? Dr William White: Right. We called the 130 or less systolic group, the intensive treatment group and the 145, the standard group. We focused on the primary endpoint was changes in mobility parameters in conjunction with changes in white matter hyperintensity lesion growth. And after a period of about three to four months of randomization, post randomization, we achieved a 24-hour systolic blood pressure about 128 millimeters of mercury in the intensive treatment group and 144 in the standard group. And we maintained a pretty good separation in blood pressure, ambulatory blood pressure throughout the three years of treatment. Now the changes in gait speed, which was one of our primary parameters for mobility actually turned out not to be different between the treatment groups. That is intensive versus standard. However, the changes in the accrual of light matter hyperintensity volume was smaller in the intensive treatment group of a 0.29% versus a 0.48% in the standard treatment group. That was significant at a P value of 0.03. We actually also had a pre-specified sensitivity analysis, sort of a per protocol analysis that allowed us to look at people who stayed in their sort of assigned treatment groups based on blood pressure throughout the three years of the trial. And in that circumstance, there was actually a stronger separation because these are people who stayed clearly at 130 or less than about 145 throughout the three years and now the differences were approximately 0.23% in the intensive group and 0.58% in the standard group. And now the P value is smaller, .0028. I think we proved in the study that maintaining a systolic blood pressure on the ambulatory recorder over 24 hours of 130 or less benefited patients by reducing the accrual of white matter hyperintensity lesions by about 40% relatively speaking compared to a standard ambulatory blood pressure value of a 145. One of course caveat is that after that happened within three years, but we did not see the expected benefit on mobility or on most of the cognitive parameters either. And while we were a little bit surprised about that, when we went back and analyzed our situation with where people started from as far as this particular cohort of patients, they might've been a little on the healthy side compared to some other studies. A very educated group, very compliant with everything that they did. And probably three years was just not long enough to show the result of this white matter hyperintensity benefit on some of the functional outcomes. Dr Carolyn Lam: That's really interesting and I'm glad you sort of tackled head on that sort of apparent dissociation between the clinical end points and the MRI end point. Could I also ask, wouldn't those findings also be consistent with SPRINT and SPRINT MIND? Dr William White: In many ways our results were consistent with SPRINT MIND, a sub-study on the SPRINT MRI sub-study. Of course, just let me mention the differences between the two studies. Of course, SPRINT was very large but there are sub-studies were not as large as the parent study. The MRI study had about 300 plus patients randomized into it, but the measurement of blood pressure was done in the standard clinical fashion and used that digital device that was able to take measurements without somebody present in the exam room. Though they were a bit lower than what I would have seen on an ambulatory monitor during the day time. And their goals were 120 systolic versus 140, whereas ours were an ambulatory systolic of 135 and 145. But the results were actually comparable because they showed a benefit with regards to lesser accrual of white matter hyperintensity volume in the intensive group versus this banner treatment group. But they also showed no differences after 3.4 years in the incidence of dementia. And they also showed in a separate study, no differences in gait speed in the population who are in intensive versus standard treatment. One would say that results were really actually comparable despite the age differences and the blood pressure measurement differences. And I think both studies really point to the fact that lower systolic blood pressures in older people should be our target because it's safer actually then than maintaining people in the 140s. Dr Carolyn Lam: Maybe the follow-up period was not long enough. Could it be possible too that maybe blood pressure control should start earlier in life. Could that be it? And then also, could you give us an idea of the kinds of changes, the magnitude of the change on MRI that you see for those of us that don't think about this all the time, is this a big change considered for your cohort or is it a little change? Dr William White: I think it's true that these people started out around 81 years old in this trial and so by the time they got to that age and had systolic hypertension for probably as many as 20 years, that some of the damage that was done was obviously permanent and we don't really know how long it took for that to accrue. What we did know is that with three years of intensive treatment, we benefited patients by reducing the continued growth or confluency of these small vessel lesions in the brain. Now the range in the amount of damage varies from about half a percent of the overall brain volume to about 5%, so a 10-fold magnitude difference in our cohort. And as a result of that, certainly somebody who's got about two to 3% of their brain occupied by better hyperintensity lesions or damage is going to have a great deal more functional disability than somebody who's .5%. I think we have to look at the outliers as well as the mean and median changes that we saw. The mean changes are not huge. The difference between 0.2 and 0.6% for example, in our protocol analysis, 0.4% to me it's clinically relevant because I know that that means that there are some people who went up by a percent or two over the years versus the standard versus the intensive treatment group. That's a big difference in an individual over that period of time. Dr Carolyn Lam: Yeah, I'd hate to think that I'm losing 1% of my brain. Dr William White: Yeah. Plus it's also where it's located because the lesions are typically around the ventricles of the brain and it's exactly where neurons are going sort of posteriorly to anteriorly to transmit information. For example, from the visual center to the sort of spatial motor cortex. And when those are interrupted, even if it's in one or 2% of the tissue, it can cause substantial difficulties for people. And it's for both the flow of cognitive information as well as this flow of a mobility and balance. I think that it is very relevant, but the gray matter is affected much less by this compared to the white matter. But there are still studies that show that gray matter sort of follows in line with that so that of course also enhances thought processes and cognitive function as well. Dr Carolyn Lam: Wow. I love the way you explained that. Very important question would of course be the safety and tolerability of this more intensive approach. Any comments there? Dr William White: Our sponsor, the National Institute of Aging did recruit a data safety monitoring board that was independent from the study for all the years. Impressively over the course of this trial, even though there wasn't a large sample, it was a 199 people, we saw a significant benefit in the intensive group for cardiovascular events, so there were less admissions for heart failure. There were less myocardial infarctions, there was less strokes. All these kinds of things that we worry about in our patients as they get older with vascular disease was reduced by about 75% in the intensive treatment arm versus the standard arm. As far as the events that we were concerned about, such as falls and syncope and presyncope and things of that nature, they were virtually identical in the intensive treatment group and `the standard treatment group. When you take that into consideration, along with the fact that you're reducing the accrual of small vessel disease in the brain, it's clear that this population, even though they're older, would benefit from a lower systolic blood pressure. Dr Carolyn Lam: Oh my goodness. Thank you so much, Dr White. That was a beautiful summary. That is the take home message right there. Listeners, I'm sure you agree with me. Thank you so much for joining us this week, and don't forget to tune in again next week. This program is copyright American Heart Association 2019.  

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 for Circulation, from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article, this issue reminds us of the importance of the physical exam in patients with heart failure and reduced ejection fraction involving those that were enrolled in the PARADIGM-HF. Remember a trial of sacubitril/valsartan versus ACE inhibition in those with a reduced ejection fraction? Can't wait to hear more of the discussion of the importance of that physical exam. Carolyn, how about you talk about your first article? Dr Carolyn Lam:                I will because this first paper reports a novel ventricular tachycardia or VT ablation strategy guided by a voltage independent mapping display during sinus rhythm. Dr Greg Hundley:             Well, Carolyn, since many of us don't do VT ablations every day, how about a little background on this one first? Dr Carolyn Lam:                Substrate modification during sinus rhythm is actually the mainstay ablation strategy for scar related VT. With the recent trend being more extensive ablation, aimed to homogenize the entire scar region. These authors are led by Dr Tung from the University of Chicago Medicine Center for Arrhythmia Care, and colleagues. They had hypothesized that a greater understanding of the nature and characteristics of the scar would be most prone to reentry, may actually improve the precision and yield of ablation. Now, they had previously demonstrated that sites critical for reentrant VT localized to regions of activation slowing during sinus rhythm or so-called deceleration zones rather than regions with latest activation. In the current study, they aim to prospectively assess the outcomes of VT ablation guided primarily by targeting these deceleration zones identified by propagational analysis of ventricular activation during sinus rhythm. Dr Greg Hundley:             Interesting. What did they find, Carolyn? Dr Carolyn Lam:                They studied 120 patients with scar related VT who are prospectively enrolled in the U Chicago VT ablation registry between 2016 and 2018, who underwent 144 ablation procedures for scar related VT. They performed high density mapping during baseline rhythm and identified the deceleration zones which all localized to successful termination sites in 95% of cases. The median total radio frequency application duration was 29 minutes to target the deceleration zone, representing ablation of 18% of the low voltage area. At a mean of 12 months, 70% freedom from VT recurrence was achieved with an overall survival rate of 87%. A novel voltage independent high-density mapping display may further identify the functional substrate for VT during sinus rhythm and guide targeted ablation thus obviating the need for extensive radio frequency delivery. Dr Greg Hundley:             Fantastic, Carolyn.                                                 Well, my first paper is from Professor Mark Nicolls from Stanford University. It's entitled Phenotypically Silent Bone Morphogenic Protein Receptor 2 or Bmpr2 mutations, that predispose rats to inflammation induced pulmonary arterial hypertension by enhancing the risk for neointimal transformation. While being the most common inherited risk factor for pulmonary arterial hypertension, Bmpr2 germ line mutations only result in disease in 20% of mutation carriers. A finding that suggest a second hit is required to elicit vascular pathology. Transgenic mouse models of Bmpr2 mutations were developed in this study to better understand the relationship between these phenotypically silent gene mutations and the predisposition to pulmonary arterial hypertension. Dr Carolyn Lam:                Huh. What did they find Greg? Dr Greg Hundley:             In this new two hit model of disease, Bmpr2 mutant rats subjected to pulmonary inflammation, developed severe pulmonary arterial hypertension with vascular remodeling and the pulmonary arterial endothelial cell transformation that occurred did so in three phases. An initial apoptosis phase induced by exogenous LTB4. Second, a proliferative phase relying on P38 mediated noncanonical TGF-beta signaling. And then finally a terminal inflammatory phase in which pulmonary arterial endothelial cells utilized the canonical TGF-beta pathway, expressed mesenchymal markers and produced LTB4, IL6 and NF-kappa beta signaling molecules. The clinical implications include that in phenotypically silent Bmpr2, haploinsufficient individuals, a second hit of pulmonary inflammation may put them at risk for subsequently developing pulmonary arterial hypertension. And this lung inflammation while usually self-limited may cause durable and inflammatory vascular lesions in these genetically susceptible patients. Dr Carolyn Lam:                Wow, that is super interesting. Thanks Greg for that great summary.                                                 Well, my next paper really looks at the temporal trends in survival after pediatric in hospital cardiac arrest in the United States. This is from Dr Holmberg from Beth Israel Deaconess Medical Center and colleagues who performed an observational study of hospitalized pediatric patients who received CPR from January 2000 to December 2018 and were included in the Get With the Guidelines resuscitation registry. Dr Greg Hundley:             Carolyn, what did they find? Dr Carolyn Lam:                They found that survival has improved for pediatric events requiring CPR in the US with a 19% absolute increase in survival for in hospital pulseless cardiac arrests and a 9% absolute increase in survival for non-pulseless events between 2000 and 2018. However, survival from pulseless cardiac arrest appeared to have reached a plateau following 2010. The increase in survival over time is reassuring and perhaps provides some evidence for the progress of quality improvement efforts. However, given the plateau and survival following 2010, there is a continued need for clinical focus and new interventions to improve outcomes of pediatric in hospital cardiac arrests. And Greg, are you now going to tell us what's in the mailbag? Dr Greg Hundley:             Absolutely Carolyn. Professor Wei, from Harvard, provides a new perspective on using the restricted mean survival time difference as an alternative to the proportional hazards model and hazard ratios for analyzing risk in clinical cardiovascular studies. In another article, Eric Peterson from Duke provides a white paper discussing randomized clinical trials versus EMR extracted data to inform new therapies in cardiovascular disease. And he really reviews what are the issues we need to overcome using these EMR strategies? And on my mind piece from Dr Glenn Levine from Baylor, discusses the role of psychological wellbeing as it relates to cardiovascular disease. And then we have a large series of letters in this issue.                                                 First, Otmar Pfister and Kari Nytrøen, each have letters regarding high intensity interval training. Dong-Vu Nguyen, asked for several points of clarification regarding the utility of BNP assessments in syncope and whether other metrics incorporating clinical information could be useful. There's a corresponding response from Christian Müller from the PRICIPLE study with great discourse. And then finally an important research letter from Dr Rodés-Cabau in Quebec, evaluates the left atrial occlude or thrombus occurrence among eight centers in Canada and in this letter provides data that suggests thrombi can occur in those that have implanted left atrial occluders and raises considerations for anticoagulation of these patients. Great set of letters in this issue of the journal. Dr Carolyn Lam:                Absolutely Greg and thanks for sharing that. Let's go onto our feature discussion. Dr Greg Hundley:             You bet.                                                 Welcome everyone to discussion of our featured article and today we have Senthil Selvaraj from University of Pennsylvania and our own Mark Drazner, associate editor at Circulation from the University of Texas Southwestern and we're going to be discussing some very interesting results regarding the physical exam as they've been generated from the PARADIGM heart failure trial. And remember that's a prospective comparison of an Angiotensin Receptor-Neprilysin inhibitor with an angiotensin converting enzyme inhibitor to determine the impact of those two therapies on all-cause mortality and also morbidity in heart failure. Senthil, welcome to this discussion. We're very excited to have the opportunity to discuss your article and I wonder before we get started, could you tell us a little bit about the background and the hypothesis for why you wanted to perform the study and then afterwards tell us a little bit about the study population and the methods. Dr Senthil Selvaraj:          I think the impetus for this study torn out of the fact that we do the clinical exam so often, and I think like many cardiology clinicians in the community, we perform this so often, but we don't know what the actual impact is of performing the clinical exam. What I wanted to understand and the primary motivation was to really understand what the change in the physical exam meant in terms of subsequent prognosis. Does decreasing congestion actually relate to improved cardiovascular outcomes? I think this is an area that is hard to study by randomized controlled trials. In my opinion I think there is not so much equipoise in performing a trial of decongestion versus no decongestion. I think this is sort of one way that we can understand epidemiologic methods, whether lowering congestion improve outcomes.                                                 I had a number of other interesting analysis. I think the first is we've had a number of studies that have evaluated the physical exam, but I think that an updated analysis in a population receiving contemporary management was particularly important, particularly given the fact that the risk rad versus insignificantly in the past couple of decades essentially related to improvements in therapy. The second is we formed the physical exam in conjunction with a number of other additional forensic markers in the use of validated risk scores that to understand those and have utility above and beyond this. For instance, can I just check a natural aside and will that be doing a physical exam. And I think while that's easier, I don't know that that necessarily is the right thing to do. And that was another motivation. Dr Greg Hundley:             What was your overall study design and your study population? Dr Senthil Selvaraj:          The overall study design was to use the PARADIGM-HF cohort. And in our analysis, we did a time updated analysis, which is different than many other analyses previously done. That means that every single point that a patient goes into a clinical trial visit, we updated their physical exam, possible because the study investigators did perform an exam at each of these visits. And so what we did was we used the physical exam and number of signs of congestion as the time bearing covariate and looked at its relationship to outcomes, but also just as importantly why might think decreasing congestion or changing congestion has really stuck out as very important about to want to feel better. And I anything quantifying that relationship while it's intuitive I think is also very important. Dr Greg Hundley:             And just remind us who's in PARADIGM heart failure? Well what was the study population? And just very quickly the randomization arms? Dr Senthil Selvaraj:          PARADIGM-HF was a randomized controlled international multicenter trial of patients with heart failure ejection fraction which has been defined in this study as less than or equal to 40%, near two, three or four symptoms, elevated natriuretic peptides, depending on the trial compared an angiotensin converting enzyme inhibitor and Angiotensin Neprilysin inhibitor to control valsartan. Dr Greg Hundley:             Tell us what were your study results? And how did they pertain to the outcomes that were gathered in PARADIGM-HF? Dr Senthil Selvaraj:          We first divided our cohort based upon the total number of signs and as might imagine increasing congestion was associated with a number of adverse clinical features. We then looked at the association between the number of signs and the efficacy outcomes, which included a primary composite outcome of time to heart failure, hospitalization as well as cardiovascular mortality and then we individually looked at those as well as all-cause mortality. And as we show in our paper, there was really a striking relationship between time updated times of congestion as well as all of the efficacy adjusted for baseline natriuretic peptides which are available in all of our participants in PARADIGM-HF as well as MAGGIC risk score and New York Heart Association class to get at the question of whether improving congestion, where the relationship congestion above and beyond symptoms is still valid.                                                 The other thing that we did is because we only looked at natriuretic peptides at baseline is that we've formed a sub study where we evaluated, since you had natriuretic peptides during follow-up as well at the one month visit and eight month visit and compare the utility of signs of congestion and outcomes and you can still see that there was a significant relationship in this sub analysis. The participants would complete NP data. We further looked at relationship and congestion and quality of life and there is a significant relationship such that for every sign of congestion that you decrease, there is a five-point increase in KCCQ, the quality of life score which some have considered to be a clinically significant increase in times of congestion.                                                 We also looked at the relationship between the treatment arm and reduction of congestion as sacubitril/valsartan was associated with significant reduction in clinical congestion, which has mirrored its impact on natriuretic peptides as well. And finally to understand whether reducing congestion was actually associated with improved outcomes, we entered both the baseline congestion and change of congestion into models that looked at the relationship with outcomes and found that change of congestion was a very strong predictor of outcomes even after baseline congestion, which we interpreted to mean that reduction in congestion was a mutable factor, and that reducing congestion is actually associated with improved outcomes. Dr Greg Hundley:             Signs of congestion on the physical exam, you had JVD, peripheral edema, rales, and then an S3 and so you're adding those up and making a score. And so when one of those particular findings dropped off in terms of score, that's what you're indicating by change in congestion, is that correct? Dr Senthil Selvaraj:          That's really correct. We analyzed this in two methods. The first is a dichotomous presence of a physical exam science. As you said, the presence or absence of JVD, the presence or absence of a DMO rales and an aspirate. The investigators also graded two of those signs of congestion, which included a DMN rale that we formed a complimentary analysis where we created a sign score where we gave partial credits to gradations of the physical exam and we saw very similar outcomes as well. Dr Greg Hundley:             Mark Drazner at UT Southwestern has done a lot looking at the importance of our physical exam and assessing patients with heart failure. Mark, how do you feel the results of this study compare with previously published works? Dr Mark Drazner:             Thanks Greg. First, always a pleasure to join you on this and I do want to congratulate Dr Selvaraj and his team on this outstanding paper to generate considerable enthusiasm among the editorial team and reviewers I'd say. It's a really interesting study for several fold and you've heard a lot of the important methods by Dr Selvaraj already. I would just highlight there've been a number of previous studies that have looked at markers of congestion from physical exam and showed that they had prognostic utility, but a major question that has been addressed to me personally and I think in the field, does that add any independent information beyond just sending BMPR natriuretic peptide level measurement?                                                 And this analysis here as you've heard, one of the big advances was that they were able to adjust for natriuretic peptide levels and showed that the exam or the markers of congestion did add independent prognostic information. I think that's an important step forward, as is bringing the relevance again about the markers of congestion and prognostic utility to patients being receiving the most modern-day therapy including ARNI therapy, which is unparalleled opportunity because of the PARADIGM trial to look at that question. I think those two are really set this paper. I think this is going to be a standard, this is the standard for assessing prognostic utility congestion in heart failure by far in the literature in my opinion. Dr Greg Hundley:             What we're saying is that our following the patients and identifying these physical exam changes during an initiation of ARNI therapy can be really helpful in determining that particular patient's long-term prognosis. Coming back to both of you, maybe first Mark and then we'll come back to Senthil, what do you see is the next study in this field? Both in terms of new therapies in heart failure and the relationship of physical exam and then also perhaps just briefly some thoughts on ARNI therapy. Dr Mark Drazner:             I think this paper highlights the incredible importance of congestion in modern day therapy. And there are a number of other studies that looked at this recently, including there's an analysis of TOPCAT preserved heart failure showing again congestion being linked to adverse outcomes. I think that question is resolved that even in modern day therapy. The next step in my opinion is to understand why clinical congestion, the pathway from clinical congestion to adverse outcomes. What are the links? Can we target those links to try to interrupt that cycle? And what is the most effective way to achieve decongestion? We heard that now ARNI appears to be a mediator of decongestion and we need more work on that I think. I would say looking at the pathway from congestion to adverse outcomes and then what is the optimal way to decongest our patients. Dr Greg Hundley:             Very good. Senthil, do you have anything to add to that? Dr Senthil Selvaraj:          I think that's great. I completely agree with Dr Drazner on this. I think one question would be to understand truly as Dr Drazner said, the optimal way to decongest patients and so for instance, the way that we have traditionally done this is by increasing diuretic. There are a number of experimental and novel ways that we can decongest patients. I think one unanswered question actually is does increasing a diuretic potentially at the expense of activating the renin angiotensin aldosterone access, actually afford benefit if you decongest patients. It's an analysis that I think is ripe and timely and not been adequately addressed. I think that that would be one potential way to go. And the second is, I think as you mentioned in clinical trials, I think clinical congestion may not be an outcome, a pre-specified outcome of course. But I do think that it is an important outcome aside from just looking at decreases in other surrogate markers such as natriuretic peptides. It's easy to perform. It's collected on many investigator visits during these trials and therefore these are ripe analyses. Dr Greg Hundley:             Listeners, we look forward to speaking with you next week and have a great week. Dr Carolyn Lam:                This program is copyright American Heart Association 2019.  

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 Gregory Hundley:       And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.                                                 Well, Carolyn, this week's feature is from Professor Carl Lindstrom from Helsinki University Hospital and the University of Helsinki and evaluates whether administration of simvastatin via nasogastric tube in brain-dead individuals prior to cardiac transplant donation improves transplant recipient cardiac-related outcomes. It is a randomized trial using an inexpensive therapy, and I look forward to that discussion with Professor Lindstrom. How about we grab a cup of coffee and start off our discussion today. Dr Carolyn Lam:                All right, so here goes. The first paper that I want to discuss really looks at the question, is DNA methylation related to incident coronary heart disease? Well, Dr Agha from Columbia University in New York and colleagues looked at this and profiled epigenome-wide blood leukocyte DNA methylation in 11,461 individuals from nine population-based cohorts in the United States and Europe using the Illumina Infinium 450K microarray and prospectively ascertained coronary heart disease events. Dr Gregory Hundley:       So Carolyn, what did they find? Dr Carolyn Lam:                Well, they found that differences in blood leukocyte DNA methylation at 52 cytosine phosphate guanine sites were associated with incident coronary heart disease or myocardial infarction with a false discovery rate of less than 0.05. Several of the differentially methylated loci mapped to genes related to calcium regulation and kidney function. Exploratory analyses with Mendelian randomization supported a causal effect of DNA methylation on incident coronary heart disease at loci in active regulatory regions with links to noncoding, RNAs and genes involved in cellular and tissue structural components.                                                 Very nice Caroline. So what's the summary for us clinically? Dr Gregory Hundley:       So, these findings really provide the first evidence that genomic regulation via epigenetic modifications in kidney function and calcium homeostasis related pathways may be involved in the development of coronary heart disease. The findings of epigenetic, loci related non-coding RNAs highlight pathways that have not immersed in genome-wide studies of coronary heart disease and therefore represent novel therapeutic targets, which thus far have not been explored. Dr Carolyn Lam:                Very good, Caroline. Well, I've got a basic paper that I want to present and it's from professor Xander Wehrens from the Baylor College of Medicine. And this study addresses factors that promote atrial fibrillation. The investigators found that reduced levels of protein phosphatase-1 regulatory subunit R3A in human atria are causally linked to abnormal calcium handling and atrial fibrillation pathogenesis.                                                 In the absence of protein phosphatase-1 regulatory subunit R3A reducing binding of PP1 catalytic subunit increases phosphorylation levels of the ryanodine receptor, R2 calcium release channel, and phospholamban. Complex zone, profiling, a technique that combines native gel electrophoresis with mass spectrometry to obtain the composition of multi protein assemblies revealed that PP1 R3A is part of a macro molecular protein complex containing the ryanodine calcium release channel and the circuit 2APLN calcium uptake transporter. Dr Gregory Hundley:       Wow. Complex zone profiling. That's so cool, but what does it all mean for us clinically, Greg? Dr Carolyn Lam:                Well reduced levels of PP1 regulatory subunit contribute to abnormal calcium release and re-uptake and atrial monocytes, thereby promoting atrial fibrillation pathogenesis. And thus normalizing levels of PP1R3A phosphatase sub unit may represent a novel therapeutic approach to manage atrial fibrillation. Dr Gregory Hundley:       That's so cool. I next have a preclinical paper which contributes really to the understanding of molecular basis of pathological myocardial remodeling in heart failure. And this is from co-corresponding authors, doctors, Jung, Liu, and Lin-Jung from Shanghai East Hospital Tongji University School of Medicine in China. And the paper really focused on Forkhead box transcription factor P1 or Foxp1 in endothelial cells. Dr Carolyn Lam:                So Foxp1 Carolyn, tell me a little bit more about that. Dr Gregory Hundley:       Is it good that you asked before I asked you. Forkhead box proteins P or Foxp are large modular transcription repressors that bind to DNA via their highly conserved Forkhead DNA binding domains. Fox p1 is highly expressed in vascular endothelial cells and it's essential for normal cardiac development.                                                 So, these authors found significantly down regulated Fox P1 expression in cardiac endothelial cells during cardiac remodeling induced by to angiotensin 2. Endothelial cell Fox P1 loss of function resulted in cardiac dysfunction following angiotensin 2 infusion and in the transverse aortic constriction model with severe cardiac fibrosis and mild adaptive cardiac hypertrophy.                                                 Whereas endothelial cell Foxp1 gain of function protected against pathological cardiac remodeling and improved cardiac dysfunction transforming growth factor beta 1 signals were identified as Foxp1 direct target genes in endothelial cells which mediated the pathological cardiac fibrosis through cardiac fibroblasts proliferation and myofibroblast formation and maladaptive cardiac hypertrophy through TGF beta 1 promoted endothelial one expression during pathological cardiac remodeling. Dr Carolyn Lam:                Wow. Carolyn, this was very sophisticated work. What do we take away from it clinically? Dr Gregory Hundley:       These data really identified endothelial Foxp1 mediated TGF beta 1 signal pathway involvement in the promotion of cardiac fibrosis and cardiac hypertrophy via TGF beta 1 induction of the endothelin one pathway. So targeted delivery of TGF beta 1 silencing RNA or small interfering RNA to inhibit endothelial cell specific TGF beta 1 for the improvement of pathological cardiac remodeling may actually represent a future novel therapeutic strategy in managing this maladaptive cardiac fibrosis and hypertrophy during progression of heart failure. Dr Carolyn Lam:                That was an excellent summary of a very technical but informative basic science paper. I'm going to shift gears a little bit and talk a little bit about a study relating to clopidogrel and aspirin from the point study.                                                 This study comes from Claiborne Johnston at the Dell Medical School and University of Texas. And in patients with acute minor ischemic stroke or high risk transient ischemic attack enrolled in the point trial. The combination of clopidogrel and aspirin for 90 days reduced major ischemic events but increased major hemorrhage compared to aspirin alone. This current paper is a secondary analysis of Point and involves 4,881 subjects in which the investigators assess the time course for benefit and risk from the combination of clopidogrel and aspirin.                                                 The primary efficacy outcome was a composite of ischemic stroke, myocardial infarction or ischemic vascular death, and the primary safety outcome was major hemorrhage. Risks and benefits were estimated for delayed times of treatment initiation using left truncated models. Dr Gregory Hundley:       So, what did the study show Greg? Dr Carolyn Lam:                Well through 90 days, the rate of major ischemic events was initially high, then decreased markedly while the rate of major hemorrhage remained low but stayed constant throughout the study. Using a model based approach the optimal change point for major ischemic events was 21 days with a hazard ratio of 0.65 for clopidogrel aspirin versus aspirin at a P value of 0.0015 compared to later at 22 to 90 days. Where that hazard ratio was 1.38 and the P value only 0.24.                                                 And the models showed benefits of clopidogrel aspirin for treatment delayed as long as three days after symptom onset. So Carolyn, the authors conclude that the benefit of clopidogrel aspirin occurs predominantly within the first 21 days and outweighs the low but ongoing risk of major hemorrhage. When considered with the results of the CHANCE study, a similar trial treating with clopidogrel aspirin for 21 days and showing no increase in major hemorrhage. The combined results suggest limiting clopidogrel aspirin use to 21 days may maximize benefit and reduce risk after TIA or minor ischemic stroke. Very practical paper. Dr Gregory Hundley:       Indeed. Thanks Greg. That was nice. Dr Carolyn Lam:                You bet. Dr Gregory Hundley:       Welcome everyone to our podcast and we're very pleased today to have Dr Antti Nykänen from Helsinki University in Finland as well as an associate editor, Justin Ezekowitz from Edmonton, Canada to discuss a very interesting randomized clinical trial related to the administration of simvastatin in those that are donors for heart transplantation and looking at subsequent outcomes in the patients that received the transplants. Antti, we're very excited for you to bring this to circulation. This particular paper and I wonder if you might outline for us what were your hypotheses that you are trying to test and what was your overall study design. Dr Antti Nykänen:            These things are routinely admitted to heart transplant recipients starting one to two days after transplantation. As previous clinical studies show that recipient that treatment has beneficial long-term effects on mortality and cardiac allograft vasculopathy. So in this clinical study, we basically tried to answer the question whether having the statin effect on the board even earlier before the transplant procurement by giving statins to the organ donor, if that would protect the transplanted hearts.                                                 And this question was based potential rapid vascular and cardioprotective effects of statin and when our previous experimental study showing that treating the organ donor with statins will decreases vascular profusion injury in a heart transplant model. So basically we went on the test donor simvastatin clinically and randomize brain dead heart transplant donors either to a control group or to receive a signal 80 milligram dose of simvastatin before organ procurement. Dr Gregory Hundley:       I'm imagining that you would administer the simvastatin through either an intravenous mechanism or perhaps an NG tube, something like that. Maybe tell us a little bit about how you accomplish this and then what were your study results? Dr Antti Nykänen:            So, the simvastatin was administered to the donor via a nasogastric tube so there is no intravenous simvastatin formulation available. It needs to be absorbed and then activated through the liver so that can form. So, what we did in our previous experimental study was that we included a few clinical human brain-dead donors and basically investigated whether by giving simvastatin through the nasogastric tube would be metabolized and if you could detect that in in the donor plasma.                                                 And that was actually the case. So in a few hours we saw up-regulated levels of simvastatin and also the active form in the donor or so basically showing off that treatment in a clinical brain dead donor of situation would be feasible. So we went on to use that method, clinical study and basically our primary outcome was plasma levels of cardiac injury biomarkers after transplantation.                                                 And interestingly by treating the donor with simvastatin decreased and recipients for troponin INT levels six hours after transplant's profusion. Therefore, it seems that organ donor’s statin treatment reduces biomarkers of myocardial injury after transplantation in a clinical setting. Dr Gregory Hundley:       And did you examine any other functional measures of these patients? For example, ejection fraction by echo or anything, or was it primarily a biomarker study? That's the first question. Second question. Do you have any other information on other organs that also may have been donated? Would the statin have impacted, for example, liver transplantation? Dr Antti Nykänen:            That's a good question. So we did follow up cardiac function and the routine and serial measurements with the echocardiographic and we did not find any changes in the left ventricle. It took some traction after transplantation.                                                 We did however find the decrease in proBNP levels into recipients. And that was maybe then at one week after transplantation and then it's leveled out after that.                                                 And then regarding the next question about other transplanted organs. So once he was in a multi organ donor situation, so the same donor could have donated kidneys or livers, lungs, pancreas. So we did a follow up of the close recipients also. And I can say that there was no adverse effects, no decline in the survival or primary function of the transplanted organs. And interestingly we did find in the liver recipient that if the recipient received the liver from a donor simvastatin treated the liver function tests were better at day seven post-transplant. Dr Gregory Hundley:       Very interesting. And then lastly, just another outcome related question. Sometimes I know these patients undergo assessments for rejection by biopsy. Any information that you can share with us on outcomes related to biopsies. Dr Antti Nykänen:            We took routine biopsies, myocardial biopsies from the recipients and we did not find any significant differences in the biopsy program rejections either at 30 days or one year after transplantation. We did also monitor, we checked some treatments, so during the first 30 days there was significant decrease in the amount of rejection treatments for hemodynamically rejects it about not for the first year. Dr Carolyn Lam:                Wow. Just fabulous results. Thank you so much Antti. So Justin, I wanted to turn the conversation over toward you. Tell us about post-transplant management of these patients and then how do you see these study results integrating into our current standards of care. Dr Justin Ezekowitz:        Thanks Greg and Dr Nykänen and thanks for also letting us look at your work, which is terrific and extremely hard to do from the translation of your original 2011 circulation publication in animals and moving forward into the current publication years later. And thinking forward into the next few years of how we translate this into practice so that the current management after transplantation obviously involve multiple anti-rejection medications and many activities around detecting rejection is one of the key ways in which patients are managed other than their hemodynamics and other things that happen early.                                                 What I was interested in is the generation of the idea where the simvastatin will really affect the clinical outcomes on the recipient and thinking that into the practice environment is, it's a very simple intervention to think about that would be easily applicable in, I think, most hospitals that do transplantation as either the recipient or the donor.                                                 And Dr Nykänen, when you think about translating this into practice over either Europe or in Finland, I don't sense that this is going to be very difficult. Statins are well tolerated. The cardiology and other communities are very familiar with using a statin. But do you anticipate any barriers to translating this into practice as I think the guidelines may pick this up as something of interest. Dr Antti Nykänen:            Yes, I think we can show that it's feasible and we did a result on the biomarkers, so indicating that the damage the heart undergoes during the transplantation was smaller after donor statin treatment, so it is feasible, it's very cheap and it generally has a good safety profile. The timeframe for the treatment also feeds into the window of creating a brain dead organ donor. So in that sense it would be applicable in a donor treatment situation. Dr Justin Ezekowitz:        Right. And so I think this is the key point is even though it's a smaller trial in terms of the cardiology thinks about its trials. This is an area that doesn't have a lot of clinical trials were randomized clinical trials and so any evidence of benefit with a known, generally considered safe medication such as a statin, you would think that we should be able to broadly apply pretty quickly even on what are often not hard outcomes that are softer outcomes.                                                 Because the benefit to risk ratio is generally favorable here. Dr Nykänen, my only other question to you is to think about the team getting this done must have been incredibly hard, but do you think there is a need for a larger trial to test this hypothesis on clinical outcomes or do you think this is really as far as you can go in the transplant world for an RCT. Dr Antti Nykänen:            So, it's been a long road from artery to single center clinical trial, which took time, so the patient numbers are fairly small in our study. We had 42 in the control group on 42 in the treatment group. I agree the risk benefit ratio is probably beneficial. But for sure it would be very nice to see larger studies that would look at the biomarker effects, but also would look at the other clinical end points. Dr Justin Ezekowitz:        Right, and that's a great point. It's only 84 patients, but a continued study of the area's important while perhaps implementation studies could go on to take what you found in both an animal translation into humans in a single center RCT and now translation into a larger population of recipients and their donors. I think that's probably the key next step in the transplantation world which has a tougher time getting larger number of patients into clinical trials for a variety of reasons.                                                 So, congratulations to you and your team in getting this one to the point where we could probably apply this in a reasonable way with reasonable safety and an expected benefit to a broader group of patients. Dr Gregory Hundley:       Well this has been a fascinating discussion, Antti as well as Justin and what a relatively simple, clever idea that could have profound outcomes for this transplant population. We certainly want to thank you Antti for bringing this to circulation and sharing it with our readership. Are there any few last words you'd like to share with us before we close today? Dr Antti Nykänen:            Very nice to see how things evolve after this. We will for sure try to look more closely at the mechanisms and follow up the patient population for a long term follow up. And I hope this will stimulate some other experiments in the field. Dr Gregory Hundley:       Justin, any parting comments from the editorial team? Dr Justin Ezekowitz:        This is a great example of a full clinical trial that is mechanistic, but also has MR outcomes, and I just want to congratulate the authors on providing a very full picture of all the pieces that it takes to do in a clinical trial environment. Plus also collecting genetic and other biomarker material and imaging material. So, my compliments to the authors both to yourself, Dr Nykänen, but also the team that you assembled over the last six or eight years of doing this project, which we know was a huge task and my congratulations to you and your team. Dr Gregory Hundley:       We want to thank Dr Nykänen and his team from Finland and Justin Ezekowitz. We look forward to chatting with you next week. Dr Carolyn Lam:                This program is copyright American Heart Association, 2019

Thanks Greg

Thanks Greg

In which we discuss having access to video games in hospitals and how games like Rogue Legacy for you to engage and learn more from the game because of it’s mechanics, also Greg writes in to provide his thoughts on game preservation. Games discussed in this episode: Keith Courage in Alpha Zones for Turbo Grafix 16 Rogue Legacy for Every Platform imaginable Minit for multiple Platforms Battlefield 2142 for PC Risk of Rain for multiple Platforms Frost Punk for PC Mario Odyssy for Nintendo Switch Dragon Ball FighterZ for Contempoary Consoles Habitica for Browser or Apps Monster Hunter World for Xbox One and PS 4   Items discussed in What we Learned this Month: Stu talks shovelware and Steam-Store issues.  Here is an article on Asset Flip Simulator: https://motherboard.vice.com/en_us/article/pax7g9/asset-flip-simulator-highlights-a-huge-problem-on-steam Steam acquires Campo Santo: https://www.polygon.com/2018/4/21/17266690/valve-campo-santo-firewatch-steam Check out what friend of the Show Fred Rojas put together on his retrospective of Keith Courage if you want to know what the game is like and where it came from: https://youtu.be/U8d71oKLSMk   What we Learned from You Discussion:   Shoutouts: If you like robots/androids, dark reflections on reality and horrible theme parks, check out HBO’s Westworld. Thanks Greg for them emails! Thanks to Joe Gottli for doing our art! Thanks to Dmitry for doing our intro/outro music! Check out Extra Life! Link: https://www.extra-life.org/ Check out Child’s Play!  Link: http://childsplaycharity.org/

(or synaesthesia) - A cross-wiring of the senses. We educate ourselves a little in the many forms that Synesthesia can take, and talk to someone who can see sounds. Thanks Greg! Contact us at - unexplainableuk@mail.com and visit the companion blog at - weirdtalesandtheunexplainable.blogspot.com See acast.com/privacy for privacy and opt-out information.

Christopher and Allan interview and have lots fun with Greg Hague. “GREG HAGUE IS THE Muhammad Ali OF REAL ESTATE.”​ – Muhammad Ali Greg Hague is a real estate game changer. Over 35 years he thrived by introducing nontraditional strategies into a traditional business. He did what others wouldn’t to achieve what others couldn’t. Greg was literally born into the business. After WWII, his dad started with no money, no connections and little education. Through long days, grit and creativity “Chubby” Hague built one of Ohio’s largest real estate firms. Greg writes about Chubby and other remarkable dads in his bestselling book, How Fathers Change Lives and on his website www.savvydad.com. An Avvo superb-rated attorney, Greg is a master level negotiator, CEO of Harvey Mackay University, keynote speaker on real estate strategy, bestselling author and a former Dale Carnegie senior instructor. He writes a newspaper column of creative life strategies, has served as a real estate expert for NPR and The Wall Street Journal, and has spoken at over 500 real estate events from Alaska to Florida. Greg is also an instrument-rated pilot and world motorcycle adventurer, having explored the U.S., Europe and Africa on two wheels. He is a fitness enthusiast, nutrition nut, father, husband and works at friendship. Bring your journal and take notes, this show is jammed with WISDOM!! Thanks Greg.... visit Greg here: http://realestatemavericks.com/ Learn more about your ad choices. Visit megaphone.fm/adchoices

"Deviate Short" A glorious return of our critically acclaimed, "Shorties" from thespeakpodcast.We had the opportunity to speak with Greg from the brand-new Deviate Brewing. If you haven't been yet,check them out. Follow them on twitter for regular menu updates. We can't wait for the End of Days!Thanks Greg!Please listen, rate, and enjoy.

Hi there, I'm so sorry for the wait. Episode 98 features Super Cobra and Reactor, both arcade ports from Parker Brothers. On May 6th I'll be looking at Realsports Football and Atari Video Cube by Atari. The contest that Greg from the SNES Podcast is sponsoring will be extended to May 5th at 11:59 PM EST. You can win a 20 dollar gift certificate to the Atari Age store, and all you have to do is tell me your favorite homebrew game for the 2600, either at 2600gamebygame@comcast.net, or on the pinned Facebook post. Thanks Greg! Episode 100 will be Pitfall by Activision. Upcoming episodes will include Shootin' Gallery and Riddle of the Sphinx by Imagic; Vanguard and Phoenix by Atari, and Oystron, INV, and Mondo Pong, all homebrews by Piero Cavina. If you have any thoughts on these games or any games I've already covered, please send them to me at 2600gamebygame@comcast.net. Thank you for listening! Pertinent Links Tax Avoiders thread on Atari Age Tax Avoiders thread 2 on AA List of Dunhill Electronics copyrights The No Swear Gamer 132 - Reactor! The No Swear Gamer Reactor Easter egg Reactor at KLOV Super Cobra at KLOV Super Cobra sweepstakes ad Reactor manual at 2600 Connection Paul Crowley's blog InfinaDyne website Charlie Heath interview by GDRI Parker Brothers reunion with Charlie Heath AA thread with Charlie Heath interview Charlie Heath's company Town Websites Charlie Heath's Reactor Easter egg on AA Proud member of the Throwback Network! Proud member of the Retro Junkies Network! Facebook page Twitter page Google + page My YouTube channel, for whatever reason Blog page Listen to the show on Stitcher! Subscribe to the show on iTunes, and leave a review! Reviews are nice! Can't get enough Ferg in your ears? Check out the Intarivisions podcast... ...and Please Stand By!

CLICK HERE FOR THE OFFICIAL LAW ABIDING BIKER WEBISTE PODCAST-In this episode of the Law Abiding Biker/Motorcycle Podcast we talk about an array of topics. Did Fonzie from the TV show Happy Days really ride a motorcycle? Does he ride a motorcycle now? Henry Winkler was the actor that played Fonzie on Happy Days and a character that we all came to know and love. He played the tough “biker” type. Here is a direct link to an article reference Fonzie along with a YouTube link: We opened the show with a little snippet of an awesome song called “Remember the Name”. You can get it on iTunes and elsewhere. Song: Remember the name (2005) Artist: Fort Minor (feat. Styles of Beyond) Album: The Rising Tied (Deluxe Version) LINK: http://en.wikipedia.org/wiki/Fort_Minor I found a great video on Facebook. It is an awesome way for bikers/motorcyclists to fold their chaps, so that they take less room in your saddle bags. Additionally, she shows how to roll them and fold them in a way that they then snap together, keeping them rolled tightly. You really must see this video. I shared the video on the Law Abiding Biker Facebook Page and put it below for your viewing. We also play a voicemail from a long time supporter of the Law Abiding Biker/Motorcycle Podcast, Greg Gaxiola. Thanks Greg for your continued support! We go over some ongoing comments on the Law Abiding Biker Media website in reference to my 2014 Street Glide Special review and video. The community is really helping each other out and there is much good information, so check it out! My 2014 Street Glide Special does have adjustable rear shocks. Their is a knob/dial behind the left saddlebag that you can turn to make the suspension softer or firmer. I have not played with this yet, but will in the future and report back. The regular Street Glide has adjustable rear air shocks that you need a bicycle stye pump for. I believe the valve stem to adjust the air shocks is also between the left saddle bag and rear fender. That’s where it was on my 2011 Street Glide anyways. Last, we review an IOS App called GroupMe. The motorcycle club I am in, Sworn Few Law Enforcement Motorcycle Club, has utilized the GroupMe App since our inception and find it to be a very useful tool for us to conduct all kinds of club business. GroupMe is a free private chatting app. You can set up as many different groups as you want and assign a photo to each. Each person can also assign themselves a photo. Additionally, you can single a person out of a group and then just talk with them one on one. The GrouMe app has worked flawlessly for our motorcycle club and it is always updated. They have even added some cool new features. You’ll have to listen to this podcast episode to get the whole scoop and review. It is super easy to contact the Law Abiding Biker/Motorcycle Podcast and Media, so get involved! Phone Voicemail: 509-731-3548 Internet Voicemail: www.LawAbidingBiker.com/VoiceMail Email or Voicemail: www.LawAbidingBiker.com/Contact Don’t forget to rate us and comment in iTunes. Also rate and us and comment in Stitcher Radio. Keep the rubber side down and the shiny side up! ___________________________________________   CHECK US OUT AND SUBSCRIBE:       Website: http://www.LawAbidingBiker.com Email & Voicemail: http://www.LawAbidingBiker.com/Contact Phone Hotline: 509-731-3548   Twitter: https://twitter.com/LawAbidingBiker Facebook: https://www.facebook.com/lawabidingbiker        YouTube: http://www.youtube.com/scrappy587     Google Plus Page: https://plus.google.com/+Lawabidingbiker587   Instagram: http://instagram.com/lawabidingbiker   RSS: feed://www.LawAbidingBiker.com/feed iTunes Direct Link to Podcast:  https://itunes.apple.com/us/podcast/law-abiding-biker-podcast/id622424087    Stitcher Radio: http://www.stitcher.com/podcast/law-abiding-biker-podcast TuneIn Radio: http://tunein.com/radio/Law-Abiding-Biker-p562288/          

This is a broadcast of a Panel Session called Meeting the needs of male victims of domestic and family violence, presented at the Australian Institute of Criminology's Meeting the needs of victims of crime conference held in Sydney on 19 May 2011. Part 5 of the Panel Session features Dr Elizabeth Celi, psychologist, author and media commentator, hosting a panel comprised of Toni Mclean, Greg Andresen and Greg Millan, taking questions from the floor.  Listen now (MP3) |  Watch presentation Elizabeth Celi: Thank you to all of our speakers today. Time certainly has moved on as we now come to the question time. So in starting to raise some of this discussion with our panel members and amongst the audience members I’ll just remind you of some of the myths and assumptions and misperceptions that have developed to date. And having worked in this field, all of us in our various capacities are very clear that male victims are there, they’re in dire need of the support and we also know the blocks in resources that they face. And we do our best in our capacity to help them on that one-on-one level. Clearly social awareness, community awareness and various service provider awareness is required so that re-victimisation or misjudgements don’t inadvertently occur. There’s still the shock and surprise that a male could experience this and how that could possibly occur. As I open it up to any questions, given we’ve got short time left, we’d be certainly interested in everyone having a chance to ask a question. Please keep any commentary as brief as possible as you get to your question and we’ll aim to have some good discussion with you. So I saw a hand up the back there. Q: Hi. Thanks for the speeches. I just wanted to ask, you know, one of the main things that you pinpointed is that men are scared to lose their kids, and access to their kids. I've got lots of friends who are not in abusive relationship but when it comes to the family court it's very hard for them even as good fathers not in a domestic situation to get access to their children. Is there any sort of progress in the family courts to, I guess, take note of these domestic situations and how do they perceive it? Elizabeth Celi: (to the panel) Any of you  want to take that? The same kind of barriers and blocks are happening there. The system being able to assist female victims in this area may have the same kind of paradigm and perception, but nonetheless they’re still male victims as well. What we’ve found in work we’ve done is to keep on informing men about these difficulties they may face in that sphere and being aware, it’s another layer that they’re needing to deal with, whilst also being distressed, going through these difficult times and incredibly concerned for their children in the mere fact of protecting them. His thinking “If I leave or if I don’t really do my best for this situation, they’ll be exposed to the same abuse and violence”. So they’re incredibly protective and loyal, obviously to their kids, and loyal to their partner in that they don’t really want to go through that system anyhow. They’ll be the last to really bring up any slander toward their ex-partner. I think it’s slow, but steady. There’s a service up in Queensland, Men’s Rights Agency, that assists in this process and is certainly more informed of the details of that, so if you want to look up their website. Greg Andresen: Dad’s in Distress as well. Elizabeth Celi: And Dad’s in Distress certainly looks specifically at the legal system with that. It (law system) is a very slow system as we all know. Yeah. Q: Thank you. Elizabeth Celi: You’re welcome. Were there any other questions? Comments? Should I take this as shock?!! Go for it. Q: I think it was Greg Andresen mentioned the research, sorry I wrote it down, I've got a bad memory… predictability. The greatest predictor of perpetration down the track was the female to male violence. I didn't write down the study but it did sound interesting. Can you tell me the name of it or where I would look that up? Greg Andresen: Absolutely. If you go to oneinthree.com.au it’s linked to there, but I will give it to you again here. So it was the National Crime Prevention Study (2001), and the title was Young People and Domestic Violence. It was produced by the Attorney General’s Department in Canberra. Because of the change of government, they’ve archived their document from their website, but there’s an active link from the One in Three website to the full PDF of that. Elizabeth Celi: Okay, other questions? Greg, perhaps you can let us know about some of the outcomes and achievements that have come since One in Three was launched 18 months ago. Greg Andresen: Okay, well the public response has been overwhelmingly positive. We’ve had many emails of support from around Australia and across the globe. Many supporters have joined the campaign and they’re listed on the website, many high profile supporters. We’ve got a lot of media coverage, in the print press, radio and online. I just talked about three-quarters of a million dollars recently committed to Mensline Australia to support male victims of family violence. I can’t say we’re directly responsible for that, but these things have been happening since we started, so we hoped we’ve played a part in that. The New South Wales Government domestic violence website now has a page for male victims. They’ve never had a page previously and we think that’s a big step forward. There is, as I mentioned, Mensline Australia now has tip sheets for male victims of domestic violence on their website, which they didn't before. We’ve commissioned some new data from the ABS from the Personal Safety Survey that was done in 2005, which shows there’s no significant difference between the levels of physical assault experienced by men and women in the home or from persons known to them, so that wasn’t teased out in the published report, so we had to commission some data for that. We’ve lodged submissions with a number of inquiries including family law inquiries to try to make sure that the family law system is responsive to the needs of male victims and their children. We’ve attended consultation processes around the National Plan to Reduce Violence Against Women and Their Children and around the New South Wales Domestic Violence Behaviour Change Programs. And I’ve been assisting Greg where I can with some information and resources for his training program. We’re collaborating with an organisation in Western Australia you may not be aware of called the Global Good Foundation, which is a charity that works in the area of domestic and family violence. And we’re working together with them so that their domestic violence campaigns and resources include the voices of both men and women. And we’ve assisted with the program I mentioned that’s running in the Hawkesbury region of Sydney, where Windsor police are referring male victims to the Hawkesbury District Health Service for phone counselling. We’ve established a data collection program with them so that we can actually keep tabs on the data around these men. So a number of things. It’s a slow, steady process of chipping away, but we feel that things are changing and it’s going to be a long road. And of course, none of that would ever take away from the need for services for women. Elizabeth Celi: So one of the key things that we’ve often found along the way, and having done several radio and TV interviews on this topic, one of the things that never ceases to amaze me is, shortly after, the myriad of phone calls and emails that come in from men absolutely relieved that someone’s spoken about it. Just relieved – in tears. And just there listening if they’ve called, or reading their emails sharing their story and offering (to me) “…if you need more information or if you need this for somewhere else, please let m know”. To be able to receive non-judgmental support and some initial understanding, knowing that they won’t be ridiculed or judged by unfortunate misconceptions that many have unfortunately received just by unawareness of people working in the field and needing to come to grips with this level of information, the dynamics involved and that men aren’t likely to tell you anytime soon. So in our capacity, in our working levels, the screening and the questioning is important. Asking the questions we may not feel comfortable to ask, or haven’t even been alerted to ask, which hopefully today has given you some thoughts of other questions to consider. Not only of men, in terms of ‘do you experience certain types of abuse’. Typically a starting point would be the verbal abuse. The level of criticism, insults, being demeaned, being belittled and the pattern or frequency of that over time and the psychological impact that can have on anyone, in particular masculine thinking, normal manhood strengths being demeaned, if not their fatherhood role or their sexual performance. And unfortunately, in this case, women’s increased verbal literacy can most certainly maim with a “sugar-coated viper-tongue”. Often men can relate to that description when you’re asking them about this kind of experience or they just start to bring it up themselves. And similarly asking women about their patterns of potential abuse or if they use any physical means. For example; “Do you throw a pan, do you threaten, do you scratch, do you throw insults or criticisms?” The kind of things that even unconsciously happen for women because of frustration or anger or the various reasons that Greg mentioned earlier, and don’t realise that, over time it creates an abusive pattern and a difficult situation in their partnerships. It’s certainly not helping them develop a respectful relationship and one where they can generate more satisfaction and fulfilment with each other. So these are very important questions to keep in mind for yourselves. Just prior to us closing up, we’d be interested to hear, in terms of your working capacity or chatting with other colleagues about this topic, what you’ve tended to come across or any thoughts, questions, uncertainties and opinions that you may have come across, if you’re willing to share. Q: I would really like to ask a question about how effective Victim Services have been in responding to the needs of male victims of domestic violence. Elizabeth Celi: What we’ve encountered so far is the shock that Greg Millan had initially mentioned. It’s initially a bit of a jaw drop, initially, of ‘oh, how do I handle this?’ Q: From Victim Services, not from... Elizabeth Celi: From Victim Services, yeah from Victim Services. And unfortunately at times, through many anecdotes and clients I’ve worked with and perhaps the others may comment as well, of unfortunately certain comments like, “What did you do to deserve it? You must have done something wrong.” Or “Come on, man up.” or “Suck it up, she couldn’t possibly hurt you that much.” So flippant comments that have come out that, unfortunately, re-victimise. And the silence is then encouraged. He’s taken a step to come out, already in a psychologically abused state, if not socially abused, financially abused and so on, and that unfortunately perpetuates him to just go back into the cave again. Similarly though, depending on the services, they have also gained some support. When people have been able to overcome some of the initial thoughts of shock and surprise, of going, “oh okay, it’s a human issue. We need to help you regain your strength and your resilience.” So there’s anecdotes and evidence on various sides. Q: I think some of the strengths have been where services have networked together and it's more the relationship of the expertise of the counsellor he's being referred to, the social worker, the psychologist, the victim services support group, and then you get a very close clique, and you know that client is going to be supported, male or female. Elizabeth Celi: And that’s why on this level we want to keep raising this social awareness on the worker level, on the service provider level so that we can be the beacons of light for the men so they don’t have to face too many barriers beyond what we face systemically anyway, in knowing what our work’s about. And being able to network and knowing he may need to be in touch with the court system somehow or a lawyer or other counsellors. Greg? Greg Millan: Sorry, I just neglected to say. I mentioned my training program: there’s some postcards here at the front if people what to know more about the training program and how you contact me. The program’s been run here in Sydney and Perth and up in the Hunter region. Every time we run a program for about 25 people, they form a network, which is what you’re saying, which is great. So they can support each other and share information and that’s how it works. There’ll be another one in Perth in September and we’re planning… I’m planning, if there’s interest, Brisbane and Melbourne. So if you live in an area where you’d like the program run, we can do it if you contact me. So there’s some information up here if you’d like that. Elizabeth Celi: Thanks Greg. Greg or Tony, do you want to make any final comments before I wrap up? Okay, well, we won’t hold you up from afternoon tea, it is the second day! So just in wrapping up with you, we do hope that your awareness is raised on variable levels as you return in to your professional capacities and hopefully open up these discussions with your colleagues in raising awareness and understanding. Please bear in mind: he’s not likely to tell you any time soon, so if we can invite you to consider the questions that I’ll put up in a moment in your own context. Just before that, each of us are happy to have a chat with you during the tea break if you’d like further information or our contact details again. So please feel free to approach us with any questions or discussion points. If we can leave you with these questions to consider within your own context. Question: “Where are we at in our views and approach toward male victims of abuse and violence?” Hopefully it’s either expanded or we’ve shifted some things for you. Importantly on the other side of the coin, Question: “Where are we at in terms of female perpetrators?” They need some assistance as well and both sides of the coin will help the overall dynamic for men and women and children, naturally. So with that, please enjoy your afternoon tea and the remainder of the conference and thank you so much for being with us for this hour-and-a-half. We appreciate your attention.

This is a broadcast of a Panel Session called Meeting the needs of male victims of domestic and family violence, presented at the Australian Institute of Criminology's Meeting the needs of victims of crime conference held in Sydney on 19 May 2011. Part 4 of the Panel Session features Greg Millan, director of Men's Health Services, giving an overview of his training program called Working with men affected by violence. In Australia, up to one in three victims of intimate partner violence are male. While many services have quite rightly been established over the past three decades to support female victims of family violence, the needs of male victims remain largely unmet. The issue of men affected by violence in intimate relationships has been reported for many years. Workers in the domestic violence, community and family relationship sectors are acknowledging this problem and seeking out training for their workers. There is only one training program for professionals and this talk will present an overview of this program and its evaluation. ‘Working with men affected by violence’ is a specifically designed training program for health, welfare and community workers that provides information and strategies for working with men who are affected by violence in their relationships.  Listen now (MP3) | Download PowerPoint |  Watch presentation Elizabeth Celi: Greg Millan is a social work trained health educator with over 30 years of experience with government, non-government and private sector organisations. He is an executive member of the Australasian Men’s Health Forum, which Australia’s peak body implementing a social approach to male health. And as you may be hearing we’re very much on the social psychology and social health avenue with male victims. So for over 20 years he has been working in men’s health promotion implementing different programs and professional training services, particularly for other service providers, health service providers and otherwise. So Greg will share that with us now. Thanks Greg. Greg Millan: Thanks a lot. Thank you very much for inviting me along today. This little slide starting my presentation actually is this rather interesting poster from Canada, which I think clearly talks to me about the fact that this whole issue has been silenced and that campaign was around working with those people that have been silenced, with men that have been silenced when we think about domestic violence. My background in this work, yes, I have been social worker for 30 years. I guess my clinical work in supporting male victims of domestic violence over the years. I've had some past clinical group work with men who have experienced childhood sexual assault, which is a different issue. I run a number of programs for men and have for a number of years. Two of those, ‘understanding relationships’ and ‘dealing with difficult emotions’, which are men only programs, have involved men talking about domestic violence. Just a quick scenario is that I was asked by Relationships Australia in Newcastle to run an ‘Understanding Relationships’ workshop for them, which I did. Very good workshop I ran over a number of nights, five or six nights. I think on the fifth night we actually talked about destructive relationships and I bring up the issue of domestic violence and other issues, drug and alcohol issues or mental health issues that could be destructive, and we had this lovely guy in the group in his 70s. Unfortunately his wife had passed away a couple of years ago and he was obviously still grieving her passing away. He was getting a lot out of being at the group and when I started to talk about domestic violence he said, “Well you know my wife used to hit me with a frying pan once a week, but isn’t that what love is about?” And before I had a chance to say anything the other guys turned to him and said, “No, I don’t think so. No, I think we better talk more about this.” So that was a moment I've always remembered that men pop up with these things out of the blue. It was interesting. I've been a longtime advocate for men who suffer violence and abuse in their relationships and I've worked in the men’s health area for a number of years and there is a huge growing awareness of – in both the health, welfare and in the men’s health sector of the needs of men affected by violence and in their relationships. So much so that since 2005 – we have national men’s health conferences every two years in this country. We started having papers and workshops in 2005. The last conference we had was in 2009 in Newcastle where there were 15 presentations at that conference on this issue and we’ve got our next one coming up in Perth shortly, so we’ve been tracking this for a while. I just wanted to briefly say, and my colleague Greg went through the effects on men, but I just wanted to talk about some myths about men affected by violence. Men affected by violence come from all walks of life, social backgrounds, cultures and sexualities. They suffer society’s stigma for not protecting themselves often. They become depressed in their isolation, as Greg mentioned, feel suicidal and sometimes can take their own lives without disclosure of anything that has been going on for them. They can be victimised because they fail to conform to the ‘macho man’ stereotype and as Greg mentioned, are often perceived as wimps or weak. They’re often disbelieved because they’re men. One of the difficulties I think, and this can be true for women as well, but when men say to their friends or it’s obvious that they’ve been the victim of some sort of violence and it’s within a relationship often their friends don’t know what to do or say. And they have very few support systems in place. I wanted to briefly mention men affected by violence in male to male relationships. I know this is a national conference. This is a poster from the AIDS Council of New South Wales that was released in March. They’ve had an anti-violence project running here for five of six years or more, but they’ve just had a re-release of it. Australian research shows that domestic violence is as prevalent amongst gay and lesbian communities as it is in the wider community. Having said that, I’d just like to also draw your attention to what we’re talking about today is male victims of domestic violence who would be predominately heterosexual because that is the world we live in, so the numbers of gay men affected by this are much, much smaller. The problem is often underreported as the system can be oppressive and hostile towards gay men. Gay men who experience violence report being afraid and revealing their sexual orientation or the nature of their relationship to those that are trying to help them. Something specific to gay males is that outing around sexuality or HIV status can be used as a form of control by the abusive partner. The other point is telling heterosexuals about violence in a gay relationship can reinforce the myth many believe that gay relationships are abnormal and this can further cause the victim to feel isolated and unsupported. I run a training program called ‘Working with Men Affected by Violence’ and I’ve run that here and in Perth and in a few other places. I run the only training program for workers in this country on this issue. I personally actually think that’s terrible that there is only one and I'm the person doing it and I haven’t run too many. But a typical one-day training program would include the following things: • A background to the issues and what we need to do • the effect of violence on a person • what is different for men - so we’re talking about men here, what is different for men from women • strategies for working with men from a strengths based perspective • a model for working with men affected by violence. I actually present a model that people can use to work with these men • men-friendly counselling and group work approaches • building services for male victims of violence into your agency and what you need to consider and • promoting the case for supporting male victims of violence and working with female perpetrators of violence, which is equally as important. Why I started doing this was I had received a number of calls from workers who had no idea what to do when that phone call arrives, and they’re in the business of supporting people, and they get a male victim of DV ringing up and saying ‘how can you help me’ and they almost freeze because they don’t know what to do or say. So we desperately need training of healthcare professionals in this country to be able to adequately answer those phone calls. These are some of the evaluation comments from past training program participants who’ve been through my program: • “The difficulty men have in communicating to others about domestic violence.” This was what was the most positive aspect of the program • “That domestic violence is a social problem rather than a gender problem as it is often perceived.” Now I guess to explain that, it’s my personal belief that we’re living in a far more violent world and that whatever you want to call it, domestic violence or intimate partner violence is a symptom of the fact we’re living in far more violent times and I see violence as a social problem – certainly with a gender determinate – but if I view it that way I think all violence is bad and that we should do something about all violence rather than view the whole issue as a gender problem and not a social problem. • Another comment from a past participant: “I now realise men go through the same issues as women.” • “Not looking at domestic violence from only a feminist perspective,” one of the participants said who came along. • “There is a clear need for services to help men by providing information, support and referral services” • “Networking and knowing others who are on the same page of the training.” What have you learned from this training? • “That the situation is similar for men as it is for women, however it’s hard for men due to socialisation and how society sees men,” and what this person means is, as Greg has elaborated, it’s very hard for men to talk about it to anybody or report it, so it’s very unreported because of all the reasons Greg gave. • “Men have the same responses and feelings afterwards as women.” They certainly do. •  “There is definitely a lack of services for men both in domestic violence and sexual assault areas.” • “Men underreport understandably and this hides the real problem” • And “The different situation for gay men affected by violence in their relationships.” So what do we need to do? We need to raise awareness I think as we pointed out of the issue in the community and the media. I remember distinctly the One in Three Campaign that Greg’s worked so successfully on was launched in November of 2009. It’s a great campaign, a great website, but when it was launched I was one of the people that the media could have interviewed across Australia, so the ABC as they often do if it’s a men’s health issue, I live in Newcastle, rung me up and said, “Greg, come in and let’s talk about this.” The ABC, the interview I had in the morning about this was like, “Greg, tell us about this brand new problem and what has caused it.” Oh good, you know it’s not a brand new problem, that’s good, but the ABC saw it that way. They really – it was a female journalist, I’ll put this into context – had great difficulty in getting her head around this problem. Where does it come from? Why didn’t we know about it? But as colleagues have said today, it has been around for a long time. I was working as hard as I could to talk about it and we were interrupted by a phone call from a guy who rang up to talk about his own abusive relationship and what went on in that in the middle of it and so that interviewed happened. Then we came back to me talking more about it, but that changed the whole nature of the interview. It is kind of interesting, but the interesting point was: the media don’t get their head around this either. The media, like everyone else sees domestic violence as something men do to women. They see it in that context only, so we do need to do a lot of work in the community, but also with the media. We need to provide education and training for, I think, domestic violence workers, community workers, health and welfare workers and I’d also say legal workers in there as well. We need to advocate more for resources and services for males affected by violence. We need to encourage the domestic violence area to rethink, refocus and retrain staff to provide services for male victims of violence and female perpetrators of violence as well. And we need to seek separate funding for support services for men and never, in any way, undermine the existing services for women. Thanks a lot.

I met Lisa Whitehouse a year ago and she told me it was her lifetime goal to volunteers overseas.She worked with the Government of British Columbia that partners with CUSO-VSO to ensure that we deliver the best possible skilled person to our projects. Government employees can apply to serve with us and return to a job with the BC Government. Lisa is the first volunteer to be sent in this partnership. There are however quite a few BC Government employees that have served with us in the past.Greg Spira was also getting ready to take an assignment in Cameroon and interviewed Lisa.Lisa is working with Children and disabilities, mostly administrative work.I cant wait to hear from her!Thanks Greg for the doing the interview so well.Lisa- Right in green suit. Pictured with RV's in Victoria and Karen Petite from BC Government. Volunteer for a better world! Join CUSO-VSO, share skills and volunteer in 43 countries in Africa, Asia, the Pacific, Latin America and the Caribbean. Volunteers, donate, share skills.www.cuso-vso.org

"Mouseketeer Greg" of Portland, Oregon has provided us all with a Fun, and INCREDIBLY COOL trip around the Disneyland Resort, as he and 3 friends attempt to follow THE EXACT PATH that I took during the "Where in the Park?" game in show #20. THIS IS NOT THE CONTEST WINNER!!! However, this 12-minute romp around the resort shows you EVERYWHERE I WENT, and he gets the answer correct! Be sure to download this video and tune in to tomorrow mornings Part 2 of the WindowtotheMagic podcast for the announcement of the winner of the iPod Shuffle! Thanks Greg!!! 12mins ))AMAZING((