Podcasts about arvc

Operators and Allocators Podcast

Play Episode Listen Later Jan 20, 2023 9:31

The following question refers to Section 7.4 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. The question is asked by New York Medical College medical student and CardioNerds Intern Akiva Rosenzveig, answered first by Cornell cardiology fellow and CardioNerds Ambassador Dr. Jaya Kanduri, and then by expert faculty Dr. Randall Starling.Dr. Starling is Professor of Medicine and an advanced heart failure and transplant cardiologist at the Cleveland Clinic where he was formerly the Section Head of Heart Failure, Vice Chairman of Cardiovascular Medicine, and member of the Cleveland Clinic Board of Governors. Dr. Starling is also Past President of the Heart Failure Society of America in 2018-2019. Dr. Staring was among the earliest CardioNerds faculty guests and has since been a valuable source of mentorship and inspiration. Dr. Starling's sponsorship and support was instrumental in the origins of the CardioNerds Clinical Trials Program.The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Question #6 Mr. D is a 50-year-old man who presented two months ago with palpations and new onset bilateral lower extremity swelling. Review of systems was negative for prior syncope. On transthoracic echocardiogram, he had an LVEF of 40% with moderate RV dilation and dysfunction. EKG showed inverted T-waves and low-amplitude signals just after the QRS in leads V1-V3. Ambulatory monitor revealed several episodes non-sustained ventricular tachycardia with a LBBB morphology. He was initiated on GDMT and underwent genetic testing that revealed 2 desmosomal gene variants associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). Is the following statement true or false? “ICD implantation is inappropriate at this time because his LVEF is >35%” True False Answer #6 Explanation This statement is False. ICD implantation is reasonable to decrease sudden death in patients with genetic arrhythmogenic cardiomyopathy with high-risk features of sudden death who have an LVEF ≤45% (Class 2a, LOE B-NR). While the HF guidelines do not define high-risk features of sudden death, the 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy identify major and minor risk factors for ventricular arrhythmias as follows: Major criteria: NSVT, inducibility of VT during EPS, LVEF ≤ 49%. Minor criteria: male sex, >1000 premature ventricular contractions (PVCs)/24 hours, RV dysfunction, proband status, 2 or more desmosomal variants. According to the HRS statement, high risk is defined as having either three major, two major and two minor, or one major and four minor risk factors for a class 2a recommendation for primary prevention ICD in this population (LOE B-NR). Based on these criteria, our patient has 2 major risk factors (NSVT & LVEF ≤ 49%), and 3 minor risk factors (male sex, RV dysfunction, and 2 desmosomal variants) for ventricular arrhythmias. Therefore, ICD implantation for primary prevention of sudden cardiac death is reasonable. Decisions around ICD implantation for primary prevention remain challenging and depend on estimated risk for SCD, co-morbidities, and patient preferences, and so should be guided by shared decision making weighing the possible benefits against the risks,

Is ARVC Outdoor Hospitality Conference and Expo Worth The Trip?

Play Episode Listen Later Jan 17, 2023 25:41

On this episode of Requity Insights, we will be covering our time at the Outdoor Hospitality Conference and Expo hosted by ARVC in Orlando, Florida. This expo is a perfect opportunity for people who are interested in or just stepping into the RV Campground space. This conference helped us to gain additional knowledge on emerging technology and market updates, while also hosting some breakout sessions. During this episode, we also touch on some detailed pieces of information regarding the market that we learned during our time there. We hope you guys found this podcast informative, don't forget to check out ARVC and what they have to offer and be on the lookout for their North Carolina hospitality expo, known as CARVC. If you attended OHCE or any other related expo, let us know what you learned! To join our investor community and stay updated on future opportunities, visit therequitygroup.com Key notes: 00:00:00 – Introduction 00:01:03 – Our expectations of arvc 00:04:42 – Summary on ARVC 2022 00:06:05 – Economic outlook takeaways 00:09:25 – How it'll effect campgrounds 00:14:15 – New revenue generators in the market 00:20:02 – Expo portion of the event 00:23:55 – The increased popularity in short-term-rentals Follow us on social media! Dylan Marma https://www.linkedin.com/in/dylanmarma/ Luis Valez https://www.linkedin.com/in/luisevelez/ The Requity Group https://www.linkedin.com/company/requitygroup Watch this podcast on YouTube https://www.youtube.com/@requity Interested in becoming an investor? Visit https://www.therequitygroup.com to learn more.

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246. Cardiovascular Genomics: Genetic Counseling & Family Screening in Arrhythmogenic Cardiomyopathies with Dr. Allison Hays and Dr. Cindy James

Play Episode Listen Later Nov 30, 2022 45:25

The CardioNerds Cardiovascular Genomics Series continues! In this episode Dr. Dan Ambinder (CardioNerds Cofounder and Interventional Cardiologist), Dr. Anjali Wagle (FIT Ambassador at Johns Hopkins) and Dr. James Sampognaro (medicine resident at Johns Hopkins Osler Medicine Residency) learn from Dr. Allison Hays (Associate Professor of Medicine, Division of Cardiology, Johns Hopkins CMR researcher and Medical Director of Echocardiography) and Dr. Cindy James (Associate Professor of Medicine and certified genetic counselor at Johns Hopkins with research focusing on cardiovascular genetic counseling and arrhythmogenic cardiomyopathies). They discuss arrhythmogenic RV cardiomyopathy as the context to learn about genetic counseling and family screening. Episode script and notes were developed by Dr. Anjali Wagle. Audio editing by CardioNerds Academy Intern, student doctor Chelsea Amo Tweneboah. This episode was developed in collaboration with the American Society of Preventive Cardiology and is supported with unrestricted educational funds from Illumina, Inc. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds. This CardioNerds Cardiovascular Genomics series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs. Check out this REVIEW describing the “Multimodality Imaging in Arrhythmogenic Right Ventricular Cardiomyopathy” by Nitin Malik, Allison Hays, and colleagues. For related episodes, please enjoy these case-based discussions: Ep 56. Case Report: Arrhythmogenic Desmoplakin Cardiomyopathy – Northwestern University Ep 74. Case Report: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) – Summa Health Pearls • Notes • References CardioNerds Cardiovascular Genomics PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Show notes - Genetic Counseling & Family Screening in Arrhythmogenic Cardiomyopathies Notes (developed by Dr. Anjali Wagle) What is the underlying pathophysiology of arrhythmogenic RV cardiomyopathy (ARVC)? Fibrofatty replacement cardiac myocytes Associated with genetically mediated disruption of desmosomal proteins This leads to thinning and weakness of the heart that can lead to aneurysms and progressive dilatation and failure of the right ventricle (RV) How is ARVC diagnosed? 2010 taskforce criteria (Marcus et al, 2010): RV structural abnormalities including findings seen on echocardiogram, MRI, and RV angiography Pathological criteria Repolarization abnormalities Depolarization/conduction abnormalities Ventricular arrhythmias Genetics and/or family history How does ARVC present? Young, healthy individual will have symptoms of arrhythmias (syncope, pre-syncope, SCD) or heart failure Family screening What are the inheritance and genetic factors of ARVC? Autosomal dominant pattern Low penetrance and variable expressivity Half of patients who are index cases will be found to have a mutation in the desmosomal gene. What are the most common mutations associated with ARVC? Most commonly the genes involved are plakophilin-2 (PKP-2) and desmoplakin. For PKP-2 the most common mutations are truncating mutations. In patients who have inherited two truncating mutations, this will result in neonatal lethality. Is there a difference in the genetic factors of left and right arrhythmogenic cardiomyopathy? ACM is disproportionally a right dominated cardiomyopathy. Left dominated cardiomyopathy has a different genetic profile. Pathogenic variants in desmoplakin disproportionally cause biventricular forms of ACM or left dominated forms.

Circulation November 8, 2022 Issue

Play Episode Listen Later Nov 7, 2022 22:26

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 cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore. And... Dr. Peder Myhre: I'm Dr. Peder Myhre from Akershus University Hospital, and University of Oslo in Norway. Dr. Carolyn Lam: Peder, I'm so excited about our future discussion. It's about a very important topic of detecting atrial fibrillation in the population using wearable devices. It talks about the Fitbit Heart Study. So exciting, but we're going to keep the audience waiting a bit, because we're going to talk about some other things in the issue. And I would love to start with this now. We know that fulminant myocarditis presentation is a rare and severe presentation of myocarditis. But, what is its natural history, and clinical features associated with poor outcomes? Peder, what do you think? Dr. Peder Myhre: Oh, that's a great question. We really don't know, because prior studies have been relatively small and selected. So Carolyn, let me know. Dr. Carolyn Lam: You're absolutely right. But today's paper from Professor Saito, from Nara Medical University in Japan and colleagues, is the largest nationwide cohort study of patients with histologically proven fulminant myocarditis presentation. They study 344 patients, hospitalized with histologically proven myocarditis, who underwent catecholamine and/or mechanical support from 235 cardiovascular training hospitals across Japan, between 2012 and 2017, and here's what they found. Over a median follow up of 600 days, the accumulative risk of death or heart transplantation at 90 days was 29%. So, really high. These were the risk factors associated with a higher risk of death or heart transplantation, and they were non-sinus rhythm, older age, ventricular tachyarrhythmia, lower left ventricular ejection fraction. Severe histological damage was also associated with a worse 90 day outcome in lymphocytic myocarditis. Cool, huh? Dr. Peder Myhre: Oh wow. That was some really solid data. And now Carolyn, I'm going to take us over to the world of preclinical science. And the next paper entitled at “APIC Associated De Novo Purine Synthesis is Critically Involved in Proliferative Arterial Disease” by Yuqing Huo from Augusta University in Georgia. Dr. Carolyn Lam: Cool. Dr. Peder Myhre: And as you know, Carolyn, vascular smooth muscle cells are extremely important in vascular health. They're located in the medial layers of arteries, and normally exhibit a contractile phenotype that contributes to the regulation of blood vessel tone, blood flow distribution, and blood pressure in normal mature blood vessels. And in response to disease processes, the vascular smooth muscle cells are switched to an activated synthetic and proliferative phenotype, that contribute to the development of a variety of arterial diseases, including atherosclerosis, in-stent restenosis, and bypass graft occlusion. And nucleotides that we are familiar with, such as ATP and GTP, are essential for a large number of biological processes in cells, including proliferation. And Carolyn, the previous studies have demonstrated that de novo synthesis of purine is a critical pathway for nucleotide synthesis. And in this study, the authors assessed the role of de novo synthesis of purine in vascular smooth muscle cells by using knockout mice. Dr. Carolyn Lam: Oh, that was beautifully explained. Thanks, Peder. So what did they find? Dr. Peder Myhre: So the authors found that the de novo purine synthesis was increased in proliferative vascular smooth muscle cells. Moreover, they identified an important enzyme in the process called A-P-I-C, APIC. Which was observed in the neointima of the injured vessels, and atherosclerotic lesions in both mice and humans. Finally, they showed that in a mouse model with knocked out APIC, the atherosclerosis and arterial restenosis was attenuated. Dr. Carolyn Lam: Cool. So tell us what the clinical implications are. Dr. Peder Myhre: So these findings provide novel insights into the reprogramming of purine metabolism underlying vascular smooth muscle cells proliferation in the development of arterial disease. And that targeting APIC may be a promising therapeutic approach to combat arterial diseases. So Carolyn, please tell me about your next paper. Dr. Carolyn Lam: Ah, thanks, Peder. Well, back to the clinical world, this time, talking about arrhythmogenic right ventricular cardiomyopathy. We know that is characterized by progressive cardiomyocyte loss and fibro fatty replacement. And we know that patients with this a ARVC are at risk for life-threatening ventricular arrhythmias and sudden cardiac death. The placement of an ICD is a crucial component of ARVC management. But arrhythmic risk stratification and the selection of the optimal candidates for ICD, especially for primary prevention of sudden cardiac death, has, of course, been challenging. As background, a ventricular arrhythmia risk calculator, in patients without previous sustained ventricular arrhythmias, has been proposed, and includes seven clinical variables derived from non-invasive tests that are routinely performed in these patients. However, the possibility of integrating additional parameters, such as ventricular tachycardia inducibility on programmed ventricular stimulation, with this risk calculator, has been suggested, but not conclusively investigated in a large cohort. And so, here comes corresponding author, Dr. Cadrin-Tourigny, from Montreal Heart Institute and colleagues, who studied 288 patients with a definite ARVC diagnosis, no history of ventricular arrhythmias at diagnosis, and programmed ventricular stimulation performed at baseline. And these patients were identified from six international ARVC registries. Dr. Peder Myhre: Oh wow. So we're talking risk stratification for patients with ARVC. Such an interesting topic, Carolyn. So please tell me, what did they find? Dr. Carolyn Lam: So, programmed ventricular stimulation significantly improved risk stratification, above and beyond the calculator predicted risk of ventricular arrhythmias, in a primary prevention cohort of patients with ARVC. And this was mainly for patients considered to be at low and intermediate risk by the clinical risk calculator. If negative, its high negative predictive value of 93% in low and intermediate risk patients, may support the decision to forego ICD use in some patients. So, programmed ventricular stimulation results may be applied to the non-invasive ARVC risk calculator, in a two step approach to facilitate personalized decision making for ICD in such patients. Dr. Peder Myhre: Thank you, Carolyn. That was a great summary and a great paper. So we're going to move in to see what else is in the mail bag, Carolyn. Dr. Carolyn Lam: You bet. There's a letter by Dr. Agirbasli regarding the article, “Coronary Artery and Cardiac Disease in Patients with Type Two Myocardial Infarction, A Prospective Cohort Study,” and this, followed by a response by Dr. Chapman. There's an ECG Challenge by Dr. [Jingnan] Han, entitled, “Tachycardia Associated with Pacing.” From our own Molly Robbins, we have highlights from the Circulation Family of Journals. And she covers the experience with stereotactic radio ablation and electrical storm, reported in Circulation: Arrhythmia and Electrophysiology. The impact of accessibility to primary care on hypertension awareness and control is reported in Circulation: CV Quality and Outcomes. There's an analysis of lifestyle factors and their impact on the risk of heart failure by background genetic risk, and that's in Circulation: Heart Failure. There's a deep learning model of PET scans and coronary flow reserve reported in Circulation: CV Imaging. And finally, OCT based measurement of stent expansion and associations with outcomes are presented in Circulation: CV Interventions. A lot. Dr. Peder Myhre: Yeah, and there's more, Carolyn. In this issue, there is an extensive Frontiers review by the AF-SCREEN International Collaboration, entitled, “Consumer LED Screening for Atrial Fibrillation.” There is also a Research Letter by corresponding author Qi Fu, from University of Texas Southwestern Medical Center entitled, “Neuro Cardiovascular Dysregulation During Orthostasis in Women with Posttraumatic Stress Disorder.” And finally, a Research Letter by Pankaj Arora from University of Alabama entitled, “Mechanical Circulatory Support Devices Among Patients with Familial Dilated Cardiomyopathy, Insights from the INTERMACS.” Dr. Carolyn Lam: That's awesome, Peder. Thank you. Now let's go onto our feature discussion on atrial fibrillation detection and the Fitbit Heart Study, shall we? Today's feature discussion is about the Fitbit Heart Study, and none other than the first and corresponding author Dr. Steven Lubitz, from Massachusetts General Hospital in Boston to join us today. Steve, welcome. Congratulations. Am I right to say, this is the largest study of its kind to look at the detection of atrial fibrillation using wearable devices? Dr. Steven Lubitz: Thanks for having me, Carolyn. And that's right, this is. Dr. Carolyn Lam: Oh my gosh. Okay. Tell us all about it, what you did, what you found. Dr. Steven Lubitz: Well, thanks, Carolyn. So as we know, undiagnosed atrial fibrillation is a potential hazard that can cause strokes. And if we can identify people who have undiagnosed atrial fibrillation early, we may be able to prevent strokes. In addition, undiagnosed atrial fibrillation may be associated with additional morbidity, which can be addressed through a number of different ways, if we can detect atrial fibrillation. Obviously, the challenge is to detect atrial fibrillation. We also know that people are increasingly wearing devices that have sensors on them, specifically using photoplethysmography technology, which can detect the pulse rate. Software algorithms can now be developed, that can assess that pulse rate for regularity or irregularity. But they really need to be assessed and validated, to minimize the potential for false positives, which can have obviously, downstream adverse consequences of their own, if atrial fibrillation is incorrectly identified or diagnosed as a result. As I was mentioning, we developed this novel software algorithm with frequent overlapping photoplethysmography, post tachogram sampling, which is unique. And then we tested the algorithm's positive predictive value for undiagnosed AFib in a large scale remote clinical trial, using a range of Fitbit wearable fitness trackers and smart watches. It was a remote trial, so participants were invited. These were people who already had a Fitbit account, they were invited to participate. And in span of just a few months, in the middle of the pandemic, over 455,000 people signed up to participate in the study. And so, big thank you to all of the participants in the study. Dr. Carolyn Lam: Wow, that is big. And what did you find? Dr. Steven Lubitz: So of the 455, over 455,000 participants that enrolled, over 4,000, had an irregular heart rhythm detection and received a notification. And after inviting those participants to attend a telehealth visit, and at that telehealth visit, the telehealth provider confirmed eligibility criteria, confirmed that they didn't have preexisting atrial fibrillation, for example, and a variety of other inclusion/exclusion criteria. They were mailed a one week ECG patch, that they applied themselves, and then returned that ECG patch. So in the end, after those exclusions, in participants that returned analyzable patches, 1057 participants were included in this ECG monitoring analytic cohort, of whom, 340 had atrial fibrillation during that ECG patch monitoring period. The primary endpoint of the study was the positive predictive value of irregular heart rhythm detection that occurred during the ECG patch monitoring period. So a participant had to have an irregular heart rhythm detection to get notified that they were eligible to meet with a telehealth provider and receive an ECG patch monitor. And then, they had to have another irregular heart rhythm detection during ECG patch monitor wear. So the primary outcome was the positive predictive value of the first irregular heart rhythm detection for concurrent atrial fibrillation that occurred during ECG patch monitoring. Dr. Carolyn Lam: Okay. Cool. So many questions here, but maybe you should tell us the results first. Dr. Steven Lubitz: Sure. So the primary endpoint, the positive predictive value of the IHRD during ECG patch monitoring was 98.2% in the overall cohort. And it was similar between men and women, and those aged 65 or older, or those aged less than 65. And I should mention that, in this study, about 13% of participants enrolled in this study overall, were above the age of 65. Dr. Carolyn Lam: And you included more women than in prior similar studies. Right, Steve? Dr. Steven Lubitz: Yeah. Dr. Carolyn Lam: I was going to congratulate you for that. Dr. Steven Lubitz: Yeah, that's right. That's right. We're very excited to see that. Dr. Carolyn Lam: Okay, so that's cool. Wow. A positive predictive value of 92%. So couple of things here with- Dr. Steven Lubitz: 98. Dr. Carolyn Lam: Sorry, 98%. That's right. Wow. Okay. Now with this AFib detection, it's always about duration. Right? And what do you call a positive alert? Could you maybe elaborate a bit about that here? Dr. Steven Lubitz: Sure. So I think this is an important point. A few points. One, the algorithm is designed. This particular algorithm requires at least 30 minutes of an irregular pulse to be detected, in order for a detection to occur. Which means that, this is unlikely to be detecting trivial amounts of atrial fibrillation. And indeed, that's what we observed. We observed that the median burden of atrial fibrillation was 7% among those who had AFib on the ECG patch monitor. We observed that the median longest episode of atrial fibrillation was seven hours. And just by way of comparison, in other studies in which ECG patch monitors have been distributed to people without this irregular pulse pre-screening, the burden is usually on the order of only a couple of percent, tops. So this, by nature, these types of algorithms, and this algorithm specifically, probably enriches for individuals who have a higher burden of atrial fibrillation. Meaning that, if these detections occur, then it's probably not detecting trivial amounts of atrial fibrillation. Dr. Carolyn Lam: Right. And a lot of it seems to send a very clear message that this study, and perhaps even the algorithm, is designed to be specific. Right? So that duration, as well as what you used as the outcome. How much price do you pay in terms of sensitivity? Do you know what I mean? Since we optimized for specificity, am I right to say that? Dr. Steven Lubitz: Sure, that's a great point. The algorithm is really optimized for specificity, as you mentioned. And although we didn't specifically calculate the sensitivity of the algorithm, in a secondary analysis, we examined the sensitivity of an IHRD during that ECG patch monitoring period, to detect any AFib that was documented on the ECG patch monitor, and it was about 67%. So we know that we probably don't detect some atrial fibrillation. Largely, that's a function of this technology at the moment. It's very difficult to assess the pulse rate during periods of activity in motion. So a lot of these algorithms, and this algorithm in particular, doesn't operate during periods of motion. The accelerometers and the devices can tell the algorithm that motion is occurring, and then the algorithm won't operate on that information at that time. So a lot of this has to do with limitations of the technology at the moment. Dr. Carolyn Lam: Ah. So the detection probably occurs best at rest or at night. Dr. Steven Lubitz: That's exactly right. And we encourage participants to wear their devices at nighttime during the study. Dr. Carolyn Lam: Oh, cool. And then of course, I suppose a question you'd anticipate, I mean, we know about the Apple Heart Study, we know about the watch study, and how does this compare? How is this technology different, and the results? Dr. Steven Lubitz: Essentially, one of the most remarkable things about these studies is that, it appears that this pulse rhythm pre-screening really enriches substantially for people who have atrial fibrillation. So for example, in the Fitbit Heart Study, we observed that about 32% of people who had an irregular heart rhythm detection and then returned an ECG patch monitor, had AFib on it. And by comparison, in the Apple Heart Study, that number was about exactly the same, just over 30% or so. So when we further compare this pre-screening type approach to confirming atrial fibrillation, using an ECG patch monitor, with other approaches in which say, elderly individuals were mailed ECG patch monitors to screen for atrial fibrillation, we usually only see detection in the order of four to 5% of people. So this irregular pulse based pre-screening markedly enriches for atrial fibrillation. And we also know, this is only a one week ECG patch monitor, and if we monitor people longer than one week, we're likely to detect more atrial fibrillation, since this is often paroxysmal atrial fibrillation that we're detecting. So there are a lot of similarities, and I think the point is that, these types of consumer electronic devices are going to be great tools for identifying undiagnosed atrial fibrillation in the community. I think we have a lot of challenges ahead of us, in terms of figuring out how to integrate that information into our routine healthcare workflow, and counseling consumers and users of these types of technology on exactly what they should be doing when they do get an alert. And then also, counseling providers on how to act on these findings, what they mean and how accurate the technology is. Dr. Carolyn Lam: Yeah. And I appreciated a sentence in your manuscript that talks of, what are our society guidelines going to say? If you could look into a crystal ball now, Steve, based on what you found, what would you advise both patients and clinicians, if you don't mind? Dr. Steven Lubitz: Well, I think that, in short, if a clinician is alerted by a patient, that they received in a regular heart rhythm detection on their device, in short, I would say, don't blow it off. Take it seriously. Because the odds are, that it does represent an abnormality, and the odds are that that abnormality is atrial fibrillation. And given the potential adverse consequences of undiagnosed atrial fibrillation, there's a real opportunity to intervene, and prevent morbidity in the patient. And then, if you're a consumer who happens to have one of these devices, and you've turned on this feature, and hopefully you have, if you do have an alert, don't blow it off. Contact a provider. Because it may very well mean that you have an irregular heart rhythm that merits attention, and could be addressed to prevent downstream consequences and morbidity for you. Dr. Carolyn Lam: Nice. And keep your Fitbit on at night. Dr. Steven Lubitz: Yes. And if you do want to maximize the utility of these algorithms that use photoplethysmography, probably wearing them at nighttime will maximize the sensitivity, or utility of the devices and algorithms. Dr. Carolyn Lam: Aw, that's just great. What nice take home messages. Thank you so much, Steve, for publishing this really unique and important study in Circulation. So audience, you heard it right here on Circulation on the Run. From me, Greg, and Peder, please do tune in again next week. Speaker 4: This program is copyright of the American Heart Association 2022. 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, please visit ahajournals.org.

Circulation September 13, 2022 Issue

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Play Episode Listen Later Sep 12, 2022 25:28

This week, please join authors Svati Shah and Senthil Selvaraj as well as Guest Editor and Editorialist Manuel Mayr as they discuss the article "Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF" and the editorial "SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism." Dr. Carolyn Lam: Welcome to Circulation On 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 Richmond, Virginia. Dr. Carolyn Lam: In today's feature paper, we will be talking about the metabolomic profiling of the effects of dapagliflozin in heart failure, and this is from the DEFINE-HF trial. It's just such a cool paper with a lot of insights you have to hear from the authors. But, before we get there, let's talk about some of the other papers in today's issue. Shall we, Greg? Dr. Greg Hundley: You bet, Carolyn. Well, how about if I go first? Dr. Carolyn Lam: Please. Dr. Greg Hundley: Thank you, Carolyn. My first paper comes to us from Professor Paulus Kirchhof from the Universitäres Herzzentrum in Hamburg. Carolyn, in the randomized EAST-AFNET 4 study, so the early treatment of atrial fibrillation for stroke prevention, these trial investigators demonstrated that systematic initiation of early rhythm control reduced adverse cardiovascular outcomes in patients with recently diagnosed atrial fibrillation and stroke risk factors. However, the effectiveness and safety of early rhythm control in patients with multiple cardiovascular comorbidities is not known. Carolyn, in this study, it was a prespecified sub-analysis of the EAST-AFNET 4 trial and it compared the effectiveness and safety of early rhythm control with usual care stratified into patients with high CHA2DS2-VASc scores of greater than or equal to 4. Dr. Carolyn Lam: Nice. Okay. Important question, what did they find? Dr. Greg Hundley: Right, Carolyn. Quite a bit of data in this study, so let's walk through it carefully. First, in regards to the study population, the EAST-AFNET 4 randomized 1093 patients with CHA2DS2-VASc scores of greater than or equal to 4, these were predominantly women, 61% female, and then also 1,696 patients with CHA2DS2-VASc of less than four, and these were predominantly men, so only 37% women. Now let's get to the date. Early rhythm control reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening heart failure or for acute coronary syndrome in patients with high CHA2DS2-VASc scores of greater than 4, but not in patients with CHA2DS2-VASc scores of less than 4. Second, now Carolyn, the primary safety outcome, so death, stroke, or serious adverse events of rhythm control therapy, was not different between study groups in patients with high CHA2DS2-VASc scores of greater than 4, but occurred more often in patients with low CHA2DS2-VASc scores randomized to early rhythm control. Now Carolyn, life threatening events or death were not different between the groups. When female sex was ignored for the creation of high and lower groups, the interaction P was not significant for the primary efficacy outcome, but remained significant for the primary safety outcome. Dr. Carolyn Lam: Oh, you are right. A lot of interesting data here. What's a take home message? Dr. Greg Hundley: Right, Carolyn. So the take home message is the following. Patients with recently diagnosed atrial fibrillation and multiple cardiovascular comorbidities should be considered to have priority access to early rhythm control to reduce cardiovascular outcomes, and a specific trial of early rhythm control in these patients is really needed as a next step. Dr. Carolyn Lam: Oh, thank you, Greg. The next paper focuses on arrhythmogenic right ventricular cardiomyopathy, which we know is characterized by a high propensity to life threatening arrhythmias and progressive loss of heart muscle. More than 40% of reported genetic variants linked to arrhythmogenic right ventricular cardiomyopathy, or ARVC, reside in a gene called plakophilin-2, or PKP2. In today's paper, Dr. Delmar and Lundby from NYU Grossman School of Medicine and University of Copenhagen, respectively, and their colleagues, described a comprehensive characterization of the ARVC molecular landscape using a multidisciplinary approach including human samples from ARVC patients with PKP2 mutations and left ventricular ejection fraction above 45%, as well as PKP2-deficient murine and human induced pluripotent stem cell-derived cardiomyocytes. They studied all of these with comprehensive proteomics and functional analysis. Dr. Greg Hundley: Wow, Carolyn, another great study in circulation combining both preclinical murine models as well as data from human subjects. So, what did they find? Dr. Carolyn Lam: Precisely, Greg. Here's what they found. Loss of nuclear envelope integrity and subsequent DNA damage is a key substrate in the molecular pathology of AR VC. The authors further showed transcriptional down regulation of proteins of the electron transcript chain as an early event in the molecular pathophysiology of the disease prior to an ejection fraction falling below 45%. This associates with increased oxidant production, with the clinical message being, therefore, that the authors propose therapies that limit oxidant formation may be a possible intervention to restrict DNA damage in ARVC. Dr. Greg Hundley: Very nice, Carolyn. Okay, our next paper comes from Dr. Donald Lloyd-Jones from Northwestern University, the Feinberg School of Medicine. Carolyn, you can tell the change in inflection of my voice because it's time for another Carolyn's quiz. Carolyn, open-ended question. Can you remind us of life's essential eight? Dr. Carolyn Lam: Oh boy, Greg. It's like asking me to name the dwarfs. I know I'm going to forget one, but here you go. Diet, exercise, cholesterol, weight, smoking, sugar must be there, diabetes, blood pressure. You see, I got seven. What's the eighth? Dr. Greg Hundley: Yeah. Remember seven dwarfs, Sleepy. Dr. Carolyn Lam: Sleep. Dr. Greg Hundley: Very good. Great job, Carolyn. Dr. Carolyn Lam: Thank you. Dr. Greg Hundley: Recently, the American Heart Association recently published an updated algorithm for quantifying cardiovascular health, the Life's Essential 8 score. In this study, the investigative team quantified US levels of cardiovascular health using the new score. They included non-pregnant, non-institutionalized individuals aged 2 through 79 years who were free of cardiovascular disease from the National Health and Nutrition Examination Surveys that were conducted between 2013 and 2018. Now, for all participants, they calculated the overall cardiovascular health score, and it ranged from 0, which is really low, to 100, which is the highest, as well as the score for each component. And Carolyn, yes, you are very close. Remember the eight? Diet, physical activity, nicotine exposure, sleep duration, body mass index, blood lipids, blood glucose, and blood pressure, and they used published American Heart Association definitions of these. The cardiovascular health scores were assessed across strata of age, sex, race, ethnicity, family income, and depression. Dr. Carolyn Lam: Okay, Greg. What did they find? Dr. Greg Hundley: Right, Carolyn. There were 23,400 plus participants, representing 201,728,000 adults and 74 million children. The overall mean cardiovascular health score was 64.7 among adults using all eight metrics, and it was 65.5 for the three metrics available of diet, physical activity, and BMI among the children and adolescents that were aged 2 through 19 years. Now, for the adults there were significant differences in mean cardiovascular health scores by sex, age, and racial ethnic group. Mean scores were lowest for diet, physical activity, and the BMI metrics. There were large differences in mean scores across demographic groups for diet, nicotine exposure, blood glucose, and blood pressure. In children, diet scores were low, 40.6, and were progressively lower in higher age groups. Large differences were also noted in mean physical activity and BMI by sociodemographic group. Carolyn, this study basically identifies wide ranges of scores across multiple domains of the essential eight, and thus, this new Life's Essential 8 score helps identify large group and individual differences in cardiovascular health. Additionally, overall, cardiovascular health in the US population remains well below optimal levels, and there are both broad and targeted opportunities to monitor, preserve, and improve cardiovascular health across the life course in both individuals, as well as the population at large. Dr. Carolyn Lam: Wow. Thanks, Greg. Truly really interesting. Everyone's going to have to pick up that paper and all the other papers in this issue, because there's also an In Depth paper by Dr. Whelton on “Harmonization of the ACC/AHA and ESC/ESH Blood Pressure Hypertension Guidelines, Comparisons, Reflections, and Recommendations. There's a Research Letter by Dr. Munshi on the accurate classification of cardiomyopathy etiology by chromatin accessibility. Dr. Greg Hundley: Carolyn, I have got to report an exchange of letters from Professor Sun and Weng regarding the article, “Legumain Is an Endogenous Modulator of Integrin αvβ3 Triggering Vascular Degeneration, Dissection, and Rupture.” And then Carolyn, lastly, there's a Perspective piece from Professor Vidal-Petiot entitled, “Thresholds for Hypertension Definition, Treatment Initiation, and Treatment Targets: Recent Guidelines at a Glance.” Well, Carolyn, how about we get on to that feature discussion? Dr. Carolyn Lam: Yes, let's go Greg. Wow, we have a star stud cast for today's feature discussion, and on a star studied topic, if I may. It's on the SGLT2 inhibitors, this time in the DEFINE-HF study and really going into the mechanism of action of SGLT2 inhibitors. Now, that's one question I personally get all the time. How do these things work? Today's paper brings us one step closer, for sure, in the understanding. I'm so grateful to have the first author, Dr. Senthil Selvaraj from University of Pennsylvania, as well as the corresponding author of the paper, Dr. Svati Shah, associate editor, as well as the corresponding author from Duke Molecular Physiology Institute. We also have Dr. Manuel Mayr who was both the guest editor and editorialist for this paper, and Dr. Mayr is from Kings College London, British Heart Foundation Center. Welcome, everyone. Senthil, get us started here. The DEFINE-HF study, just a quick summary, what that was about and then what you did, what you found. Dr. Senthil Selvaraj: Absolutely. Good morning, everyone, or maybe good evening for your time, Carolyn, but we were very excited about this study and the ability to do targeted metabolomic profiling in DEFINE. This audience is well familiar with the fact that SGLT2 inhibitors are foundational therapy in heart failure reduced ejection fraction, and the interesting thing is, despite a lot of literature, we still don't know why. Whether it relates to change in inflammation or endothelial function, but given the mechanism of action, metabolism is sort of at its core. So in this study we sought to identify metabolic pathways that were associated with dapagliflozin treatment using this targeted metabolomics platform in which we assayed 63 metabolites, acylcarnitine, which are markers of fatty acid oxidation, several amino acids, and ketone-related metabolites. To do this, we studied 234 participants from DEFINE, which is a 12-week placebo-controlled trial of dapagliflozin in this population, and we perform principal components analysis for dimensionality reduction techniques. In this study, briefly we found that, first, our principal components analysis yielded 13 different factors that accounted for the substantial proportion in the variation of the data, and that two in particular, ketone-related metabolites and short acylcarnitines in factor 6, as well as medium-chain acylcarnitines in factor 7 were differentially associated with dapagliflozin treatment. Specifically, there were increases in several ketone-related metabolites and short acylcarnitines, as well as several medium-chain acylcarnitines, really speaking to, potentially, changes in fatty acid as well as ketone biology with dapagliflozin treatment. The second aim of our study was to look at changes in metabolites and changes in endpoint studying DEFINE, which included NT-proBNP as well as KCCQ scores. We found that dicarboxylate long-chain acylcarnitines and aromatic amino acids really related to worsening heart failure endpoints there. So, a lot to impact, a lot that we found, and appreciative about the opportunity. Dr. Carolyn Lam: Oh, wow. Thank you so much for that amazing summary. Svati, I've heard you speak so many times on metabolomics on our calls, but this is really so important. First, I think the question is, congratulations for thinking ahead of time to collect the samples and to do all of this. Congratulations on that. Could I ask if you went in with any specific hypothesis or were you surprised by these findings, Svati? Dr. Svati Shah: Yeah, Carolyn, thank you so much. It was such a pleasure to work with Senthil on this and I really want to highlight what an incredible early career investigator he is. He's really going to set the metabolism world on fire. I also wanted to say thank you to the PI of the clinical trial, the parent clinical trial DEFINE-HF Mikhail Kosiborod, who did the really hard work of collecting the samples along with the clinical trial itself. To me, what's really cool is to be able to take a clinical trial like this with really important clinical outcomes well adjudicated and to be able to dig into the mechanism at a metabolic level of what might be going on with SGLT2 inhibitors. Going into this, Carolyn, we suspected that ketone-related biology was at play. There have been studies in other populations, non-HFrEF populations, that have shown that SGLT2 inhibitors have what appears to be beneficial impacts on ketone biology and induced ketosis. So, going into this, we suspected that this ketone pathway was going to come up. I think what's exciting is, not only did we find that the ketone pathway was differential modified by dapagliflozin, but that it wasn't at the level of severe ketosis that we would be concerned about. And then secondly, we found pathways of fatty acid oxidation. Some related to the effects of the medication and some related to changes in functional outcome. So it really enhanced beyond what we already knew about ketone biology, expanded our understanding of potential mechanisms of SGLT2 inhibitors, and expanded this into the HFrEF space, Carolyn. Dr. Carolyn Lam: Oh, that's so nice. I'm bursting with questions, but I really, really have to ask Dr. Manuel Mayr, first, could you put these findings into context for us and tell us what they mean clinically? Dr. Manuel Mayr: Yeah, Carolyn. First of all, I want to join you in congratulating the authors to this important study. As Svati mentioned, previous studies have reported effects of SGLT2 inhibitors on ketone bodies, but the present study really adds to the literature because it uses the state of the art metabolomic techniques. It uses a technique called mass spectrometry, but they also have a rating of, I think, in total, 63 metabolites in over 200 patients. Mass spectrometry is becoming increasingly important for cardiovascular precision medicine because we can use it in clinical trials to provide an unbiased assessment of metabolites and proteins. So it's a very versatile technology. I think this study really adds to the rapidly growing literature that SGLT2 inhibition is a principle of unloading the failing heart from metabolic stress. Dr. Carolyn Lam: Wow, I really like that and your editorial is just beautiful. I love that you say, "After the serendipitous findings of improved heart failure outcomes with SGLT2 inhibitors, mechanisms were postulated, but studies, such as the one we're discussing, are needed to really uncover what's the real thing." Now, I know this may sound really oversimplified and so on, but I'd really love for Senthil or Svati to just bear with me as I ask, what are you going to say to people who go, "Okay, then we should just be downing ketones," Or, "We should be Working on the fatty acid parts of it," Or taking conclusions like that. What would you say to something like that? Dr. Senthil Selvaraj: I'm happy to go first. It's a really wonderful question and I do think that this study raises the question of whether we should be exogenously increasing ketone levels to provide some sort of benefit. I would say the jury's still out there. I think it's a hot topic right now. But there are also differences between how we raise key tone levels, whether you do that endogenously in the body, or whether you give something like a ketone supplement, so exogenous ketone supplementation. And I think that there are completely different physiologies there. So more to come. I think there are a lot of studies in this space. The ketogenic diet is something that I'm often asked as well, whether that might provide benefit to heart failure. There are a lot of ways that I can, but one thing that we need to be mindful of is the fact that it will reduce glycogen stores as well, which may impact exercise capacity. So, we need more data. I would say the other thing that we found in our studies, while they were increased in ketone levels and markers of fatty acid oxidation with dapagliflozin treatment, we aren't necessarily sure that those mediate the benefits of SGLT2 inhibitors. DEFINE has important clinically relevant endpoints, but it is not an event-based trial. And so we don't know and we can't link the changes in metabolites with changes in outcomes quite yet. Dr. Svati Shah: Carolyn, just to add to the wonderful response that Senthil just gave, I think we do have to be careful. We don't know whether these are direct effects of SGLT2 inhibitors or whether these are related to the caloric loss that we know happens with these medications. I think it's important to point out that we're looking in the blood, we don't actually know what's happening at the tissue level, so we do have to be a little bit careful. We have made inferences that this is reporting on substrate fuel selection in the heart, but we also suspect that skeletal muscle and other organs are heavily involved in some of the pathways we're seeing. So I just wanted to make those important caveat to the epidemiologic work that we do. Dr. Carolyn Lam: And those are so important, so thank you Senthil and Svati. Manuel, I'd love to invite your thoughts because you did sort of point out some of these points in your editorial. Could you maybe discuss a bit of those and raise any questions, perhaps? Dr. Manuel Mayr: Yes. I think Svati and Senthil have nicely mentioned already that these measurements are performed in plasma. So the changes in plasma could be due to, for example, increased production in the liver due to decreased consumption in other tissues. So I guess the next step would be, and I would be really interested on what the authors want to pursue, is to provide direct evidence for the energetic hypothesis, that really the heart is consuming these keto bodies and what type of measurements could be performed to provide direct evidence in humans for these metabolic hypothesis. Dr. Senthil Selvaraj: That's a really great question, Manuel. There was a really nice study that was published about a year or two ago in Science in which the authors did coronary sinus sampling. So really to get arterial venous gradients, measure substances in the arterial system as well as the coronary sinus venous system and get extraction. I think that that study would be very interesting to understand. You take patients on SGLT2 inhibitors, those who are not, and to understand what is the heart chewing on. Obviously more invasive than some other approaches, but other studies that I think would be really interesting in those space would be flux studies and stable isotope studies. Again, as Svati really nicely mentioned, these are systemic physiology snapshots whenever we do less localized techniques like that, but they're still very important because heart failure is a systemic process. Dr. Carolyn Lam: Anything to add, Svati? Dr. Svati Shah: No, I think you said it beautifully. I'll just say on the sort of epidemiologic side, to be able to link this to harder outcomes, DEFINE-HF wasn't really designed to be able to do that. So as we expand our understanding of SGLT2 inhibitors, understand different populations, and to link these pathways to more objective outcomes, I think, will be really useful, also. Dr. Carolyn Lam: Indeed. Manual, in your editorial, you actually discuss some of your own work, which may be the ones that Senthil is actually talking about. What is your view? Dr. Manuel Mayr: Well, I think I'm very excited that beyond fatty acid metabolism and glucose metabolism, ketones have extracted increasing attention. Ketone body metabolism, I think, has long been underappreciated. We still need to understand to what extent it really acts as a fuel and that it can help to overcome the energy deficit that creates heart failure. I think, as mentioned by Svati and Senthil, we need more studies in this area, and of course other trials are ongoing where they're going to measure, for example, the phosphocreatine to ATP ratio by using phosphor-NMR spectroscopy. So we get direct evidence whether there really is an energetic improvement upon SGLT2 inhibition. I think this will be studies to look forward to and to add to the growing literature that metabolism is important as a therapeutic target for heart failure. Dr. Carolyn Lam: Oh, such exciting times. You mentioned the EMPA-VISION trial in your editorial. I think I'm trying to tell everybody, you have to pick up the paper and the editorial. You're going to learn so much. This is so cool. Thank you so, so much all of you for being on this podcast, for sharing your thoughts. I'm sure everyone has learned a lot and enjoyed it just as I have. On behalf of Greg and I, thank you for being here, thank you for joining us today, and don't forget to tune in again next week. Thank you. Dr. Greg Hundley: This program is copyright of the American Heart Association 2022. 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, please visit ahajournals.org.

MC Fireside Chats - August 3rd, 2022

MC Fireside Chats

Play Episode Listen Later Aug 3, 2022 57:55 Transcription Available

On today's episode of MC Fireside Chats, sponsored by Fireside Accounting, industry experts talked about the latest news and trends in the camping and RV industry. We were joined by Casey Cochran, Director of Business Development at Campspot Software; Randy Hendrickson, Founder & CEO of United Park Brokers; Sandy Ellingson, an RV Industry Consultant; Ruben Martinez from the American Glamping Association and Mark Koep, Founder, and CEO of CampgroundViews.com The open discussion started with the reaction to the formation of National Association of RV Parks and Campgrounds' (National ARVC) Campground Standards Task Force, which according to a release, aims to focus on the pursuit of building a voluntary baseline and advanced standards for the private campground industry. Koep said that more than a task force, it is now, more than ever, needed to have a strong national association. “The release claims that they [ARVC] represented 13,000 park owners in the United States, and that's just factually untrue…So where my first issue comes in is that we need a strong national association of campgrounds and RV parks in the United States to represent the interest of the owners and the industry at that level,” Koep said. He also added that small park and campground owners do not have time, energy, or money to follow certain standards that the recently formed task force would impose. “Why do we need this task force? What is the purpose of it?” Ellingson reiterated the need for a strong representation and how standardization will impact owners and operators. “I am a firm believer that if we're going to talk about standardization, let's just say it's about safety and security. So if there should be a task force, it should be a task force at the state level, run by the states, and that information possibly shared with the national organization,” Ellingson said. Martinez also shared how the glamping industry went on the same path in the past but went towards resources, tools, and education instead of policing and standardizing. “It's going to be a very hard pathway forward to be a policing agency versus tools, resources, education, and assistance,” Martinez said. The guest experts also highlighted the importance of dialogue with stakeholders, listening, relooking, and asking what would be the outcome following the forming of a task force. Hendrickson said the absence of information and methodology of the task force is what makes it questionable to park owners and operators. Meanwhile, Cochran hopes that the names in the task force who built their campground from the ground up would have the best interests of smaller parks Pivoting away from the topic of standardization, Koep said that the high gas prices, inflation, and other economic challenges that impacted travel had changed the consumers. “The consumers have changed significantly, people are still traveling, they're still camping. The campgrounds, in general, are doing well. It's nice to see that the resiliency of our industry is showing forth right now in face of all the noise that is out there,” he said.

Fiauna Lund: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). Status 6 Heart Transplant Candidate, Author, Mother, Wife, and Friend

Yakety Yak

Play Episode Listen Later Aug 2, 2022 62:56

This is a special episode featuring my friends, Aaron and Fiauna Lund. Oftentimes, when we hear that friends and neighbors are facing challenging trials, many of us are at loss not knowing how to reach out or what we can do to support and love them. I'm grateful they were willing to courageously share their story so that we can rally and offer encouragement and prayers as we Seek and Expect Miracles for Fiauna. Last November (2021) Fiauna was diagnosed with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). This news was especially difficult to accept because Fiauna has dedicated her life to sharing her talents and time teaching others to be passionate about health and wellness with her heart-healthy, active lifestyle. She shared the following post on FB which describes her current status as she patiently awaits a heart transplant: "Seek and expect miracles. Truly prophetic advice I heard recently that I'm choosing to embrace right now. What I've learned about miracles is that, for the most part, they are a matter of perspective. You can choose to accept them, or choose to look right past them, waiting for something…more? I posted Tuesday that I was admitted to the hospital where I would likely wait for a heart transplant as soon as a donor became available. That was the plan—a plan I agreed to and felt really comfortable with…until I didn't. I started to panic. Had I made the right choice? Were we going in the right direction? My gut (or the Spirit) was screaming at me to talk about other options. When the team of doctors and the transplant coordinator, met with us Wednesday morning we discussed those options and arrived at a new plan. At first I didn't trust the doctors, the plan, my own ability to make the right choice, but the more I sat in the feeling—the doubt and confusion—the more at ease I became. Does that even make sense? The plan proposed now is to keep me listed for transplant at status 6; discontinue the medication I was taking that, while very effective, was making me very sick; try another medication under medical supervision to make sure it works without intolerable side effects. If all goes well, I can go home Monday or earlier. The peace I felt when the new plan was proposed was undeniable. I've been wrestling mentally and perhaps spiritually with the concept of heart transplantation. I mean, think about it. They're going to cut into my chest and remove the most vital of organs, the powerhouse of the body, the first sign of life. Before my parents even knew I existed, the cells of my little embryonic heart were already beating. For a moment I will be without that beating heart. And from that moment on, in order to live someone else has to die. That's heavy. A weight I've been trying to carry—and I thought I was carrying successfully until this dry run. This trip to the hospital has let me process things differently. I was given the miracle of CLARITY. The miracle of recognizing spiritual influence, and of PEACE —even if only for a moment.' Fiauna is a wife, mother to four children, and writer. She's written and published two novels: "Indigo" and "In the Twilite" https://www.amazon.com/Fiauna-Lund/e/B006LPTUMW%3Fref=dbs_a_mng_rwt_scns_share *Please consider becoming an Organ Donor*

peace spirit friend fb seek clarity status candidate transplants indigo lund heart transplant organ donors cardiomyopathy ventricular expect miracles mother wife arvc

Circulation June 21, 2022 Issue

Play Episode Listen Later Jun 20, 2022 23:41

This week, please join author Roderick Tung, editorialist William Stevenson, and Associate Editor Sami Viskin as they discuss the article "First-Line Catheter Ablation of Monomorphic Ventricular Tachycardia in Cardiomyopathy Concurrent with Defibrillator Implantation: The PAUSE-SCD Randomized Trial" and the editorial "Can Early Ablation of Ventricular Tachycardia Improve Survival?" Dr. Greg Hundley: Welcome listeners to this June 21st, 2022 issue of Circulation on the Run. And I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Listeners, what a very interesting forum that we're going to have in this session today with Dr. Rod Tung, bringing us an article from first line catheter ablation of monomorphic ventricular tachycardia in cardiomyopathy with concurrent defibrillator implantation. Some results from the Pause sudden cardiac death randomized clinical trial. This article is really interesting because it is collecting data from multiple centers from multiple countries in Asia. But before we get to that article, why don't we grab a cup of coffee and go through some of the other articles in the issue? Well, the first is entitled cardiovascular magnetic resonance for rejection surveillance after cardiac transplantation. And it comes to us from Dr. Jim Pouliopoulos from the Victor Chang Cardiac Research Institute. In this study, CMR based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between cardiovascular magnetic resonance and endomyocardially based measures of cardiac rejection and determine the CMR cutoff values between various cardiac rejection grades. Then after that, a prospective randomized noninferiority pilot study was undertaken in adult orthotopic heart transplant recipients who were randomized at four weeks post orthotopic heart transplant to either CMR or endomyocardially based rejection surveillance. And clinical endpoints were also assessed at 52 weeks. And so listeners, what did this investigative team find? Well, despite similarities in immunosuppression requirements, kidney function and mortality between the groups, the rates of hospitalization and the rates of infection were lower in the CMR group. On 15 occasions, patients that were randomized to the CMR arm underwent endomyocardial biopsy for clarification or logistic reasons, representing a 94% reduction in the requirement for endomyocardially based surveillance. And so listeners, a noninvasive CMR based surveillance strategy for evidence of rejection in the first year after orthotopic heart transplantation is feasible. And interesting, listeners, these results really suggest the possibility for further studies to confirm whether CMR and perhaps in combination with other modalities could be used to survey orthotopic heart transplant patients for acute rejection without necessarily having to undergo endomycardial biopsy. There's an excellent editorial by Dr. Jim Fang from the University of Utah who also reviewed this paper. Well, listeners, let's next turn to the world of preclinical science. And this paper comes to us from professor Simon Sedej from Medical University of Graz. It involves the insulin and insulin growth factor one or IGF-1 pathway. And that is known as a key regulator of cellular metabolism and aging. Now, although its inhibition promotes longevity across species, the effect of attenuated IGF-1 signaling on cardiac imaging really remains controversial. So what did the authors find? Well, they found that cardiomyocyte IGF-1R over expression in mice resulted in physiological hypertrophy and superior cardiac function in early life, but led to accelerated cardiac aging, heart failure and reduced lifespan in late life. Mechanistically, increased cardiomyocyte IGF-1R signaling accentuated cardiac dysfunction by reducing autophagy and mitochondrial oxidative capacity at old age, and therefore clinically pharmacologic inhibition of cardiac IGF-1R signaling in late life could suppress the age related deterioration of cardiac performance and perhaps increase lifespan. And therefore age should be considered as a major outcome determinant in future clinical trials, testing IGF-1R P13K inhibitors for cardiac benefits. Well listeners, what is our next study? And this study is somewhat related to our feature discussion, which we'll get to in a few minutes. It's from Dr. Paolo Della Bella from San Rafael Hospital, and it is a two phase prospective multicenter randomized clinical trial that was performed to evaluate the benefit of ablation after first implantable cardiovert defibrillator, or ICD shock. And patients with ischemic or nonischemic dilated cardiomyopathy and primary or secondary prevention indication for ICD were enrolled in an initial observational phase until first appropriate shock. And that was phase A of the study. Then afterwards, they were re-consented and patients were randomly assigned in a one-to-one fashion in the second phase or phase B to immediate ablation. That's within two months from shock delivery or continuation of standard therapy. And the primary endpoint of the study was a composite of death from any cause or hospitalization for worsening heart failure. And amiodarone intake was not allowed except for documented atrial tac-arrhythmias. So listeners, what were the results from this trial? Well, ventricular tachycardia ablation after first appropriate shock was associated with a reduced risk of the combined endpoint of death or worsening heart failure for hospitalization, lower mortality and fewer ICD shocks. And these findings therefore provide support for considering ventricular tachycardia ablation after the first ICD shock. Now this study and the feature which will be coming up in a few minutes is nicely reviewed in an editorial from Bill Stevenson at Vanderbilt University. Well listeners, what other articles are in this issue? Well, from the mail bag, we have a research letter from Professor Solomon entitled Health Status Trajectories Before and after hospitalization for Heart Failure. Also, there is a second research letter from Professor Eikelboom entitled Rivaroxaban 2.5 Milligrams Twice Daily Plus Aspirin Reduces Venous Thromboembolism in Patients with Chronic Atherosclerosis. And then next there's an ECG challenge from Professor Rosenfeld entitled Around and Around, a Wide Complex Tachycardia. Well listeners, what a great series of articles. And now we're going to get on and visit with Rod Tung, Sami Biskin and Bill Stevenson to evaluate first line catheter ablation of monomorphic ventricular tachycardia in cardiomyopathy, concurrent with defibrillator implantation. Well, listeners, welcome to this June 21st feature discussion. And we're very fortunate today to have with us Dr. Roderick Tung from the University of Arizona in Phoenix. We also have our own associate editor, Dr. Sami Viskin from Tel Aviv Medical Center in Tel Aviv, Israel, and Dr. Bill Stevenson from Vanderbilt University in Nashville, Tennessee. Welcome gentlemen. Well, Roderick, we're going to start with you. Rod, can you describe for us some of the background information that went into the construct of your study and what was the hypothesis that you wanted to address? Dr. Roderick Tung: Well, thank you, Greg, Pause is really the culmination of a lot of personal academic and cultural exchanges between many Asian centers and particularly in China. In terms of exchanges, where we would go across overseas, do a lot of different VT cases. And this all started in about 2013. And at that point in time, I was struck by a lot of differences that we were seeing, particularly whenever they wanted us to do a case, it tended to be a nonischemic etiology patient, and they always wanted to see some sort of epicardial procedure. And these are the ones that are enriched for epicardial substrates. As many listeners know, the ischemics tend to have more endocardially based scars. And that's why epicardial BT ablation is typically reserved for those that either have failed endocardial or those ARVC patients or non-ischemic cardiomyopathy. So that was the first thing, is there's a paucity of ischemic cardiomyopathy in Asia, which is still inexplicable. The second thing that was really interesting in my observations going to Asia was that the defibrillator penetration and adoption is not widespread like it is in America. And in a very Amero-centric view, we always think that, oh, well, everything else is a departure from a standard of care. Well, when you look at 1.4 billion people, that's a really significant population at risk for sudden death that's not being treated the same way that we typically see it in a lot of Western cultures. So I felt like it was a perfect fertile grounds for clinical exploration. And that's really where Pause was born, is to be able to look at the impact of catheter ablation and ICD therapies on the risk of sudden death. And that's really how the trial began. Dr. Greg Hundley: And what was the hypothesis, Rod, that you wanted to address? Dr. Roderick Tung: Well, when we started designing Pause in 2014, 2015, there had only been two prior trials that were published and that was Smashed VT in New England Journal. And then there was VTAC by Karlheinz Cook in Lancet. So really the hypothesis was to be able to assess whether preemptive or first line catheter ablation at the time of defibrillator implantation, which is not what we do in the US, we usually wait till there's therapies, if that decreases the composite endpoint of recurrent VT cardiovascular hospitalization mortality. Dr. Greg Hundley: Very nice. And so describe for us, Rod, your study population, and then the design that you use to address the hypothesis. Dr. Roderick Tung: So this was a randomized controlled trial, multicenter across 11 centers in China, Korea, Japan, Taiwan. These were really well respected and regarded academic centers. I do want to give a shout out to many of them, Kyoko Sojima, who trained with Bill Stevenson, wrote so many seminal papers in VT. In Japan, Akid Nogogami who really was charged with and responsible for opacity some of the mechanisms of particular VT, then there's Yao Yin in Beijing who's done great work in atrial fibrillation, cardiac neuroablation. Ming Long Chen, Chan Yang Jeng. So some really great names, and it was done over 11 centers, one to one randomization between control, which was just ICD, and the active arm was ICD with catheter ablation within 90 days of the ICD implantation. Dr. Greg Hundley: And how many patients, and then what were your study results? Dr. Roderick Tung: So we ended up with 121 patients that were randomized, 61 versus 60, 180 were eligible and screened. And what was really also different about this trial compared to others is that we involved a non-randomized registry. Those were patients that refused to be randomized, and most typically didn't want to have a defibrillator. And that's where the cultural differences of ICD acceptance are different. For two reasons. Number one, physicians actually don't truly believe a lot of the defibrillator data is relevant to non ischemics in Asia and the Asian population. So there's actually a little bit of an academic barrier of generalizing historical ICD data to Asia, which I observed with a lot of the physicians. And number two, patients sometimes don't want that technology in there, and they have different ideas of sudden death. So these patients were actually put into a registry and followed prospectively with catheter ablation alone without background ICD therapy. And that's very unique because the amount of data that has been prospectively followed for ablation sans ICD therapy is very few. So that was 47 in the registry. And there was 121 that was one to one randomized. Dr. Greg Hundley: And what did you find? Dr. Roderick Tung: Well, we found that those that underwent concomitant ablation with their ICD implantation that presented with monomorphic VT had a lower rate of the composite triple endpoint of VT recurrence, cardiovascular hospitalization, and death. This was largely driven by a nearly 20% absolute risk reduction in VT recurrence. There was a 4% absolute risk reduction in cardiovascular hospitalization, but this is not significant. And mortality rates were low. It was seven and 8% in those arms. So one of the things that we were hoping to get to was actually looking at mortality, but I think this is challenging with background ICD therapy there. And number two, it's challenging because mortality rates are lower in non-ischemic cardiomyopathy. And that's because they don't have the concomitant comorbidities of peripheral vascular disease, coronary artery disease, older age, cetera. So we actually had a pretty low rate of mortality, which we were hoping to get to, but that wasn't able to be assessed in this because of the low rates. Dr. Greg Hundley: Very nice. Well, now listeners, we're going to turn to our own associate editor, Dr. Sami Biskin. And Sami, many papers come across your desk. What attracted you to this particular study? Dr. Sami Viskin: Well, we need to better define what is the optimal timing for VT ablation in patients with the organic heart disease. As we have seen many patients that are referred too late for ablation, where they already have an arrhythmic storm and recurrent shocks. And on the other hand, we have seen studies like the Berlin Study from Cook that fail to show any benefit on endpoints like heart failure or mortality. So the study by Tung arrived shortly after the different study by Paolo Della Bella, the PARTITA study, that was also studying patients at an earlier stage. So in the Partita study, they were studying patients at the time of the first ICD shock. And then Rod came with this study where he studied patients at the time of ICD implantation. Now, usually authors ask to get an executive review of their article. In this occasion, we as the editors, we saw the opportunity and asked Rod to submit his paper as fast as possible and made the correction as soon as possible so we could get the two papers dealing with early VT ablation in the same issue with an invited editorial by Dr. Stevenson so we could put everything in context. Dr. Greg Hundley: Very nice. Well, Bill, Sami has set you up very nicely here. And as the editorialist, help us put these results from Rod into the context of what we know already today in this sphere of investigation pertaining to VT shocks, defibrillator implantation. Dr. William Stevenson: Yeah. So first I want to congratulate Rod on a very important study. It has been so difficult to conduct randomized trials of VT ablation and intervention, and to be able to bring this to fruition and internationally in Asia is really quite an accomplishment. We definitely need more information that guides us as to when VT ablation should be performed in people who have defibrillators and are having spontaneous episodes of VT. And we know that in patients with ischemic heart disease, with coronary artery disease, post infarct VTs, that catheter ablation can reduce the episodes of recurrent VT and reduce shocks from VT. And this is a very important quality of life issue for patients with defibrillators. But we haven't really had good data, certainly not randomized multicenter data in other patient populations. And we still are grappling with, does a reduction in VT episodes improve other outcome measures? Does it really improve quality of life? Does it reduce hospitalizations? Does it translate to a reduction in mortality? And so Rod's study, one of the strengths of it being in Asia is that there were a lot of patients who had non-ischemic causes of heart disease. And more than a third of patients had arrhythmogenic right ventricular cardiomyopathy, and his study makes it clear that those patients really benefit substantially with a reduction in VT episodes. And that overall, VT episodes are reduced in all three of the subgroups of different diseases, the ARVC and the ischemics and the non ischemics that were included in the trial. But I think it's worth digging in a little more to the non-ischemics, because they did not seem to receive the benefit that the arrhythmogenic right ventricular cardiomyopathy and the ischemic cardiomyopathy patients received. So that the efficacy was largely driven by the benefit in the ischemics and the ARVC patients. So one of the important considerations I think is when you're in your office with a patient who has a defibrillator and has had episodes of VT, and you're considering does this patient need a VT ablation? I think that if they've got ischemic cardiomyopathy, this data strongly supports that approach. If they've got arrhythmogenic right ventricular cardiomyopathy, again, ablation is very likely to reduce their episodes of VT/ for the non-ischemic group, which is about a third of the patient population that Rod studied, the data are less convincing in that group. And we know that's a harder group to achieve success with, with ablation. So we'll definitely want more data in that group. And I'm looking forward to some of the more detailed and sub-study sorts of analyses that I'm sure Rod is planning. Dr. Greg Hundley: Very nice, Bill. Well, listeners, and Bill you've teed it up nicely to really sort of circle back through each of you and ask, what is the next study to be performed in this space? So we'll start with Rod and then Sami, and then finish up with you, Bill. So Rod, what is the next study that you see needs to be performed really in follow up to yours? Dr. Roderick Tung: Well, we're thinking Pause too might be a nice just ARVC study alone, because again, inexplicably, there's a very high incidence of ARVC in Asia, and I was always taught that this was a disease from the Veneto region of Italy. And that might not be the case, or there's a lot of sarcoid mimicking of it as ARVC and undiagnosed. But we're thinking about a Pause too being an ARVC study, maybe without background I,CD therapy with background ICD therapy, this might provide justification for that. Because again, those in the registry did quite well, but that's because they were younger and had ARVC and normal LV function. So that might be a nice area to explore worldwide. And then lastly, just to put things in perspective for the Circ listeners, you need 8,400 patients in paradigm to show benefit mortality and heart failure hospitalization for an ARNI. Right? For IRNESTO. We're talking about 120 patient studies when we talk about VT ablation, with these very complex ablation trials. So I think we just need larger trials. And the hard thing for us as VT ablation centers is we often will get patients that have had recurrent VT after a failed procedure. So it's hard to come by these that are very early, but I think we need 500 patient studies, a thousand patient studies. And also for the listeners, it's very hard to show mortality reduction with a background ICD therapy. And that's the problem, is that ICD is so effective as an abortive treatment that it's very hard to show reduction and mortality. You'd have to show it in terms of heart failure. Dr. Greg Hundley: Very nice, Rod. And Sami, what would you like to add? Dr. Sami Viskin: Oh, obviously the last word on the optimal timing of VT ablation is not out there. And we need more studies to really define when is the appropriate time for the VT ablation. That's what we need. Dr. Greg Hundley: Very good. And Bill? Dr. William Stevenson: Yeah, I agree with Sami. And with rod, we need larger studies to assess the benefit, to really help guide our clinical decision making that can get at quality of life issues as well as the mortality and cardiovascular hospitalization issues in even more detail. But this is a wonderful first initial step into the ischemic, non-ischemic and ARVC populations. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Rod Tung from university of Arizona, Phoenix, Dr. Sami Viskin from the Tel Aviv Medical Center in Tel Aviv, Israel, and Dr. Bill Stevenson from Vanderbilt University in Nashville, Tennessee, for bringing us this study that highlighting among patients, particularly with ARVC in an ischemic cardiomyopathy from Asia across multiple centers in different countries that early catheter ablation performed at the time of ICD implantation really reduced the composite primary outcome of VT recurrence, cardiovascular hospitalization, or death. And these findings were really nicely driven by a reduction in the ICD therapies. Well, on behalf of Carolyn and myself, I 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, 2022. 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, please visit ahajournals.org.

Circulation May 10, 2022 Issue

love running identity loss team services iron man curious perseverance killed worried postpartum reds physical therapy pee go ahead dealing with loss insidetracker arvc

Play Episode Listen Later May 9, 2022 18:07

This week, please join Guest Host Mercedes Carnethon and Author Brendon Neuen as they discuss the article "Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People With Type 2 Diabetes: A Meta-Analysis of Individual Participant Data from Randomized, Controlled Trials." 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, this week's feature paper is on one of my favorite topics, SGLT2 inhibitors. And this time, looking at their association with the risk of hyperkalemia in people with type-two diabetes. Now this is something we've all been waiting to look at. It's a meta-analysis of individual participant data from randomized controlled trials, so a very important, clinically applicable discussion coming right up. But first, I'm actually going to talk to you about text messages. Dr. Greg Hundley: Wow, Carolyn. I can't wait to hear about this article. Dr. Carolyn Lam: Well, specifically the TEXTMEDS randomized clinical trial, which is our first paper today. It is a trial that examined the effectiveness of text-message delivered cardiac education and support on medication adherence following an acute coronary syndrome. Dr. Carolyn Lam: This is from Dr. Clara Chow from University of Sydney and her colleagues, who performed a single blind multi-center randomized controlled trial of post-ACS patients across 18 rural and urban centers and three time zones in Australia. The control group received usual care, and the intervention group additionally received multiple motivational and supportive weekly text messages on medications, and healthy lifestyle, with the opportunity for two-way communication. Dr. Greg Hundley: Wow, Carolyn. So text messaging to facilitate medication adherence. I can't wait to hear. So what did they find? Dr. Carolyn Lam: I think the design, it's such a neat study. However, the study found no significant impact on the primary outcome of medication adherence at six and 12 months, nor on LDL cholesterol or blood pressure. Dr. Carolyn Lam: However, intervention participants were more likely to achieve a normal body mass index and to eat guideline-recommended servings of fruit and vegetables. Qualitative analysis demonstrated a high level of acceptability, utility in being a unified source of information, high program engagement, and emotional support, especially during times of uncertainty. Dr. Greg Hundley: Interesting, Carolyn. Sounds like an impact on diet, so what did we learn from this study? Dr. Carolyn Lam: Well, customized and personalized text message-based prevention programs are indeed a scalable and low-cost means of delivering consistent education and support to patients following hospitalization for ACS. So this study shows it's feasible. The lack of impact, however, on medical adherence, though with better adherence to healthy lifestyle practices, suggests that maybe external factors, such as cost, may strongly influence medical adherence. These need to be addressed, in addition to education programs, to improve medical adherence. But all of this is discussed in a beautiful editorial entitled, "Opportunities and Challenges of Mobile Health Tools to Promote Health Behaviors" by Drs. Sharma and Avram. Dr. Greg Hundley: Very nice. Carolyn, what a great summary. Well, my paper comes to us from Professor Mario Delmar from New York University School of Medicine, and Carolyn, exercise training as well as catecholaminergic stimulation increases the incidence of arrhythmic events in patients affected with arrhythmogenic right ventricular cardiomyopathy or ARVC, and this correlates with plakophilin-2 mutations. Now, Carolyn, separate data show that reduced abundance of plakophilin-2 leads to dysregulation of intracellular calcium homeostasis, and Carolyn, these authors studied the relation between exercise and or catecholaminergic stimulation, intracellular calcium homeostasis, and arrhythmogenesis in plakophilin-2 deficient murine hearts. Dr. Carolyn Lam: Ooh. So what were the effects? Dr. Greg Hundley: Right, Carolyn. For training, the mice underwent 75 minutes of treadmill running once per day, five days each week, for six weeks. And the authors observed that exercise disproportionately affected calcium intracellular homeostasis in plakifilin-2 deficient hearts, in a manner facilitated by stimulation of intracellular, beta-adrenergic receptors or hyper-phosphorylation of phospholamban. Dr. Greg Hundley: Now these cellular changes created a pro-arrhythmogenic state that can be mitigated by plakophilin receptor blockade. Additionally, Carolyn, these authors' data unveiled an arrhythmogenic mechanism for exercise-induced or catecholaminergic life-threatening arrhythmias in the setting of a deficit in plakophilin-2. They suggest that membrane-permeable beta blockers are potentially more efficient for ARVC patients. Dr. Greg Hundley: And also they highlight the potential for ryanodine-receptor channel blockers as treatment for the control of heart rhythm in this population at risk, and propose that plakophilin dependent and phospholamban-dependent, ARVC-related arrhythmias have a common mechanism. Dr. Carolyn Lam: Wow, thanks again, Greg. That was really, really a nice explanation. Well, for this next original paper, it looks at the question of the association between major bleeding and non-major clinically relevant bleeding, with subsequent mortality in hospitalized patients, and authors did this by exploring this relationship in the MAGELLAN and MARINER trials of extended thrombo-prophylaxis in hospitalized medical patients. Dr. Greg Hundley: Wow. Carolyn. I can't quite remember, and maybe for our listeners, remind us of the design of the MAGELLAN and the MARINER trials. Dr. Carolyn Lam: These trials evaluated, whether rivaroxaban compared with enoxaparin or placebo, could prevent venous thromboembolism without increased bleeding. The authors, led by Dr. Spyropoulos from the Feinstein Institute of Medical Research in New York, hypothesized that patients with major bleeding, but not those with non-major clinically relevant bleeding, would be at an increased risk of all-cause mortality. So Greg, would you like to guess what they found? Dr. Greg Hundley: Oh, Carolyn, you've put me on the spot here. I'm not sure. Dr. Carolyn Lam: Maybe just, did the authors get it right or wrong? Just.... Dr. Greg Hundley: I'm saying, they got it right. Dr. Carolyn Lam: Oh, always clever. They found that compared to patients with no bleeding, the risk of all-cause mortality for patient with non-major clinically relevant bleeding was not increased in MARINER, but was increased in MAGELLAN. Major bleeding, however, was associated with a higher incidence of all-cause mortality in both studies, while trivial bleeding was not associated with mortality in either study. These results really inform the risk benefit calculus of extended thromboprophylaxis in medically ill patients. Dr. Greg Hundley: Wow. Carolyn, great presentation. We've got some other articles in this issue. And let me tell you about two that I have. First is a Research Letter from Professor Frankel entitled "Trends in Opioid Use after Cardiac-Implantable Electronic Device Procedures in the United States, between the years of 2004 and 2020." And Tracy Hampton, from the National Association of Science Writers, presents some very recent news in the world of cardiology. Dr. Carolyn Lam: Nice. Well, there's an exchange of letters as well between Drs. Yang and Nagareddy regarding the article "Retention of NLP3 Inflammasome-Primed Neutrophils in the Bone Marrow is Essential for Myocardial Infarction-Induced Granulopoiesis." And finally, in the Editor's Page, a nice piece from Drs. Joe Hill, Darren McGuire, and James de Lemos on “Circulation: Best Papers, 2021.” Gosh, really, really nice issue. Now let's go on, though, to the feature discussion, yeah? Dr. Greg Hundley: You bet. Dr. Mercedes Carnethon: Welcome to this episode of Circulation on the Run podcast. My name is Mercedes Carnethon, one of the associate editors, and I'm a professor of preventive medicine at the Northwestern University Feinberg school of Medicine. I'm really excited today to have a guest with us. Dr. Brendon Neuen, who has shared with us his really outstanding research on SGLT2 inhibitors and the risk of hyperkalemia in people with type-two diabetes, a meta-analysis. So welcome to our podcast today, Brendon. Dr. Brendon Neuen: Thanks very much for having me Mercedes. It's a real pleasure to be here. Dr. Mercedes Carnethon: Well, thank you for joining us. We're really pleased that you chose Circulation to share with us your really important findings. Can you tell us a little bit about the rationale for your study and how you carried out your work? Dr. Brendon Neuen: Yeah, absolutely. So we know that in people with diabetes and people with CKD, hyperkalemia is a common occurrence, and it's a problem for two reasons as you'd be aware. Firstly, it is associated with cardiac dysrhythmias and secondly, perhaps at least as importantly, it limits the optimal use of treatments that reduce kidney disease progression and heart failure events. So that is, agents that block the renin angiotensin aldosterone system. Dr. Brendon Neuen: We now know, and we've got robust evidence from large outcome trials, that SGLT2 inhibitors reduce the risk of heart failure and kidney disease progression in people with and without diabetes, but we haven't really, up and until now, systematically evaluated their effect on potassium outcomes, particularly hyperkalemia. And so we set out to assess whether these agents affect serum potassium levels and alter the risk of hyperkalemia as well as hypokalemia. Dr. Mercedes Carnethon: Thank you. That sounds like a really excellent and well needed study, given how much we've heard within the field about the benefits of SGLT2 inhibitors. It's nice to see a careful evaluation of what some of the considerations are in their use. So tell us a little bit about how you carried out this study and what you ultimately found. Dr. Brendon Neuen: What we did was, we identified clinical trials that enrolled people with type two diabetes at high cardiovascular risk or with chronic kidney disease. And what we did is, we approached the investigators of each of these trials and asked them to collaborate on a large meta-analysis using individual participant data. Dr. Brendon Neuen: What that allowed us to do was, then, standardize across all of the trials of different outcome definitions, and allowed us to assess the effective SGLT2 inhibitors on a primary outcome of time to first serum potassium greater than or equal to six, defined as serious hyperkalemia, as well as hypokalemia, investigator-reported hyperkalemia events, and a range of other potassium-related outcomes in a broad population, including people with chronic kidney disease, people with heart failure, and people using different concomitant medications, such as diuretics and MRAs in the background. Dr. Mercedes Carnethon: So thank you, Brendon, for the explanation of the use of the meta-analytic design and the entry criteria of type-two diabetes and chronic kidney disease. Can you tell us, what were the outcomes across these studies? Dr. Brendon Neuen: The primary outcome we evaluated was time to first serious hyperkalemia, defined as a serum potassium greater than or equal to six, as well as a range of other potassium-related outcomes, including investigator reported hyperkalemia, change in potassium over time, as well as hypokalemia, defined as a serum potassium less than 3.5. Dr. Brendon Neuen: What we found was that overall SGLT2 inhibitors reduce the risk of serious hyperkalemia by about 16%. And that effect was consistent across the agents within the class, and across different subpopulations and trials. This effect was supported by a 20% risk reduction in investigator-reported hyperemia events and importantly, there was no difference in risk of hypokalemia, that is a serum potassium less than 3.5, between SGLT2-treated and placebo-treated participants. Dr. Mercedes Carnethon: Thank you for that summary. You know, one of the very impressive aspects of this clinical trial is certainly the size and the number of participants. Brendon, I was really struck by your description of the consistency of findings across the subgroups. And in particular, when I reviewed the findings in the paper, I noticed that serious hyperkalemia was higher in those with poorer kidney function. Did you find that surprising? Dr. Brendon Neuen: From clinical practice, we know that one of the major determinants of hyperkalemia risk is kidney function. It's a major problem that we run into in people with more advanced CKD. And what that means is that for people with more advanced chronic kidney disease, who are at high risk of hyperkalemia, the absolute benefits of SGLT2 inhibition on hyperkalemia risk are likely greater in these individuals, because they're at high risk of this outcome. Dr. Brendon Neuen: Other patients who might be at increased risk of hyperkalemia include those with heart failure or those taking mineralocorticoid receptor antagonists at baseline. And so you'd expect that if the relative effects are consistent across many subgroups, then the absolute risk reductions are likely to be larger in people taking MRAs or people with more advanced CKD. Dr. Mercedes Carnethon: Thank you so much for summarizing the importance of these findings and what they mean for our clinical audience. It's wonderful to have this sort of information from a meta-analysis because it allows us large sample sizes, where we can do things like you describe, such as describing subgroup effects. Dr. Mercedes Carnethon: It also presents us with very robust evidence that can be taken into clinical practice for our clinical audience to use. Based on what you found, how do you anticipate that these findings can be used by our clinicians? Dr. Brendon Neuen: Well, thanks, Mercedes. I think the reduction in risk of hyperkalemia that is observed in these data suggests that SGLT2 inhibitors might enable better use of other proven therapies that reduce cardio-renal risk in people with chronic kidney disease and people with heart failure. We all know that in treating these high risk patients, hyperkalemia is a problem. And by reducing the risk of hyperkalemia with SGLT2 inhibitors, it might enable better use of renin angiotensin system blockade and mineralocorticoid receptor antagonists in people with chronic kidney disease and heart failure. Dr. Mercedes Carnethon: So you've provided a really excellent overall summary of the impact of these finding for clinical practice and the possible next steps. I wanted to end on a note of asking you what surprised you about these findings that might lead to further future investigations. Dr. Brendon Neuen: Thanks, Mercedes. I think that's a really interesting question. What was somewhat surprising, but also reassuring, was the consistency of the treatment effect on hyperkalemia, regardless of how we defined it, whether that was defined based on investigator-reported hyperkalemia events or central laboratory-measured serum, potassium levels, the treatment effect was very consistent. And I think that gives us some confidence about the robustness of these findings and their application to clinical practice. Dr. Mercedes Carnethon: Well, thank you so much, Brendon. I have really enjoyed this discussion with you today and this really important paper that is describing an important safety outcome for SGLT2 inhibitors in patients with type two diabetes. And again, I really want to thank you for sharing your excellent work with us here at Circulation. I anticipate that our readership, when they leave this podcast and pick up their journals, will be thrilled to read about all of the details about the excellent work that you and your team have carried out. So thank you very much for joining us today. Dr. Brendon Neuen: Thanks very much for having me, Mercedes. It was a real pleasure. Dr. Mercedes Carnethon: Thank you, and thank you again to our audience for joining us for this episode of Circulation on the Run. Speaker 5: This program is copyright of the American Heart Association, 2022. 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, please visit ahajournals.org.

73: How Running Nearly Killed Kate and Dealing with Loss of Identity

Female Athlete Nutrition

Play Episode Listen Later Apr 14, 2022 54:27

In this episode of the Female Athlete Podcast, I talk with physiotherapist and host of the More Than Miles podcast, Dr Kate Mihevc Edwards. We start by discussing her work as a physiotherapist treating athletes. Kate explains how she sees the body holistically, looking beyond the injury site to find the route cause and prevent future issues from arising. We touch on what to look for in a physiotherapist, and how to find a trustworthy and knowledgeable professional. Kate shares her own story as an endurance athlete, an identity she held closely until a near-death experience brought that to an end. Despite being an accomplished runner and triathlete, Kate explains how training for a half-Ironman postpartum nearly ended in disaster. Throughout her training cycle, Kate describes how she battled increasing negative self-talk and overwhelming fatigue, things she attributed to being out of shape and new motherhood. After several episodes of hitting extremely high heart rates and chest tightness -episodes of cardiac arrhythmias that could've been fatal- Kate embarked on a year long diagnosis journey which saw her become more and more restricted in her activity habits. Kate was eventually diagnosed with a rare genetic cardiac condition, arrhythmogenic right ventricular cardiomyopathy (ARVC), and underwent heart surgery. We discuss the warning signs Kate overlooked, despite being a medical professional herself: blacking out, confusion, dizziness and a racing heart rate. Kate explains how doctors continued to disregard her symptoms even though she knew something was wrong, underscoring the importance of trusting your gut, self-advocacy and finding a professional who specializes with athletes, such as sports cardiologist Dr Kim who we had on Episode 72 of the Female Athlete Podcast. This episode covers loss of athletic identity and finding joy outside of sport. Kate shares the work she is doing to treat athletes holistically, expanding their identities beyond sport. Kate has written two books, ‘Racing Heart' and ‘Stop and Pee', which combine personal anecdotes with actionable advice and resources for us all. We touch on returning to exercise postpartum and exploring new activities during different times in life. Use code RISEUPNUTRITION for 25% off any InsideTracker plan + free results review over phone/ email with a registered dietitian, me! Follow Dr Kate on Instagram @katemihevcedwards Twitter @KateEdw96114704 and Facebook @KateMihevcEdwards Find more on her websites https://www.katemihevcedwards.com/ https://www.precisionpt.org/ Check out her podcast Mind Over Miles https://www.katemihevcedwards.com/morethanmilespodcastshow-notes Dr Kate Mihevc Edwards' Official Bio Dr Kate Mihevc Edwards is a physical therapist, author, speaker and educator helping to widen the lens on treating and caring for endurance athletes. Through 12+ years of successfully treating thousands of frustrated athletes while navigating her own injuries and health struggles, Dr Kate knows and believes that an athlete's success is so much more than their body or their sport. Dr Kate employs a holistic approach focusing on the whole athlete, as well as their identity outside of athletics. Dr Kate founded Precision Performance and Physical Therapy in 2015 and co-hosts the Mind Over Miles podcast. She is the author of two books: Go Ahead, Stop and Pee: Running During Pregnancy and Postpartum and Racing Heart: A Runner's Journey of Love, Loss and Perseverance, leveraging her position as an educator and a clinic owner to educate healthcare providers and athletes about cardiac disease in athletes. Learn more about Lindsey's Services and the Team at Rise Up Nutrition: www.riseupnutritionrun.com Worried that you have RED-S? Curious to know how we could help or how you can recover fast?! Download the RED-S Recovery Race & see how you place for more support:www.riseupnutritionrun.com/reds

Uncovered Episode 15, Adam Hoerdt

Table Ronde

Play Episode Listen Later Dec 15, 2021 15:46

In the latest episode of Uncovered, join Bruce de la Cruz as he speaks with Adam Hoerdt, a retired math teacher who is biking across the country to raise funds and spread awareness of a Arrhythmogenic Right Ventricular Myopathy (ARVC), a genetic disease of the heart that has affected his family immensely. Adam Hoerdt's story begins with the tragic passing of his wife Jackie in 2001, from a sudden cardiac arrest. At the time, the doctors had no idea what caused the arrest. It was only in 2018 when Adam's oldest son Greg had his first cardiac arrest were they able to determine the cause of his and Jackie's condition: ARVC. ARVC is a genetic condition that breaks down the walls of the heart, causing irregular heartbeats that can prove fatal. Many athletes suffer from the disease, and the first symptoms are usually unprecedented cardiac arrests in young adults. Adam was inspired to bike across Canada when Greg entered into a vegatitve state as a result of ARVC in September 2020. The 3 main goals of the ride taken from their Gofund me page are as follows: “Raising awareness of ARVC for all Canadian families and health care providers” “Provide support for families diagnosed with ARVC at our soon-to-be-launched website (www.arvcfamilysupport.org)” “Raise funds to help the research and clinical care efforts at the Peter Munk Cardiac Centre at the UHN in Toronto” Right now, Adam is nearly done with the 3250 Km ride from Newfoundland to Ontario, having started in late August, with his final stop in Kitchener-Waterloo. He plans to continue the ride once spring has come around. The thing that Adam wants people to take away from his story the most is that even though you can't always predict what happens to us, whether it be negative or positive, you can still choose what to do next.

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Circulation November 16, 2021 Issue

united states new york canada pennsylvania british columbia fireside chats jellystone arvc

Play Episode Listen Later Nov 15, 2021 32:01

Please join authors Babken Asatryan and Anwar Chahal, and Associate Editor Ntobeko Ntusi as they discuss the Primer article "Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review." 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 at Richmond, Virginia. Well, Carolyn this week, our feature discussion, we're not going to go with one of our original articles, but we are going to feature a primer and a primer is a state of the art review article. The topic is going to be on arrhythmogenic cardiomyopathy and we'll be looking at the role of inflammation and the immune response in arrhythmogenic cardiomyopathy. But before we get to that feature, how about we grab a cup of coffee and talk about some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I would, because guess what? I'm going to be talking about prescription opioids. We know these are a major contributor to the ongoing epidemic of persistent opioid use. What do you think is the incidence after cardiac implantable electronic device procedures? Greg, let's start with a Greg Hundley quiz. I'll give you multiple choice, how about that? Do you think it is 1%, 10%, 25%. 50%? Dr. Greg Hundley: All right, Carolyn, I'm going to guess here. I'm going to go 10%. Dr. Carolyn Lam: Smart. Well, guess what? Today's paper actually gives us insight into that question, it's from Dr. Frankel from the hospital of the university of Pennsylvania and his colleagues, and these authors performed a retrospective cohort study using data from a national Administrative Claims Database from 2004 to 2018 of patients undergoing cardiac implantable electronic device procedures. Adult patients were included if they were opioid naive during the 180 day period before the procedure and did not undergo another procedure with anesthesia in the following 180 days. Dr. Carolyn Lam: Persistent opioid use, which is what we're interested in, was defined by filling an additional opioid prescription more than 30 days following the procedure. So, here's your answer. Of the more than 143,000 patients meeting these inclusion criteria, 11%, so you were right Greg, 11% filled an opioid prescription within 14 days of surgery. Among these patients, persistent opioid use occurred in 12.4% of patients, 30 to 180 days after surgery. The likelihood for developing persistent opioid use was increased for patients who had a history of drug abuse, pre-operative muscle relaxant or benzodiazepine use or opioid use in the prior five years. Also, patients who have prescribed more than 135 milligrams of oral morphine equivalence had a significantly increased risk of persistent opioid use. Dr. Carolyn Lam: Now, this is important because all physicians who perform cardiac implantable electronic device procedures and care for these patients should be aware of the risk of persistent opioid use. This is discussing in editorial by Dr. Kandil from UT Southwestern. Dr. Greg Hundley: Very interesting Carolyn, so connecting sometimes the prescription use of opioids after cardiac implantable electronic devices. Great presentation. Well, my first paper comes to us from the world of preclinical science and it's from our prior editor in chief Dr. Joseph Loscalzo from Brigham and Women's Hospital and the Harvard Medical School. So Carolyn, interferon gamma, producing CD4 positive and CD8 positive T-lymphocytes, have been identified as the predominant pathological cell subsets in human atherosclerotic plaques. Dr. Greg Hundley: While the immunological consequences of these cells have been extensively evaluated, their interferon gamma mediated metabolic effects on endothelial cells remains unknown. So Carolyn, the purpose of this study was to determine the metabolic consequences of the T-lymphocyte cytokine interferon gamma on human coronary artery endothelial cells. Dr. Carolyn Lam: Interesting. So what did Dr. Loscalzo and colleagues find? Dr. Greg Hundley: Right, Carolyn. So, the authors found that interferon gamma impairs endothelial glucose metabolism via altered tryptophan metabolism while depleting NAD plus, which results in a metabolic shift toward increased fatty acid oxidation, and therefore, Carolyn, this work suggests a novel mechanistic basis for pathologic T-lymphocyte endothelial interactions in atherosclerosis, mediated by interferon gamma, linking endothelial glucose, tryptophan, and fatty acid metabolism with NADH and ATP generation and their adverse endothelial functional consequences. Dr. Carolyn Lam: Oh, very nice, Greg. Thank you. The next paper describes a comprehensive characterization of cardiomyopathy caused by filament C truncating variance. Dr. Greg Hundley: Whoa. Okay, Carolyn. Now what is filamin-C? Dr. Carolyn Lam: I thought you may ask and I wasn't going to quiz you, see Greg? The filamin-C gene can cause a striated muscle protein that crosslinks actin and anchors cell membrane proteins to the cytoskeleton, sarcolemmal and sarcomere Z-disc. So, the co-corresponding authors of today's paper Drs. Mestroni and Taylor from University of Colorado, Denver Anschutz Medical Campus, analyzed longitudinal clinical data from an international multicenter cohort of 85 carriers of this filamin-C truncating variants. And this is what they found. Dr. Carolyn Lam: First, the cardiomyopathy associated with filimin-C truncating variants appeared to be a disease with heterogeneous phenotypic presentation, ranging from typical dilated cardiomyopathy to arrhythmogenic, right ventricular cardiomyopathy, and with frequently overlapping forms. Dr. Carolyn Lam: Number two, left ventricular ejection fraction was associated with the risk of death, either all cause or non-arrhythmic, heart transplantation, or LVAD, but not with the risk of sudden cardiac death or major ventricular arrhythmias, highlighting the need for alternative strategies of stratification of the arrhythmic risk in these patients with the filimin-C truncating variant cardiomyopathy. Dr. Carolyn Lam: And number three, this cardiomyopathy was associated with a high risk of ventricular arrhythmias with frequencies of life-threatening ventricular arrhythmias, not significantly different from things like Lamin and desmoplakin cardiomyopathy. Dr. Greg Hundley: Well, Carolyn, just fantastic. My next paper comes to us from Professor Lena Claesson-Welsh from Uppsala University and Carolyn, palmdelphin belongs to the family of paralemmin proteins implicated in cytoskeletal regulation and single nuclide polymorphisms in the palmdelphin locus that result in reduced expression are strong risk factors for development of calcific aortic valve stenosis, and predict the severity of the disease. Dr. Carolyn Lam: Wow, interesting. Palmdelphin, great. So tell us, what did they find and what are the clinical implications please? Dr. Greg Hundley: Right, Carolyn, great question. So first, calcific aortic valves stenosis patients with the single nucleotide polymorphism RS754 3130 express reduce palmdelphin levels in valve endothelial cells, which shows hallmarks of palmdelphin deficiency, such as loss of cytoplasmic RanGAP1, altered nuclear morphology and nuclear rest of P53 of P21. Carolyn, second, gene-regulatory changes affecting actin reorganization, are detected in seemingly healthy regions of calcifying bowels, in agreement with disturbed actin-dependent processes, being an early event, instigating the calcific process. And so Carolyn, the take home message is that palmdelphin is prominently expressed in endothelial cells and the presence of the palmdelphin single nucleotide polymorphism correlated both with a Barrett endothelium and calcific aortic valve stenosis suggesting that endothelial cell dysfunction is essential in development of calcific aortic valve disease. Dr. Carolyn Lam: Oh, wow, wow. Thank you for translating that into the clinical implication. Thanks Greg. Let's maybe discuss what else is in today's issue. There's a prospective piece by Dr. Kirchof entitled “In Patients With Recently Diagnosed Atrial Fibrillation, Think Anticoagulation And Rhythm Control.” There's an exchange of letters between Drs. Liao and Hakala regarding the article Cardiovascular Risk Factor Trajectory Since Childhood And Cognitive Performance In Midlife, The Cardiovascular Risk In Young Finns, study. Dr. Greg Hundley: And Carolyn, I've got a research letter from Professor Ramin entitled “Association Between Sarcomeric Variants In Hypertrophic Cardiomyopathy In Myocardial Oxygenation, Insights From A Novel Oxygen-Sensitive CMR Approach.” Well, how about now we get onto that primer feature discussion relating to arrhythmogenic cardiomyopathy? Dr. Carolyn Lam: Yay. All right, let's go, Greg. Dr. Greg Hundley: Well, listeners, we are now onto our feature discussion and this week we've got a different aspect to the feature discussions. We're going to work through a review article and what we call as a primer. It's one of our state-of-the-art family of publications, where we take a topic and perform a review on a new evolutionary concept that might be occurring in a particular field. This week, we are going to discuss arrhythmogenic cardiomyopathy and we have with us two of the authors of this primer, Dr. Babken Asatryan from Bern, Switzerland and also Dr. Anwar Chahal from Lancaster, Pennsylvania. And of course, as always, we invite one of our associate editors and we have with us this week Ntobeko Ntusi from South Africa. Welcome gentlemen and Babken, let's start with you. Can you give us just a little bit of review regarding arrhythmogenic cardiomyopathy? We hear that term as opposed to arrhythmogenic right ventricular cardiomyopathy, and then maybe also, what are the underlying fundamental histopathologic and pathophysiologic findings associated with this disease? Dr. Babken Asatryan: Thank you, Greg. It's really an absolute pressure being here and thank you for your invitation again. So arrhythmogenic cardiomyopathic is genetically-determined heart disease and the common cause of sudden cardiac death in individuals younger than 40 years of age, it's characterized pathologically by fibrosis and/or fibro fatty infiltration of the myocardium. This infiltration provides a substrate for electrical and stability and leads to ventricular arrhythmias ranging from isolated premature ventricular contractions to sustain ventricular tachycardia and ventricular fibrillation. Live ventricular arrhythmias are cardio manifestations of the orthogenic cardiomyopathy, and they typically occur at early stages of the disease, preceding pathological and functional abnormalities. We call that a concealed stage of the disease. Dr. Babken Asatryan: The typical form for arrhythmogenic cardiomyopathy, which has been previously termed as arrhythmogenic right ventricular cardiomyopathy, primarily affects the right ventricle and has been recognized for decades. Following implementation of postmortem autopsy, increased use of contrast, enhanced cardiac MRI, and improved understanding of the genotype phenotype correlations, more recently cases with more pronounced left ventricular involvement have been discovered as well as cases with biventricular involvement of the disease. Dr. Babken Asatryan: Nowadays, we believe that around 60% of cases have also left ventricular involvement, even if they're diagnosed based on the 2010 task force criteria for arrhythmogenic cardiomyopathy. Causative variants in desmosomal genes are identified in about 60% of patients with typical arrhythmogenic right ventricular cardiomyopathy. Dr. Babken Asatryan: Recently, there have been studies reporting non-desmosomal gene variants in patients with arrhythmogenic right ventricular cardiomyopathy, as well as in those left ventricular and biventricular forms of the disease. But the left ventricular form is quite new to us, so we are learning a lot every day about this disease. Dr. Babken Asatryan: The pathogenesis of this condition appears to be quite complex. We know that these pathogenic variant in desmosomal genes can initiate several pathways and these could be gene dependent. What we do know, that these eventually lead to fibrosis and fibro fatty infiltration of the myocardium, which is the hallmark feature of arrhythmogenic cardiomyopathy. Dr. Greg Hundley: And patients present generally when, in terms of lifespan? Dr. Babken Asatryan: So, patients present in between 30 to 40 years of age, there's a typical presentation for arrhythmogenic cardiomyopathies but young presentations are also common nowadays, particularly. So, programs in families, they usually present 30 to 40 years of age. But in families, we do discover patients who have typical arrhythmogenic right ventricular cardiomyopathy or left and right ventricular involvement were younger at age, but they still need the criteria. Dr. Greg Hundley: And then when we diagnose this condition, do we also need to think about, at least clinically, looking for other affected individuals within a family? Dr. Babken Asatryan: Absolutely. So most of the arrhythmogenic biventricular cardiomyopathy, arrhythmogenic left ventricular cardiomyopathy cases are autosomal dominant diseases. So, this means if an individual carries a pathogenic variant in one of the genes responsible for the condition, the likelihood that the first degree family members will carry the same variant is about 50%. The disease however, presents with reduced penetrance and variable expressivity. Some of the family members may have just arrhythmias and others may develop arrhythmias and structural heart disease. And some of the individuals who carry pathogen occurrence in desmosomal are the genes responsible for the condition may not show phenotype at all. So, that makes the decision-making in families quite challenging. Dr. Greg Hundley: Very nice. Well, thank you so much Babken and now, we're going to turn to one of your co-authors, Anwar and Anwar, in this primer, you start to present a new sort of theme, that inflammation actually may play a role in this disease, at least in terms of adverse events. Can you describe a little bit what your team was thinking here and what took you in this direction and what are some of the research that you've revered here that supports this new line of thinking? Dr. Anwar Chahal: Thanks, Greg and Ntobeko, for first, the kind invitation to come on this podcast. I must add that I normally listen to the podcast and very much enjoy it, so it's a great honor and privilege for us. Dr. Anwar Chahal: Let me contextualize it, I think it's important to think about what are problems are when we evaluate cases, whether that's the program or the family members, and try to determine what's actually going on. There's been a number of changes over the last 15 years that really evolve around a better understanding and the availability of multimodality imaging, which has altered the way we evaluate these cases. If you look at the 2010 taskforce criteria, for example, they talk about volumetric changes and injection fractions by echo or MRI, and even ventriculogram synapse on fluoroscopy, which I don't think many people do anymore, but they don't mention gadolinium enhancement, and there is an updated version that will come out and talk about that, and the advantages of MRI and even contrast-enhanced CT, and now 18F-FDG, CT PET imaging. Dr. Anwar Chahal: So, the patient journey and the problem that we face is that actually some people present with very unusual features, chest pain, troponin rise, undergo coronary angiography, normal coronary arteries, or unobstructed coronary arteries. We put them through MRI scanners and we see a little bit of gadolinium enhancement. We follow them over the next five years or so, and it develops into taskforce criteria, positive ARVC. So, that's the sort of clinical angle where we've started to see this. Dr. Anwar Chahal: As we put people through scanners, we see the hearts lights up on PET scanners, pretty reproducibly and reliably, that tells us that there's some inflammation there. We look back into the literature and actually very, very early work that was done, autopsy-based, some of it endomyocardial biopsy-based describing lymphocytic infiltrates. Usually that's dry, as you say, or sterile, but there have been reports of even viral pathogens. Dr. Anwar Chahal: That's where it stirred this debate up for us about whether there's this signal that we're seeing there, what is it? What's actually going on? It raises a question, we recognize the other mechanisms, the fiber fatty replacement, the apoptotic pathways, that contribute to that. But there's such variable expressivity with this disease. It's a difficult disease to pin down and it raises a question. What are these other effect modifiers? Is there something else that we do not recognize? And that's really what's driven this. Dr. Anwar Chahal: Our group of co-authors are leaders in the field. Some of them are colleagues in veterinary medicine, Dr. Anna Geltser, and we work together on boxer dog patients. So, she is a practicing vet and a scientist, and has lots of boxer dogs with arrhythmogenic cardiomyopathy. We've been looking at how we could utilize that as a model to test some of the findings that we have in humans and pioneering work really by Bob Hamilton in Toronto, in this paper where they described anti-DSG2 antibodies, which were found not only in humans, whatever the underlying genotype, but also in boxer dogs with arrhythmogenic cardiomyopathy. And that's been followed up with work from Europe, describing anti-heart antibodies, anti-intercalated disk antibodies. Dr. Anwar Chahal: It doesn't really matter what the genotype is, but we're seeing these antibodies there and we're seeing these positive scans indicating inflammation. So the big question is, is this inflammation of primary insult or is it secondary? Is it that the heart in somebody with a genetic cardiomyopathy is predisposed, maybe the remodeling is affected. Bob Hamilton thinks this is probably the best explanation to explain why, whatever the genotype, that these antibodies were positive, that actually that myocardium becomes exposed. The epitope of DSG is now exposed to the immune system, which mounts an antibody response, and hence you see the rise in these antibodies, but it's possible it could it be primary as well. With COVID, and this is a bit of a stretch, so just bear with me there, with COVID we've been recognizing that there's myocardial injury. Dr. Anwar Chahal: There's not as much myocarditis as we expected, but there's been, with virus SARS-CoV-2, we know regular human coronavirus is a recognized cause of viral myocarditis. So, the question really arose are we going to see a lot more of this myocarditis? In our lab discussion, it was, "Well, do you think we're going to see something similar in that we've seen with arrhythmogenic cardiomyopathy, these genetically predisposed individuals are more likely to get invaded? Now, we haven't really seen that with COVID and I won't delve too much into it, but going back to the classical viral infections that we see with myocarditis, here's a really, really interesting biological link. Most of them invade through the desmosome, so with SARS-CoV-2, we see the ACE2 receptors as the way the virus really invades. But with these regular coxsackie virus, for example, parvovirus, a lot of them invade through the desmosome, and that's where we thought, here's a link. Dr. Greg Hundley: Very nice. Ntobeko, you see a lot of papers come across your desk. What attracted you to this group of investigators and this particular review article? Dr. Ntobeko Ntusi: Thank you very much, Greg. I want to start by congratulating Babken, and Anwar for a really fantastic submission, which as an associate editor, was an absolute pleasure to handle. There really are six things that stood out for me about this article. The first one really relates to the question that you ask Babken, which relates to the nomenclature and people have traditionally thought of this is a disease of the right ventricle. I think it's now timely to consider a clear change in nomenclature, that recognizes not only right ventricular involvement, but also left ventricular involvement. And the common finding of biventricular disease in patients with ACM. Dr. Ntobeko Ntusi: The second really important contribution for me from this primer was that we've always thought of arrhythmogenic cardiomyopathies as a genetic disorder with abnormalities in the genes, encoding components of the desmosome. Many groups recently, including our own group that described novel mutations for arrhythmogenic cardiomyopathy in adhering to poultry and other genes outside of the desmosome are showing that the genetic underpinnings are much wider. But the key contribution here is really the consideration of the centrality of inflammation to the pathogenesis of this disease. Anwar has spoken to some length about that, so I won't rehash those comments, but for me, what is key for future work in this area is really to clarify whether the inflammation, as in with many other forms of cardiovascular disease, is merely an epiphenomenon, or whether it plays a critical role in the causal pathway for the phenotypes that we see. Dr. Ntobeko Ntusi: The next important feature for me was the review of the literature and evidence in the association with myocarditis. So, we've seen lots of case reports and small case series showing young people presenting with myocarditis and meeting either the Dallas criteria histologically, or the Lake Louise criteria on imaging, and then subsequent genetic testing confirming the diagnosis of an arrhythmogenic cardiomyopathy. I thought for the first time with quite a compelling review of the link between these two. Dr. Ntobeko Ntusi: The fourth important contribution relates really to the contribution of imaging modalities, both in diagnostics, but critically in risk stratification for this clinical entity. And for me, the importance of cardiovascular magnetic resonance, either with planimetric mapping or late gadolinium enhancement to really add to our ability to predict future events. Dr. Ntobeko Ntusi: Then there's been quite a number of publications in the last five years that have clarified our understanding of the at risk patient with arrhythmogenic cardiomyopathy who's likely to suffer a sudden cardiac death event. This tends to be somebody who was young, who was male, who has a history of documented non-sustained ventricular tachycardia or a history of syncope and on ECG, quite extensive T wave inversion. So again, this is nicely reviewed, and we think about those as candidates who'll benefit from implantation of an ICD. Dr. Ntobeko Ntusi: Then I thought for me, the last really nice contribution from this piece was the review of advancing our understanding of the hot phase. So in all forms of heart muscle disease, we speak of the presentation of patients with the chest pain syndrome, with a troponin leak, but unobstructed coronaries. On further investigation, we don't really find any other evidence of an inflammatory event. We call this a hot phase. And in some case reports in small case series, endomyocardial biopsy has revealed the association of these, whether in TCM, HCM, or arrhythmogenic cardiomyopathy with lymphocytic infiltration. I thought this was all very nicely reviewed. Dr. Ntobeko Ntusi: So, the question that really left me with having read this review, was whether in the future, we may actually need to consider targeting inflammatory pathways as a therapeutic target in this heart muscle disorder. Thanks Greg. Dr. Greg Hundley: Yes. Thanks so much in Ntobeko. You've really led us to the next question that I'm going to ask both Babken and Anwar, you've discussed where do you feel this field is moving and what is the next study or series of studies we need to perform. Babken, first you, and then Anwar. Babken, what do you think is the next study to be performed in this space? Dr. Babken Asatryan: I so much agree with Ntobeko, that perhaps understanding better what can be targeted in these patients, in order to prevent development of phenotype or least to prevent cardiac events, is perhaps the most important next step. In our first figure, we have summarized this potential mechanisms, involving inflammation leading to with arrhythmogenic cardiomyopathy in these patients. We have also highlighted the potential mechanisms that perhaps in the future can be targeted. This could include both targeting the inflammatory cytokines, as well as the primary agents that cause the myocardial inflammation in patients, depending on the results that we will receive over the next years and perhaps animal models should be the next step to better understand how similar arrhythmogenic cardiomyopathy phenotype, where inflammatory contributors to the phenotype are important. And then we can understand whether this can be the same in humans as well. Dr. Greg Hundley: Very nice. And Anwar, do you have anything to add? Dr. Anwar Chahal: Yes. So, agree with that. I guess I would add what are we doing to try to help decipher this? So some of the work that we're doing, I mentioned earlier with the boxer dog patients, who have arrhythmogenic cardiomyopathy. So some of the aspects that we're actually looking at is taking swab cells to see if we can phenotype as a alternative tender myocardial biopsy. And one of the co-authors, Angeliki Asimaki, really pioneered that as a alternative tool because the desmosis are ubiquitous and this may help us phenotype patients better. But also, we want to look at using that as a tool in the pheno copies of arrhythmogenic cardiomyopathy. So we would advocate, re-phenotyping people as well as possible and trying to use some of these techniques. Dr. Anwar Chahal: The next thing we're really looking at is antibody based tools, either working with collaborators, who've already described these antibodies such as anti-DSG2, anti-heart antibody, and anti-skeletal disc to see if we can develop those and perhaps identify others in both human and ox models. And that will then hopefully open the way for us to develop therapeutics that may be able to target those and address that, and maybe use these antibodies as markers to see disease progression, or halting of disease. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Babken Asatran from Bern, Switzerland, Anwar Chalal from Lancaster, Pennsylvania, and our own associate editor, Ntobeko Ntusi from South Africa, really helping us see this new scientific consideration regarding the potential role of inflammation in causal pathways of adverse manifestations of arrhythmogenic cardiomyopathy. 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. 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.

Shut the Puck Up Episode (Guest Greg Dobson)

Shut The Puck Up

Play Episode Listen Later Oct 29, 2021 102:22

Ben and Tyler are joined by Greg Dobson to talk hockey from around the league and Greg tells us about the Jordan Boyd Foundation and what ARVC an inherited heart condition is. Give it a listen and check out the foundations website below. https://www.jordanboyd.ca/

shut puck dobson arvc

MC Fireside Chats - September 29th, 2021

MC Fireside Chats

Play Episode Listen Later Sep 29, 2021 60:34 Transcription Available

This week on MC Fireside Chats, presented by Modern Campground, we'll be discussing the upcoming fall conferences in the United States and Canada. Lori Severson from the brand new Campground Owners Expo - COE will join us, along with Joss Penny from British Columbia to talk about their respective conferences. Plus, we'll hear from Joe Duemig a supplier from App My Community about vendor interest in these shows, as well as discuss ARVC, KOA, Jellystone, and state conferences like New York and Pennsylvania.

6: A Law Enforcement Career Lost to ARVC | Today Corporate Security. Brent Hughes

Transition Drill

Play Episode Listen Later Sep 27, 2021 58:03

years, serving the cities of Menlo Park and Gilroy. His assignments included Gang and Narcotics teams, SWAT, and traffic motor officer. In 2018 Brent received the Life Saving award for saving two residents of Gilroy as well as being named Officer of the Year. In 2019 Brent was diagnosed with Arrhythmogenic Right Ventricular Cardiomyopathy or ARVC. This is an inherited condition which causes a deterioration of the heart. To make it worse, the condition is exacerbated by physical fitness. This diagnosis caused his law enforcement career to come to an abrupt end, but it also caused Brent mental health issues by having to walk away from a career he loved. In 2020, Brent transitioned from law enforcement into the corporate security field. Today he is a Security Program Manager at Zoox. FOLLOW, SUBSCRIBE, LISTEN, AND WATCH THE PODCAST: https://linktr.ee/transitiondrillpodcast CONNECT WITH BRENT LinkedIn: https://www.linkedin.com/in/brent-hughes-25b6ba48/

lost career gang officer hughes law enforcement swat lifesaving narcotics menlo park gilroy zoox corporate security arvc

Ontario man, whose family has been devastated by heart disease called ARVC, starts cross-Canada bike ride in Newfoundland to raise money and awareness

CBC Newfoundland Morning

Play Episode Listen Later Sep 3, 2021 6:05

Adam Hoerdt of Ontario has started a Cross-Canada bicycle ride in Newfoundland, to help raise research money for a heart disease called Arrhythmogenic Right Ventricular Cardiomyopathy, or ARVC. The disease killed his wife 20 years ago and has left his 23-year-old son in a vegetative state. The CBC's Martin Jones reached Hoerdt as the cyclist passed the 600km mark of his ride.

family starts ontario cbc newfoundland heart disease devastated raise money bike rides martin jones cross canada arvc

A Ride for ARVC

The St. John's Morning Show from CBC Radio Nfld. and Labrador (Highlights)

Play Episode Listen Later Aug 27, 2021 6:50

Adam Hoerdt speaks to us about this cross-country bicycle ride that kicks off right here in St. John's.

ride arvc

Circulation July 6, 2021 Issue

education wellness disease tests heart health cardiac genetic testing healthcare workers building better disease prevention sick kids cibc sudden cardiac death arvc

Play Episode Listen Later Jul 6, 2021 23:44

This week's show features a panel discussion between authors Adrian Wells and Hyeon Chang Kim as they discuss their articles "Improving the Effectiveness of Psychological Interventions for Depression and Anxiety in Cardiac Rehabilitation PATHWAY—A Single-Blind, Parallel, Randomized, Controlled Trial of Group Metacognitive Therapy" and "Associations of Ideal Cardiovascular Health and Its Change During Young Adulthood With Premature Cardiovascular Events: A Nationwide Cohort Study." 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, also your co-host. And Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, we're starting off the month with double features, and these are just so interesting. The first paper talks about psychological interventions for depression and anxiety in cardiac rehabilitation. And the next talks about ideal cardiovascular health and its change during young adulthood and how that relates to premature cardiovascular events. Cool, huh? Dr. Greg Hundley: Absolutely. Well, Carolyn. How about we grab a cup of coffee and start discussing some of the other articles in the issue? And I could go first. Carolyn, the first article that I've got is from Mrs. Elizabeth Jordan from Ohio State University Wexner Medical Center. And it really pertains to cardiomyopathies. And remember, Carolyn, classically, we categorize hypertrophic, dilated, and arrhythmogenic right ventricular cardiomyopathy. And each has a signature genetic theme. Hypertrophic cardiomyopathy and ARVC are largely understood as genetic diseases of sarcomere or desmosome proteins. But in contrast, there are over 250 genes spanning more than 10 gene ontologies that have been implicated in dilated cardiomyopathy. And therefore, it really represents a very complex and diverse genetic architecture. So to clarify this, a systematic curation of evidence to establish the relationship of genes with dilated cardiomyopathy was conducted by an international panel with clinical and scientific expertise in dilated cardiomyopathy genetics. And they evaluated evidence supporting monogenic relationships of genes with idiopathic dilated cardiomyopathy. Dr. Carolyn Lam: Oh, wow. That sounds like a lot of work. And what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So in the curation of 51 genes, 19 had high evidence. 12 are definitive strong, and seven moderate. And notably, these 19 genes only explain the minority of cases, leaving the remainder of dilated cardiomyopathy genetic architecture really incompletely addressed. And clinical genetic testing panels include most high evidence genes. However also, the panel noted that genes lacking robust evidence are very commonly observed clinically. Dr. Greg Hundley: So Carolyn, the take home message from this international panel is that while dilated cardiomyopathy genetic testing panels include an average of about 60 genes, when curating published evidence for dilated cardiomyopathy, only 19 have really emerged as high levels of evidence. And then in this study, 51 genes were evaluated. And the 19 genes appraised as high evidence were recommended to be routinely used in the genetic evaluation of dilated cardiomyopathy. And one more point. Rare variants from genes without moderate, strong, or definitive evidence should not be used in clinical practice to predict dilated cardiomyopathy risk most importantly when also you're screening at risk family members. Dr. Carolyn Lam: Wow. Very nice. Stunning numbers. Well, my paper is identifying a novel therapeutic target in pulmonary arterial hypertension. Do you want to know what that is? Dr. Greg Hundley: Ah, yes, Carolyn. Very interesting. So what is it? Dr. Carolyn Lam: It's switch-independent 3A. Which is an epigenetic modifier, which is drastically down-regulated in pulmonary arterial hypertension patients and rodent models of pulmonary arterial hypertension. And strongly associated with decreased bone morphogenic protein receptor type two, or BMPR2 expression. So this switch-independent 3A overexpression up-regulated BMPR2 expression by modulating critical epigenetic pathways and decreasing a specific transcription factor binding to the BMPR2 promoter in pulmonary vascular smooth muscle cells. Furthermore, aerosolized lung-targeted gene transfer of adeno-associated virus zero type one and containing switch-independent 3A reversed and prevented pulmonary arterial hypertension phenotype in preclinical animal models. So this beautiful study, from Dr. Hadri from Icahn School of Medicine at Mount Sinai in New York and colleagues, really suggests that switch-independent 3A can be a clinically relevant molecule for the treatment of pulmonary arterial hypertension. Dr. Greg Hundley: Wow, Carolyn. Really nice. Very intricate science for the study of pulmonary hypertension. Well, my next paper actually comes to us from Dr. Joe Hill and colleagues at UT Southwestern Medical Center. And Carolyn, as we know, cardiac hypertrophy is an independent risk factor for heart failure. Of course, the leading cause of morbidity and mortality globally. And the calcineurin NFAT, or nuclear factor of activated T-cells pathway, and the MAP kinase ERK, or extra cellular signal regulated kinase pathway, contributes to the pathogenesis of cardiac hypertrophy as an interdependent network of signaling cascades. However, Carolyn, how these pathways interact really remains unclear. And so Dr. Hill and colleagues engineered a cardiomyocyte-specific ETS2, a member of the E26 transformation specific sequence or ETS domain family knockout mouse, and investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were also used to evaluate ETS2 function in cell growth. Dr. Carolyn Lam: Wow. Okay. So what were the results, Greg? Dr. Greg Hundley: Right, Carolyn. Three main findings. First, ETS2 is activated by ERK1/2, or extracellular signal-regulated kinase 1/2, in both hypertrophied murine hearts and in human dilated cardiomyopathy. Second, ETS2 is required for both pressure overload, and calcineurin induced cardiac hypertrophy responses involving signaling cascades distinct from, but interdependent with ERK1/2 signaling. And third, this group discovered that ETS2 synergizes with NFAT to transactivate RCAN1-4, an established downstream target of NFAT, or nuclear factor of activated T-cells. And they identified an MIR-223 as a novel transcriptional target of NFAT ETS2 in cardiomyocytes. Dr. Carolyn Lam: Wow. Wow. That sounds like a lot of detailed work. Could you tell us what the clinical implications are, Greg? Dr. Greg Hundley: You bet, Carolyn. So in aggregate, these findings unveil a previously unrecognized molecular interaction between two conical hypertrophic signaling pathways, MAP kinase-driven hypertrophy, and calcineurin driven hypertrophy. And therefore, as pathological cardiac hypertrophy is an established risk factor for heart failure development, this unveiling of novel signaling mechanisms really is of potential clinical relevance. Dr. Carolyn Lam: Thanks, Greg. Well, let's round up with what else there is in this week's issue. There's a Frontiers paper by Dr. Chris Granger. And it's a big call to action to the cardiology community, to incorporate SGLT2 inhibitors and GLP-1 receptor agonists for cardiovascular and kidney disease risk reduction. There's a Joint Opinion piece from the American Heart Association, World Heart Federation, American College of Cardiology, and European Society of Cardiology on, “The Tobacco Endgame: Eradicating a Worsening Epidemic,” by Dr. Elkind. Dr. Greg Hundley: Oh great, Carolyn. Well, I've got an On My Mind piece from Professor Bhatt. And it's entitled, “Does SGLT1 inhibition Add Benefit to SGLT2 Inhibition in Type 2 Diabetes Mellitus?” And next, Dr. Viskin has an ECG Challenge entitled, “Long QT Syndrome and Torsade de Pointes Ultimately Treated With Quinidine, The Concept of Pseudo Torsade de Pointes.” And then finally, there's a Letter to the Editor by Dr. Lu regarding the article, “Association of Body Mass Index and Age with Morbidity and Mortality in Patients Hospitalized with COVID-19, Results from the American Heart Association COVID-19 Cardiovascular Disease Registry.” Well, Carolyn, I can't wait to get on to this double feature. Dr. Carolyn Lam: Me too. Let's go. Dr. Greg Hundley: Welcome, listeners, to our feature discussion today. And again, we're going to create today a forum, because we have two very interesting papers to present during this timeframe. Our first is going to come to us from Dr. Adrian Wells from University of Manchester. And our second paper will come to us from Dr. Hyeon Chang Kim from Yonsei University. I want to welcome you both, gentlemen. And Adrian, I would like to start with you. Tell us a little bit about the background related to your study. And then what was the hypothesis that you wanted to address? Dr. Adrian Wells: Okay, well thank you for inviting me to take part in this podcast. Following cardiac events, around one in three individuals will develop significant anxiety and depression symptoms. And we know that anxiety and depression can have an impact on prognosis, quality of life, future outcomes. Psychological treatment isn't routinely offered in cardiac rehabilitation for anxiety and depression, despite the fact that we identified that many of our patients felt that they would benefit from a psychological intervention to address these issues. And they felt that their needs were not really being met. So our primary question was, can we improve psychological outcomes in patients with cardiovascular disease? Dr. Greg Hundley: Very nice. And Adrian, what was your study population? And also, what was your study design? Dr. Adrian Wells: So we selected patients who entered cardiac rehabilitation in the UK. So these are patients with acute coronary syndrome, revascularization, stable heart failure, heart transplantation, and so on. And so, a wide group of individuals. We recruited 332 patients, all of whom had had anxiety and depression scores of eight or more. So these were people showing mild to severe levels of psychological distress. We conducted a two arm single blind randomized controlled trial, with 332 patients who were randomly allocated to one of these two conditions. And we assessed anxiety and depression symptoms before treatment at four months and at 12 months. Dr. Greg Hundley: Describe a little bit some of the specifics of your intervention. And then what did you find? Dr. Adrian Wells: We use relatively recent new treatment called metacognitive therapy. And this was delivered in a group format over six sessions. And we trained cardiac rehabilitation staff, nurse consultants, physiotherapists, in the delivery of this intervention. Metacognitive therapy works on helping patients discover unhelpful patterns of thinking, such as worrying and ruminating ,and excessive threat monitoring. And to reduce those patterns of thinking that contribute to anxiety, depression, and poor adaptation following stressful life experiences. Dr. Greg Hundley: And what did you find? Dr. Adrian Wells: Well, what we found was that the addition of metacognitive therapy to treatment to usual cardiac rehabilitation, significantly improved outcomes at four months and 12 months. What was striking about this was that our effect sizes were modest and moderate to large. They seem to be larger than those obtained in other studies or psychological treatments. And of note, the treatment seemed to impact well on both anxiety and depression symptoms. Whereas other types of intervention evaluated in the past have tended to treat the depression, but not so much the anxiety. Dr. Greg Hundley: Very good. So it sounds like a group-based intervention. And I'm assuming maybe participants interacted not only with your staff, but with one another. How would you put your results really in the context with other research that's going on in this space? Dr. Adrian Wells: Well, there have been a number of studies in the past that have looked at individual and group-based treatments, and patient preference for different types of intervention. I think this is the first study to use a clear manualized intervention that's based on the psychological theory of mechanisms that contribute to the maintenance of psychological problems. Obviously, this tended to use more prescriptive interventions like anxiety management, stress management, taking techniques from a range of different sources. So I think there's a difference of conceptual basis to this kind of intervention. And it's something that is highly manualized and structured, and in fact can be delivered by a range of different healthcare professionals. Dr. Greg Hundley: Very nice. And also during cardiovascular rehab. Correct? Dr. Adrian Wells: Absolutely, yeah. During cardiac rehab. One interesting finding... And we were a little concerned that this might adversely affect attendance at cardiac rehab. But we found that the treatment was well tolerated, and it didn't have any negative impact on attendance at these other sessions. Dr. Greg Hundley: Excellent. Well, congratulations on this new finding. Well, listeners, we're next going to turn to Dr. Hyeon Chang Kim from Yonsei University in Korea. And Yong-Chan, could you describe for us also the background related to your study, and the hypothesis that your research wanted to test? Dr. Hyeon Chang Kim: Thank you for inviting me to this wonderful discussion. South Korea is among the countries with the lowest cardiovascular mortality in the world. And the rate is even decreasing. However, cardiovascular risk factor is worsening. Especially in younger generation in Korea. So these young people may not have a very high cardiovascular risk, but I wanted to know the potential impact of worsening cardiovascular risk profile in this younger Korean generation. And furthermore, I wanted to know how much we can lead youth cardiovascular risk by improving their cardiovascular health profile. Dr. Greg Hundley: Very nice. And so tell us about your study design and what was the study population, related to your study? Dr. Hyeon Chang Kim: My study is basically based on the national health checkup program and national health insurance claim database. In Korea, adults over the age of 20 and employed workers of all ages are required to take general health checkup every two years. The participation rate is between 70 and 80%. So we identified three and a half million adults, age 20 to 39 years, who complete the health checkup. And cardiovascular health scores was calculated as the number of ideal cardiovascular health component, which include non-smoking, moderate physical activity three times a week, body mass index below 2030, normal blood pressure, normal cholesterol and normal fasting glucose. So the score can range from zero to six. And higher score meaning better cardiovascular health. Our outcomes were myocardial infarction, stroke, heart failure, and cardiovascular deaths in about 16 years. In addition, we also evaluate the risk of cardiovascular disease. According to two year change in how the vascular health score using repeated health checkup data. Dr. Greg Hundley: Very nice. So evaluating a set of behavioral patterns and risk factors in younger individuals, and then predicting what their longer term adverse cardiovascular outcomes would be. So what did you find? Dr. Hyeon Chang Kim: So even in this relatively low risk population, better cardiovascular health score was associated with significantly lower cardiovascular risk. About 20% reduction per one point higher score. And more importantly, people with improving cardiovascular score over two years showed leading toward cardiovascular risk. Even if their baseline cardiovascular health score was very low. Dr. Greg Hundley: Really unique findings. Tell us about the impact of your results relative to other studies published in this space. And was this also.... This was unique, because it's an Asian population, Dr. Hyeon Chang Kim: Asian population. And we are among the very low risk population. And even in this low risk population, cardiovascular health score was... Fear can be a good predictor of cardiovascular risk. And compared to many Western countries, we have very low cardiovascular risk. And our population was younger than most other studies. So we can provide some evidence that even in the higher risk population, they can do much better, based on our study. Another important thing, we can check the impact of a changing cardiovascular score, even in the younger generation. Dr. Greg Hundley: Very good. And just as a frame of reference for our listeners. Give us some characteristics, if you wouldn't mind, on what really constitutes practically a low risk score, versus what would constitute a high risk score Dr. Hyeon Chang Kim: In this younger Korean population, their cigarette smoking, and their obesity, and physical inactivity are the most common causes of worsening cardiovascular profile. And the behavioral risk factor also can attack the blood glucose and cholesterol blood pressure. So in this younger generation, they're keeping the good behavior. Past behavior is very important and it's beneficial in the very long-term. Dr. Greg Hundley: Very nice, well listeners. We're going to turn to our experts here. Two very interesting studies. And ask them both, what do they think is the next study that needs to be performed in their respective areas of research? So Yong-Chan, we'll start with you. Since we just discussed your paper. What do you think is the next study to be performed really in this sphere of research. Dr. Hyeon Chang Kim: Korea is a relatively low cardiovascular risk, has a very small size, and no racial diversity. But even in this country, disparity and inequality in cardiovascular health is becoming an important issue. So I want to identify subcultural relatively poor cardiovascular health among younger population. And also I want to find ways to improve their cardiovascular score. The conventional approaches, such as education and mass campaign, are less effective oppose this younger adults have a poor socioeconomic status. So, we may need to develop newer target-specific strategies to improve their cardiovascular health. Dr. Greg Hundley: Good. And Dr. Wells, our agent will turn next to you. What do you see is the next area of investigation or research study that needs to be performed in your sphere of interests? Dr. Adrian Wells: Well, I think the next step is to look at rollout of this intervention. Is that feasible, and how acceptable is this to cardiac services? In fact, the National Institute of Health Research have just awarded us some funding to examine feasibility and barriers to implementation in the healthcare system. In addition to that, we're beginning to examine the effects of metacognitive therapy with other health conditions, such as cancer in children and adolescents. Dr. Greg Hundley: Nice. Well listeners, we have had just a wonderful discussion today from both Dr. Adrian Wells from University of Manchester. Who brought to us combining a group-mediated, psychological stress-reducing, anxiety-reducing, intervention to the cardiac rehab sphere. And how impactful that was in reducing both anxiety, and overall depressive symptoms. And then also exciting research from Dr. Hyeon Chang Kim from South Korea. Identifying for us that in Asian population, as well as what we know in other races, those individuals in their twenties to thirties with favorable lifestyle habits, have reduced cardiovascular risk much later in life. Dr. Greg Hundley: Well, on behalf of both Carolyn and myself, we want to wish you a great week. And we'll 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.

VS Sudden Cardiac Death: Building Better Tests to Save More Lives

SickKids VS

Play Episode Listen Later Apr 15, 2021 24:41

In 1990, 20-year-old rower Heather Cartwright was at the peak of her athletic powers. But as she crossed the finish line during a race that summer, she collapsed and nearly died. The cause? Arrhythmogenic right-ventricle cardiomyopathy, or ARVC—a rare, hereditary disease that can cause sudden cardiac death. Many die not knowing they have it. But thanks to SickKids researchers—and supporters like Heather and her family—a new test can detect this often-invisible disease.For more information on this episode, visit sickkidsfoundation.com/podcast/cardiacdeath. And to fund research like this, go to sickkidsfoundation.com/donate.SickKids Foundation is proud to recognize CIBC as the Premier Sponsor of the SickKids VS Podcast.

04 Dr. Jonathan Kim: Sports Cardiology & Return to Endurance Exercise Post COVID-19

More Than Miles

Play Episode Listen Later Mar 31, 2021 30:51

In this episode Dr. Kate and Dr. Kacy speak with Sports Cardiologist, Dr. Jonathan Kim about what athletes needs to know about their heart. We discuss return to exercise post COVID-19, signs and symptoms of cardiac disease and much more.#Physical therapy #runningmedicine #cardiacdiseaseinathletes #ARVC #suddencardiacdeath #caridacscreeninginsports #precisionptatl #precisionptserenbe #morethanmiles #endurancemedicine #runningdocs #running #triathlon #endurancesports #enduranceathleteguru #katemihevcedwards #ExerciseafterCOVID19 #Covid19 #runningCOVID

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106. Case Report: A Hole in the HFpEF Diagnosis – Boston University, Massachusetts General Hospital, and Brigham and Women’s Hospital

running medicine dying ga injury athletes recognize physical therapy triathlon cardiac owner ceo arvc

Play Episode Listen Later Mar 8, 2021 60:35

CardioNerds (Amit Goyal & Karan Desai) join Dr. Alex Pipilas (FIT, Boston University) and Dr. Danny Pipilas (FIT, MGH) for in Boston, MA. Adult congenital heart disease expert Dr. Keri Shafer (Brigham and Women’s Hospital) provides the E-CPR expert segment. They discuss a case of heart failure secondary to sinus venosus defect with partial anomalous pulmonary venous return. Claim free CME just for enjoying this episode! Jump to: Patient summary - Case media - Case teaching - References Episode graphic by Dr. Carine Hamo CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Patient Summary A 78-year-old woman with atrial fibrillation and heart failure with preserved ejection fraction presented with recurrent dyspnea and volume overload. A transthoracic echocardiogram demonstrated severe right ventricular enlargement and dysfunction. A CT pulmonary angiogram demonstrated partial anomalous pulmonary venous return and a transesophageal echocardiogram revealed a sinus venosus defect with left to right shunting. A right heart catheterization with oximetry saturation (“shunt run”) demonstrated pulmonary hypertension and a large left to right shunt (Qp/Qs ~ 3). She was referred for cardiac surgery and underwent repair of the sinus venosus defect and baffling of the anomalous pulmonary venous flow to the left atrium. Case Media ABCClick to Enlarge A. CXR, B. ECG, C. TR Velocity TTE: PLAX TTE: RV Outflow TTE: AP4 TEE: Sinus Venosus ASD TEE: Sinus Venosus ASD 2 Episode Schematics & Teaching Pearls It is critical to determine whether there is more to a diagnosis of heart failure with a preserved ejection fraction. Utilize all available clinical data and risk calculators to determine if there are more appropriate diagnoses causing the patients symptoms, especially when certain aspects of the presentation does not add up.Right ventricular failure may be related to pressure overload (i.e., pulmonary hypertension, PV stenosis), volume overload (i.e., tricuspid regurgitation, left to right shunt lesions), or primary myocardial process (i.e., ischemia, infiltration, ARVC). In cases of severe right ventricular enlargement and dysfunction without apparent cause, look for a left to right shunt lesion (i.e., VSD, ASD, PAPVR). Sometimes further imaging (TEE, cardiac CT, cardiac MRI) is necessary to detect these lesions if not visualized on TTE.Left to right shunts can be quantified in the cardiac catheterization laboratory by measuring oxygen saturation in each chamber and detecting an O2 “step up” (increase in oxygen saturation from one chamber to the next). Large left to right shunts are quantified using the Fick principle and comparing the ratio of pulmonary blood flow (Qp) to systemic blood flow (Qs).Large left-to-right shunts can cause right ventricular volume overload and pulmonary hypertension. Patients often present with signs and symptoms of right ventricular failure including shortness of breath, exercise intolerance, volume overload, atrial arrhythmias, and recurrent heart failure. Some may develop right-to-left shunting and possible paradoxical embolism.ACC/AHA guidelines recommend closure of a sinus venosus defect if the PA systolic pressure is < 50% systemic pressures AND PVR is 2/3 of systemic systolic pressure and/or PVR >2/3 SVR. Quotable: About ACHD - “As we go through this physiology, I just want to remind all of the listeners out there that you have the opportunity to apply the knowledge you have from medical school about physiology to the adult human heart. You can’t make assumptions as we sometimes do in the setting of normal cardiac anatomy.

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02 Why it Took Nearly Dying to Recognize Athletes are More than Just Their Sport

More Than Miles

Play Episode Listen Later Mar 3, 2021 39:38

Dr. Kate Mihevc Edwards, is a physical therapist and Owner/CEO of Precision Performance and Physical Therapy in Atlanta, GA. She shares her story of love, loss, and perseverance after being diagnosed with a genetic heart condition. This is a conversation about listening to our bodies, signs of cardiac disease, and coping with loss.#Physical therapy #runningmedicine #cardiacdiseaseinathletes #ARVC #suddencardiacdeath #caridacscreeninginsports #precisionptatl #precisionptserenbe #morethanmiles #endurancemedicine #runningdocs #running #triathlon #endurancesports #enduranceathleteguru #katemihevcedwards

James Taylor | Embracing the Challenge

GIVING THE GAME AWAY

Play Episode Listen Later Jan 24, 2021 63:02

With 27 ODIs and 7 Test matches under his belt, former England cricketer, James Taylor, was an extremely talented batsman and fielder, who was renowned for his work ethic and physical fitness. And it was his exceptional fitness levels that ultimately saved his life, when in 2016, he was diagnosed with arrhythmogenic right ventricular cardiomyopathy or ARVC, a life-threatening heart condition, similar to the one sustained by Fabrice Muamba. If it wasn't for James' excellent fitness, it is unlikely that he would have survived. Unfortunately, the condition forced Taylor's retirement and robbed him of more success as an England cricketer. However, prior to the diagnosis in 2016, Taylor had already achieved so much in an England shirt. He scored a 98* versus Australia in a World Cup, and later scored a hundred against the same opposition. He was a big game player, and was always confident that he would perform in high-pressured situations due to the hard-work and preparation he put in off-the-field. Perhaps James' fondest memory on a cricket pitch was actually the two incredible catches he took in Johannesburg during a historic series win against South Africa. Such is the cruel nature of sport, it was just a matter of weeks after the highs of Jo'burg that James received the devastating news that his playing career was over. Not only could James no longer play cricket again, the sport that he loved and had spent most of his life playing, but he could no longer play any sport at all, or any activity that could increase his heart rate whatsoever. For someone who loved competing, training, and staying fit - that was an extremely tough blow. But what's incredible about James is his sheer positivity, and shortly after the diagnosis, he changed his focus from what he couldn't do to what he can do. He is still involved in the game, working as a coach, as a commentator and also as a selector for the England team. In his new role as selector, James was able to contribute to England's World Cup heroics in 2019, and although James is unable to don the England whites any more, it is certain that he will still bring so much positivity to cricket in this country in the years to come.

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Slices of Wenatchee: Local Teacher Survives Near-Fatal Heart Attack

Slices of Wenatchee

Play Episode Listen Later Dec 5, 2020 5:08

Good Morning it's Saturday December 5th, and this is The Wenatchee World's newest podcast, Slices of Wenatchee. We're excited to bring you a closer look at one of our top stories and other announcements every Tuesday, Thursday, and Saturday. Today, we're focused on 44 year old Eastmont teacher Kai Knell who survived a near-fatal heart attack despite working out five days a week and eating healthily. Today's episode is brought to you by Equilus Group Incorporated. Equilus Group, Inc is a Registered Investment Advisory Firm in the states of Washington, Oregon, and Idaho. Equilus Group, Inc- Building Your Financial Success. Learn more at Equilusfinancial.com. Member SIPC and FINRA. And before we begin, do you want to share your home's holiday light display with the valley? You can add your festive decorations to our interactive map by visiting wenatcheeworld.com/holidaylights Now our feature story. At 44, Eastmont history teacher Kai Knell was a picture of health. The former Wildcat and WVC basketball star worked out five days a week and ate healthily. But on the morning of Oct. 28, his life changed. His wife Mariah found him lifeless, changing colors, and she immediately called 911. She performed CPR and once the paramedics arrived, they worked on Kai for nearly an hour, shocking his heart three times to get it beating. Kai was placed into an induced coma to prevent any further damage to his body and brain. At that time the Doctors were unsure if Kai would be able to wake up... But about 24 hours later, he awoke from the coma and completely shocked the doctors. For a healthy guy and lifelong athlete, it just did not make any sense. He wondered if he ate something bad, but he was soon diagnosed with arrhythmogenic right ventricular cardiomyopathy or ARVC which can lead to sudden death. Kai told us that “The life expectancy for males that have it is around 41. It's prone to people that are athletes or marathon runners. With that type of genetic condition, the more you exercise, the more the heart tissue turns into fat.” Now... Kai has to take medication daily and carries a defibrillator with him in case his heart stops again… and he's had to curtail most strenuous activities…. perhaps the toughest pill of all to swallow for a lifelong athlete. To read more more about Kai's journey and what the Wenatchee community is doing to help him recover, head over to www.WenatcheeWorld.com. Just in time for the holidays - The Foothills Magazine Wine Issue. Read up on local wine ratings from the 2020 NCW Wine Awards. Pick up your free copy of the November December issue of Foothills available now at free rack locations throughout North Central Washington. Next, every week we're profiling one of the recipients of the World's 30 Under 35 awards. That was Armando Bendito-Zepeda, a 26-year-old accountant from Wenatchee who is on his way to becoming a certified public accountant, taking the time this spring to help explain the CARES Act in Spanish to local business owners. His dedication to family and community landed him a spot on this year's 30 Under 35 list, the Wenatchee Valley Business World program that honors young professionals well on their way to being community leaders. Bendito-Zepeda's work ethic is inspiring and at 23, just one year out of college, he purchased a home for his parents and two younger sisters. He has since added a second house, with plans to purchase more. He told us that his parents, who are immigrants, have always been there for him. And said that “I kind of kept that in the back of my head. They moved here so I could have a better life.” Bendito-Zepeda said he's also planning to expand his mission to provide stable living environments and quality homes for low-income families on government assistance Finally, some local history, Wenatchee Valley History is brought to you by NABUR – your trusted neighborhood community. NABUR is a free online forum you can trust to connect with your community, focus on facts & make a difference. Join the conversation! Visit wenatcheeworld.com/nabur. Did you know that Pangborn Memorial Airport is named for Clyde Pangborn, who, in 1931 was the first pilot to fly non-stop across the Pacific Ocean? He took off from Japan with an intended destination of Seattle... but he and his co-pilot landed right here in Wenatchee instead. Thanks for listening. Today's episode is brought to you by Equilus Group, Inc- Building Your Financial Success. Learn more at Equilusfinancial.com The Wenatchee World has been engaging, informing and inspiring North Central Washington Communities since 1905. We encourage you to subscribe today to keep your heart and mind connected to what matters most in North Central Washington. Thank you for starting your morning with us and don't forget to tune in again on Tuesday! Support the show: https://www.wenatcheeworld.com/site/forms/subscription_services/ See omnystudio.com/listener for privacy information.

74. Case Report: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) – Summa Health

Play Episode Listen Later Oct 22, 2020 73:57

CardioNerds (Amit Goyal & Daniel Ambinder) join Summa Health cardiology fellows (Jack Hornick, Phoo Pwint Nandar, and Sideris Facaros) for a hike on the Towpath Trail at Cuyahoga Valley National Park in Akron, Ohio! They discuss an informative case of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) complicated by ventricular tachycardia & cardiogenic shock. Dr. Kenneth Varian provides the E-CPR and program director, Dr. Marc Penn provides a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident, Eunice Dugan, with mentorship from University of Maryland cardiology fellow Karan Desai. Jump to: Patient summary - Case media - Case teaching - References Episode graphic by Dr. Carine Hamo The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus. We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director. CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademySubscribe to our newsletter- The HeartbeatSupport our educational mission by becoming a Patron!Cardiology Programs Twitter Group created by Dr. Nosheen Reza Patient Summary Coming soon! Case Media 123Click to Enlarge A. Post cardioversion ECG: NSR, low voltage, incomplete RBBB, PVCB. TTE: RV enlargement C. TTE: Tissue Doppler velocity (S') low TEE Episode Schematics & Teaching The CardioNerds 5! – 5 major takeaways from the #CNCR case Coming Soon References Coming Soon! CardioNerds Case Reports: Recruitment Edition Series Production Team Bibin Varghese, MDRick Ferraro, MDTommy Das, MDEunice Dugan, MDEvelyn Song, MDColin Blumenthal, MDKaran Desai, MDAmit Goyal, MDDaniel Ambinder, MD

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56. Case Report: Arrhythmogenic Desmoplakin Cardiomyopathy – Northwestern University Feinberg School of Medicine

coach running strength welch identity shift farm boy arvc

Play Episode Listen Later Sep 14, 2020 65:23

CardioNerds (Amit Goyal & Daniel Ambinder) join Northwestern University cardiology fellows (Sarah Hale, Sarah Chuzi, and Graham Lohrmann) for burgers and a great case by the Chicago River! They discuss a fascinating case of arrhythmogenic desmoplakin cardiomyopathy. Dr. Lisa Wilsbacher provides the E-CPR and program director Dr. Benjamin Freed provides a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident Richard Ferraro with mentorship from University of Maryland cardiology fellow Karan Desai. Jump to: Patient summary - Case figures & media - Case teaching - References - Production team Episode graphic by Dr. Carine Hamo The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus. We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director. CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademySubscribe to our newsletter- The HeartbeatSupport our educational mission by becoming a Patron!Cardiology Programs Twitter Group created by Dr. Nosheen Reza Patient Summary A male in his early 40s presented for second opinion regarding multiple ICD shocks. 10 years prior he was diagnosed with a "weak heart," thought secondary to a viral illness and a dual-chamber ICD was placed at that time. He noted shocks occurring for the first time 5 years prior, at which time amiodarone was started. They recurred two years prior, when he was diagnosed with paroxysmal atrial fibrillation. Finally, he was hospitalized one month before presentation with multiple ICD shocks and was found to have high defibrillation thresholds (DFTs) and amiodarone was stopped. He then presented for a second opinion from the Northwestern CardioNerds! The patient had been doing well on GDMT and had NYHA Class I symptoms (Enjoy Ep #13 - Approach to GDMT). He did note a family history of a cousin with "cardiac issues" and did not know his father's family history. Physical exam demonstrated bradycardia and ECG demonstrated an a-paced, v-sensed rhythm at 50 bpm. TTE demonstrated a moderately dilated LV with LVEF 30%, globally reduced LV function and multiple wall motion abnormalities without a vascular distribution. PET-CT was performed which showed diffuse uptake and high-intensity signal at the inferolateral and basal anterior walls. Cardiac MRI showed diffuse circumferential epicardial delayed enhancement with associated diffuse, enhancing thickening of the pericardium favoring inflammatory versus fibrotic process. Patient was initially diagnosed with cardiac sarcoid and started on prednisone and weekly methotrexate. On return of genetic testing, patient found to have a pathogenic variant for desmoplakin gene, and it was felt his cardiomyopathy was secondary to desmoplakin Left Dominant Arrhythmogenic Cardiomyopathy (LDAC, or left-dominant ARVC) presenting with inflammatory myocardial injury. On follow up the patient remained listed for transplant, and DFTs improved off amiodarone. Case Media CXRECGCardiac MRIPET CT (Cardiac Sarcoid Protocol)Click to Enlarge Episode Schematics & Teaching Created by Dr.

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Running, Farm Boy Strength And Identity Shift From Athlete To Coach With Dennis Wayne Welch

Operation SuperCoach

Play Episode Listen Later Jul 7, 2020 40:28

In episode 003, I am interviewing Dennis Wayne Welch - the head coach and founder of the Endurance Project. Dennis coaches primarily obstacle racing athletes, helping over 200 of them make it to podium. In this episode, we talk about running, and how it can be anything from a method of transportation to an obsession. We also talk about the aspects of fitness that are universal and others that are specific - tune in to learn about "farm boy strength". Dennis also talks about his ARVC diagnosis (a rare heart condition), and how that prompted an identity shift from competitive runner to running coach. Learn more about Endurance Project at: https://dwenduranceproject.com/

Pediheart Podcast #123: A Novel Autoantibody Test For Brugada Syndrome

Play Episode Listen Later Jun 26, 2020 35:11

This week we speak with Professor Robert Hamilton of University of Toronto about a recent potentially groundbreaking work on a novel approach to the diagnosis of Brugada syndrome using an immunological test. How accurate is this test for diagnosis of this often elusive syndrome? Is autoimmunity the cause of disease or are the antibodies just a marker of disease. What's the latest on Professor Hamilton's work on testing for ARVC (reviewed previously in episode 43)? Dr. Hamilton provides us with lots of answers this week. For those interested in collaborating in his studies, his email and that of his research coordinator are in the podcast this week. doi: 10.1093/eurheartj/ehaa383

Pediheart Podcast #123: A Novel Autoantibody Test For Brugada Syndrome

Double Trouble Podcast - O&J Phelps

Play Episode Listen Later Jun 26, 2020 35:11

Double Trouble S2 E7 JAMES TAYLOR

Play Episode Listen Later Jun 12, 2020 105:34

This week we hear the Inspirational story of a former England cricketer who had his career instantly ended due to lifechanging undiagnosed heart condition. ARVC

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Circulation June 09, 2020 Issue

Play Episode Listen Later Jun 8, 2020 23:56

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 associated editor from the Pauly Heart Center at VCU health in Richmond, Virginia. Well Carolyn, this week's feature investigates the compass trial and is going to examine the role of combination antiplatelet and anticoagulation therapy in patients with diabetes and cardiovascular disease. But before we get to that feature discussion, how about we grab a cup of coffee and jump in and discuss some of the other papers in the issue? Dr Carolyn Lam: You bet, Greg. I've got my coffee right here, and I'd like to start by talking about paclitaxel containing devices. You may already know this, but it was nice to revise that these significantly reduce re intervention in patients with symptomatic femoral, popliteal, peripheral artery disease, as we may expect. However, a recent aggregate data meta-analysis reported increase late mortality in pad patients treat it with these paclitaxel containing devices. Thus today's authors, Dr Rocha-Singh from Prairie Heart Institute of Illinois at St. John's hospital and their colleagues performed an individual patient data meta-analysis to evaluate mortality using data from eight randomized controlled trials of FDA approved paclitaxel coated devices using de identified data that was provided by manufacturers. Dr Greg Hundley: Well, Carolyn, what did they find? Dr Carolyn Lam: So in 2,185 patients and 386 deaths from eight paclitaxel coated device trials with a four year median follow-up, there was a 4.6% absolute risk of increased mortality associated with paclitaxel coated device use compared to balloon angioplasty at a median of four years follow up, significant loss to follow up and withdrawal rates of 24% and 23% in balloon angioplasty and paclitaxel cohorts respectively through five years were observed. Recovery of lost vital status data reduced the observed paclitaxel device associated mortality rate. And there was no paclitaxel drug dose mortality relationship identified. Dr Greg Hundley: Oh, Carolyn, I think this is really an important finding, and we have a nice editorial, don't we? So what was the take home message? Dr Carolyn Lam: Yeah. In fact, this was discussed in an important editorial by doctors Royce, Chakraborty and Dao from the USFDA. Now listen up. So based on the prior aggregate data meta-analysis and subsequent FDA review, FDA had already communicated that clinicians should consider the increased rate of long-term mortality when making treatment recommendations. They had also implemented updated labeling for this device class to communicate the risk. So in this editorial, the FDA commended the authors of the current individual patient data meta-analysis for providing important information towards signal refinement, and also commend at their collaboration with device manufacturers to work together with a shared goal of patient safety. Now, there are still many unanswered questions, including the mechanism for the observed increase in late term mortality associated with these devices and how the benefit risk profile of these devices may shift across various patient populations. Dr Greg Hundley: Well Carolyn, my paper comes from Professor Antje Beling from Charité – Universitätsmedizin Berlin in Berlin. And it investigates heart specific immune responses in an animal model of auto immune related Meyer carditis mitigated by an immuno proteasome inhibitor and a genetic ablation. So Carolyn, this study used mouse models to understand mechanisms involved in immune checkpoint inhibitor related Maya carditis, a phenomenon that we can observe in 5% to 10% of patients that are receiving these checkpoint inhibitors for treatment of their cancer. Dr Carolyn Lam: So what did they find, Greg? Dr Greg Hundley: Several things, Carolyn. All immuno proteasome deficient strains of mice showed mitigated auto-immune related cardiac pathology with less inflammation, lower pro-inflammatory and chemo tactic cytokines, less interleukin 17 production and reduced fibrosis formation. The auto-immune signature during experimental proponent I auto immune carditis with high immuno proteasome expression, immunoglobulin G deposition, interleukin 17 production in heart tissue, and troponin I directed humeral auto immune responses was also present in two cases of immune mediated related my carditis. Thus demonstrating the activation of heart specific autoimmune reactions by this checkpoint inhibitor related myocarditis therapy. So Carolyn, perhaps by reversing heart specific auto immune responses, immuno proteasome inhibitors applied to these mouse models demonstrated their potential to, in the future, aid in the management of auto-immune bio carditis in humans, possibly including cases with immune mediated myocarditis heart-related specific auto-immunity. Dr Carolyn Lam: Oh, that's really nice, Greg. Thanks. How about a quiz? Remember what desmoplakin is Greg? Dr Greg Hundley: I think this is going to do something with right ventricular cardiomyopathy. Dr Carolyn Lam: Very nice. Desmoplakin is the primary force transducer between cardiac desmosomes and intermediate filaments. And mutations in Desmoplakin indeed cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of desmoplakin cardiomyopathy have been limited to small case series. Today's paper, by Dr Helms from University of Michigan and colleagues is the largest series of desmoplakin mutation carriers reported to date. Dr Greg Hundley: So Carolyn, what did they find here? Dr Carolyn Lam: Among 107 patients with pathogenic desmoplakin mutations and 81 patients with pathogenic Plakophilin-2 mutations as a comparison cohort, they found compelling evidence that desmoplakin cardiomyopathy is a distinct form of cardiomyopathy marked by a high proclivity for left ventricular hypertrophy and arrhythmias and associated with intermittent myocardial inflammatory episodes that appear clinically similar to myocarditis or sarcoidosis. Furthermore they found that diagnostic and risk stratification variables that performed well for Plakophilin-2 associated ARVC exhibited poor accuracy for the diagnosis and risk assessment of desmoplakin mutation carriers. So these results strongly indicate that a genotype specific management approach is essential for desmoplakin cardiomyopathy. Dr Greg Hundley: Wow, Carolyn. Lots of great science in this issue. Well, just like last week, we have got a lot of other papers in this issue. So let me tell you about a few that I've had a chance to preview. The first is a research letter by our own Dr Hesham Sadek from UT Southwestern Medical Center involving the homotypic fusion generates multi nucleated cardiomyocytes in the murine heart. Next is an ECG challenge. It's from Dr G. Neil Kay at the University of Alabama at Birmingham, and really reviews an ECG in a patient that presents with pulmonary embolism. Next, there's a case series from Dr Nil Uriel from Columbia University Medical Center regarding the variety of cardiovascular presentations of COVID-19. Next there's an on my mind piece that comes to us from Dr Ersilia DeFilippis from Columbia University College of and Physicians and Surgeons. And it involves cardiopulmonary resuscitation during this COVID-19 pandemic. And it presents a view from trainees on the front lines. Next, Carolyn, one of your faves, Dr Leslie Cooper from the Mayo Clinic provides an informative white paper on the description and proposed management of acute COVID-19 cardiovascular syndromes. Next is a paper from Dr Francine Marquez from Monash University, and it's a perspective piece on the impact, strategies and opportunities for early and mid-career cardiovascular researchers during the COVID-19 pandemic. So many studies have been stopped and this very nice article highlights the new opportunities in this pandemic. Next, Dr Anabel Volgman from Rush University Medical Center has a piece on the seniors on the sidelines, and it's a call to action. And then finally, Dr Andrew Chapman from University of Edinburgh and professor Christian Mueller from the University Hospital of Basel exchange letters to the editor regarding a prior article of high sensitivity cardiac troponin, and the universal definition of myocardial infarction. Dr Carolyn Lam: Nice. There's also a research letter by Dr Sandoval and colleagues who described the transition to using high sensitivity troponin T in a United States regional healthcare system, namely the Mayo Clinic enterprise. And they really showed that a small increase in MI diagnosis in part due to an increase in type two MI diagnosis occurred without an overall increase in hospital admissions or resource utilization using the high sensitivity cardiac troponin T implementation. And if I may mention, there is also a beautiful white paper by Dr Sana Al-Khatib, whom I was very lucky to coauthor with. And it's on the advancing research on the complex interrelations between atrial fibrillation and heart failure. This a report from the National Heart Lung and Blood Institute virtual workshop. Wow. A bonanza of an issue. Thanks so much, Greg. Let's move on to our feature discussion now. Dr Greg Hundley: Look forward to it. Dr Carolyn Lam: Today's feature discussion was in fact a late breaking clinical trial presentation at the American College of Cardiology meeting this year, 2020. And it's all about the compass trial, this time focusing on diabetes. I'm so, so pleased to have with us, the corresponding author Dr Deepak Bhatt from Brigham and Women's Hospital, as well as Dr Gregory Lip from University of Liverpool who was not only the guest editor, but also an editorialist for this paper. So welcome gentlemen. Deepak, could I start with you? This was an incredible presentation that was very well discussed. ACC not virtually, but I'm just so glad that we can have you on this podcast to tell us again, please, the rationale, the key findings and why this paper is just so important. Dr Deepak Bhatt: So the background really is that prior studies and particular registry studies, the reach registry, for example, have shown that patients with concomitant CAD and/or PAD, that is coronary artery disease and/or peripheral artery disease, plus diabetes, are folks that are extremely high risk of future ischemic events. This is true even if they are apparently stable outpatients. At any rate in the compass trial, these sorts of patients with CAD or PAD, stable patients, both with and without diabetes who are enrolled 27,000 plus patients randomized. And there were three arms in this study, aspirin alone, rivaroxaban alone and aspirin plus low dose rivaroxaban 2.5 milligrams twice a day. And that was the winner, that combination sometimes referred to as dual pathway inhibition significantly reduced the schemic events versus aspirin alone, a significant reduction in cardiovascular death MI stroke, as well a lower rate significantly so of cardiovascular death, and even all-cause mortality was lower. So the overall trial was positive, but what we wanted to examine in this analysis was specifically how to patients with diabetes fare, knowing that they're a higher risk group in general across multiple registries and studies? And indeed we found that they were higher risk, those with diabetes versus those without diabetes and compass, and indeed, though their relative risk reductions were similar, those patients with diabetes had numerically larger, absolute risk reductions than those without diabetes with this regimen of low dose rivaroxaban plus aspirin versus aspirin alone. Dr Carolyn Lam: Thanks Deepak. And I just have to refer the listeners to those beautiful figures in your paper. I mean, just one look at it really explains exactly what you were saying and really highlights that patients with diabetes are at higher risk of adverse events and also in one of the graphs of bleeding. Greg, could I bring you in here? You mentioned that in your editorial as well, that there has to be importantly acceptable bleeding risks. Could you expand on that? Dr Gregory Lip: The compass crowd was a game changer and in this high-risk subgroup, as Deepak elegantly has described. These are diabetic patients, and then we also have the subgroups we call with or without PCI. And those would be so of course, being the higher risk group of patients. Nonetheless, the comparison was basically a dual pathway inhibition, but a combination rivaroxaban plus aspirin compared to aspirin alone. But a high cardiovascular risk and high bleeding risk tend to track each other. So it was important that we certainly want to reduce the adverse outcomes of cardiovascular endpoints, we should certainly individualize our assessment of our patients and make sure that a patient is not an excessive high bleeding risk. I think overall, the study is very reassuring because there was no significant access in the overall population of the subgroup, at least in relation to fatal bleeding, critical organ bleeding or intracranial hemorrhage by dual path inhibition. But I think we, as physicians, just need to assess the patient in front of us just to make sure that particular patient is not at high risk particularly of bleeding, given that high risk of bleeding also generally is high cardiovascular risk as well. Dr Carolyn Lam: Thank you, Greg. And Deepak, perhaps maybe some words from you about this sort of risk benefit ratio? How do you see it? How do we apply these results? Dr Deepak Bhatt: I totally agree with everything Dr Lip said. Really, the key message when we're talking about antithrombotic numbers, something Dr Brunwald had said in this context, that is, there's no free lunch. When it comes to antithrombotics, there's always bleeding risks. There's just no way around that. In any trial that is adequately powered long enough, we'll find that, and that can include bad bleeding. Now, fortunately there was no significant excess and failure endocranial bleeding within the trial or within the subgroup of patients with diabetes. But nonetheless one needs to be cautious because these of course are carefully selected patients at low bleeding risk to get into the trial. There was a run in period. So when applying to real life, of course, there's the potential for bleeding. So we need to be really cautious about that. And it's also not a stat. So if we were talking about secondary prevention, either with or without diabetes, CAD, PAD, both of them together, of course, all those patients should be on Statin assuming they don't have a real type of contraindication. So that's kind of a no brainer. That's a matter of implementation science. A lot of patients that should be on Statin aren't, but that's not an issue of science. We already know the answer there. Here, it's not the case of everyone that is like this who has diabetes, or even who doesn't, who has CAD or PAD should be on this regimen. It needs to be carefully selected patients, patients that are a low bleeding risk. And sometimes doctors ask, "Well, how do you tell that?" Well, it's not always easy, but for sure there's some things that predict future bleeding risks such as prior bleeding. So prior bleeding, anemia, those are powerful predictors of future bleeding. And one would want to be really cautious in these largely stable outpatients that we're talking about in the compass trial in intensifying their antithrombotic regimen. But in the right patients, I think it's a really effective way of reducing important future vascular risk, whether that's cardiovascular risk consisting of MI related end points, stroke, peripheral ischemic end points, including amputation, which was significantly reduced in the trial, and within the subgroup of those with diabetes. So it's a matter of balancing those, but I do think with careful decision-making on the part of the physician, with discussion with the patient, with their understanding of the risks and benefits of intensifying the antithrombotic regimen beyond aspirin, there are a substantial number of patients who could benefit. Dr Gregory Lip: I whole fully agree with Deepak's comments. And we do have to bear in mind also that risk is also a fairly dynamic process and we may well be assessing the patient as the one off initially while we are initiating treatment. But of course risk, whether from cardiovascular risk or whether from bleeding risk particularly, also is influenced by increasing age and by incident comorbidities, which really means that risk reassessment should be performed in every patient we contact. With bleeding risks in particular, there are modifiable bleeding risk factors that we can mitigate. So proactive assessment or rather reassessment of risks, whether both from cardiovascular events and/or bleeding, is necessary as we follow up these patients. Dr Carolyn Lam: Thank you, both. Deepak, I'm just going to build a bit on your analogy of no free lunch. And maybe sort of a general question do you both, because it seems like we've got a bonanza of a buffet now when it comes to diabetes, especially with the new anti-diabetic drugs. So how do you think this fits in altogether? You talked about Statins. We now talk about low dose rivaroxaban in addition to aspirin, and you think diabetic patients should be treated with all? Maybe Deepak first, then Greg. Dr Deepak Bhatt: What a terrific question. In fact, that was asked of me by the late-breaking clinical-trial panel clinical trial panel. They said, "Well, how does it fit in? Because these data look terrific, but there's also other new diabetes drugs and approaches." So for sure, I would say again, barring a real contraindication, I would say everyone that we're talking about here should be on a statin and preferably if they can tolerate it, a high intensity statin. And if that doesn't do the trick in terms of LDL goal, I would say zetomyde. And potentially if they're in a region of the world where it's affordable a PCSK9 inhibitor. Then beyond that, I think we've got to pay attention to triglycerides these days, not just LDL cholesterol and if it's some patient that's sort of like REDUCE IT, well then, they should be on eicosapentaenoic. So we can modify LDL related and triglyceride related risks without too much effort or too much in the way of side effects. Then beyond that, I would say, we've got to think about blood pressure, inadequate control, especially in those with diabetes, but even those without that have cardiovascular disease. And then we have to think about glycemic control. And I don't mean the old-fashioned way, but I mean with some of the newer drugs. SGLT2 inhibitors in particular have been found to be useful for both. That's just the glycemia control part of things, more importantly, cardiovascular outcomes. In particular, heart failure and renal related outcomes. And then GLP 1 agonist as well have been shown to be very useful once more modifying cardiovascular outcomes, including atherosclerotic outcomes. So there is, as you say, quite the buffet. And assuming a patient can tolerate that polypharmacy and afford it, I do think the majority of patients with diabetes should be treated that well. And that's of course on top of lifestyle modification, weight loss is particularly important, plant-based diet, et cetera. But on top of that, then, with all those things that are being done and a patient is still at high ischemic risk but is at low bleeding risk, that's where I think, even in the deceptively stable appearing outpatient, it's worthwhile just running a mental checklist and saying, "Okay, are they on an SGLT2 inhibitor? Check. Did In someone measured their triglycerides? Check." And then on that checklist is, "Yeah, could they tolerate being on more than just aspirin alone in terms of bleeding risk? And if the answer to that is yes, might they benefit from adding this on?" And there are a lot of patients these results apply to, and I think a proportion of those patients who are otherwise optimally treated for their risk factors are the ones to target. Dr Carolyn Lam: Beautifully put. And Greg? Dr Gregory Lip: Deepak does raise an increasingly applied concept in how we approach our patients at high risk of cardiovascular events. That's the so called integrated or holistic approach to management. Because we have in the past tended to just focus on one strand of management. For example, we may well just be putting a lot of focus when on the analytic reduction and ignoring the rest. Well, we can't do that these days. We have to manage the whole patient and not just the bit of the patient. And this brings in this holistic approach, this integrated approach. And I think Deepak summarized that very nicely. It may require a number of medical approaches or medication-based approaches, but we have to practically look at the comorbidities like blood pressure reduction and also the lifestyle changes that Deepak's already summarized. So a holistic and integrated approach to our care of these patients. And in fact, some of the more recent studies showed nicely how this results in better outcomes in our patients at high cardiovascular risk. Dr Carolyn Lam: And in fact, those were exactly the last words of your editorial. A holistic and integrated care approach. Beautifully done, thank you both so much for this excellent discussion. Thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again. Next week. Dr Greg Hundley: This program is copyright the American Heart Association 2020.

Circulation May 05, 2020 Issue

Play Episode Listen Later May 4, 2020 19:17

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 this week really examines long-term efficacy of drug eluting stents versus coronary artery bypass grafting in those patients with left main disease. Really looking at long-term extended follow up from the PRECOMBAT trial but before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? And I'll start off. My first article is a basic science paper looking at catecholamine sensitive and ventricular tachycardia in ARVC. And it comes from Dr Long-Sheng Song from the University of Iowa Carver College of Medicine. So, the study from Dr Song used protein mass spectrometry analyses and that identified integrin beta one is downregulated in those patients with arrhythmogenic right ventricular cardiomyopathy hearts without changes to calcium handling proteins as adult cardiomyocytes express only the beta-1 D isoform, they generated a cardiac specific beta-1 D knockout mouse model and perform functional imaging and biochemical analyses to determine the consequences from integrin beta-1 D loss of function in hearts in vivo and in vitro. Dr Carolyn Lam: Nice, very elegant design. So what were the results Greg? Dr Greg Hundley: Well Carolyn, the authors found that integrin beta- 1D deficiency and RyR2 serine 2030 hyper phosphorylation were detected by Western blotting in left ventricular tissues from patients with ARVC but not in patients with ischemic or hypertrophic cardiomyopathy. And in the mouse experiments, beta-1 D negative or knockout mice exhibited normal cardiac function and morphology, but presented with catacholamines sensitive polymorphic ventricular tachycardia consistent with increased RyR2 serine 2030 phosphorylation and apparent calcium handling in beta-1 D knockout cardiomyocytes. So Carolyn, in conclusion, the authors found their data suggest that integrin beta-1D deficiency represents a novel mechanism underlying the increased risk of ventricular arrhythmias in patients with ARVC. Dr Carolyn Lam: Okay. You told us about integrin beta-1 D and I'm going to tell you about apolipoprotein M. So Greg, what do you know about apolipoprotein M? Dr Greg Hundley: Well, Carolyn, at seven o'clock the morning, I seem to have forgotten a little bit about that. Can you remind me what apolipoprotein M is? Dr Carolyn Lam: Sure Greg, very happy to. So apolipoprotein M or apoM mediates the physical interaction between high density lipoprotein particles and sphingosine 1-phosphate and exerts an anti-inflammatory and cardio-protective effects in animal models. Now listen on, listen on. So authors, Dr Chirinos from Perelman Center for Advanced Medicine, University of Pennsylvania and Dr Javaheri from Washington University School of Medicine and co-authors hypothesized that reduced levels of apoM would be associated with worse outcomes in human heart failure. Specifically, they tested the hypothesis that reduced circulating apoM would be associated with the risk of death, a composite of death, ventricular assist, device implantation or heart transplantation and a composite of death, heart failure related hospitalization among adults with heart failure and rolled in a large multicenter Penn heart failure study. They did stratified analysis in patients with heart failure with reduced and preserved ejection fraction and even replicated these findings in two independent cohorts, the Washington University heart failure registry and a subset of the TOPCAT trial. What they found was that reduced apoM plasma protein levels indeed were associated with adverse outcomes in heart failure including both HFpF and HFrF. The relationship between reduced apoM and outcomes and heart failure was particularly pronounced when concentrations of its binding partner sphingosine 1-phosphate were also reduced. ApoM protein levels were associated with inflammation in human heart failure and thus the conclusion being that apoM represents a risk marker in human heart failure. Further studies are of course needed to assess whether it could be a therapeutic target as well. Dr Greg Hundley: Very good. Carolyn. So more information for the world of heart failure isn't it. I'm going to sort of switch over to coronary artery disease and talk about low attenuation non-calcified plaques that are sometimes appreciated on cardiac computed tomography scans. And in this study, Dr Michelle Williams from the University of Edinburg evaluated the results from the multi-center SCOT-HEART trial or the Scottish computed tomography of the heart. So Carolyn, the future risk of myocardial infarction is commonly assessed using cardiovascular risk scores, coronary artery calcium score or coronary artery stenosis severity and the authors assessed in 1,769 patients about 56% men and the average age 58 years and they followed them up for a median of 4.7 years and looked at whether noncalcified low attenuation plaque burden on coronary CT angiography might be a better predictor of the future risk of myocardial infarction. Dr Carolyn Lam: Interesting. So what did they find? Dr Greg Hundley: Well, low attenuation plaque burden was the strongest predictor of myocardial infarction irrespective of cardiovascular risk score, coronary artery calcium score or coronary artery area stenosis. And patients with low attenuation plaque burden greater than 4% were nearly five times more likely to have subsequent myocardial infarction and the hazard ratio was 4.65 with a confidence interval of two to more than 10 and a half. So in conclusion, Carolyn in patients presenting with stable chest pain, low attenuation plaque burden is the strongest predictor of fatal or nonfatal myocardial infarction and these findings may add to classical risk predictors of myocardial infarction. Dr Carolyn Lam: Wow. Important findings. Okay, let's go onto what else is in this week's journal issue. There's an online mind by Dr Jaffe. It's on the universal definition of myocardial infarction. It talks about both present and future considerations. There's an ECG challenge by Dr Arias and what's described as spontaneous wide QRS complex rhythm in a patient with wide QRS complex tachycardia. Dr Greg Hundley: Very good, Carolyn. Well, I've got two other articles. Another on my mind piece from Professor Peter Nagele from the University of Chicago Medicine and it discusses a simplified proposal to redefine acute MI versus acute myocardial injury. Looking at that troponin question. And then finally Dr Fabian Hoffman from the Heart Center and University of Cologne has a research letter on providing new data regarding the evolution of pulmonary hypertension during severe sustained hypoxia. Well Carolyn, how about we get onto that feature discussion looking at left main disease and whether we should place an intercoronary stent or undergo coronary artery bypass grafting. Dr Carolyn Lam: Important question. Let's go, Greg. Dr Greg Hundley: Welcome everyone to our feature discussion today that really pertains to interventional cardiology and we're very fortunate to have Duk-Woo Park from Asian Medical Center in Seoul, South Korea and our own associate editor, Dr Manos Brilakis from the Minneapolis Heart Institute. Well Duk-Woo, we'd like to get started with you and could you tell us a little bit about the background data and the hypothesis related to your research study? Dr Duk-Woo Park: Our research, it was the 10-year report of the PRECOMBAT trial. If I'm going to first introduce the background over the last half of a century bypass surgery, it was a mainstream, the number one choice of on protecting the main disease. Yeah. Did you know unprotected left main disease, the one were very high risk of coronary artery disease and owing two and the supply, the large burden of myocardium. But the last two decades, 20 years. Their remarkable evolution in PCI field including development adaption of a drug eluting stent and the adaption of intravascular ultrasound as well as experience of intervention or catalyst expertise. So on the basis of such evolution, many interventional cardiologists think about that, a PCI with a drug eluting stent. Will it be non-inferior to a standard type A surgery? Sometime for single region PCI could be very nice alternative option for unprotected left main disease that the reason why we're going to start quick on the trial. This trial already done 15 years ago at the time. We designed this PRECOMBAT trial on the basis of that background. Dr Greg Hundley: Very good. Well can you tell us a little bit about the study population of this trial and what was your study design? Dr Duk-Woo Park: This is a open library trial design and we at first time we evaluated the noble unprotected left main disease and the for considerable for clinical and ethic eligibility, initially assessed by intervention or cardiologists as you as a cardiac surgeon and the reason why we try to pick up the post treatment eligible population and then at the screening initial re-screen the nearly 1,400 patient and then finally 600 of patient who was our individuation one arm is drug eluting stent, first-generation ciphers 10 versus another arm is convention or a coronary artery bypass stent grafting. Dr Greg Hundley: What were you looking for your outcome measures and how long did you follow these patients? Dr Duk-Woo Park: Initially and the BDN two year follow and are published in England, the journal of medicine nearly eight years ago. And then we did five year follow-up at the publish the JAG in five years ago and the this time is a, we did complete that 10 year follow up all the render mutation population and the median follow-up duration is nearly more than 11 years and we complete 10 year follow-up and the key outcome was PCI is a comparable apart from surgery for treatment of left main disease. Dr Greg Hundley: And were there other outcomes that you were looking for? Dr Duk-Woo Park: We evaluated several important clinical outcomes. We primary end the point we select competent outcome compass of all cause of mortality by myocardial infarction, stroke, or ischemia-driven target vessel revascularization. Secondary outcome was each component of a primary outcome all-cause mortality as you raise the harder clinical and the point like compost outcome like this am I sure. So finally we did not any statistical difference with the regard to primary composite outcome as well as a hard clinical compost outcome as death or stroke. Finally, we did not detect all-cause mortality. One exception or difference was a target vascularization as well as a repeat rebase collateralization was a much higher after PCI than after bypass surgery. Dr Greg Hundley: So overall, in this more lengthy follow up of 10 years. The primary outcomes were similar between the two interventional arms, but there was a difference in target vessel revascularization. With that being more frequent after PCI as compared to bypass, were there any other subgroups that tended to have distinctions or discrepancies between your primary outcome? Dr Duk-Woo Park: As the sensitive to analysis, in circulation we supply the subgroup analysis or more, we did not find any differential treatment. IPEC according to subgroup in age group, diabetes and clean-cut presentation or in environmental coronary embolism shock versus application. We didn't find any interaction effect, just the except the extent of disease vessel, left or main. We the three best three digit bypass surgery was better than PCI. However we did not do any P value. Adjust them on. So interpretation is should it be cautious. Dr Greg Hundley: Well you know as an interventional cardiologist, what new information does this bring and how do you interpret the results of this study relative to other studies that have been published in the past? Dr Emmanouil Brilakis: I think this is a very timely study, especially since about a year ago we did have the five-year outcomes from two other similar trials, the Excel file and the Nobel trial which say randomized patients with unprotected left main disease to either PCI or bypass. And actually those studies had some differences which are also relevant to the present study. So for example, Excel overall the outcomes were similar. There was a higher all-cause mortality in the PCI where normal had better outcomes in terms of death, MIT VR, but there was no difference in mortality. So I think the natural question that comes up from the studies was whether mortality is different with PCI versus coronary bypass and you know the PRECOMBAT, the 10 years. It's really suiting in that respect because it doesn't show any difference in the overall mortality. So I think this comes very timely and the answers a lot of questions. Of course there's limitations with the sample size and the number of patients treated, but I think although it's a very timely result. Dr Greg Hundley: Maybe I'll start first with you, Manos and then I'll circle back to you. Duk-Woo. Manos what do you see is the next important study to perform in this field? Dr Emmanouil Brilakis: I think the natural question here is these outcomes which are similar but use first generation drug eluting stents, which we no longer use. He did use high proportion of five which is an excellent feature in, again congratulate Duk-Woo and the other co-investigators for doing such a high rate of follow-up. But we now know that the techniques, for example, for bifurcations, maybe the DK crush or double DK crush might be a better technique to do. So in my mind, the next question would be if who use the current, a much improved the drug eluting stent and state of the art bifurcation techniques. For example, DK crush where the double-kiss crush bifurcation would, the outcomes have been different and perhaps PCI will be similar, even better than bypass in long-term outcomes. So for me this next study will be state of the art techniques, state of the art materials and long-term for follow-up as in frequently. Dr Greg Hundley: Duk-Woo. How about from your perspective? Dr Duk-Woo Park: You know, a future perspective is a very difficult to expect. Our trial is the longest to follow-up trial. We have the nation are insurance support and we nearly a hundred percent pop picked up fighters status, but I think most of them interventional cardiologists as well as a cardiac surgeon. One true additional longest follow-up Excel and Noble trial. The reason why we didn't do additional random trial using additional second generation drug eluting stent. We already do exit trial approximately 2000 and noble trial and more than thousand patients we already do and the two trial a complete five-year follow and most of the trial is as well as the clinician want to extend the follow-up of Excel and Noble trial but I don't know how much that extended of a follow-up would be possible. Dr Duk-Woo Park: The next step as you know the intervention or cardiac surgeon still debate about the long-term mortality issue after release of exited five-year-old research and the data peak issue, European association cardiac thoracic group. We did draw the endorsement of a guideline so I think an additional stem we require the individual patient level data analysis involving, Excel, Nobel, Syntech and PRECOMBAT trial would be required to provide the more definite compelling evidence for mortality difference as well as the have the end point and including or so some end point to repeat revascularization. We do allow individual patient data analysis. That would be next. The short step, next the long step, we definitely require extended follow-up, Excel and Noble trial. Dr Greg Hundley: Very good. Well listeners, this has been another very informative feature discussion where we've compared PCI and coronary artery bypass grafting in those with left main disease. And now from this PRECOMBAT trial, 10 years of follow up showing very similar outcomes related to death, myocardial infarction and stroke in the two randomized arms. We want to thank Dr Duk-Woo Park and Dr Manos Brilakis for presenting this information and as we move forward, their insights as to next studies with newer technologies and different examinations of stents. More long-term follow-up from ongoing trials and then individualized patient assessments. Listeners, we hope you have a great week and hope everyone is staying safe in this COVID crisis. Take care. This program is copyright of the American Heart Association 2020.

Circulation April 14, 2020 Issue

Circulation: Arrhythmia and Electrophysiology On the Beat

Play Episode Listen Later Apr 13, 2020 21:28

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: I'm Greg Hundley, associate editor from the VCU Pauley Heart Center in Richmond, Virginia. Dr Carolyn Lam: Greg, amyloid cardiomyopathy is the rage. I cannot tell you the number of discussions I've had on the topic. Of course, it was tafamidis, the amazing results with that trial that really made us realize we need to pick this up. But have you ever thought about the cost effectiveness of tafamidis for amyloid cardiomyopathy? Well, guess what? We're going to have a whole feature discussion just about that. But first let's go to our summary, shall we? Dr Greg Hundley: You bet, Carolyn. Well, let me get started. I'm going to talk about regulation of cell cycle growth as well as division in regard to cardiac regeneration. My first paper comes from Dr Lior Zangi from the Mount Sinai School of Medicine. Well, Carolyn, have you ever wondered why the adult mammalian heart has limited regenerative capacity? Dr Carolyn Lam: All the time, Greg. Dr Greg Hundley: Well, of course you have. It's mostly due to postnatal cardiomyocyte cell cycle arrest. In this study the investigators evaluated the effect of pyruvate kinase muscle isozyme 2 and cardiomyocytes through models of loss, that is cardiomyocyte specific PKM2 deletion during cardiac development or gain using cardiomyocytes specific PKM to modified mRNA to evaluate PKM to function and regenerative effects post-acute or chronic MI in mice. Dr Carolyn Lam: Nicely described. What did they find, Greg? Dr Greg Hundley: What they found is that PKM2 is expressed in cardiomyocytes during development and immediately after birth, but not during adulthood. Using cardiomyocytes PKM to modified RNA, they found that cardiomyocyte targeted strategy following acute or chronic MI resulted in increased cardiomyocyte cell division, enhanced cardiac function, and improved long-term survival. They found that PKM2 regulates the cardiomyocyte cell cycle and reduces oxidative stress damage through anabolic pathways and beta-catenin. Dr Carolyn Lam: Cool, Greg. Man, this cardiac regeneration really, really is a hot area. Dr Greg Hundley: Carolyn, that is so insightful because these results really impact research toward unlocking pathways that could be involved in induction of myocyte cell division and regeneration in those sustaining MI or conditions like MI. Dr Carolyn Lam: Nice. Well, Greg, I'm going to change tones here and ask you, can we prevent atrial fibrillation with treatments for diabetes? Well, guess what? We have a paper next. It's from Dr Wiviott from the TIMI Study Group and his colleagues who really reason that since atrial fibrillation is associated with hypertension, obesity and heart failure in patients with diabetes and SGLT2 inhibitors have been shown to lower blood pressure, reduce weight, and reduce hospitalization for heart failure in these patients, perhaps SGLT2 inhibitors may also reduce the risk of atrial fibrillation. They explored the effect of Dapagliflozin on the first and total number of atrial fibrillation and atrial flutter events in patients from the DECLARE-TIMI 58. As a reminder, they had type two diabetes with either multiple risk factors for or known atherosclerotic cardiovascular disease. Now importantly, atrial fibrillation events were identified by a search of the safety database using these MedDAR preferred terms. Now what they found was Dapagliflozin reduced the risk of atrial fibrillation events during follow-up as well as the total number of atrial fibrillation events in patients with type two diabetes. These reductions were consistent across major subgroups including sex, presence of atherosclerotic cardiovascular disease, history of atrial fibrillation, history of heart failure, history of ischemic stroke, HBA1C groups, body mass index groups, blood pressure or EGFR. They looked at all these subgroups because these are all clinical factors, well established, with associations with the risk of atrial fibrillation. Dr Greg Hundley: Wow, Carolyn. Another sort of feather in the cap for the SGLT2 inhibitors. What does this mean for clinical practice? Dr Carolyn Lam: Ah. I'm not going to answer it here. I am going to say everybody has to read the excellent editorial by Dr Granger from Duke University and Dr Mahaffey from Stanford University School of Medicine. But what I will tell you is their concluding sentences. They said, "This report provides evidence that Dapagliflozin appears to reduce atrial fibrillation events in patients with diabetes and coronary disease and multiple risk factors. It also raises the issue of how to determine when effects on a secondary outcome, particularly one collected without the rigor of systematic collection using perspective definitions and case report forms, whether or not these are reliable." So must read. Dr Greg Hundley: Absolutely. Carolyn, my next study comes and evaluates arrhythmogenic right ventricular cardiomyopathy and is really investigating the concept of auto immunity, looking at associations of circulating anti heart and anti intercalated disc auto antibodies with disease severity and family history. The paper comes from Professor Alida Caforio from the University of Padova. Again, looking at the role of auto antibodies in patients with ARVC. An interesting topic. Dr Carolyn Lam: Yeah, that's really novel. What did they find? Dr Greg Hundley: They investigated ARVC pro bands, so those that sort of started with the disease process in a family and noted an increased frequency of serum organ specific anti heart autoantibodies and anti-intercalated disc autoantibodies in a sizeable arrhythmogenic RVC cohort as compared to controls. They found that positive AHA status. Dr Carolyn Lam: Anti-heart antibodies. Dr Greg Hundley: Yep. Was associated with lower left ventricular ejection fraction, a higher frequency of cardiac symptoms and implantable cardioverter defibrillator implantation. Positive AIDA was associated with lower ejection fractions in both the right and the left ventricle. Dr Carolyn Lam: AIDA being the anti-intercalated disc auto antibodies. Wow. That is interesting. But what are the clinical implications? Dr Greg Hundley: Well, the presence of both these organ specific AHA and AIDA antibodies provides evidence of autoimmunity in the majority, so 85% of familiar, and almost half, 45%, of sporadic ARVC. In programs and in effective relatives, these antibodies were associated with the disease severity features. So really a link with this auto immunity and ARVC. Dr Carolyn Lam: Yeah. I never thought of ARVC as an autoimmune disease. Very interesting. But let me also tell you what else is in this week's issue. There are letters to the editors, one from Dr Kaski regarding the mag STEMI randomized control trial questioning whether improving coronary vasal motion can be equated to restoring patient's cardiovascular health. Interestingly with a letter in response from Dr Sabatine. There's also a research letter by Dr Alahmad on the cardiovascular mortality and exposure to heat in an inherently hot region and where they were was Kuwait. They also drew some implications for climate change. Very interesting piece. There's also an ECG challenged by Dr Verma describing conduction abnormalities and ischemic cardiomyopathy in an 84-year-old man. Dr Greg Hundley: Very nice. Carolyn, in the mailbag, there's a nice research letter from Dr Nicholas Leeper from Stanford University School of Medicine. It's entitled “The 9p21 locus promotes calcific atherosclerosis.” Our own Josh Beckman has an on my mind piece regarding “The Big Mac Attack on Peripheral Arterial Disease.” Dr Carolyn Lam: I love that. I just love the titles Josh comes up with. Dr Greg Hundley: Then finally Bridget Kuehn has a very nice sort of correspondence on Cardiovascular News regarding cardiac imaging on the cusp of artificial intelligence. What a revolution we have ahead, Carolyn, and I know that's a topic that's true to your heart. Dr Carolyn Lam: It is. I loved her paper. Dr Greg Hundley: Okay. Carolyn, how about we get onto that feature article? I'm waiting to hear about the cost effectiveness of tafamidis. Dr Carolyn Lam: Me too. Dr Greg Hundley: Well listeners, we have got a great discussion for our feature publication today and we have Dr Dhruv Kazi from Beth Israel Deaconess in Boston and our own associate editor, Dr Justin Ezekowitz from University of Alberta. Well, as we get started, Kazi, can you tell us a little bit what was the hypothesis that you wanted to test with this study and maybe even before that a little bit of background with transthyretin amyloid and tafamidis? Dr Dhruv Kazi: Yeah. Transthyretin amyloidosis is a subgroup of patients who present with heart failure with preserved ejection fraction, which we know is a heterogeneous condition that has been pretty resilient to effective guideline directed therapies over the past decade. It's a subgroup of patients generally presenting in their 70s with slowly declining quality of life and a median survival of about three years. It hadn't had an effective therapy before and so when tafamidis, which is a stabilizer of transthyretin and prevents its deposition in the myocardium, was developed and tested in a randomized clinical trial that showed an improvement in survival, a reduction in heart failure hospitalizations and a slowing of decline and quality of life. It was viewed as a really big win for the heart failure community. What came as a surprise though is the pricing. It was launched in 2019 at $225,000 a year. We set out to ask, given that this is a severe disease without alternative treatments, is this price tag generating enough value? Is this a cost-effective therapy? The background here again is that oncologic therapies have had a long history of very high prices for rare diseases and severe diseases. But this is the first time we're seeing this in cardiology. Can we think more broadly about how we're going to tackle this issue? Not just for tafamidis but also for other drugs that come down the pipe. Dr Greg Hundley: Wow. $225,000 per year. Tell us what was your study design, and how did you go about evaluating this issue? Dr Dhruv Kazi: We started off with the one phase three trial of the drug that has been published and simulated in a mathematical model the population that would be eligible for this therapy, reproduced the events, heart failure hospitalizations, debts, quality of life that were seen in the trial for the first three years, and then extrapolated beyond the trial based on what we know about HFpEF and what we know about transthyretin amyloidosis. It's a mathematical model that first reproduces what was seen in the trial and then extrapolates beyond what we think is the best guess of what happens to these patients. We tested a variety of scenarios whether the drug continues to be effective, whether the effectiveness declines over time or the effectiveness ceases immediately after three years. Dr Greg Hundley: What did you find? Dr Dhruv Kazi: What we found was interesting and it surprised us a little bit, which is that in the base case, which is assuming that the drug stays effective beyond three years, the drug is actually very effective in the traditional sense. It added 1.3 quality adjusted life years. For context here, this is about twice the effect size you expect to see with Entresto, and the HFpEF patients. So here's a drug that we've accepted and HFpEF has part of guideline directed medical therapy. Tafamidis in that best-case scenario is about twice as effective, but it is not cost effective. Because you're paying $225,000 for every year that the patient is on the medication, its incremental cost effectiveness ratio compared with usual care was $880,000, so well above what we would consider value for money. That's the best-case scenario assuming that the drug is permanently effective, if the drug's effect wanes over time, which is very likely as these patients get older and sicker, then the drug gets even less economically attractive. Dr Greg Hundley: You've pointed out in your article, if you had 120,000 transthyretin patients in the United States, that would translate to how many dollars? Dr Dhruv Kazi: We estimate that if all of those 120,000 patients received tafamidis, the healthcare spending would go up by $32 billion a year and most of it is towards the drug. But the caveat is that we think 120,000 patients in the US is a very conservative number because the diagnostic technology for amyloid cardiomyopathy has improved substantially over the last five years so that we no longer need biopsies. We can use nuclear scans to diagnose the disease and we have pretty good to genetic testing to identify the genetic variant of the disease. We think that number is probably closer to 200,000 or even higher because the healthcare expenditure is almost entirely driven by drug costs. The more patients we diagnosed, the bigger the budget's impact on healthcare spending. Dr Greg Hundley: Oh my. Well Justin, for our listeners, Justin resides in Canada. Justin, what do we do with these results? I mean this is quite a sticker shock for probably an important therapy for this patient population. Dr Justin Ezekowitz: Greg, it's a great issue and Kazi, thank you very much for this terrific, easily understandable manuscript that I think everybody should read as it's very well written and easy to understand for us non-health economists. The sticker shock is a bit of a tricky one because we always want to do what's best for our patients. When we look at that budget impact analysis, the challenge is what do we think internationally? The US is critical in terms of understanding this, but then for the rest of the world, there's certainly almost no willingness to pay at this threshold and with an uncertain incidence of amyloidosis globally, but also within the US and Canada and the difficult in diagnosis already, I think we're going to have to realize what can we do for our patients and who benefits the most with this drug given its importance and its efficacy? Kazi, you mentioned another thing which I think is critical is what happens after 30 months if the effect wanes and where does that take us for the impact on cost and effectiveness over time but also the budget impact analysis? Because the second drug or third drug may very well come along that may fill that niche. Dr Dhruv Kazi: Justin, that's a really good question. I mean the study only goes to 30 months and that's the only one randomized trial for tafamidis that we're working off of. So there's substantial uncertainty about what happens to this drug beyond 30 months. It's reasonable to assume that some of the effect persists, that as patients get older, get sicker, that effectiveness will wane over time. Which ties very closely to the cost effectiveness. So if the patients continue to take the drug but it's not as effective as you can imagine, it becomes less cost effective. This also has implications for other drugs coming down the pike, which may or may not be more effective than tafamidis. They may or may not be tested head to head with tafamidis. Physicians are going to be left with the question, very clinically relevant question, of which drug to start with, how do you switch on them the next generation or more expensive drugs that come down the pike? We'll have to rely on both real-world evidence and to some extent mathematical modeling to use our best judgment on developing a treatment strategy for these patients. But rest assured that our current regulatory framework means that the drugs coming down in the future will be more expensive than tafamidis and hence, this is a good time to have the conversation about cost effectiveness and our willingness to pay for innovation. Dr Greg Hundley: What needs to happen next to help either lower cost or develop some sort of competition in the treatment of this disease to lower the cost? Dr Dhruv Kazi: I can take a stab at that. Greg, I think the findings of this particular drug in transthyretin amyloidosis is illustrative of the challenges that lie ahead. I think there are clinical research and policy implications. As clinicians, it's really important for us to know that this high cost of the drug is not a theoretical challenge. It's a practical challenge for our patients. The majority of these patients are going to be on Medicare part D. We estimate that the out of pocket costs is going to be in the range of $8,000 to $9,000 a year even with Medicare part D, which is a big amount of money for our fixed income seniors. I encourage our clinicians to have this conversation about out-of-pocket costs with patients, not just when you start the therapy but throughout the year. We know that the Medicare part D copays change over the course of the year based on where they are in the insurance plan. Having this conversation may help preclude costs related non-adherence. We might be able to identify patients early or at risk, put them into patient support programs or switch them to alternate therapies that may not be as effective but at least are likely to offer the patient some support. From a research perspective, we really need to figure out what subgroup of patients are more likely to benefit. Let's say we have 200,000 patients with transthyretin amyloidosis in the US. We need more research, and the company is not going to be vested in doing this research, it's going to have to be NIH funded research to identify subgroups of patients who benefit most from this drug, both in the short term and over the long term. From a policy perspective, what this drug pricing issue is telling us is that we provided incentives for companies to innovate in the rare disease orphan drug program. These incentives are working. More than half of the drugs that are coming out now or have in the past year are under this rare disease umbrella. But these drugs, once they're approved, are super expensive. We need to figure out a regulatory framework where we continue to incentivize innovation for rare diseases for orphan drugs, but at the same time tie those incentives to the final pricing to ensure that the patients get access to the drug and not just the wealthy patients who can afford the copays, but all patients who would benefit from the drug. One of the things that comes to mind as clinicians and researchers is that particularly in cardiology, we are obsessed with innovating, with regards to new molecules and new technology. I would like us as a community to focus not just on molecules but also on markets because the innovation is not meaningful if our patients cannot have access to them. This year being the presidential election year, we're going to hear a lot about drug pricing. What I hope that this example shines a light on is that drug pricing is complicated and trying to figure out the right framework to incentivize innovation while it's still ensuring access is going to take thoughtful interventions, regulatory interventions, and clinicians should very much be a part of that process. Dr Greg Hundley: Well listeners, we've heard a wonderful discussion here highlighting a new therapy for a disease process that's being increasingly diagnosed with our aging population and new technologies, magnetic resonance, echocardiography that identify this condition. But then how are we going to afford some of the therapies that are moving forward and design a system that emphasizes not only scientific discovery, but cost effectiveness? We want to thank Dr Dhruv Kazi from Beth Israel Deaconess and also Justin Ezekowitz from the University of Alberta. We hope you have a great week and look forward to speaking with you next week. This program is copyright the American Heart Association 2020.

Circulation: Arrhythmia and Electrophysiology January 2020 Issue

Play Episode Listen Later Apr 3, 2020 16:47

Paul J. Wang: Welcome to the monthly podcast On the Beat, for Circulation: Arrhythmia and Electrophysiology. I'm Dr Paul Wang, editor in chief with some of the key highlights from this month's issue. In our first paper in the real time mapping of AF drivers RADAR study, Subbarao Choudry and associates examined in a single arm first in human investigator-initiated FDA IDE study, a novel system for real time, high resolution identification of atrial fibrillation, AF drivers, in persistent or long-standing persistent AF. They enrolled 64 subjects at four centers, 73% male age, 64.7 years, BMI 31.7. LA size 54. Longstanding AF, 83% longstanding persistent, 17%. prior AF ablation, 41%. After 12.6 months of follow-up, 68% remained AF free off all antiarrhythmics. 74% remained AF free and 66% remained AF, AT and A-flutter free on or off antiarrhythmic drugs. AF terminated with atrial fibrillation ablation in 35 patients, 55% overall. And in 23 out of 38, 61% of de novo ablation patients. For patients with AF termination during atrial ablation, 82% remained AF free and 74% AF, AT or A-flutter free during follow-up on or off antiarrhythmic drugs. Patients undergoing first time AFib ablation had higher rates of freedom from AF than the redo group. In our next paper, David Briceño and associates examined 19 consecutive patients presenting with left bundle branch block ventricular tachycardia in the setting of arrhythmogenic right ventricular cardiomyopathy, ARVC, with procedures separated by at least nine months and a mean of 50 months. The authors found there was no significant progression of voltage bipolar 38 centimeters squared versus 53 centimeters squared, p=0.09 or unipolar 116 centimeters squared versus 159 centimeters squared, p=0.36 for the entire group. There was a significant increase in right ventricular RV volumes, percentage increase 28%. 206 milliliters versus 263 milliliters, P less than 0.001 for the entire study population. Larger scars at baseline but not changes over time were associated with a significant increase in RV volume, p=0.006 for bipolar and p=0.03 for unipolar. Most patients with progressive RV dilatation, 57%, had moderate in two patients or severe in six patients, tricuspid regurgitation recorded either at initial or repeat ablation procedure. The authors found that in patients with ARVC presenting with recurrent ventricular tachycardia, more than 10% increase in right ventricular endocardial surface area of bipolar voltages consistent with scar is uncommon during intermediate follow-up. Most recurrent ventricular tachycardias are localized to regions of prior defined scar. In our next paper, Susan Heckbert and associates examined detection of atrial fibrillation in 1,556 individuals participating in an ancillary study involving ambulatory ECG monitoring part of the cross-sectional analysis in the multiethnic study of atherosclerosis, MESA, a community based cohort study that enrolled 6,814 Americans free of clinically recognized cardiovascular disease in 2000 to 2002. Among 1,556 participants, 41% were white, 25% African American, 21% Hispanic, 14% Chinese, 51% were women mean age 74 years. The prevalence of clinically detected atrial fibrillation after 14.4 years follow-up was 11.3% in whites, 6.6% in African Americans, 7.8% in Hispanics and 9.9% in Chinese and was significantly lower in African Americans than in whites in both unadjusted and risk factor adjusted analyses, p less than 0.001. By contrast, in the same individuals, the proportion of monitor detected atrial fibrillation using a 14-day ambulatory ECG monitor was similar in the four race or ethnic groups. 7.1%, 6.4%, 6.9% and 5.2% compared with white, all p greater than 0.5. The authors concluded that the prevalence of clinically detected atrial fibrillation was substantially lower in African Americans than white participants with or without adjustments for atrial fibrillation risk factors. However, unbiased atrial fibrillation detection by ambulatory monitoring the same individuals reveal little difference in the proportion with atrial fibrillation by race, ethnicity, supporting the hypothesis of differential detection by race, ethnicity in the clinical recognition of atrial fibrillation. In our next paper, Maria Teresa Barrio-Lopez and associates examined the presence of epicardial connections between pulmonary veins and other anatomical structures. The authors considered an epicardial connection was present if one, the first pass around the pulmonary vein antrum did not produce pulmonary vein isolation. And two, subsequent atrial activation during pulmonary vein pacing showed that the earliest site was located away from the ablation line and later activation sites were obscured near the ablation line. Out of the 534 patients included, 72 or 13.5%, were found to have 81 epicardial connections. There was a significant association between the presence of epicardial connections in structural heart disease, 15.3% in patients without epicardial connections versus 36.5% in patients with epicardial connections, p less than 0.001. In patent foramen ovale, 4.6% versus 13.5%, p=0.002. The presence of a left common trunk was significantly associated with the absence of epicardial connection. 29.6% in patients without epicardial connections versus 16.2% in patients with epicardial connections, p=0.014. Patients with epicardial connections had a lower acute success of pulmonary vein isolation compared to patients with epicardial connection, 99.1% versus 86.1%, p less than 0.001. After adjusting for age, sex, type of atrial fibrillation, left atrial area, hypertension, structural heart disease, presence of left common trunk, patent foramen ovale and time for atrial fibrillation and diagnosis to the ablation, the authors found a significantly higher risk of atrial tachyarrhythmia recurrences in patients with epicardial connections compared to patients without epicardial connections, hazard ratio 1.7, p=0.04. In our next paper, Benzy Padanilam and associates examined the role of premature His complexes to differentiate AV nodal reentry tachycardia from atrioventricular reentry tachycardia high output pacing at the distal His location delivered premature His complexes. Atrioventricular reentrant tachycardia was predicted when late premature His complexes perturbed tachycardia or when early premature His complexes led to atrial advancement by amount equal or greater than the degree of premature His complex prematurity. Among the 73 SVTs, the test accurately predicted atrioventricular reentry tachycardia, n=29 in AV nodal reentry tachycardia, n=44 in all cases. Late premature His complexes advanced the circuit in all 29 atrioventricular reentry tachycardias in none of the AV nodal reentry tachycardias, sensitivity and specificity 100%. With earlier premature His complexes, the degree of atrial advancement was equal or greater than the premature His complex prematurity in 26 out of 29 atrioventricular reentrant tachycardia and none of the AV nodal reentrant tachycardias, 90% sensitivity and a 100% specificity. The mean prematurity of the premature His complex required to perturb AV nodal reentry tachycardia was 48 milliseconds, range 28 to 70 milliseconds. And the advancement less than the prematurity of the premature His complex, mean 32 milliseconds range, 18 to 54 milliseconds. In our next paper, Masateru Takigawa and associates examined the recurrence rate and mechanisms of atrial fibrillation ablation related atrial tachycardia recurrence among 147 patients with atrial tachycardias treated with arrhythmia system. 46.3% had recurrence at a mean of 4.2 months and 44 patients received a redo procedure. Atrial tachycardia circuits in the first procedure were compared to those in the redo procedure. Although mappable atrial tachycardias were not observed in seven patients, 68 atrial tachycardias were observed in 37 patients during the first procedure, perimitral flutter in 26 patients, roof-dependent macroreentrant atrial tachycardia in 18, peritricuspid flutter in 10, non-macro atrial tachycardia in 14 and focal atrial tachycardia in three. During the redo atrial tachycardia procedure, 54 atrial tachycardias were observed in 41 patients, perimitral flutter in 24, roof-dependent macroreentrant atrial tachycardia in 14, peritricuspid flutter in one, non-macroreentrant tachycardia in 14, and focal atrial tachycardia in one. Recurrence of perimitral flutter and roof-dependent macroreentrant atrial tachycardia were observed in 57.7% and 44.4% respectively, while peritricuspid flutter did not recur. Either the same focal atrial tachycardia nor the same non-macroreentrant tachycardia were observed except in one case with septal scar related to biatrial tachycardia. Epicardial structure related to atrial tachycardia were involved in 18 out of 24 or 75% in perimitral flutter, in 28.6% in roof-dependent macroreentry atrial tachycardia, in 28.6% in non-macroreentry tachycardia. Out of the 21 patients with a circuit including epicardial structures, six patients treated with ethanol infusion in the vein of Marshall did not show any atrial tachycardia recurrence although 53.3% treated with radiofrequency showed atrial tachycardia recurrence, p=0.04. In our next paper, Yaya Yu, Xuecheng Wang and associates compared the incidence and characteristics of ablation related asymptomatic cerebral emboli between high resolution diffusion weighted DWI and conventional DWI image. They examined 55 consecutive atrial fibrillation ablation patients undergoing high resolution DWI one day prior to ablation and repeated high resolution DWI and conventional DWI within 48 hours of post ablation. The authors found that high resolution DWI revealed a higher incidence of acute asymptomatic cerebral emboli compared to conventional DWI, 67.3% versus 41.8%, p less than 0.001. And significantly more asymptomatic cerebral emboli, 106 versus 45 lesions, p=0.001. For asymptomatic cerebral emboli, seen on both scans, the size measured by high resolution DWI was larger, 5.42 versus 4.21 millimeters, p less than 0.001. No patients had any impaired neurocognitive performance during follow-up. Impaired left ventricular ejection fraction, p=0.012 and low interoperative activated clotting time ACT p=0.009, level was associated with occurrence of asymptomatic cerebral emboli in a multivariate analysis. In our next paper, Ahmed AlTurki and Mariam Marafi and associates performed a systematic review and meta-analysis to assess the risk of stroke, myocardial infarction and death following postoperative atrial fibrillation after non-cardiac surgery. The authors included 28 studies, enrolling 2,612,816 patients in their final analyses. At one month, in ten studies, postoperative atrial fibrillation with associated with approximately three-fold increased risk of stroke, odds ratio 2.82, p less than 0.001. Postoperative atrial fibrillation was associated with ≈4-fold increase in the long-term risk of stroke, odds ratio 4.12, p ≤ to 0.001. In eight studies with 12 months or greater follow-up, there was a significant increase in the risk of stroke and myocardial infarction associated with postoperative atrial fibrillation, odds ratio 3.44, p value, p less than 0.001. And odds ratio for myocardial infarction 4.02, p less than 0.001. Postoperative atrial fibrillation was associated with a threefold increase in all of cause mortality 30 days, 15.0% versus 5.4%, odds ratio 3.36. In a research letter, Zhiyong Qian, Xiaofeng Hou, Yao Wang and associates validated physiological left bundle branch block pacing using high density ventricular mapping in a swine model. In another research letter by Shinsuke Miyazaki and associates, the authors examined whether the durability of pulmonary vein isolation can be predicted by the time to isolation in second generation cryoballoon ablation. That's it for this month. We hope that you will find the journal to be the go-to place for everyone interested in the field. See you next time. This program is copyright American Heart Association 2020.

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Scott From The Mighty 100 Shares Of How Exercise Almost KILLED Him Despite Running A PT Business | The Afro Ndiritu Podcast | #001

10K/Month Podcast For Online Coaches With Afro Ndiritu

Play Episode Listen Later Dec 19, 2019 43:22

After graduating from the EIF in 2008 with his Reps affiliated Master Trainer Certification Scott moved to Canada to work on the biggest loser and warrior programs in British Columbia. This is where his passion for transformative work started. Scott then went onto work with the western naturals bodybuilding affiliate, training competitors & preparing athletes for competitions. Scott then left Canada to work for Steiner Transoceanic as a Cruise ship physique coach and personal trainer. This gave Scott the opportunity to work all over the world with a huge amount of clientele with a large variety of backgrounds from royalty to celebrity & everything in between. After landing back on English shores Scott went on to found the Mighty 100 training model and transformation centre. Scott continues to work with company's such as Lionsgate studios and sports England and is constant pursuit of what he calls the perfect training model for changing lives. Shortly after Scott graduated he got to see the value of his work and the impact it had on people's lives. He vowed to change the lives and state of one million people. He is currently no where near that target, he is however, "as you will discover" driven to accomplish this task through his innovate schemes /methods and his "can do" ethos. He continues to inspire others throughout his journey as he balances being a father, husband, business owner AND dealing with his rare heart condition, Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). 1:46: What does fitness mean to you? 2:04: Why it is important? 6:58: What does that your fitness look like now? 8:00: Do you think that it is typical for men in sports to struggle after they stop playing? 9:19: What do you think is the biggest excuse for men not to exercise? 12:50: What got you into the fitness industry? 14:10: Is it a challenge to have ARVC and be a role model for fitness? 16:35: Why didn't you ‘duck out' in the end? 18:07: What is the most common mistake men make when trying to improve their fitness? 20:50: What is the biggest fitness myth out there? 23:15: What is your view on the current state of the fitness industry? 25:51: How did you start The Mighty 100? 31:10: What advice would you give a man who is just starting out on their fitness journey? 32:30: What is your best experience with fitness? 35:35: What does Masculinity mean to you? 36:40: Why do you think Masculinity is portrayed so badly? 41:07: What does word empowerment mean to you? 41:37: If you could give one message to all the Men out there what would it be and why? 42:06: How can this platform help you? 42:30: Where can people find you? --- Send in a voice message: https://anchor.fm/the-10kmonth-podcast/message

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34 November 2019

Play Episode Listen Later Dec 4, 2019 12:31

Jane Ferguson: Hi there. Welcome to the November 2019 issue of Getting Personal: Omics of the Heart. I'm Jane Ferguson. This is your podcast from Circulation: Genomic and Precision Medicine. Let's get started. First up from Eric Curruth, Christopher Haggerty and colleagues from Geisinger, we have a paper entitled, “Prevalence and Electronic Health Record-based Phenotype of Loss-of-function Genetic Variance in Arrhythmogenic Right Ventricular Cardiomyopathy-associated Genes”. In this study, the team set out to understand the phenotypic consequences of variants and desmosome genes which has been associated with a arrhythmogenic right ventricular cardiomyopathy or ARVC. In clinical genetic testing, secondary findings of pathogenic or likely pathogenic variants in desmosome genes are recommended for clinical reporting. However, relatively little is known about the phenotypic consequences of these variants in a general clinical population. The team obtained whole exome sequencing data for over 61,000 individuals from the DiscovEHR cohort, part of the Geisinger MyCode Community Health Initiative. They then screened individuals for a putative loss of function variants in PKP2, DSC2, DSG2, and DSP. They evaluated ARVC diagnostic criteria using previously conducted ECG and echocardiograms and performed a phenom-wide association study or PHeWAS using EHR derived phenotypes. They found 140 people with an ARVC variant in one of the four genes, none of whom had an existing diagnosis of ARVC in the EHR. Further, there were no measurable differences in their ECG or echocardiogram findings compared with matched controls. There were also no associations with any heart disease phenotypes as assessed by PHeWAS. Overall, they report a prevalence of ARVC loss of function variants of around one in 435 in a general clinical population of predominantly European descent, but they did not find evidence that these variants associated with specific phenotypes. Thus, the clinical relevance of putative loss of function variants in desmosome genes still remains to be determined. The next paper is titled, “MRAS Variants Cause Cardiomyocyte Hypertrophy in Patients-specific iPSC-derived Cardiomyocytes”. Additional evidence for MRS as a definitive Noonan syndrome susceptibility gene. This comes from Erin Higgins, Michael Ackerman, and colleagues from the Mayo Clinic. They were interested in understanding whether a recently identified Noonan syndrome variant in the MRS gene was necessary and sufficient to cause Noonan syndrome with cardiac hypertrophy. They generated induced pluripotent STEM cell or IPS C lines from patient derived cells carrying the glycine 23 veiling variant and MRS. In addition to isogenic control cells where the pathogenic variant was corrected back to wild-type using CRISPR CAS nine gene editing, they also created a disease model cell line by introducing the MRS variant into unrelated control cells. They then comprehensively characterized the phenotypes of the three cell lines using a variety of approaches including microscopy, immunofluorescence, single cell RNA seek, Western blot, qPCR, and live cell calcium imaging. Both the patient derived and the disease model IPS cardiomyocytes were larger than control cells and demonstrated changes in gene expression and intracellular pathway signaling characteristic of cardiac hypertrophy. The patient and disease model cells also displayed impaired calcium handling. Through in-vitro phenotyping, the team was able to demonstrate that the glycine 23 veiling MRS variant elicits a cardiac hypertrophy phenotype and IPSC cardiomyocytes, that strongly suggests that this variant is responsible for the observed Noonan syndrome associated cardiac hypertrophy in the effected patients. Next up is a review from Christopher Lee, Iftikhar Kullo, and colleagues also from the Mayo Clinic on “New Case Detection by Cascade Testing in Familial Hypercholesterolemia: A Systematic Review of the Literature”. In this review they set out to systematically assess cascade testing programs for familial hypercholesterolemia, a disease which has a prevalence of about one and 250 but is estimated to be diagnosed in under 10% of patients. They identified published studies across the world which had conducted cascade testing and had reported the number of index cases and number of relatives tested and had also specified their methods of contacting relatives and testing. Using these criteria, they identified 10 studies for inclusion spanning several European countries, South Africa, New Zealand, Australia, and Brazil. The team calculated the proportion of relatives testing positive and the number of new cases per index case to facilitate comparison between studies. The mean number of programs was 242 with an average of 826 relatives per study. The average yield was 45%, ranging from 30 to 60%. the mean new cases per index case was 1.65 with a range of 0.22 to 8.0. Studies that use direct contact versus indirect contact for relatives and those that tested beyond first degree relatives had a greater yield. Further, active sample collection versus collection at clinic and using genetic testing versus biochemical testing was similarly associated with a higher yield. Despite differences between the United States and other countries, applying these strategies when establishing new cascade testing programs in the US may help promote success of these programs. Our next paper concerns “Randomization of Left-right Asymmetry and Congenital Heart Defects: The Role of DNAH5 in Humans and Mice”. And this was conducted by Tabea Nöthe-Menchen, Heymut Omran, and colleagues from University Children's Hospital Muenster and the PCD study group. They were interested in understanding the relationship between congenital heart defects and laterality defects where internal organs are atypically positioned, such as in a mirror image as occurs in situs inversus. Ciliary dyskinesia is thought to play a role in situs inversus and the most frequently mutated gene in primary ciliary dyskinesia is DNAH5. The team does hypothesize that DNAH5 mutations may play a role in congenital heart disease. They characterized phenotypes in 132 patients with primary ciliary dyskinesia carrying disease causing DNAH5 mutations and also studied left right access establishment using a DNAH5 mutant mouse model. 66% of patients in their study had laterality defects, 88% of whom presented with situs inversus totalis and 6% presented with congenital heart disease. In the mass model, they observed immotile cilia, impaired flow with the left right organizer and randomization of nodal signaling with normal reversed or bilateral expression of key molecules. Their study thus demonstrates that mutation of DNAH5 is associated with congenital heart defects and they further highlight the ciliary mechanisms underlying defects and development of left right positioning during embryogenesis. Consideration of celiopathy related symptoms may be warranted when examining patients with congenital heart defects. Next up, we have a research letter from William Goodyear, Marco Perez and colleagues from Stanford University on “Broad Genetic Testing in a Clinical Setting Uncovers a High Prevalence of Titan Loss-of-Function Variants in Very Early-Onset Atrial Fibrillation”. They were interested in understanding genetic determinants of atrial fibrillation and hypothesized that causal genetic variants would be enriched in individuals with very early onset AF, who are diagnosed with AF under the age of 45 with no other significant comorbidities. They identified 25 families comprising 23 unrelated patients with very early onset AF who had been evaluated and received genetic counseling at Stanford between 2014 and 2018. The mean age of AF diagnosis was 27.2 years and 76% of patients were male. 40% of patients had a first or second degree relative with very early onset AF, while 36% at first or second degree relatives with either early onset idiopathic cardiomyopathy, unexplained sudden death or strokes. 85% of patients were identified as having at least one rare variant in a cardiomyopathy associated gene. Six patients carried actionable pathogenic or likely pathogenic variants, four of which were in the titan gene. A subset of individuals were further evaluated by MRI or computed tomography on average 817 days after their first presentation and this revealed high rates of cardiac abnormalities including reduced ventricular function, chamber enlargement, borderline LV non compaction, or late gadolinium enhancement. These were not noted on echocardiogram at presentation, suggesting there may have been subsequent disease development or progression. Overall, this study highlights a high rate of familial disease and implicates an association between very early onset AF and rare variants in titan before the clinical onset of cardiomyopathy. The final letter this month comes from Yu Xia, Shaoxian Chen, Ping Li, Jian Zhuang and colleagues from Guangdong Academy of Medical Sciences and is entitled, “A Novel Mutation in MYH6 in Two Unrelated Chinese Han Families with Familial Atrial Septal Defect”. They report on two unrelated families who presented with secundum atrial septal defect or ASD2. Whole exome sequencing revealed a novel variant and the MYH6 gene in both families, with the same variant present in all effected individuals but not in unaffected family members or unrelated controls. Because other variants in MYH6 have been reported to effect myofibril formation. The team studied the effect of the novel variant on the myofibrillar organization through transient transfection of CTC 12 cells. The MYH6 E526K variant was associated with a reduced striated I pattern and increased non-striated patterning. There was no effect on ATPase activity. Protein modeling suggested a variant of the effective position would reduce hydrogen bonding between alpha helices in the actin interface two region, increasing the volume of the cavity between the alpha helices and promoting the exposure of the alkaline side chain in the actin binding region. This could impair the interaction between the myosin motor head and actin. What these data suggests are that this novel MYH6 heterozygous variant may underlie ASD2 in two unrelated Chinese Han families by impairing myofibrillar organization. That's all for November 2019. Thank you for listening and I look forward to being back in December for the final episode of 2019. This podcast was brought to you by Circulation: Genomic and Precision Medicine and the American Heart Association council on genomic and precision medicine. This program is copyright American Heart Association 2019.

Circulation October 29, 2019 Issue

Play Episode Listen Later Oct 28, 2019 23:07

Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: I'm Greg Hundley, Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article today involves bleeding and new cancer diagnosis in patients with atherosclerosis and it emanates from Dr John Eikelboom from McMaster University who addresses the question of whether incident GI or GU bleeding when treating cardiovascular disease with anticoagulation is associated with incident cancer. Now, that's a common occurrence that we see frequently clinically, and I'm really interested to hear those results. Dr Greg Hundley: How about we start with our articles. And Carolyn, maybe I'll go first this time and my first paper is on mapping and ablation of ventricular fibrillation associated with early repolarization syndrome and it's from Professor Nademanee from Chulalongkorn University. Carolyn, this multicenter study evaluated mapping and ablation of ventricular fibrillation substrates and VF triggers in early repolarization syndrome, also called ERS or J wave syndrome, JWS, among 52 ERS patients for women who are averaged age 35 years with recurrent ventricular fibrillation episodes. Ablations were performed on one. VF substrates defined as areas that had late depolarization abnormalities characterized by low-voltage fractionated late potentials and two VF triggers. Dr Carolyn Lam: So... What did they find? Dr Greg Hundley: So first there were two phenotypes of ERS/JWS. Group one included those with late depolarization abnormalities with the underlying mechanism of high-amplitude J wave elevation that predominantly resided in the right ventricular outflow tract and the right ventricular inferolateral epicardium. They served as excellent targets for ablation. And two, the other was with a pure ERS devoid of VF substrates, but with VF triggers that are associated with Purkinje sites. The catheter ablation of the arrhythmogenic substrates with late depolarization abnormalities was very effective in preventing VF recurrence in group one patients and ablation of VF triggers emanating from the Purkinje system was effective in treating the group two patients. Dr Carolyn Lam: Wow, thanks Greg. My first paper is a first randomized double-blind placebo-controlled trial examining the early effects of SGLT2 inhibitors on clinically important endpoints in patients with heart failure and reduced ejection. Recall that outcome trials in patients with type 2 diabetes have demonstrated reduced hospitalization for heart failure with SGLT2 inhibitors. However, few of these patients had heart failure and those that did were not really fully well characterized. Dr Carolyn Lam: So DEFINE-HF was an investigator-initiated multicenter randomized controlled trial of heart failure patients with left ventricular ejection fraction less than 40, New York Heart Association Class II to III, GFR above 30, and elevated natriuretic peptides. This DEFINE-HF was published by Dr Kosiborod from St. Luke's, Mid America heart Institute and colleagues. In total, 263 patients were randomized to dapagliflozin 10 milligrams daily or placebo for 12 weeks. There was a dual primary outcome and the first was mean NT-proBNP and the second proportion of patients with a five or more point increase in heart failure disease specific health status on the Kansas City Cardiomyopathy Questionnaire or KCCQ overall summary score or a 20% or more decrease in NT-proBNP. Dr Carolyn Lam: So here's what they found. There was no significant difference in average six and 12 weeks adjusted NT-proBNP with dapagliflozin versus placebo. However, for the second dual primary outcome of a meaningful improvement in KCCQ overall summary score or NT-proBNP, significantly greater proportions of patients treated with dapagliflozin experienced clinically meaningful improvements in heart failure-related symptoms, functional status, and quality of life or natriuretic peptides compared to placebo, and these results were consistent among patients with or without type 2 diabetes. Dr Greg Hundley: Wow, Carolyn, another sort of feather in the cap for SGLT2 inhibitors. What are the clinical implications specifically for this study? Dr Carolyn Lam: Yeah, I couldn't agree with you more Greg, and these findings in particular suggest that dapagliflozin may have a favorable effect on improving disease-specific health status after 12 weeks of treatment in patients with heart failure and reduced ejection fraction. These beneficial effects of dapagliflozin may potentially extend to patients with or without type 2 diabetes. Interesting that the first primary outcome of NT-proBNP was not significantly different. I'm sure we'll hear more. Dr Greg Hundley: Very good. Well, my next paper comes from Dr Jeffrey Saffitz from Beth Israel Deaconess Medical Center and it really relates to therapeutic modulation of the immune response in arrhythmogenic cardiomyopathy. Carolyn, inflammation is a prominent feature of arrhythmogenic cardiomyopathy, but whether it contributes to the disease phenotype is not really known. So in this study, the authors sought to define the role of inflammation and the pathogenesis of arrhythmogenic cardiomyopathy by characterizing NF kappa beta signaling in ACM models both in vitro and in vivo and in cardiomyocytes from patient-induced pluripotent stem cells. Dr Carolyn Lam: Wow, that sounds like a lot of work. So what did they find? Dr Greg Hundley: First they found that NF kappa beta signaling is activated in cardiac myocytes in arrhythmogenic cardiomyopathy. Second, BAY 11-7082, a small molecule inhibitor of NF kappa beta signaling prevented development of major features of the disease phenotype. And third, cardiac myocytes express large amounts of inflammatory cytokines and chemotactic molecules in arrhythmogenic cardiomyopathy, reflecting activation of an innate immune response in the heart. Dr Greg Hundley: So Carolyn, clinically important features of ARVC or arrhythmogenic cardiomyopathy, myocardial injury and arrhythmias are driven by activation of an immune response in the heart. And the results of this study suggest that Anti-inflammatory drug therapy should be studied to determine if it could be an effective mechanism-based strategy to reduce myocardial damage and risk of sudden death in patients with arrhythmogenic cardiomyopathy. Dr Greg Hundley: So Carolyn, how about the other articles in this issue? Can you tell us a little more about them? Dr Greg Hundley: Oh, I would love to. We have a primer from Dr Weissgerber entitled Reveal, Don't Conceal Transforming Data Visualization to Improve Transparency, and this primer really outlines strategies for selecting the correct type of figure based on a study design, sample size, and type of variable. It examines techniques for making effective dot plots, box plots, and violin plots and illustrates how to avoid sending mixed messages by aligning the figure structure with the study design and statistical analysis. A really nice primer. Dr Greg Hundley: We also have a perspective from Dr Verma entitled More Credence for SGLT2 Inhibition. Talk about even more feathers in the SGLT2 inhibitor cap. Dr Greg Hundley: There's an On My Mind article from Dr Godier on specific antidotes for direct oral anticoagulant reversal. Is it a case closed or a cold case? Dr Godier really concludes with saying that the availability of specific antidotes provides in itself reassurance, but whether DOAC reversal translates into clinical improvements remain unknown and this leaves clinicians in kind of an awkward position and the case is not closed. Read more. It's a very nice piece. Dr Greg Hundley: We also have a research letter from Dr Mills very interestingly showing that endothelial progenitor cells do not are originate from the bone marrow. Very interestingly, Dr Mills systematically studied the origin of endothelial progenitor cells in people with sex-mismatched bone marrow transplantation using two complimentary methods and found that all the clones formed from single cells were actually derived from the recipient rather than from the donor bone marrow, thus suggesting that endogenous neovascularization in the heart is driven by tissue resident endothelial progenitor cells without a direct contribution from bone marrow cells. A very important piece because it goes against prior pieces and it's consistent with others, so do read this research letter. Dr Greg Hundley: Finally, there's a cardiovascular key series from Dr Uriel and title It's All About the Tissue and it's a rare case of acute cardiogenic shock. Dr Greg Hundley: Wow, Carolyn, what great summaries and articles we have in this issue, but how about now we go and learn a little bit more about that GI tract in our feature article? Dr Carolyn Lam: You bet, Greg. Dr Greg Hundley: Welcome everyone to our feature discussion and today we're going to meet with Dr John Eikelboom from McMaster University in Ontario, Canada and our own associate editor, Dr Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. The feature discussion paper focuses on the development of lower gastrointestinal bleeding or genitourinary bleeding that may occur in patients with cardiovascular disease that are receiving anticoagulant therapy. Dr Greg Hundley: So first John, I was wondering, could you tell us a little bit about the hypothesis and why you wanted to conduct this study? Dr John Eikelboom: Intriguingly, we set out to do a trial of antithrombotic therapy in cardiovascular disease and our intent originally was not to look at cancer specifically in relation to bleeding. In fact, normally in our cardiovascular trials we don't even collect cancer. But the background story is that there is a hypothesis and there are data that aspirin protects against gastrointestinal cancer and in the COMPASS trial we were testing a regimen that omitted aspirin. So we were concerned that by omitting aspirin this might lead to an increase in cancer. So as a safety measure we very carefully collected all types of cancer during this trial. We were very much reassured that none of the antithrombotic regimens were associated with an increase in cancer, but then we noticed there was a very high rate of cancer diagnosis, about 4% during the course of the trial, and cancer was as common as cardiovascular events. This observation prompted a secondary analysis to see who was having the cancer and in particular with our interest in bleeding where the bleeding identified patients who were subsequently diagnosed with cancer. Dr Greg Hundley: Can you tell us a little bit about the design of your study and your study population? Dr John Eikelboom: The COMPASS trial was designed to test whether an antithrombotic regimen containing rivaroxaban might be more effective than aspirin in preventing cardiovascular events. We included people with chronic coronary artery disease or peripheral artery disease who were randomized to one of two rivaroxaban regimens or aspirin. The results of this main analysis have been previously published the rivaroxaban regimen was associated with more bleeding than aspirin and in particular more gastrointestinal bleeding. Of course, it was more effective than aspirin in reducing the composite of cardiovascular death, stroke, or myocardial infarction. So in this analysis, we then drilled down on the bleeding story and in particular on the gastrointestinal or genitourinary bleeding because bleeding into a hollow viscus has previously been identified as a marker of cancer risk. Dr Greg Hundley: And who did you include in this study? Dr John Eikelboom: We included people with chronic coronary or peripheral artery disease, that is people who were some time away from an acute event. They were more or less stable, although the term chronic is probably better. They were on effective secondary prevention strategies. They'd be your typical patient that a cardiologist, an internist, a vascular specialist, or a neurology would see in their outpatient clinic, an ambulatory patient, where the focus of the clinician would be on cardiovascular prevention. Dr Greg Hundley: And how many subjects were in your study? Was this a large study? Dr John Eikelboom: The study included 27,395 patients from 33 countries and 602 centers, so yes, a large study with a very broad inclusion criteria. This result therefore also is very widely applicable to the secondary prevention cardiovascular populations. Dr Greg Hundley: So what did you find? What were your results? Dr John Eikelboom: We found that there are several highlights. The first, as I've already alluded to, new cancer diagnosis was found in one of 25 people of comparable frequency to the composite of cardiovascular death, MI, or stroke. So that's the first finding. The second funding was that bleeding was very common, that is any bleeding, major or minor, about 10% of the population during an average of two years of follow-up. Then the third and the most relevant finding to our report is that bleeding was a powerful predictor of a new cancer diagnosis. To describe that a little bit more carefully, among those with bleeds about 10% were diagnosed with a new cancer of any type. And then when we look specifically at gastrointestinal bleeding, it's again around the same proportion of those with GI bleeding who are diagnosed with gastrointestinal cancer but compared with those who did not have gastrointestinal bleeding, those with gastrointestinal bleeding had a twentyfold increased hazard. In other words, the GI bleeding was a very powerful predictor of news GI cancer diagnosis. Likewise, genitourinary bleeding was a very powerful predictor of new genitourinary cancer diagnosis, about a thirtyfold increased hazard. And when we separated out the urinary bleeding that was the most powerful predictor about a hundredfold increase. And the converse, if we look at bleeding in other areas, they was an association with cancer, but it was much weaker, and this really focuses the attention on bleeding into a hollow viscus, GI tract, the genitourinary tract, and in particular the urinary tract, and it sends up a red flag for clinicians if you bleed into these areas there is a very great increase in the hazard of new cancer diagnosis. Dr Greg Hundley: Fantastic, John. So just two quick points and then we wanted to ask Shinya to help us put this study in perspective. The average age of the patients, what was that in this study, what was the gender breakdown, and then did you find any more frequent association of cancer with genitourinary bleeding in men versus women? Dr John Eikelboom: The average age was 68 and about one fifth where women, so that is pretty typical of cardiovascular trials, although an area of separate interest because women were relatively underrepresented. Of course, that's another story. In terms of cancer prediction, we didn't separately explore this in men and women and indeed the cancers were dominated by the urinary tract and the GI tract with far fewer genital tract cancers. So we're not really in a position to answer that question. I do accept that very important consideration because clearly, we're going to investigate differently in a man compared with a woman if they have genitourinary tract bleeding. Dr Greg Hundley: Well, Shinya, we appreciate having the opportunity to speak with you as an associate editor of Circulation. How do we implement or interpret this data in the context of administration of both aspirin as well as other anticoagulant strategies? Dr Shinya Goto: This paper is very important. I mean, that we are cardiologists, we believe we are very away from that cancer, but John and COMPASS group demonstrated cancer is much commonly occurred than we expected, almost similar rate as cardiovascular death within two year in patients recognized coronary artery disease and peripheral artery disease. They are on antiplatelet or anticoagulant agent aspirin, 2.5 milligram b.i.d. of rivaroxaban, plus over 5 milligram b.i.d. of rivaroxaban alone. So CAD/PAD patient on antithrombosis, we have to care about cancer. And as John beautifully pointed out, if the patient experienced bleeding, like GI tract bleeding, we have to care seriously about hidden GI tract cancer. If a CT scan found GU bleeding, it is an important sign of concealed genitourinary tract cancer. We are very close, so it's a kind of bridging discipline. Cardiology should be close to oncology. As John pointed out, the patient at 68 average age, not so old, it's typical of age of the patient treated by cardiologist. But you know, the message is strong: We have to be careful about the cancer and we have to be careful especially if we found anything in GI tract or GU, so the message is clear. Dr Greg Hundley: Well, thank you Shinya. Shinya, I wanted to ask you, what do you think is the next study to be performed in this area of investigation? Dr Shinya Goto: If we conducted a cardiovascular trial, it would be nice to add cancer as an endpoint, especially for long-term trial. Dr Greg Hundley: John, do you have any perspectives? Where do you see your research going in this area over the next five years? Dr John Eikelboom: In addition to the very important point raised by Shinya, I think there are two additional considerations. The one is we need to better understand whether the apparently earlier diagnosis of cancer that can be achieved by exploring bleeding in these cardiovascular patients can improve clinical outcome. We certainly hope that this is good news for patients because we hope to be able to diagnose cancer earlier. The second big question is if we were more diligent in screening for bleeding and in particular occult bleeding in the cardiovascular patient, would that lead or help us to diagnose the cancer earlier? Dr Greg Hundley: Well listeners, we've had a great discussion from Dr John Eikelboom from McMaster University in Ontario, Canada, and our own Shinya Goto from Tokai University School of Medicine in Kanagawa, Japan. They have highlighted to us this important study result indicating an association of detection of cancer when we observe gastrointestinal and genitourinary bleeding after treatment with both anticoagulant and antithrombotic therapy. And so for Carolyn Lam and myself, Greg Hundley, we wish you a great week and we look forward to catching you On the Run next week. Dr Carolyn Lam: This program is copyright American Heart Association 2019.

33 October 2019

Learn True Health with Ashley James

Play Episode Listen Later Oct 21, 2019 9:10

Jane Ferguson: Hello. Welcome to episode 33 of Getting Personal: Omics Of The Heart, your podcast from Circulation: Genomic and Precision Medicine. I'm Jane Ferguson. This episode is from October 2019. Let's get started. First up is a paper from Sébastien Thériault, Yohan Bossé, Jean-Jacques Schott and colleagues from Laval University, Quebec and INSERM in Mont. They published on genetic association analyses, highlight IL6, ALPL and NAV1 as three new susceptibility genes underlying Calcific Aortic Valve Stenosis. In this paper, they were interested in finding out whether they could identify novel susceptibility genes for Calcific Aortic Valve Stenosis, or CAVS, which is a severe and often fatal condition with limited treatment options other than surgical aortic valve replacement. They conducted a GWAS meta-analysis across four European ancestry cohorts comprising over 5,000 cases and over 354,000 controls. They identified four loci at genome-wide significance, including two known loci in LPA and PALMD as well as two novel loci, IL6 which encodes the interleukin six cytokine, and ALPL, which encodes an alkaline phosphatase. They then integrated transcriptomic data from 233 human aortic valves to conduct the transcriptome wide association study and find an additional risk locus associated with higher expression of NAV1 encoding neuron navigator one. Through fine mapping, integrating conservation scores, and methylation peaks, they narrowed down the putative causal variants at each locus identifying one snip in each of PALMD and IL6 as likely causal in addition to two candidates snips at ALPL and three plausible candidate snips in NAV1. Phenome-Wide Association Analysis, or PheWAS of the top candidate functional snips found that the IL6 risk variant associated with higher eosinophil count, pulse pressure and systolic blood pressure. Overall, this study was able to identify novel loci associated with CAVS potentially implicating inflammation and hypertension in CAVS etiology. Additional functional studies are required to further explore these potential mechanisms. Next up is a paper from Elisavet Fotiou, Bernard Keavney and colleagues from the University of Manchester. Their paper entitled Integration of Large-Scale Genomic Data Sources With Evolutionary History Reveals Novel Genetic Loci for Congenital Heart Disease explored the genetic etiology of sporadic non syndromic congenital heart disease using an evolution informed approach. Ohnologs are related genes that have been retained following ancestral whole genome duplication events which occurred around 500 million years ago. The authors hypothesized that ohnologs which were retained versus duplicated genes that were lost were likely to have been under greater evolutionary pressure due to the need to maintain consistent gene dosage. For example, as could occur when the resulting proteins form complexes that require stochiometric balance. Thus, ohnologs may be enriched for genes that are sensitive to dosage. The group analyzed copy number variant data from over 4,600 non syndromic coronary heart disease patients as well as whole exome sequence data from 829 cases of Tetralogy of Fallot. Compared to control data obtained from public databases, there was evidence for significant enrichment in CHD associated variants in ohnologs but not in other duplicated genes arising from small scale duplications. Through this and various other filtering steps to prioritize likely variants, the group was able to identify 54 novel candidate genes for congenital CHD highlighting the utility of considering the evolutionary origin of genes in the search for disease relevant biology. Next, we have a clinical letter entitled Pathological Overlap of Arrhythmogenic Right Ventricular Cardiomyopathy and Cardiac Sarcoidosis from Ashwini Kerkar, Victoria Parikh and colleagues at Stanford University. They describe a case of a 50 year old woman previously healthy and a long distance runner who presented with tachycardia. She was found to have normal left ventricular size but severe right ventricular enlargement and systolic dysfunction. Genetic testing using an Arrhythmogenic Right Ventricular Cardiomyopathy or ARVC panel identified a variant in DSG2. through cascade testing it was found that two of the patient's three children also carried this variant. The patient experienced worsening RV failure and subsequently underwent heart transplantation at age 55. Pathology of the heart showed evidence of cardiac sarcoidosis. There have been some previous reports of overlap in ARVC and cardiac sarcoid pathology but not in cases with a high confidence genetic diagnosis such as this one. This case raises the possibility of shared disease mechanisms underlying ARVC and cardiac sarcoidosis and suggests that therapies aimed at immune modulation may also have utility in ARVC. However, further work is required to test this hypothesis. Our next paper is a perspective piece from Babken Asatryan and Helga Servatius from Bern University Hospital. In Revisiting the Approach to Diagnosis of Arrhythmogenic Cardiomyopathy: Stick to the Arrhythmia Criterion!, they outline the challenges in defining diagnostic criteria for a Arrhythmogenic Right Ventricular Cardiomyopathy or ARVC, given the variable presentation of the disease. Given recent advances in knowledge, particularly in recognizing disease overlap with Arrhythmogenic Left Ventricular Cardiomyopathy or ALVC and Biventricular Arrhythmogenic Cardiomyopathy, a new clinical perspective was warranted. The Heart Rhythm Society updated their recommendations this year to introduce a new umbrella term that better encompasses the spectrum of disease, Arrhythmogenic Cardiomyopathy or ACM. This recommends the arrhythmia criterion Should be used as a first line screening criteria for ACM. This is a broad criteria and a definitive diagnosis of ACM requires exclusion of systemic disorders such as sarcoidosis, amyloidosis, mild carditis, Chagas disease, and other cardiomyopathies. Implementation of this new approach to diagnosis may require more extensive investigation of arrhythmias including the use of ambulatory ECG monitors or cardiac loop recorders. These changes may also affect who's referred for genetic testing, potentially shifting diagnoses towards genotype rather than phenotype based disease classifications. Despite challenges and adopting new approaches, it is hoped that these changes will ultimately serve to improve risk stratification and allow for improved disease management and intervention to prevent sudden cardiac death. We end with a scientific statement chaired by Sharon Cresci and co-chaired by Naveen Pereira with a writing group representing the AHA Councils on Genomic and Precision Medicine, Cardiovascular and Stroke Nursing and Quality of Care and Outcomes Research entitled Heart Failure in the Era of Precision Medicine: A Scientific Statement From the American Heart Association. This paper provides a comprehensive overview of the current state of omics technologies as they relate to the development and progression of heart failure and considers the current and potential future applications of these high throughput data for precision medicine with respect to prevention, diagnosis and therapy of heart failure. They discuss advances in genomics, pharmacogenomics, epigenomics, proteomics, metabolomics, and the microbiome, and integrate the findings from this rapidly developing field as they pertain to new methods to diagnose, treat, and prevent heart failure. And that's it for October. I hope to see many of you at AHA Scientific Sessions in Philadelphia in November and look forward to bringing you more of the best new science next month. Thanks for listening. This podcast was brought to you by Circulation: Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2019.

university care european philadelphia manchester era integration stanford university diagnosis rv quebec cleveland cavaliers implementation genetic mont pathologies american heart association cardiovascular heart failure acm precision medicine ecg genomic chagas chd lpa congenital heart disease inserm gwas outcomes research tetralogy fallot laval university jane ferguson il6 heart rhythm society arvc nav1 american heart association council bern university hospital circulation genomic

383 America's Healthy Heart Doc, Cardiologist Dr. Joel Kahn Explains Why Sauna, Heat and Light Therapy Is So Helpful For The Cardiovascular System, Weight Loss, Detoxification, Energy Production, and Anti-Aging Through Collagen Production

Play Episode Listen Later Oct 2, 2019 61:55

The Three Products/Companies Mentioned In Today's Interview and How To Get The Special Listener Discounts: 1) Sunlighten Sauna - Give them a call and mention Learn True Health with Ashley James. They offer financing and have several light therapy systems, including a small handheld device and a portable sauna! Here is the link to the Sunlighten Handheld Device: https://www.sunlighten.com/luminir/?leadsource=LTH&utm_source=LTH&utm_medium=Partner&utm_campaign=LTH 2) The Magnesium Soak! Visit LivingTheGoodLifeNaturally.com and use coupon code LTH for our listener discount. 3) Energy Bits and Recovery Bits Algae! Visit Energybits.com and use coupon code LTH to get 20% off! Buy the Recovery Bits for the detoxifying chlorella! Dr. Joel Kahn: www.drjoelkahn.com Author 5 books all in the shop at my website Clinic www.kahnlongevitycenter.com Sauna Therapy and Heart Health with Dr. Joel Kahn https://www.learntruehealth.com/dr-joel-kahn Highlights: Benefits of sauna therapy Benefits of Magnesium soak Benefits of ENERGYbits and RECOVERYbits Plant-based vegan diet is good for heart health Diet and fitness of mind and body are important The science of light therapy for healing Benefits of Infrared sauna Waon therapy of Japan Importance of light for our health Benefits of near infrared sauna Benefits of red light Photobiomodulation Sunlighten lumiNIR Saunas and weight loss Kahn’s three tips: meditation, organic chlorella, HIIT workout Congenital heart conditions in children and adults People should be concerned about their arteries ARVC heart condition Organ meats and processed fat to heal autoimmune diseases Books and doctors that Dr. Kahn follows Kahn’s homework for listeners In this episode Dr. Joel Khan will share with us his three tips to a good cardiovascular health, the importance of light to our health. Ashley and Dr. Khan will also discuss the science of light therapy for healing and how important diet and fitness for our body is. [0:00] Intro: Hello, true health seeker. Welcome to another exciting episode of Learn True Health podcast. You’re going to love today’s interview with cardiologist, Dr. Joel Khan. He’s a very unique cardiologist. He’s been a plant-based vegan for over 42 years. And he has this unique perspective on the body. He believes the body has an amazing ability to heal itself. And we just need to support it with the right diet, nutrients, lifestyle. And that we can support the body’s ability to heal and prevent disease. And isn’t that wonderful? Don’t you want a doctor that believes that you can be healthy? He shares a lot of great information today. We talked a lot about using heat therapy and the different spectrums of light to help the body heal. And he says so much in such a short period of time. There’s so many details. He opened up so many rabbit holes that I know listeners are going to think to themselves, “Man, I need to get a pen. I got to write that down.” And I want to let you know that we actually transcribe our interviews. We’ve been doing that for the last few months. We hired two wonderful transcriptionists. And we have been transcribing all of the interviews. So a big shout out, thank you to the transcriptionists, who helped us to transcribe. Because our listeners really love going to learntruehealth.com. And then you can click on the episode. And I know that everyone’s been loving being able to have access to all the transcripts. So that when a guest shares so much wonderful information, like telling us about what books we should read, and what supplements we should try, or what lifestyle habits, tips and tricks we should try, we want all the details. And instead of having to listen to the episode two or three times, you can go the transcript and find exactly what the doctor said, which is really exciting. So that is my gift to you, the listener, so that you can make sure that you take all this information and help to transform your life and the health of your whole family and everyone you love. So make sure that you take advantage of our transcripts by going to www.learntruehealth. com. Now, in this episode we mention three things. So I want to make sure that I cover it in the intro. A lot of the discussion is about sauna therapy, specifically using sunlight. And Sunlighten is the only company I have found and I have looked that is ultra low EMF that is non-toxic. And it uses the full spectrum near, mid, and far infrared. So they’re absolutely wonderful. I highly recommend calling Sunlighten and in talking to them about their different systems. They have what’s called the Solo System, which is portable. So you don’t need – if you don’t have a lot of space and you can just tuck it away under the bed or tuck it away in the closet when you’re not using it. That’s a really great solution for those who don’t want the bigger sauna. Which I have the big one, the wooden one, and I love it. Basically, two people can fit in it. It’s kind of like having a TARDIS, for those who know Doctor Who. It does not look very big but two people can fit in it which is really cool. And it has the full spectrum of near, mid, and far infrared. And we’ll get a little bit into that in the show today. The benefits of those different spectrums. If you want to learn more specifically about Sunlighten, I did two interviews. One with the cofounder and one with their manager, Alicia. So Connie Zack being the founder. You can go to learntruehealth.com and you can search in the search bar for Sunlighten or for sauna and find those episodes. And enjoy learning more about why I specifically love Sunlighten as a company when it comes to doing sauna therapy versus all the other companies out there. I’m really sold. I’ve really enjoyed my sauna. And I’ve gotten a lot of great health benefits. It’s helped me with my detox tremendously. It’s helped me with my liver. I had liver problems and it really helped me with that, It helped me with my weight loss. So I feel it is high quality and very effective. So that’s Sunlighten. Give them a call. They give our listeners a great deal. They give us free shipping. And they also throw in something else that’s really cool. And the special kind of keeps changing just depending on what’s going on in the office there. But they always give the listeners a really great discount or really great special. So make sure that you mention Learn True Health with Ashley James so that you get our listener special. Now, we mentioned two other things. One is the magnesium soak. You have heard me rave about it over and over again. And I love soaking in magnesium while in my sauna. You only need a few cups of water in, like, a foot basin. And it is so wonderful. It opens up all the circulation. It really aids in the detoxification and feeding your liver all those wonderful nutrients it needs to help you with detoxification. So it’s a great one-two punch. And then the third thing, are the ENERGYbits. Actually, specifically, the RECOVERYbits, which is chlorella. Chlorella is an algae that chelates heavy metals. And so it’s wonderful to eat before you get in the sauna because it aids in binding to the heavy metals and releasing them from our body. It also helps with melatonin production so that it actually aids in deeper sleep. And I’ve done about five interviews I think on the ENERGYbits. So you can type algae into the search function in learntruehealth.com to be able to listen to those episodes where we talk about spirulina and chlorella and all their health benefits. And it’s just wonderful. You can go to energybits.com and use coupon code LTH to get 20% off. And make sure that you grab a bag of the ENERGYbits for your daytime energy. They’re wonderful. They’re spirulina. They actually taste really good compared to all the other spirulinas out there. They don’t have any of the lead or heavy metals that other companies have been known to have. Because ENERGYbits does very rigorous testing. And they have a pure water source when they grow their algae. So lots of great information that you can learn by going to learntruehealth.com and typing in algae and listening to those episodes. But just try it and see how you feel. Buy a bag of Energybits, buy a bag of RECOVERYbits. And RECOVERYbits is for the detoxification. ENERGYbits is for energy. And they don’t have any caffeine. It’s just all algae. But it delivers to the body all the nutrients that it needs to make energy and support hormone health. And I could go on and on. So you can check out those interviews. But those are the three things that we had mentioned in the episode. And I want to let you know that all three of those things you can get a listener discount for. So to get the magnesium soak, you go to livingthegoodlifenaturally.com and type in the coupon code LTH at checkout. ENERGYbits is energybits.com and type in the coupon code LTH at checkout. And then for your listener discount for Sunlighten, call them up, talk to one of their wonderful salespeople, and mention Learn True Health with Ashley James for the listener discount. And if you have any questions about any of these because I use them all the time and my whole family actually. We soak in magnesium. We eat the ENERGYbits and the RECOVERYbits. And we sweat in our sauna – in our Sunlighten Sauna. And so if you guys have any questions for me and my experience, please email me, support@learntruehealth.com. I’d love to hear from you. Excellent. Enjoy today’s episode and have yourself a wonderful rest of your day. [8:04] Ashley James: Welcome to the Learn true health podcast. I’m your host, Ashley James. This is Episode 383. I am so excited for today’s interview. We have with us Dr. Joel Kahn. He’s an amazing cardiologist. But even more than cardiology. Because I’ve dived into your interviews and some videos, you’re kind of going up against Joe Rogan in a very polite interview. I was waiting for the gloves to come off. It’s very interesting to be a plant-based cardiologist and help people to reverse disease naturally with natural medicine, with food because we can heal the body with food. And that you are surprisingly an expert in so many of these fields. Some of my listeners – so I told them I was interviewing you – said, “I love him. I love his podcasts.” And so I started listening to your podcasts. And it’s amazing just how much you read and how much you share with the listener. So I definitely recommend listeners check out Dr. Joel Kahn’s podcasts. It’s such a pleasure to have you here today. [9:02] Dr. Joel Kahn: Well, thank you. It’s really a nice and sincere. A little different than the standard credential introduction. And that’s pretty cool. Yeah, I call it a p-cast. A little bit different than yours. I would never have stayed doing podcasts for two-and-a-half years if I was taking long periods to interview people. So I just talk for 20 minutes. I teach on some subject. I call it a p-cast. It’s like a P in the pod, as you know from listening. But anyways, enough about that. But I do. At age 60, I have this insane hunger to learn and learn what isn’t whoo as opposed to science. And that can be really tough sometime. If we can acknowledge that there’s whoo whoo advice out there all over the place. [9:45] Ashley James: I like that you brought up your age because if listeners go and check out and saw your videos, they’re going to look at a young man who looks about 40, who is incredibly handsome, has tons of energy, and looks like he could win a boxing match against anyone. Like, you just look so good. And then when you said you’re 60, I’m like, “I really don’t believe it.” So that’s the power of the whole food plant-based diet is we actually become more energetic and look younger and have less disease. [10:16] Dr. Joel Kahn: Number one, you know, you’re just smothering me with kindness. I just told you before we went on, I’m going to be out in Seattle for a high level medical conference in a few weeks. Now we’re going to have to find a wonderful plant restaurant and go celebrate with your husband and all that. But I actually adopted a plant diet at age 18. It wasn’t a master plan. It was in the time that we had Veggie Grill and Beyond Meat and all the movement that’s going on now, good and bad. It was a college reaction to horrible food and a good salad bar. But that was the last burger chicken piece of turkey I ate was 1977. So you know, every inch of augury and other crucial parts of my body have been bathe in broccoli and cauliflower and rubella for a very long time. And I’m grateful that that was kind of a cork and kind of a twist of fate that in a cardiology career couldn’t have been a better plan if I have had the insight. But it was an insight. It was just a quick little college dorm survival play that I just never went back. [11:20] Ashley James: And a friend in college who went raw vegan because he didn’t have a fridge. So he just bought a bunch of fruit, like apples and basically lived on it. And it turned out he became – it made him incredibly healthy. That was like, “Whoa. That’s a really interesting survival mechanism.” At what point in your career as a cardiologist did you realize that how you’re eating was the optimal diet for heart health? [11:44] Dr. Joel Kahn: Yeah, it didn’t take long. I actually got into a quick little program at the University of Michigan [inaudible 00:11:49]. I actually was accepted to med school at 17 or 18. And began some medical courses that early. And I was eating plants. I didn’t talk much about it because there wasn’t really a platform. And I didn’t know it was a therapy. If I had dug a little deeper, but I had no Sherpa to guide me, I could have found Nathan Pritikin in the 60s and 70s. I could have found even a couple older pioneers that I now know and study and respect. But really, I started practicing cardiology. I was like this animal in the cath lab. You’re having a heart attack, you’re having chest pain, I have your balloon, I have your aggressive therapy seven days a week. And three weeks after that, Dr. Dean Ornish, one of the most eminent and deserving of appreciation lifestyle medicine doctors, published a paper. And I mean, I’m three weeks. And this guy that the answer to heart disease is, you know, procedures and balloons. And he puts out data that says you can actually halt and reverse heart disease with a lifestyle that was centered on whole food plant-based. And added two things I love, fitness and mind body, and yoga, socialization. And I said, “Wow.” So I’ve literally taught thousands of patients every month of my career since I begun. And it’s all serendipity. I’m just very fortunate. And I am proud to say I kind of grew up in this movement. But it wasn’t exactly proofed inside. I didn’t have a psychic tell me to do this things. It just played out well. I could have, you know, read a paper about bacon and I would have been just messed up for the rest of my career. But I invested well in the plant-based movement in terms of energy and personal health. [13:32] Ashley James: Well, and it shows. You’re now – is it 42 or 43 years that you’ve now been vegan? And I mean, I am blown away. But there’s the evidence for you. If we eat a whole food plant-based diet, the way down the road we’re going to look younger and feel younger. And there’s so much science now showing that it prevents and reverses disease. So you love diving into all these different topics. And we have some questions from the listeners that we’ll get to in a little bit. But I wanted to dive into this topic of saunas and infrared and red light. Because Sunlighten Sauna – actually Alicia at Sunlighten is the one that hooked us up for this interview. And she said that you are an amazing expert at understanding the science. And I’ve been raving about my experience with my Sunlighten. It has really helped me in my health journey. And also using light therapy like red light therapy. But I don’t understand the science. And so I’d love for you to teach us a bit about it. What made you want to dive into learning about sauna therapy and using these kind of light therapies for healing? [14:36] Dr. Joel Kahn: I took my nutritional knowledge and had my standard cardiology career and did that for a long time. Always offering these patients more than just prescriptions. But about ten years ago, I found a program at a university that you could call Integrative Cardiology. Like some people go back and get an MBA in the weekends at Harvard or whatever. I found the equivalent but it was in my field. But the integrated science based use of food and supplements and stress. And one of the topics was a presentation – several hours – on the science. And I stress, everything I do as odd as it is sometimes, is stimulated when I find that there’s actually science. It’s credible in hopefully multiple studies. So about 30 plus years ago, and I can’t tell you who was the first that had the spark, but in Japan they started applying infrared saunas. So you’ve got your steam sauna at 180 degrees. A lot of health clubs. Some people have that adapter in their shower and they can make it all steamy. You’ve got kind of the dry Tucson, Arizona sauna with a little box in the corner. Some people have that at home. And then infrared, it’s a little different. It looks like the wood box of an Arizona sauna. But in the walls are very special panels, infrared emitting panels. We have our – it doesn’t need to be real science-y. I mean, everybody’s sitting in a room right now that probably has a light bulb that’s emitting a spectrum of light. Some are purple, some are greens, some are red, some are blue, yellow wavelengths that make it look white in that combination. But it turns out that there is a slice of light energy called infrared. And we can’t see it. It’s not a visible light. And these researchers in Japan built infrared saunas. Boxes that have these panels and emit infrared energy. And they would take various – first they did animal studies, which is ultra cool. And the animal study showed a beneficial response to blood vessel function, muscle function, the real basic chemistry. It turns out, we actually have receptors in ourselves. You know, you think we really are more like plants and we think we are like plants. There actually is a very cool science that actually says we’re not so different than the birch tree and the oak tree you might be seeing out a window, perhaps. But anyways, we have receptors in these basic models. And then they started studying sick heart patients in Japan. And these were in academic centers and they published data. You have high blood pressure, you use an infrared sauna. There’s a Japanese word called waon, W-A-O-N. It means healing warmth. And most of the literature anybody could put in their browser, waon, W-A-O-N, therapy and start reading about it. Fifteen minutes in an infrared sauna, usually about 130 hundred or 140 degrees if you give it time to heat up. Then these people would be wrapped up in towels, drink some water, and rest. Because they were not really healthy athletes. They were people with blood pressure and heart damage and heart attacks. And over the course of 10 or 15 years, they showed that blood pressure responded; congestive heart failure, a really serious diagnosis, responded; artery measures showed improvement. They actually have done some modest sized randomized studies. Sick people got infrared saunas, sick people just got standard therapy, there was an improvement in survival and hospitalization. And in Japan, infrared sauna is used as a first line therapy right there with medication or surgery or whatever else you need. But God knows, until those few hours of lectures, I had never heard in any university -and I’m a professor at a university in Detroit – about any of this. And it’s easy. Now, read the literature, read the literature. It was real. And it’s been reproduced. So most of us, thank goodness don’t have bad arteries, don’t have congestive heart failure. Most of us aren’t mice in laboratories. But you know, for many ways of supporting our health, I tell my patients, there’s two therapies you don’t know about probably. One a little pricier and one a little less pricey. They both involve using light to accentuate our health and accelerate our energy production and benefit our weight and benefit our skin and benefit our blood pressure. And the higher end one is to research and get a really good infrared sauna like Sunlighten makes. I have one in my bedroom. And their brand called full spectrum. And this is science again. But it’s far infrared, near infrared, and mid infrared in each of those wavelengths. When you turn it on, it’s hot, you can’t see the light waves but they’re there. Each of them has a different effect. But the near infrared, which is abbreviated in the literature NIR, is really cool because that stuff really works on our muscles. And athletes, if any athletes are listening, many, many professional athletic teams will have various kinds of light therapy and infrared sauna. Because before an athletic event like a football game or after, before basketball or after, recovery pain or they call it delayed onset muscle soreness or DOMs can all be treated. And everything I just said has science and publications. It’s not again to whoo but just not very well known. And I got excited. So many, many of my patients do enjoy it. There may be some other benefits. So you know, we all know it’s the Debbie Downer talk. City water, air, plastics that wrap our burger, whether it’s a Beyond Meat burger or a Black Bean Burger, wherever you’re buying, all these chemicals, these endocrine disrupting chemicals are affecting our fertility and our thyroid and our weight. And one way to get them out – because it’s really hard to keep from having any of them, of course, we want to try and create a lifestyle where we don’t have plastics everywhere and exposure. Air fresheners and perfumes that are all affecting our endocrine system. Infrared sauna does cause you to detoxify and eliminate these better than just gym sweating. You can imagine somebody did a study, “I’m going to run around a gym and collect sweat droplets from people at an elliptical. And I’m going to go to an infrared sauna room and collect sweat droplets from somebody just sitting still.” And there’s more toxins concentrated in the sweat from an infrared sauna than there are from exercising. And of course both are good. And there are even some gyms now that have put infrared panels in the walls of the gym so you get double whammy. But yeah, very cool stuff for the science of waon therapy and infrared sauna. [21:24] Ashley James: You mentioned that we have receptors on our cells, is that to receive light? To receive infrared? Can you tell us a bit more about that. [21:33] Dr. Joel Kah: Yeah. So just switching gears a little. Infrared is there but you can’t see it. Then there’s red light. Red lights, easy. I mean, it looks like the matrix. It’s bright. I mean, it’s the one with the one band of the full spectrum. And a prominent researcher at Harvard by the name of Michael Hamblin, H-A-M-B-L-I-N, PhD or MD – I think a PhD – has spent 30 years and many, many publications and textbooks that costs $700. The official name is Photobiomodulation, photolight bio or biology, and we can change our biology through light. But it’s often called the low level laser or red light therapy. But it turns out every one of us have, I think it’s fair to say, billions and billions of mitochondria in our muscles, heart muscles and skeletal muscles, particularly. They’re making all that energy. If anybody’s had the biology background, the ATP energy that keeps our heart strong and our muscles strong, and the rest. And there is a receptor in the system that makes energy. It’s an enzyme called cytochrome c oxidase. And that receptor will respond to red light. And when it is exposed to red light, it will accelerate this process of making energy. It also creates more nitric oxide. If you ask an athlete who knew biology or a trainer, if you created more nitric oxide that was free to circulate and help an athlete’s blood vessels and you created more efficiency in making ATP in their muscles, do you think it would benefit an athlete either performance or recovery? And they think, “I got it. I’d pay a fortune for such.” It turns out red light does that. Proven. The science is known. And it’s a little different. When you get an infrared sauna, you’re getting near infrared energy. And it’s a wonderful thing and it will activate this receptor. But you also might want to explore the field of Photobiomodulation using red light. So Sunlighten has this wonderful little handheld device called lumiNIR. There’s some things that red light does that go beyond near infrared and the combination is the powerhouse. I literally use a red light panel in my near infrared sauna and I get both. Because I wouldn’t be getting red light in my sauna alone. But for all the listeners who want to keep their skin youthful, there’s an FDA approved. This is science backed by years of analysis. That it may promote collagen production, relieve aging spots, wrinkles in the skin. It’s the vanity part. But who doesn’t. You know, eating healthy is clearly beauty inside out is clearly real and the key. But I’m not against using safe therapies that keep us looking a little more youthful. So in the past 12 months, I’ve added red light therapy for 12 or 15 minutes a day. And it’s not tanning and you’re not going to burn yourself. And just another add on to health. It’s fascinating, you know, fascinating. [24:38] Ashley James: Yeah. I have one of Sunlighten’s lumiNIRs. It’s a handheld device and they have those different attachments. You can do the blue light or the red light and depending on whether you want to support like a joint pain or you want collagen production. It’s very interesting. And I know Sunlighten and gives our listeners a discount. I’m not sure what it is but I’ll find out for the listeners. So bios photo modulation, you mentioned that it helps the body – helps the mitochondria to produce more ATP and they’ve been able to prove this. Or is it that it helps the production of nitric oxide. [25:12] Dr. Joel Kahn: It actually does both. So if you really want to go deep – here we go. It’s called uncaging nitric oxide on this enzyme. Here, you got a muscle cell in your pectoral muscles because you like to do bench presses. In that muscle, there are thousands of mitochondria. And in those mitochondria, there’s a pathway to make ATP energy so you can lift those weights. The cytochrome c oxidase, for reasons I don’t understand, it actually takes and traps nitric oxide. And the nitric oxide doesn’t do what it’s supposed to do, which is keep your arteries youthful and prevent plaque. And it kind of clogs up the electron transport chain. So when you’re exposed to red light and infrared light, the nitric oxide gets bumped off and it goes and circulates and it does what it’s supposed to do. Suddenly this little fly in the ointment of making ATP is removed. So you actually get both benefits, which is crazy. I mean, it’s so crazy to think that red light and infrared light can do something that is – you know, I’m still blown away how advanced the science is. We’re talking thousands of research articles and basic science and human science. So there’s even reports – and this is science where I wouldn’t say it. You know, how many people deal with Hashimoto’s thyroiditis, an autoimmune disease of the thyroid. There are small series that exposing your neck using a red light device like the lumiNIR converts your immune system. It’s called macrophage 1 or macrophage 2. But they stop attacking your own thyroid. And there are reports up substantial 30 or 40% of people no longer needing thyroid replacement after a while. Everybody needs to work with their healthcare team. Of course, their healthcare team won’t have ever heard of this. But if you do look online, Photobiomodulation Hashimoto’s, you can read about it. It’s real science. [27:07] Ashley James: Oh, that is fascinating. Do you think it has something to do with the fact that it decreases inflammation? [27:12] Dr. Joel Kah: It decreases inflammation by changing the activity of kind of white blood cell or kind of inflammatory. So I’ll call them back macrophage. Exactly. [27:22] Ashley James: Because I know that in the 3-in-1 Sunlighten – not the handheld but the big Sunlighten Sauna that has the near, mid, and far infrared – that is incredibly anti-inflammatory to be in. That people notice decreases in pain and inflammation and joint pain. And then I’ve been told the lumiNIR – because I don’t have joint pain – but I’ve been told the lumiNIR has been really helpful for people with joint pain even when it’s like rheumatoid arthritis where there’s an autoimmune component. And you’ve seen the science to back this up. [27:51] Dr. Joel Kahn: It probably is multiple pathways that lead people with fibromyalgia and more defined autoimmune conditions, like you mentioned, to respond to full spectrum infrared sauna. Because it probably is detoxification. Some will lose weight, which may help. And then finally, this nitric oxide, ATP energy, something like fibromyalgia, some people believe strongly is a mitochondrial energy deficit problem. So if you can safely non-invasively and frankly rather cost effectively deal with it, then you might as well just power up and get rid of the pain. [28:34] Ashley James: Right. I love it. And you mentioned that saunas help with weight loss. I’ve used the sauna to help with detoxification because I was having problems with weight loss when it came to detoxification. My liver would get all really pissed off. I switched to a plant-based diet and everything’s working a lot better now that I’m doing that and doing the sauna. What can you share with us about, from the standpoint of heart health, cardiovascular health, and how saunas help with that, how does the sauna therapy, this heat therapy, help us with detoxification and weight loss? [29:10] Dr. Joel Kahn: Yes. Well, it’s actually a very efficient way. It’s interesting. There’s some data that cold therapy is a very efficient way to accelerate your weight loss. So I have adopted this crazy habit I hate that after workout, I jump in the shower. And at least part of it, I douse myself and cold water. It does wake you up like no other. I hate everything about it. Because there’s nothing more comforting than a hot shower but a cold shower. And on the flip side, the efficiency of burning calories in an infrared sauna is as high as many ellipticals and treadmills. And it might be roughly 500, 600, 700 calories an hour. So you know, it doesn’t replace – number one, if you’re a good athlete and you can really get good workouts, please do it. There’s all kinds of cardiovascular benefits. Some people have reasons that they can’t really get that high level workout. And many people do both. They’ll get the – you know, they CrossFit or the HIIT or yoga or whatever it is and then they’ll add in some saunas on top of it. So it can be very helpful with the calories in, calories out. The calorie out part of weight loss, I had, unfortunately, in a medical conference, the misfortune of breaking a foot on an escalator two months ago. So I’ve had to give up – it’s recovering very well. But I’ve had to give up the treadmill, elliptical, Concept 2 rower, and all the things I like to do yoga. So I’m spending more time in an infrared sauna and been able to maintain my weight. I mean, a lot of upper body work and such. I shifted. But just a personal example, you know, add that in. And it may be too. There’s this theory – this gets a little whoo – we really are exposed to a lot of garbage, pesticides, herbicides, these endocrine disrupting chemicals. And a lot of them do get – they’re fat soluble chemicals, particularly PCBs and DDT. And these things are unfortunately highly concentrated in fish. So fish eaters are much more exposed to these things. But you may need to get rid and reduce your burden on some of these chemicals to really lose weight. Because there’s like this battle, if I keep my fat, I dilute these chemicals and they’re less toxic to my physiology. And if I lose weight, and they’re all released in the bloodstream, I may feel bad. Kind of like the Keto flu or the kind of ill feeling that people get the first couple days of some kind of detox. So sweating them out as a real efficient way in a sauna to reduce your burden and accelerate weight loss. Now, everything I just said is a little blurry in terms of, “Do we absolutely know?” But that is a strong theory that people feel reflects life in 2019 and 2020. [31:57] Ashley James: And it’s been my experience too. I kept hitting a wall. Every time I lose a few pounds, I get really over toxic and my liver would inflame. I went for ultrasounds and blood work and it was sure enough, my liver was really pissed. And my Naturopath didn’t know what was going on. He was trying to throw some supplements at me to support the liver. But I had to basically stop weight loss and then wait for it to calm down then start again. I was just sick of it. And so finally my niche process was like, “You really should get a sauna.” And that’s why I dived into studying all the different types of saunas. And I came across Sunlighten Sauna and discovered that that was my favorite out of all the other companies. Really low EMF, nontoxic. And then when I started using it, it was like a light bulb went off inside me. It was the total difference. I feel happier when I use it. I get better sleep. I don’t have my inflamed liver anymore. The weight loss has been consistent. So I’ve become this raving fan about Sunlighten. But again, I didn’t understand the deep science behind it. And so I love that you’re saying that the receptors in our body, the cells have receptors for light. And I’ve heard from other people that light is like a nutrient. And we are starving our body because of modern day society. We’re actually starving from the full spectrum that we need. So it’s like we’re nutrient deficient and the nutrient is light. [33:23] Dr. Joel Kahn: So that that circles back to something I said a while about how similar we are to plants, which is a novel idea. But of course plants can take light and use them to stimulate the production of energy. It powers them. They have chlorophyll. There is a report in 2014 and I wrote a little blog about it back then. It was so interesting, it made some headlines. It wasn’t a human study but it was a mammal study. And we do not think that we can be out in the sun and create energy out of that process. We’re not plants. But that did occur in mammalian cells. And there may be a whole spectrum of we know light helps you make vitamin D, which is an important health supporting. Some people say hormone and vitamin. There is some data you can make more nitric oxide by being in the sun. And people that live in lower portions in the United States have lower blood pressure than people who live in northern portions. And it all correlates how many hours a day there’s sunshine. But whether we actually can energize and feel better, of course, intuition says, take a vacation in the sun. And it feels great. And it may be partly that we have still pathways that aren’t completely understood in these cytochrome C oxidase pathways may indeed be part of it. So it’s very cool. And you know, as I say one of the easiest health blaze is to get more light or get more red light with dedicated products. These used to be extremely expensive. You’d have to spend $10,000 to 30,000 to go to a health spa or a dermatology office. But it’s much different now for way, way under $1,000. You got a great system. [35:05] Ashley James: Yeah. I really like the lumiNIR and all that you can do with it with all the different attachments. Like you said, you can do the anti-aging. There’s an attachment specifically for helping skin with acne and healing the skin. And I really geek out on helping people with pain and decreasing pain and supporting healthy tissue. So there’s so many different benefits to making sure we’re exposed to light either getting out in the sun or getting in a Sunlighten Sauna. But being able to expose yourself to the different and full – as much as you can full spectrum of light. Now, I know we’re under a time constraint and I definitely want to make sure I get to the listeners questions because I posted on the Learn True Health Facebook Group some questions. [35:50] Dr. Joel Kahn: Let me just – before we leave the sauna, let me just shout out three – again, I told everybody I already like science. So I’m going to give three very nonscientific tips here. [36:01] Ashley James: Okay. Great. [36:01] Dr. Joel Kahn: Well, the first one is okay. I do my meditation. Which isn’t absolutely regular but I do it in the infrared sauna. I call it saunatation. I’m already isolated. I’m already cleansing physiologically my body, why not cleanse some of the stress. So I encourage people that’s just a perfect place to do that. That’s number one. Number two, I actually do take a big handful of organic chlorella about half-an-hour before getting in the sauna. Because I want to be a plant. And I don’t know for sure if that works. But my blood level of chlorophyll is extremely high from taking 25 or 30 little tablets. Like anybody can buy of high quality chlorella. And it just feels good. And the third one, and please don’t do this if you’re not really healthy and know your status. There’s sort of this strategy, go do a HIIT workout for 10 or 15 minutes after you’ve taken a little handful of niacin, a B vitamin that makes you sweat and turn red. And you might feel very poorly on it so be careful. But it’s over the counter. You know, so take your knives and do your workout and pop in a sauna. You want to have a detoxifying sweat, you will have a detoxifying sweat. [37:17] Ashley James: Very interesting. So you’re inducing the niacin flush. Is that like opening up capillaries around the surface of the skin? [37:27] Dr. Joel Kahn: That’s exactly what you’re feeling on the surface of the skin. Clearly, if you’re not healthy, if you’ve had a bad reaction to niacin – I mean, it’s not a medical therapy and niacin is an over the counter vitamin. So I don’t think I’ve completely violated my Hippocratic oath. And I’ve done it a thousand times and so far still alive and kicking. But it’s an interesting little play. [37:51] Ashley James: Now, I’m going to have to try that. I’ve definitely have some niacin here on the shelf. I’m going to have to try that for sure. I usually get the no-flush niacin. But to want to do it on purpose to open up all the blood flow to the surface to increase the sweating and detoxification, that sounds like a really fun experiment. I’m kind of like — you know, you hear about this term biohacker. I love experimenting on myself in a safe way. You know, try it out. And I feel like my listeners do the same. They love trying different things, especially when they learn from great guests like you and seeing how it works for them. I have two more things to add to your routine – or one more thing for you to add to the routine is trying a magnesium soak while you’re in the sauna. And I’ll make sure I send you some information on it. But it’s transdermal. It’s a liquid. And you just put a few cups of water with a foot basin while you’re in the sauna, and you absorb a ton of magnesium. And so a lot of my listeners, including myself, love doing that in the sauna as well. And that also opens up the blood flow. And then my favorite – and I definitely encourage you to try it out – my favorite chlorella brand – I’ve tried a bunch of them – and I found that ENERGYbits, they make one called – [39:06] Dr. Joel Kahn: That’s what I just swallowed. [39:07] Ashley James: Yes. RECOVERYbits are my favorite because it tastes amazing. All the other ones kind of tastes fishy to me or stale. And ENERGYbits has been consistent with their quality and their testing. I’ve had Catharine Arnston, the creator of ENERGYbits on the show many times. And so yeah, we’re on the same page. I’m so excited to introduce you the magnesium soak. I’ll make sure I send you some information because I know that you’ll really enjoy adding that to your sauna routine and seeing how you how you feel about it. So let me get to the listener questions because I know that we’re under time constraint and I want to respect your time. Daniela, first of all, says that your – she’s the one that said your podcast is absolutely amazing. So I want to shout out to Daniela. She was really looking forward to hearing our interview. Naomi has a really interesting one. Her dad had a valve replacement surgery recently because of a narrow valve. And the doctor said it was congenital. But none of his symptoms started until he was 70. And they’re like, “Well, you know you were born with it.” But none of his symptoms started until his 70 and now they’re seeing narrowing of the arteries. Of course, that can be – as you and I know – corrected with wonderful whole food plant-based diet with no oil. What do you say to that when people say – when doctor said, “Well, that’s just congenital. You were born with it.” But the disease never occurred until they were much later in life. [40:28] Dr. Joel Kahn: Go back to Daniela. Thank you, Daniela, for listening to Heart Doc VIP. Okay. I just wanted to say thank you to her because that was kind of you. But to go to this question. There is a – the number one most common birth condition, congenital heart condition, is actually what her father had. The last valve of the heart when the heart pumps hard to get all the blood out to the body, it goes through a valve called the aortic valve. That looks like a Mercedes Benz or a peace sign, three little parts. They open, they shot. One person people are born where there’s two pieces, not three. It’s called a bicuspid aortic valve. It looks like your rear end. It has two pieces, not three. But we don’t call it a tush valve. It’s a bicuspid valve. Now, you can now call it a tush valve. And because it’s abnormal, 100,000 heartbeats a day. By the time you’re 40 or 45 or 50 or 55, there’s some scarring, some calcification. And the valve may no longer open enough so you start to get shorter breath, tighten the chest, dizzy. And at that point, you may need something done about it. There’s nothing you can do about being born with it. It’s common. You might ask a doctor. There is some family history. So your listener might ask her doctor, “Are you sure there’s no murmur there when you listen to my heart with the stethoscope?” But there’s really no absolute necessity to make the diagnosis early, early. But they’re just finish it up. Occasionally with that valve – right above the heart is called your aorta. The aorta may be a little enlarged. That’s a little more important of a finding earlier in life. You shouldn’t probably be snapping or catching 300 pound lifts in CrossFit if you knew your aorta was enlarged. So it might be worth pursuing it with what we call an ultrasound of the heart or echocardiogram, if there really was any question your doctor thought they heard something or there really is a strong family history. I’ll give you one last little tip because your listeners deserve the best of the best. There is a class of antibiotics – I’m totally shifting gears but I’m coming back to your listeners question. They are called fluoroquinolones. But you might know him by Cipro, ciprofloxacin, Levaquin, levofloxacin. These are actually the most commonly prescribed oral and IV antibiotics in the United States. It is now apparent after 30 years of using them, that they weaken our collagen. They cause rupture [inaudible 00:42:57]. Your Achilles can get inflamed or rupture after a seven to ten day course. But now in the last three or four years, your aorta, the most important blood vessel in the body, can get weakened and damaged after just a week or ten days on these antibiotics. And very recently, even heart valves, all of these structures are made of collagen. These antibiotics have – it took years to identify. It’s not common. But when you talk about tens of millions of prescriptions, if it’s only 1% or 1.5% of people, it’s still a lot of people. Which is why somebody like this father – I mean, anybody within a large aorta should now know that there’s FDA warnings about maybe not using this class of antibiotics that are used for prostate and urinary and bronchitis in the hospital and in the office. I’ll say as I was just on the doctor show being interviewed on this topic, because it is really important and hot. And Drew Ordon, the plastic surgeon with the white hair and wonderful guy said, “I’m Levaquin right now for my prostate and this is scaring me.” And it is being recommended that you ask your doctor maybe shift antibiotics to another one. So circling back to your question, it’s 1% of people born with an abnormal valve. It might also cause their aorta to be enlarged. If you knew your aorta was enlarged, you do not want to take these classes of antibiotics. And even if your aorta isn’t enlarged, for the sake of your Achilles tendon and other structures, you still might want to ask, ” Can I have a penicillin or sulfa?” Older antibiotic like Macrobid. These drugs have been out for decades. It’s interesting. It’s not the only drug. We’ve learned new things about old drugs that are frankly changing practice and fairly scary. Next question. Next question. [44:50] Ashley James: Thank you so much for warning us. Kelly asks, “Are there any recommendations he has for children who are born with heart conditions such as ASD, PFO, etc.? [44:59] Dr. Joel Kahn: These are interesting questions because, again, birth defects are rarely the common questions that are asked. I’m certainly welcome to have them. I mean, so you can -the second most common birth defect after the valve is a little hole in the heart called a PFO, Patent Foramen Ovale. Usually very innocent. And then there’s a larger hole called ASD, Atrial Septal Defect. And then there are more complex where it might be apparent before birth or at birth that this is a child that has serious problems, blue babies and developmental problems. But you know, just like that listener’s Father, it took decades. There are people that have had this hole in their heart for it 20, 30, 40 years. And then they begin to get shorter breath or then they begin to get fatigue. So there isn’t a diet, there isn’t a lifestyle, there isn’t a sauna treatment for everything in life. You just need, at that point, good medical care. And sometimes ultimately, a procedure that more and more is not surgery. More and more, it’s some kind of procedure where they don’t have to crack your chest open. But people should be much more concerned about their arteries getting clogged and the risk of heart attack and stroke. Because the frequency of that from age 35, 40, 45, and up is a thousand times more of a concern than finding out unexpectedly at age 70. You’ve got a valve or a hole in your heart issue. They’re all important. [46:31] Ashley James: Right. That we can prevent heart disease with whole food plant-based diet with no processed foods would be much better for most of the population. And then there’s a small percentage that has a birth defect but could still – even with a birth defect, couldn’t we still optimize our heart health with a really good heart health diet? [46:50] Dr. Joel Kahn: Yeah. Always. And there’s an insane number of reasons to as early as you can in life learn the clues. Don’t smoke, stay thin, get fitness, get sleep, manage stress, eat more fruits and vegetables, whole grains, and legumes. And anybody around you does. Be the champion of whole real foods from plant sources. Don’t smoke. If I said it twice, it deserves to be said twice. [47:17] Ashley James: Don’t vape. [47:17] Dr. Joel Kahn: If nothing happens during your life, you’ve just probably added a dozen plus years of good health and reduce risk of diabetes, cancer, brain disease and heart disease. If something comes up in your life, you’re showing up in the best shape possible. So yes, we buy life insurance, we wear seatbelts, we wear bicycle helmets, we’re into the mode of taking certain precautions even though they’re relatively unlikely. Whereas, heart disease is incredibly likely and we neither look for it nor do we really work very hard to prevent it. [47:50] Ashley James: My dad died of heart disease. My mom died of cancer. And that’s one of the biggest reasons why I do this show. I can’t save my parents. I don’t have a time machine. But I can help my listeners save theirs and save themselves. And we can. We can prevent and reverse disease and add years to your life with all the things you’ve talked about. You know, we’re on a roll. Heidi says, “I have a question as well. My husband has a rare genetic heart condition called ARVC. His arteries are perfectly healthy but it’s electrical part of the heart that’s not. Do you have any advice for anyone with this condition?” [48:26] Dr. Joel Kahn: Yeah. Again, an important but very unusual birth abnormality, the right side of your heart, it just doesn’t form normally. And it makes people prone to serious fast heartbeats that could cause you to blackout or worse. And you work with certain cardiologists called electrical cardiologists and sometimes you need that fancy pacemaker called a defibrillator. And they can be life saving for certain people. And the same comment, show up to that challenge in life. You know, why is that gentleman’s arteries clean? And that’s a very complex question of genetics and lifestyle and fitness and all. But if you start eating plant-based at age 18, as I had the good fortune by luck, you probably are going to show up for that procedure with your arteries clean. And I know at age 60 mine are squeaky clean. There’s ways to get a quick CAT scan and confirm that and there. So it’s always best. The best protection is to stay out of the hospital on as few medicines as you can with as few doctor procedures as you can. The number three cause of death in the United States is medical procedures and medications that go wrong. Number three causes of death are heart disease and cancer. So the best plan is not need to be there. And I run from hospitals even though I am part of them and I will say I’m on staff with them. But in terms of my own health, I do not trust what goes on in hospitals. [49:56] Ashley James: Thank you. I love this. We have to walk that fine line of understanding when we want to go to allopathic medicine and when we don’t. This show obviously celebrates all the times we don’t want to go to allopathic medicine but allopathic medicine has its place. And if my heart was beating to the point where it’s blocking out, I’d really want to see a good electrical cardiologist. Is that what it’s called? I definitely want to go see a really good one. But for prevention and for optimizing our health, then we can do it through diet. I interviewed Dr. Esselstyn and he has seen people with even four blockages in the heart, reverse it within months of going on a whole food plant-based diet, as you I’m sure have seen and know. So it’s just amazing what the body can do when we give it the nutrition it needs. Teresa asks – she says, “Many of the autoimmune neuro disease experts insist on good fats in the diet. Added fats like ghee, tallow, lard and coconut oils, mostly for cooking and to drizzle over vegetables for absorption. I personally have trouble breaking down fats and proteins and I’ve had to take digestive enzymes with every meal. Is it really necessary to add all that extra fat for MS, ALS, and even Hashimoto’s? I followed Dr. John McDougall for years and felt great. But that was before autoimmunity. So she then developed an autoimmune condition.” And she says, “Also, the experts talk about organ meats for autoimmunity. What could replace a nutrient density in a plant-based diet?” So she doesn’t want to have to eat organ meats and all this processed fat but she wants to heal her body. Do you have any advice for her? [51:37] Dr. Joel Kahn: Yeah. And I think it gets to just a fundamental question. Where do you get your advice? Do they have any conflicts in the advice they’re giving? And are they really trained to give advice? Because every trainer or every dietitian – at least a dietitian has some formal training if they’re an RD, every health coach can get a blog and YouTube and give advice. Go find me data that you need to eat organ meats to heal neurologic or autoimmune disease. And let’s talk about randomized studies that are out there. And you know, not everything in the world that’s great has to be plant-based. So there’s so many reasons to talk about a whole food plant-base for the environment, for animal rights, and animal cruelty and suffering. And for the gigantic database that it is the best plan to preserve and protect your health in general and for both brain and autoimmune diseases. I spent the weekend with Dr. Terry Wahls of HLS. And many people will know she’s a medical doctor with a breakout book called The Wahls Protocol a couple years ago. She’s redoing it right now. And she had disabling multiple sclerosis. She was an internist in the University of Iowa at the VA. And kind of created her own plan of hyper nourishment with ten servings a day of organic leafy greens and smoothies and salads and mushrooms and onions and garlic. And a few servings of animal foods during the week. Far less than the typical Paleo diet. Lots of omega-3 rich foods. And I was asking her by and she recovered her own health. She’s helped so many people recover. I mean, I’m not going to argue with her. She’s walking and riding her bike and she was in a wheelchair. I’m going to tell her diet is other than optimal. It worked out optimally for her and a lot of other people. There is a similar plan that is all plant-based that’s taught by a physician in Houston, Brooke Goldner, G-O-L-D-N-E-R and her book called Goodbye Lupus or Goodbye Autoimmune Disease, her new book. So you can do it super clean whole food plant-based, super clean almost plant-based as Dr. Wahls teaches. But it’s not all that gook you talked about. And what I love about, particularly Dr. Wahls right now, she took her own personal health crisis and recovery. Her broad experience teaching other people within the VA and other medical systems in the University of Iowa. And now she’s actually doing prospective randomized published studies. You can’t jack with somebody who’s done that kind of science. And I’ll say no disrespect, but it kind of is disrespect. Show me Dr. David Perlmutter’s prospective peer reviewed studies or Dr. Mark Hyman or Dr. Bill Davis. I mean, these are the giants of some of this weird stuff. I mean, bone marrow and bone broth. I know it’s trendy. But let’s talk about where we follow the typical scientific path of you got a hypothesis, you arrange a study, you do it, you publish it. Dr. Wahls sure [inaudible 00:54:32] has. So my brain favorites are two neurologists by the name of Sherzai, S-H-E-R-Z-A-I. Which is Dean and Ayesha Sherzai, academic neurologists in Long Beach and Loma Linda with a book called The Alzheimer’s Solution. And I would follow their program for brain and neurological health in that book. [54:56] Ashley James: Thank you so much. That was great. I love the books that you let us know about because those are going to be great guests for the show. I’m definitely going to ask them all to be on the show. And those will be great resources for the listeners as well. It has been such a pleasure having you on the show. I know time just flies. And I know you’ve got to go. Before you do, is there any advice that you’d like to leave listeners with or homework that you’d like to leave the listeners with? [55:25] Dr. Joel Kahn: That’s an interesting question, homework, because that’s exactly the expression I use with my patients. So, “Here’s your homework. And I can’t do this all for you. And I can guide you to people.” I believe my opinion are credible and we should spend time. I mean, everybody should watch Forks Over Knives on Netflix. Or if there’s anybody left that has a DVD player. It’s still available. I give my patients the option of taking a DVD home or watch it on Netflix. If you want to upgrade that, you might watch What The Health from 2017. And very soon you’ll be able to watch Game Changers. A new movie that was in the theaters that will be released on iTunes very soon. I mean, I’ve seen all those movies. You know, there are a lot of health movies that I don’t think represent fairly. But surely Forks Over Knives, which is Dr. Caldwell Esselstyn and Dr. Caldwell, I would certainly say, are fair. Other homework, let’s see. You know, get familiar with pubmed.gov. It can be a slippery slope. But that’s the national library of medicine and 30 million scientific articles. You can’t get the full article on everyone but you can and a lot. And like, if you don’t believe me on red light therapy or photobiomodulation and Hashimoto’s, that’s where you go. You go there. And you know, it’s a little tough sometimes to read the scientific articles but that’s a good habit. I mean, you could, I will say, also, put it bone broth and health. That’s where you want to look. You’ll find nothing. Actually, you’ll find one article that says it’s dangerous and toxic in terms of lead levels in bone broth causing bones that your cooking to release some of the stored lead that is in them. But you know, these kind of habits is something if you really want to get as credible as you can. You might know learn simple skills to do. [57:24] Ashley James: Oh, I love it. Yes, PubMed. Let’s advocate for ourselves by looking into the science. Absolutely. I went to the movie theaters and saw the Game Changers in the movies. And I went with actually one of our listeners who’s a friend of mine, Naomi. A big shout out to her. And the whole time we kept looking at each other going, “We have to get this person to watch this. Oh my gosh. We got to get our parents to watch this.” We can’t believe it. Like, I am so excited that October 1st when it comes out on iTunes, I’m going to buy the digital copy and get as many of my friends and family to watch it. And I really love that it just shows – it blows this idea that that [inaudible 00:58:01] totally out of the ballpark. And it shows that if you want to have really great sexual health and great muscle and great strength and endurance and all that, men and women get it from a whole food plant-based diet. That’s such a cool – and it is really a game changer. Dr. Joel Kahn, it has been such a pleasure having you on the show today. You are welcome back anytime you want to come share with our listeners. It was a true pleasure to have you today. [58:30] Dr. Joel Kahn: Well, it is mutual fan club, mutual Seattle fan club. And yeah, I look forward doing that. I’d be happy to help you contact any of those other people if you want to get them on because I think your listenership would love them. [58:43] Ashley James: Awesome. That sounds great. Thank you. — Outro: Hello true health seeker. Have you ever thought about becoming a health coach? Do you love learning about nutrition? And how we can shift our lifestyle and our diet so that we can gain optimal health and happiness and longevity? Do you love helping your friends and family to solve their health problems and to figure out what they can do to eat healthier? Are you interested in becoming someone who can grow their own business? Support people in their success? Do you love helping people? You might be the perfect candidate to become a health coach. I highly recommend checking out the Institute for Integrative Nutrition. I just spent the last year in their health coaching certification program. And it really blew me away. It was so amazing. I learned over 100 dietary theories. I learned all about nutrition. But from a standpoint of how we can help people to shift their life and shift their lifestyle to gain true holistic health. I definitely recommend you check them out. You can Google Institute for Integrative Nutrition or IIN and give them a call. Or you can go to learntruehealth.com/coach and you can receive a free module of their training to check it out and see if it’s something that you’d be interested in. Be sure to mention my name, Ashley James and the Learn True Health podcast. Because I made a deal with them that they will give you the best price possible. I highly recommend checking it out. It really changed my life to be in their program. And I’m such a big advocate that I wanted to spread this information. We need more health coaches. In fact, health coaching is the largest growing career right now in the health field. So many health coaches are getting in and helping people because you can work in chiropractic offices, doctors offices, you can work in hospitals. ,You can work online through Skype and help people around the world. You can become an author. You can go into the school system and help your local schools shift their programs to help children be healthier. You can go into senior centers and help them to shift their diet and lifestyle to best support them in their success and their health goals. There’s so many different available options for you when you become a certified health coach. So check out IIN. Check out the Institute for Integrative Nutrition. Mention my name. Get the best deal. Give them a call and they’ll give you lots of free information and help you to see if this is the right move for you. Classes are starting soon. The next round of classes are starting at the end of the month. So you’re going to want to call them now and check it out. And if you know anyone in your life who would be an amazing coach, please tell them about it. Being a health coach is so rewarding and you get to help so many people. Get Connected With Dr. Joel Kahn! Website Facebook Twitter Instagram Books by Dr. Joel Kahn The Plant Based Solution The Whole Heart Solution The No B.S. Diet

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Circulation October 1, 2019 Issue

Play Episode Listen Later Sep 30, 2019 26:38

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 at Circulation and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, have you ever wondered about instead of coding a stent, coding balloons with paclitaxel? Well, the feature article day is going to look at mortality assessments of paclitaxel-coated balloons in a meta-analysis from the ILLUMENATE clinical program, the three-year outcomes. Do you have a paper you want to start us off? Dr Carolyn Lam: I sure do. First of all, we know that diabetes impairs atherosclerosis regression following cholesterol lowering in both humans and mice. Now in this process of plaque regression, what's the role of functional high density lipoprotein or HDL, which is typically low in patients with diabetes? Well, this first paper that I chose looks just at that and it's from Dr Fischer from New York University School of Medicine and colleagues, who aimed to test if raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages and enhances atherosclerosis regression following cholesterol lowering. So to do this, the authors used aortic arches containing plaques, which were developed in LDL receptor null mice, and these were transplanted into either wild type or diabetic wild type or diabetic mice transgenic for human APL lipid protein A1, which have elevated functional HDL. Dr Greg Hundley: So Carolyn, what did they find in this interesting study? Dr Carolyn Lam: Well, diabetic wild type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. The benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte neutrophil production capacity. ACL also suppressed the general recruitability monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2 phenotype, which is an atherosclerosis resolving state. There was also a decrease in plaque neutrophil extracellular traps or nets, which are atherogenic and increased by diabetes. So raising apolipoprotein AI and functional levels of HDL promoted multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques in diabetic mice after cholesterol lowering. And this may represent a novel approach to reduce cardiovascular risk in patients with diabetes. Dr Greg Hundley: Really interesting, Carolyn. Well, I'm going to talk to you a little bit about a large study in patients with valvular heart disease and it's a contemporary presentation and management study and it's from the Euro Observational Research Program Valvular Heart Disease II, Roman numeral two, survey. And the corresponding author is Professor Bernard Iung from Bichat Hospital. So the VHDII survey was designed by the Euro Observational Research Program of the European Society of Cardiology to analyze actual management of valvular heart disease and compare practice with guidelines. Now in short, patients with severe and native valvular heart disease or previous valvular intervention were enrolled prospectively across 28 countries over a three-month period in 2017. Indications for intervention were considered concordant if the intervention was performed or scheduled in symptomatic patients corresponding to class one recommendation specified in the 2012 ESC and in the 2014 American Heart Association American College of Cardiology valvular heart disease guidelines. Dr Carolyn Lam: Wow. So what did they find, Greg? Dr Greg Hundley: Okay, so there's 7,247 patients. 4,483 were hospitalized, and 2,764 were outpatients, and they were included across 222 centers. The median age was 71 years and 1,917 patients were over the age of 80, and 3,400 were women. Now, aortic stenosis was present in 2,000 plus patients, aortic regurgitation in 279, mitral stenosis and 234, mitral regurgitation in 1,114. And multiple left-sided valvular heart disease was present in 1,297, right-sided valvular heart disease in 143, and 2,028 patients had prior vascular intervention. So the decision for intervention was concordant with class one recommendations in symptomatic patients with severe single left-sided valvular heart disease in 79.4% of those with AS, 77% with aortic regurgitation, 68.5% for mitral stenosis, and 71% for primary MR. Valvular interventions were performed in 2,150 patients during the survey. Of them, 47.8% of the patients with single left-sided native valvular heart disease were in New York Heart Association class three or four, and transcatheter procedures were performed in 38.7% of the patients with AS and 16.7% of those with MR. Dr Carolyn Lam: Wow, Greg. So what are the take home messages? That was a lot of numbers. Dr Greg Hundley: Yep. Lots of data there. And so couple things. First, recommendations for interventions in symptomatic patients with severe valve disease are better applied today in this paper than in the previous European survey conducted in 2001, particularly for those individuals with aortic valve disease. Second, multi-modality imaging is now more frequently used, but stress testing remains underused in asymptomatic patients. And finally, transcatheter therapies are now widely used in patients with stenotic valve disease, and we would expect that, particularly for the use in the elderly. Dr Carolyn Lam: Great, Greg. So what are the clinical implications? Dr Greg Hundley: Okay, so Carolyn, first, late referral for intervention shows the need for increasing awareness of valvular heart disease by general practitioners and cardiologists. Second, the high burden of elderly patients highlights the need for multidisciplinary heart team approaches to assess the risk benefit ratios of the different modalities of valvular interventions. And finally, number three, echocardiographic quantification of regurgitation should be more accurate and pay more attention to quantitative measurements. Those are the main take homes from this large registry analysis. Dr Carolyn Lam: Nice. Thanks, Greg. My next paper is the characterization of the first transgenic mouse model of ARVC 5. Now, that is the most aggressive form of arrhythmogenic right ventricular cardiomyopathy caused by a specific mutation in transmembrane protein 43. So this paper's from co-corresponding authors, Dr Lara-Pezzi from CNIC in Madrid and Dr Garcia-Pavia from Hospital Universitario Porto de Hero in Madrid, and with their colleagues, they generated transgenic mice over expressing transmembrane protein 43 in either it's wild type or that specific mutant form in postnatal cardiomyocytes under the control of alpha-myosin heavy chain promoter. And they found that these transgenic mice expressing the specific mutant in transmembrane protein 43 showed fibro fatty replacement of the myocardium and died at a young age. The model confirmed that transmembrane protein 43 is mostly localized at the nuclear membrane and provides new information regarding the pathophysiological mechanisms underlying ARVC five. One of them is that the GSK3 beta signaling pathway plays an important role in this disease. Dr Greg Hundley: So that's great, Carolyn. Sounds like we have a new model that's been created by this group and certainly this disease has spread. It's something we definitely worry about. Do you see any therapeutic implications for their work? Dr Carolyn Lam: Great question, and indeed the authors tested two new therapeutic approaches for ARVC five. In the first they found that targeting fibrosis really had no beneficial effect. But in the second, they found that inhibition of GSK3 beta improved cardiac function and survival, thus opening the way to a new therapeutic approach focused on GSK3 beta inhibition in patients with ARVC five. Dr Greg Hundley: Very good. So we look forward to seeing what the results of that study will be. How about now we talk about some of the other articles in this issue? Dr Carolyn Lam: I love that. I think it's a great idea to tell everybody about this amazing issue. So we start with an article from our Global Rounds, and this time from Argentina, so a great status update and future strategies for cardiovascular disease in Argentina. We also have a perspective paper and that's on the new World Symposium on Pulmonary Hypertension guidelines, really questioning some of the cutoffs that we've taken for granted and asking, "Should 21 be the new 25?" Intrigued? Well, you really need to pick this one up and read it. And then there's a white paper, and this is a report from the 2018 NHLBI workshop that really talks about unlocking the secrets of mitochondria in the cardiovascular system and asking if this may be a path to cure in heart failure. We also have a research letter, and I love these. They're so succinct and really contain an important message. And this one talks about the evolution of Medicare formulary coverage changes for antithrombotic therapy after the guideline update. So very topical subject. Dr Greg Hundley: Very good, Carolyn. So I've got a couple. There's a Paths to Discovery article that John Rutherford did discussing with Paul Zimmet regarding reflections of the evolving global diabetes epidemic. Second, there is a very nice On My Mind piece from Samuel Tretheway from Birmingham, England who discusses medical misinformation, kind of like medical fake news. And he discusses how this occurs and it depends on the motivation of both authors and publishers, and he reviews responsibilities of all of us, how to avoid generating this type of material. And then finally, a really interesting Cardiology News piece by Bridget Kuehn, who discusses diet and microbes in heart failure, and with that there's a very nice piece of artistry work that would be great for your office. So that's all included in the journal. Dr Carolyn Lam: Oh, you got us all curious. Finally, I just want to highlight, we have a section called Highlights from Major Meetings, and this time from my part of the world with Dr Aijun Sun and Dr Junbo Ge summarizing the 13th Oriental Congress of Cardiology takeaways. Cool issue, isn't it? Dr Greg Hundley: Absolutely. So how about onto our feature discussion? Dr Carolyn Lam: You bet, Greg. Dr Greg Hundley: Welcome everyone to our feature discussion. And this afternoon or this morning, wherever you may be, we are going to have an opportunity to discuss the utility of paclitaxel-coated balloons in terms of management of patients with peripheral arterial disease. And our article today comes to us from Bill Gray and colleagues from Mainline Health in Philadelphia, Pennsylvania. And we have our own Josh Beckman, associate editor from Vanderbilt, who will be joining us in the discussion. Bill, welcome to Circulation. We really appreciate you sending us this article. Can you tell us a little bit about the background of why you wanted to perform your study and also, what was your study design, study population? Dr William Gray: The study was really prompted by a prior report by Katsanos et al in JAHA about nine months ago. When we started this study, it was much more fresh. And what we did was we realized we had data from multiple studies using the Stellarex drug-coated balloon that we could use to address some of the issues raised with the Katsanos paper. Just to review that briefly, the Katsanos paper suggested that there was a significant mortality signal in patients who were randomized to drug-coated balloons using paclitaxel versus PTA or patients randomized to drug eluting stent versus PTA or other stents. That signal was seen late at two years and at five years, and so we sought a given the data, the tightly controlled and well-reported data and this experience to see if we could see a signal as well. The study design really involved taking all the data from the randomized trials, and there were two, which comprised an aggregate of about 600 patients, unequally randomized, about 400 in the drug-coated balloon arm and about 170 or 200 patients in the PTA arm. And then we also looked at all the poolable data, which was controlled data, so we had two randomized control studies I mentioned just a minute ago, as well as three single arm studies in one registry. Now, these had quality oversight and data reporting. And then those data were adjudicated for adverse events, including death, by a blinded third party CEC, and then those data reported out by Kaplan–Meier estimates as well, and then we do a multi-variable analysis looking at predictors of death, and then I can talk about that in a moment. Importantly, the data here has followed out to three years. As I mentioned before, the original paper which incited the concern had reported unequal deaths at two and five years, so we're somewhere splitting that difference. That's the genesis of the study and the study design. Dr Greg Hundley: So Bill, tell us now about the results. Dr William Gray: It turns out the baseline characteristics were largely similar between these trials and the patient arms, even though they weren't strictly speaking the same trials, except that the drug-coated balloon arm was a bit younger and smoked more frequently, so they were at a little bit more risk. In the randomized control analysis, which was done first, there was no difference in all-cause mortality between the PTA patients and the patients who received paclitaxel drug-coated balloons. That was true at one year, two years and three years. When we looked at the pooled analysis, which included not only the drug-coated balloon randomized trial patients, but also all the single arm studies and registries, we also found that there was no differences between those treated with drug-coated balloons in those additional studies and the control group of 170 patients in the randomized trial arm of PTA alone. Interestingly, when we started to look at the multi-variable analyses, we did something that we ordinarily would not do, but because of the pressing issue around paclitaxel mortality, we actually did a standard covariate analysis looking at predictors and then we forced drug and drug dose into the model to see if they would come up positive as a predictor of outcome. As you might expect, not surprisingly, we found that age, congestive heart failure, diabetes and renal insufficiency were the four major predictors of mortality in a group of patients who were largely claudicates with significant peripheral vascular disease. No surprise there. We all know the patients don't die of claudication, they die of cardiovascular disease, and this I think bears that out. When we force drug into the model, in point of fact, not a dose nor the presence of drug had any impact on death rates in the model, so there was no predictive value there whatsoever. Those are the results. Again, they're out to three years, and I think one of the important things that we have to recognize is that the numbers are relatively small and the follow-up is relatively limited and by itself, although it doesn't show any signal, it probably doesn't stand on its own to refute a larger meta-analysis, but does I think contribute to the dataset that is becoming more evident that the individual analysis do not appear to show mortality effects. Dr Greg Hundley: Very good. So this is Dr Josh Beckman at Vanderbilt University. Josh, could you talk to us a little bit and put this paper in perspective relative to the prior published literature in terms of how you manage patients with peripheral arterial disease? Dr Joshua Beckman: I have to say first, I'm really glad that we're able to publish this paper from Bill Gray and his group. We are, and I'm going to put this in really muted terms, in extraordinary times. I have never seen what is going on now happen with any other technology or really even medical therapy in the 20 plus years I've been a practicing physician. I think for the audience, it's really important to understand what is going on right now because if you don't pay attention to this space, you may not realize what's really been happening. Bill did a nice job at telling you why he did the study, which was this Katsanos aggregate level meta-analysis that was published in JAHA back in December. On the basis of this paper, there has been a rapid development of worry and concern that these devices may be associated with late mortality. This concern has spread to the Food and Drug Administration, which has now put out three letters to healthcare professionals, each of them basically suggesting that you should choose non drug-coated either balloons or stents first, and if you want to use these, you have to have an extended conversation with the patients discussing the risks. And so in response to this aggregate level meta-analysis, which had an extensive number of lost to follow-up patients and didn't account for crossovers and the usual problems with this kind of information, I have been really impressed by the community of people who are interested in this topic and work with these kinds of devices. And by that, I mean, the response has not just been a series of editorials. The response has really been, "Let's find every single piece of data that we can find to see whether or not this signal holds up," because as evidence-based physicians, we take one piece of data and say that it is one piece of data, and then we have to put it into the context of all of the other pieces of data that were published. And so I know that Dr Gray is old enough to remember 10 years ago when these devices were being used in the coronary arteries with drug eluting stents. And as far as anybody can tell with studies that were two to three times larger or meta analyses two to three times larger than the study published in December, there was no mortality signal. It should be made clear that in doses that dwarf the doses from these devices, when these medications are given to pregnant women who have breast cancer, not only is the mother fine but the fetus is fine. And so I think paper that we are discussing this morning in particular, but the group of investigators in the space has really stepped forward to publish as much data as possible to fill out our understanding and place the original study in the correct context. And so when you understand what's happening in the community, and there's been a significant reduction in the use of these devices on the basis of that one publication at the expense of patients for whom these devices are really much better at limb outcomes, then you can understand why we were so interested in the paper by Dr Gray. This is another brick in creating the foundation to really have a fuller and better understanding of any possible relationship between the use of these devices and a nonspecific increase in mortality two to five years later, which as far as I can tell, I've never seen something that may end up being a poison that doesn't have a specific mechanism of causing morbidity or mortality. And so when we got this paper, I was really happy to be able to work with Bill and bring it to the level that it is now so that when it's published in October, it's going to be another really important contribution and I just want to congratulate the authors for doing that work. I will say, and I'd like to get Bill's perspective on how he thinks the information that's now being published is going to help us understand what to do with these devices. Dr William Gray: Yeah, that's a great question, and I want to emphasize something you brought up, which I did not, which is at the aggregate level data that Katsanos used to publish his analysis was really all he had access to, which means that he had some numerical data from prior published publications but did not have patient level data. And so what Josh is referring to appropriately is the concept that each individual holder of those data, those patient level data, are now coming forward with their own analysis of those data at a patient level, which allows us to look more granularly and more clearly at the causes of death. For example, in this study, the causes of death did not cluster around cancer. They were largely cardiovascular, and they were not dis-equally distributed or unequally distributed between the two groups. So I think that patient level data, to get back to your original question, Josh, the patient level data will be incredibly important from each of the experiences with the various drug-coated balloons and drug eluting stents on the market because it does allow us to look more closely at the mechanism of death and whether there's any putative cause that might be assigned to paclitaxel. As you mentioned, the pharmacology of this is not understandable. The only type of pharmacology that would work like this was if paclitaxel was radioactive and accumulated a hazard along the way, but we know that's not true. I think extend your question, it's important to say that both the FDA and other independent groups like VIVA have looked closely at the meta analytic data both from a patient level and aggregate level data set, and they have seen a signal at five years. The problem with that is that data starts to winnow down very quickly at five years. There's not a lot of numbers, so that's the first problem, and the meta-analysis that have followed the publication by Katsanos. The second problem is, as Josh alluded to, there's a lot of missing data. Either patients withdrew or got lost to follow-up, and that didn't happen at an equal distribution between the control and the active arms, so there's some ascertainment bias there. And lastly, there's a crossover, that is patients who are in the control arm crossed over near as we can tell at a rate of about one in five or one in four to an active arm in the first year alone, which means they need to be reassigned to a risk pool that includes the original assignment of paclitaxel randomization. My sense is that those data will not get any better in the near-term future because the problems I just listed are not going to go away anytime soon. And so we are left with these individual patient level data and other big data, like Medicare analyses of tens of thousands of patients or Optum insurance analyses of again, tens of thousands of patients, which actually show no difference between the treatment with paclitaxel in the real world and patients treated with non-paclitaxel devices. So while we are comfortable and happy to publish these data and we think that are meaningful in terms of contributing to the larger dataset, we recognize the flaws and the limitations in the meta-analysis, which will not be solved soon or quickly. Dr Joshua Beckman: So, I totally agree with what you just said. I will also say that every time data like this is published, it adds to the picture to make our understanding clearer. And you are responding directly to the Food and Drug Administration, who basically said they are not settled on this question either. It is noted, they are worried about it, and what they've really asked for is for more data to be published. And so when people analyze data like these, I think it is really helpful to the rest of us to create a fuller and more granular picture of the overall state of the field. Dr Greg Hundley: We want to thank again both Josh for his time and Bill for his time. Hope you have a great week, and both Carolyn and I look forward to sharing with you again next week. Take care everyone. Dr Carolyn Lam: This program is copyright American Heart Association 2019.

ai england food european philadelphia medicine hero pennsylvania argentina journal run discovery singapore madrid birmingham fda richmond medicare new york university paths esc acl fischer vanderbilt vanderbilt university american heart association pta drug administration cardiology a1 circulation m2 ldl cec indications hdl apl european society optum jaha on my mind pulmonary hypertension cnic vcu health duke national university nhlbi john rutherford bill gray kaplan meier arvc william gray carolyn lam world symposium gsk3 intrigued well new york heart association

Circulation September 17, 2019 Issue

Play Episode Listen Later Sep 16, 2019 24:36

Dr. Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, you know I'm vegetarian and any paper on plant-based diet will always interest me, and of course, we have one as a featured paper this week, very interestingly talking about changes in plant-based diet quality, meaning that there could be good plant-based diets and not so good plant-based diets. I mean we all know that potato chips, for example, are still plant-based. But, anyways, so this feature paper discusses the changes in these plant-based diet quality and association with total and cost-specific mortality. Neat, huh? Dr. Greg Hundley: Yeah. I can't wait to hear about that one. I know that's a favorite topic of yours. How about if we have a sip of coffee and jump into our other articles? Dr. Carolyn Lam: Sure. I'm sipping away, and have already picked my first paper. This talks about mutations in plakophilin 2, which are the most common cause of gene-positive familial arrhythmogenic right ventricular cardiomyopathy. Dr. Greg Hundley: No quizzes for me on plakophilin 2, please. Dr. Carolyn Lam: All right, well, let me tell you all about it. Plakophilin 2 is classically defined as a protein of the desmosome, which is an intracellular adhesion structure. Studies though have suggested that plakophilin 2 also translates information at the initiation. Recent studies have also shown that plakophilin 2 translates information initiated at the site of cell to cell contact into intracellular signals that maintain structural and electrical homeostasis. Now, the important thing is that mutations in plakophilin 2 associated with most cases of gene-positive arrhythmogenic right ventricular cardiomyopathy or ARVC. However, the molecular and cellular mechanisms responsible for arrhythmias in ARVC remain unclear. Dr. Carolyn Lam: In today's paper, Doctors Delmar and Cerrone from New York University School of Medicine and their colleagues studied the role of cardiomyocyte plakophilin-2 expression in cardiac function. To do that, they utilized a cardiomyocyte-specific, tamoxifen-activated, plakophilin-2 knockout murine line. They found that loss of plakophilin-2 expression caused, as an early event and predominantly in the right ventricle, a non-transcriptional and likely arrhythmogenic, connexin-43-dependent disruption of calcium homeostasis. Dr. Carolyn Lam: The phenotype included accumulation of calcium in three intracellular compartments, the junctional sarcoplasmic reticulum, the cytoplasm, and the mitochondria. Right ventricular myocytes also showed increased eagerness of ryanodine-receptor-2 channels to release calcium from the sarcoplasmic reticulum. Intrinsic ryanodine-receptor-2 properties were also modified further contributing to the pro-arrhythmogenic state. In summary, the authors postulated that disruption of calcium homeostasis in the right ventricle is a major arrhythmia trigger in patients with ARVC. The data identified both the ryanodine-receptor-2 channel and the connexin-43 hemichannel as targets for antiarrhythmic therapy in this population. Dr. Greg Hundley: Very interesting that ARVC is such a worrisome concern, and gathering this mechanistic information is just so helpful. Dr. Carolyn Lam: Exactly. Dr. Greg Hundley: I have a basic science paper, but it was actually interesting because of the conduct was in many, many human subjects. It emanates from the large Million Veteran Program. There are a whole list of coauthors that are recognized as equal contributors, but Scott Damrauer actually serves as the corresponding author from the VA Medical Center. What it's addressing, about 13% of African American individuals carry two copies of the APOL1 risk alleles, G1 or G2, that are associated with a one and a half to two and a half fold increase in the risk of chronic kidney disease. Dr. Greg Hundley: There've been conflicting reports as to whether an association exists between these APOL1 risk alleles and cardiovascular disease independent of the effects of the APOL1 on kidney disease. Here, the investigators thought to test the association of these G1 and G2 alleles with coronary artery disease, peripheral arterial disease, and stroke among African American individuals in the Million Veterans Program. Dr. Carolyn Lam: Seems like a great study population and designed to look at this. What did they find? Dr. Greg Hundley: Among 30,903 African American Million Veterans Program participants, 3,941 or about 13% carried the two APOL1 risk allele, high-risk genotype. Individuals with normal kidney function at baseline with the two risk alleles had a slightly higher risk of developing coronary artery disease compared to those with no risk alleles. Similarly, modest associations were identified with incident stroke and peripheral arterial disease. However, when modeling both cardiovascular and renal outcomes, APOL1 was strongly associated with incident renal disease while no significant association with the cardiovascular disease endpoints could be detected. In conclusion, what the authors are indicating is that the APOL1 risk variants display a modest association with cardiovascular disease, and this association is likely mediated by the already previously known association of APOL1 with chronic kidney disease. Dr. Carolyn Lam: Interesting. Dr. Carolyn Lam: My next paper also has to do with chronic kidney disease and this time looking at metformin use and clinical outcomes in patients with diabetes with or without heart failure or kidney dysfunction. We know that metformin is the first-line therapy for type 2 diabetes, although its effects on the cardiovascular system are actually, not fully proven. In this next paper, the authors examine metformin use in the SAVOR-TIMI 53 Trial. Dr. Greg Hundley: Tell us a little bit about that SAVOR-TIMI 53 Trial. How is that organized? Dr. Carolyn Lam: Just as a reminder, the SAVOR-TIMI 53 trial was a multinational, randomized, controlled cardiovascular outcomes trial that compared the dipeptidyl peptidase-4 or DPP4 inhibitor, Saxagliptin, with placebo, enrolling almost 16,500 patients with type 2 diabetes and cardiovascular disease or elevated cardiovascular risk. Dr. Carolyn Lam: Now, in the current paper led by Dr. Bergmark from TIMI study group in Brigham and Women's Hospital and Harvard Medical School, the authors performed the post hoc analysis and looked at patients in SAVOR-TIMI 53 with baseline biomarker samples of whom there were more than 12,000 patients and classified these patients as ever versus never taking metformin during the trial period. The associations between metformin exposure and outcomes were estimated using inverse probability of treatment weighting, Cox modeling. Dr. Carolyn Lam: They found that among patients with type 2 diabetes and high cardiovascular risk in the SAVOR-TIMI 53 trial, metformin use was associated with lower rates of all-cause mortality including after adjustment for clinical variables and biomarkers, however not lower rates of the composite endpoint of cardiovascular death, MI or stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease. Dr. Greg Hundley: Excellent. Dr. Greg Hundley: I'm going to transition to another clinical trial and this one is looking at ezetimibe in elderly patients and looking at efficacy for preventing cardiovascular-related events. The paper comes from Yasuyoshi Ouchi from Toranomon Hospital in Japan. Evidence regarding the primary prevention of coronary artery disease events by LDL-C/lipid-lowering therapy in order individuals that are above the age of 75 years, is somewhat incomplete. This trial tested whether LDL-C lowering with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. They implemented a multicenter, prospective, randomized but open-label, blinded, endpoint, however, evaluation design conducted among 363 medical institutions in Japan. Dr. Greg Hundley: In the study, there're 3,796 patients that are aged greater than 75 years with elevated LDLC without a history of coronary artery disease that already were receiving dietary counseling. They're randomly assigned one-to-one to receive as ezetimibe 10 milligrams once daily versus usual care with their randomization stratified in a block design on age, sex, and baseline LDL-C. The primary outcome is the composite of sudden cardiac death, myocardial infarction, coronary revascularization, and stroke. Dr. Carolyn Lam: Ooh, so tell us the results. Dr. Greg Hundley: There were several patients that had to be excluded, so what ended up happening, there's 1,716 and then 1,695 that are included in each of the two respective arms for the primary analysis. What they found is that as ezetimibe reduced the incidents of the primary outcome. Then, regarding some secondary outcomes, the incidents of composite cardiovascular events and coronary revascularization were lower in the ezetimibe group than in the control group. But, there was no difference in the incidents of stroke, all-cause mortality, or adverse events in the two different groups. Dr. Carolyn Lam: Can you sum it up for us, Greg? What should we take home regarding ezetimibe and what further do we need to do? Dr. Greg Hundley: Good point, Carolyn. I think what we can take away from this study is that LDL-C lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals greater than 75 years of age with an elevated LDL-C. However, remember, it was open label, so I think a placebo, controlled, randomized clinical trial will be required to validate the data that were obtained in this study. I think another study is probably going to be needed. Dr. Carolyn Lam: Thanks, Greg. Well, let's move on to our feature discussion, shall we? Dr. Carolyn Lam: Today's feature paper is of personal interest to me and I'm sure of widespread interest to everybody. Why? It's on plant-based diet. We've heard a lot about it. I'm vegetarian and very, very loudly self-confessed, but does the quality of a plant-based diet actually matter? Such an important question. Dr. Carolyn Lam: I'm so pleased to have the authors of this very remarkable paper, Dr. Megu Baden as well as Dr. Shilpa Bhupathiraju, both from the Harvard T.H. Chan School of Public Health; and our associate editor, Dr. Mercedes Carnethon from Northwestern University Feinberg School of Medicine. Welcome, ladies. What a nice chat we're going to have on this very personal topic to me as well. Dr. Carolyn Lam: First of all, maybe, could I ask, Shilpa, do we need another study on plant-based diet? Could you tell us the rationale for what you did this time? Dr. Shilpa Bhupathiraju: Like you said, when we talk about plant-based diets and what people usually think is, well, it's vegetarian or not. But, I think there's much more to a vegetarian diet. It's the quality that matters. Previous studies really then differentiate the quality of a vegetarian diet. To this extent, we developed plant-based diet indices, which actually capture the quality of a plant-based diet, so we have an overall plant-based diet index which captures the amount of plant-based foods; a healthy plant-based diet index, which captures the quantity of healthy plant-based foods; and again, the unhealthy plant-based diet index, which captures the quantity of unhealthy, plant-based foods. Dr. Carolyn Lam: Thanks. Meg, if you don't mind, I know everybody is asking this as they're listening. Could you give us some examples of what an unhealthy plant-based diet index would consist of compared to healthy? Then, perhaps, tell us a little bit about your study and what you found. Dr. Megu Baden: First of all, let me explain again. In this study, we use three versions of plant-based diet indices that can assess the quality of plant foods in general population. The first index is an overall plant-based diet index, PDI for short. A second one is a healthful plant-based diet index, HPDI. The third one is an unhealthful plant-based diet index, UPDI. In order to create these indices, we divide all food groups into three larger categories. One is the healthy plant foods, which contains whole grains, fruits, vegetables, nuts, legumes, vegetable oils, tea, and coffee; less healthy plant foods such as fruits juice, refined grains, potatoes, sugar-sweetened beverages, and sweets or desserts; and animal foods, which is animal food, dairy, eggs, fish, meat, miscellaneous animals-based food. Dr. Megu Baden: We investigated the association between preceding trailblazing changes in these indices and subsequent total and cause basic mortality in two large US cohorts. We found that compared with participants whose diet remained stable, the hazard ratio for total mortality, among those risks, the greatest increase in PDI was 0.95; for the greatest increase in HPDI, the healthful versions of the PDI was 0.90; and the greatest increasing in unhealthful PDI was 1.12. In contrast, the hazard ratio among participants with the greatest difficulty is in PDI, was 1.09; the greatest decrease in healthful PDI was 1.10; and the greatest decreasing in unhealthful PDI was 0.93. For CVD mortality, the risk was 7% lower for our 10 point increase in PDI, and 9% lower for HPDI and 8% higher for UPDI. Dr. Megu Baden: In summary, we found that improving plant-based diet quality over a 12-year period was associated with a lower risk of total and CVD mortality, whereas increased consumption of unhealthful plant-based diet was associated with a higher risk of total and CVD mortality. Dr. Carolyn Lam: Could I ask, Shilpa, to maybe add a line of ... have you applied this information in any way yourself or with patients, or is there an overwhelming take-home message you'd like people to remember? Dr. Shilpa Bhupathiraju: Yeah, I'm not a clinician myself, but I'm a public health researcher. I'm in India currently and I'm giving a talk to South Asians and the emphasis on vegetarianism. But, again, the quality of the vegetarianism is important. Being a vegetarian is not enough, but what goes into it is really important. If it's a white rice and sugar-sweetened beverages, it's not good, so really the emphasis should be on whole grains, consuming more nuts and legumes. I think that's important. Dr. Carolyn Lam: Oh, that's great. Mercedes, we've discussed this paper as associate editors, so proud to be publishing this in circulation. Could you share some of your thoughts on the implications of these findings? Dr. Mercedes Carnethon: The authorship team has done an outstanding job of clarifying a very complicated issue. I think what we really like about this and the ways in which it really adds to the literature, what you point out, that every vegetarian diet isn't the same. I was very impressed with the thought that went into classifying vegetarian foods as healthy or unhealthy. I would be interested in hearing more from the authors, particularly, since I feel they did a good job of how they dealt with complicated foods or mixed foods. I think one example given was a pizza, which has tomato sauce, but it also has other things, so I would love to hear from the authors how they classified complicated foods. Dr. Shilpa Bhupathiraju: The decision to classify pizza as an animal food was somewhat, I would say, arbitrary. I do agree that there's lots of tomato sauce, but again, I think the decision that went to it, it does have a ton of cheese, processed cheese, I think that's why we classified that as an animal food. The other complicated foods are mixed dishes that we struggled with were cream soups. We thought about what the base was or what the general preparation of that would be. Given that heavy cream is a major ingredient, so those were again, classified as animal foods. Dr. Mercedes Carnethon: I think there's a lot of logic in that and I really like the thought and care that you put into that. The other questions I have, I feel that you did a really nice job of, are even portion sizes. Tell me how you handled portions. Dr. Megu Baden: We basically take the information from our food frequency questionnaire. All of them are per the serving sizes, so we considered how participants reported how often on average they had consumed each food of our standard portion size in the past year. I know it's difficult to indicate the portion size. Shilpa, would you add something for the portion size for that? Dr. Shilpa Bhupathiraju: Yes. Like Megu said, we use standardized portioning sizes, so a cup of fruit, a cup of vegetables, an eight-ounce, or a cup of tea or coffee, so that's how we use what people use in general. The portion sizes are all specified on the food frequency questionnaire, so the nurses or the health professionals, they understand exactly what they're reporting. Is it a glass of fruit juice or half a glass? Then, we can word those frequencies into standardized serving sizes onto servings per day. Dr. Carolyn Lam: Great. Shilpa, could I follow up from Mercedes very important question? How does the index account for portion size too, as an is too much of even a good thing become a bad thing? You know what I mean? Dr. Shilpa Bhupathiraju: The index itself is a score. The way we capture it, as you know, everything is converted from frequencies into servings per day for each participant. Then, what we did was we divided the participants based on the distribution of the data into quintiles. Those in the highest category of the healthy plant foods received the highest points. The scoring varied a little bit based on which index we were calculating. But, in general, what we did was we divided everybody into five groups or quintiles. Then, the scoring varied depending on what we were calculating. For the HPDI, which is the healthy plant-based diet index, those in the fifth group or the highest intake received the maximum number of points, which was five. For the unhealthy plant-based diet index, those people received the reverse scoring, so they received zero points. Essentially, the participants were divided into quintiles and the scoring was done accordingly. Dr. Carolyn Lam: Maybe I could ask you a question on a different track, and I'm not sure if you have some answers here, but I noticed that your study population was impressive, almost 49,500 women from the Nurses' Health Study, almost 26,000 men from the Health Professionals Follow-up Study. Did you find any sex differences? Dr. Shilpa Bhupathiraju: We didn't find any sex differences. We did some sensitivity analysis by cohort and we didn't find a statistically significant interaction, which is I think good to note because we would expect the effects to be similar in men and women. Dr. Carolyn Lam: I think both men and women need to hear that. None of us are excused from, I suppose, trying to gear towards a healthy plant-based diet. I think that's what I'm hearing. Mercedes, do you have more thoughts to add? Dr. Mercedes Carnethon: I do. One thing I really like about this particular paper is the way the you acknowledge some of the limitations that we face when interpreting findings from observational studies, particularly observational studies of a health behavior when we know that health behaviors often cluster or correlate with other health behaviors. Can you tell us a little bit about some of the cautions and interpretation that you certainly acknowledged and presented very well? Dr. Shilpa Bhupathiraju: Sure. Our primary analysis was looking at changes, so long-term changes. When people change a diet or their lifestyle, they change something else. As you can see from our paper, those who improve the plant-based diet quality, we're also, in general, tended to be healthier. This being an observational study, we tried to control for those as to the greatest extent possible, but again, they could be residual confounding. We maybe failed to measure for certain things that we were unaware of or that we did not measure. I think we really can't get at causality, but I think the consistency of the evidence from our previous papers and from this paper point to a suggestion that improving plant-based diet quality is definitely associated with better health outcomes and a lower risk of death. But, again, it is important to know that this is observational and there could be changes in other health behaviors that we did not measure that could explain this association. But, we did as well of a job as we could in trying to control for these changes and other behaviors, lifestyles or even health conditions. Dr. Mercedes Carnethon: Thank you. Dr. Carolyn Lam: Thank you so much, Meg and Shilpa. You've been listening to Circulation on the Run. Don't forget to tune in again next week. Dr. Carolyn Lam: This program is copyright American Heart Association 2019

Pediheart Podcast #83: Clinical Presentation of Pediatric Patients at Risk for Sudden Cardiac Arrest

Play Episode Listen Later Sep 6, 2019 29:48

This week's episode is co-branded with SADS.ORG and we review a paper on the clinical presentation of those who have conditions associated with sudden cardiac death. Are there questions about the patient and family history and physical examination signs that can improve the identification of those at risk before an event of cardiac arrest? We review this important question and others with Assistant Professor of Pediatrics at Washington University in St. Louis, Dr. Aarti Dalal. Referenced also in this discussion is the following webpage: https://www.sads.org/Library/School-Materials/Risk-Assessment#.XW25gy2ZOu4.DOI:10.1016/j.jpeds.2016.06.088

Pediheart Podcast #83: Clinical Presentation of Pediatric Patients at Risk for Sudden Cardiac Arrest

Play Episode Listen Later Sep 6, 2019 29:48

27 August 2019

That Bad Review with Adrian Easdown

Play Episode Listen Later Aug 27, 2019 8:23

Jane Ferguson: Hello, and welcome to Getting Personal, Omics of the Heart, your monthly podcast from Circulation: Genomic and Precision Medicine. I'm Jane Ferguson. It is August, 2019, and this is episode 31. Let's get started. Our first paper comes from Freyja van Lint and Cynthia James, from University Medical Center Utrecht, and is entitled Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Desmosomal Variants Are Rarely De Novo, Segregation and Haplotype Analysis of a Multinational Cohort. In this study, the team was interested in exploring variants that are associated with arrhythmogenic right ventricular cardiomyopathy or ARVC. ARVC is often attributable to pathogenic variants in genes encoding cardiac desmosomal proteins, but the origin of these variants had not been comprehensively studied. The investigators identified ARVC probands meeting 2010 task force criteria from three ARVC registries in the United States and Europe and who had undergone sequencing of desmosomal genes. All 501 probands, 322 of them, or over 64%, carried a pathogenic or likely pathogenic variant in the desmosomal genes PKP2, DSP DSG2, DSC2, and JUP. The majority of these, over 75%, we're not unique with these variants occurring in more than one proband. The team performed cascade screening and were able to identify the parental origin of almost all of the variants. However, they identified three de novo variants, including two whole gene deletions. They conducted haplotype analysis for 24 PKP2 variants across 183 seemingly unrelated families and concluded that all of these variants originated from common founders. This analysis sheds light on the origin of variants in desmosomal genes and suggests that the vast majority of these ARVC variants originate from ancient founders with only a very small proportion of de novo variants. These data can inform clinical care particularly concerning genetic counseling and cascade screening of relatives. The next paper continues a theme of cardiomyopathy and comes from Derk Frank, Ashraf Yusuf Rangrez, Corinna Friedrich, Sven Dittmann, Norbert Frey, Eric Schulze-Bahr and colleagues from University Medical Center Schleswig-Holstein. In this paper, Cardiac α-Actin Gene Mutation Causes Atrial-Septal Defects Associated with Late-Onset Dilated Cardiomyopathy, the team was interested in understanding the genetics of familial atrial-septal defect. They studied large multi-generational family with 78 family members and mapped a causal variant on chromosome 15q14, which caused nonsynonymous change in exon 5 of the ACTC1 gene. In silico tools predicted this variant to be deleterious. Analysis of myocardial tissue from an affected individual revealed sarcomeric disarray, myofibrillar degeneration, and increased apoptosis. Proteomic analysis highlighted extracellular matrix proteins as being affected. The team over-expressed the mutation in rats and found structural defects and increased apoptosis in neonatal rat ventricular cardiomyocytes and confirmed defects in actin polymerization and turnover which affected contractility. These data implicate the variant in ACTC1 as causing atrial-septal defects and late-onset cardiomyopathy in this family and revealed the underlying molecular mechanisms affecting development and contractility. The next paper is entitled Characterization of the CACNA1C-R518C Missense Mutation in the Pathobiology of Long-QT Syndrome Using Human Induced Pluripotent Stem Cell Cardiomyocytes Shows Action Potential Prolongation and L-Type Calcium Channel Perturbation, and it comes from Steven Estes, Michael Ackerman and colleagues at the Mayo Clinic. They set out to use patient-derived human induced pluripotent stem cells to understand the pathogenicity of a variant in the CACNA1C gene in Long-QT Syndrome. They obtained cells from dermal punch biopsy from an individual with long-QT and a family history of sudden cardiac death who carried an R518C missense mutation in CACNA1C. Starting with fibroblasts, they reprogrammed the cells into iPSCs and then differentiated these into cardiomyocytes. They corrected the mutation back to wild type using CRISPR/Cas9 and then compared the cardiomyocytes carrying the original patient mutation with isogenic corrected cardiomyocyte controls. They found significant differences in action, potential duration, and in calcium handling. Patch clamp analysis revealed increased L-type calcium channel window current in the original mutation-carrying cells in addition to slow decay time and increased late calcium current compared with the isogenic corrected control human iPSC cardiomyocytes. These data strongly suggest that CACNA1C is a long-QT susceptibility gene and demonstrate the potential in using patient-derived iPSCs and CRISPR/Cas9 to understand underlying mechanisms linking variants to disease. The final paper this month is Blood Pressure-Associated Genetic Variants in the Natriuretic Peptide Receptor-1 Gene Modulate Guanylate Cyclase Activity and comes from Sara Vandenwijngaert, Chris Newton-Cheh and colleagues on behalf of the CHARGE+ Exome Chip Blood Pressure Consortium, the CHD Exome+ Consortium, the Exome BP Consortium, the GoT2D Consortium, the T2D-GENES Consortium, and the UK Biobank CardioMetabolic Consortium Blood Pressure Working Group. This team wanted to understand how variants in the NPR-1 gene affect the function of the atrial natriuretic peptide receptor-1. They performed a meta-analysis across over 491,000 unrelated individuals, including both low frequency and rare variants in NPR-1 to identify their association with blood pressure. They identified three nonsynonymous variants associated with altered blood pressure at genome-wide significance and examined the function of these variants in vitro. Using cells expressing either wild type NPR-1 or one of the three identified variants, they explored the impact of the variants on the ability of cells to catalyzes the conversion of guanosine triphosphate to cyclic 3′,5′-guanosine monophosphate in response to binding of atrial or brain natriuretic peptide. Increased levels of cyclic GMP are known to decrease blood pressure by inducing by natriuresis, diuresis, and vasodilation. Two variants which associated with high blood pressure in the population meta-analysis were associated with decreased cyclic GMP in response to ANP or BNP in vitro, while one variant which associated with lower blood pressure in humans was associated with higher cyclic GMP production in vitro. These data show that variants affecting loss or gain of function in guanylate cyclase activity could have downstream effects on blood pressure at the population level. That's it for this month. Thank you for listening. We will be back with more next month. This podcast was brought to you by Circulation: Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2019.

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65. Paul Bambei – CEO of ARVC on The Pros and Cons of Emotional Decision Making, the Growth of a Recession Proof Industry & Attracting Diverse Minority Groups

Play Episode Listen Later Jul 14, 2019 42:15

Paul Bambei is the President and CEO of the Association of RV Parks & Campgrounds (ARVC), based in Denver, Colorado. Adrian was fortunate enough to catch up with Paul at the Tourism Innovators Conference held at the Gold Coast in June 2019 and chat with him about the parallels and differences between the Australian and American markets. In this week’s ... Read More The post 65. Paul Bambei – CEO of ARVC on The Pros and Cons of Emotional Decision Making, the Growth of a Recession Proof Industry & Attracting Diverse Minority Groups appeared first on Adrian Easdown.

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Who is least adherent to statins, and more

MDedge Cardiocast

Play Episode Listen Later Feb 22, 2019 6:59

Silent strokes are common after noncardiac surgery, troubling news about nonadherence to statins, what cardiologists need to know about ARVC, and how gender inequality in medicine affects the health of all women.

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Episode 22 Nov 2018

Play Episode Listen Later Jan 28, 2019 12:34

Jane Ferguson: Hello, welcome to Getting Personal: Omics of the Heart, Episode 22. This is a podcast from Circulation: Genomic and Precision Medicine, and the AHA Council on Genomic and Precision Medicine. I am Jane Ferguson and it's November 2018. Our first article comes from Carlos Vanoye, Alfred George and colleagues from Northwestern University Feinberg School of Medicine and is entitled, High Throughput Functional Evaluation of KCNQ1 Decrypts Variance of Unknown Significance. So a major growing problem in clinical genomics is that following the identification of a variant that is potentially linked to a disease phenotype, without further interrogation, it's really hard to make sense of the functional significance of that variant. Right now, the large number of variants of unknown significance lead to confusion for patients and clinicians alike. To allow for accurate diagnoses and the best treatment plans, we need a way to be able to screen variants to assess their function in a fast and cost-effective manner. In this paper, the authors decided to focus in the KCNQ1 gene, a cardiac ion channel, which can affect arrhythmias. They aim to assess whether a novel high-throughput functional evaluation strategy could identify functional mutations, as well as an in vitro electrophysiological approach. Which is effective, but expensive and time-consuming. Their approach capitalized on an existing automated electrophysiological recording platform that had originally had been developed for drug discovery essays. They selected 78 variants in KCNQ1 and assessed their function using the High-Throughput platform, which coupled high efficiency, cell electroporation with automated plain or patch clamp recording. They compared the results to traditional electrophysiological essays and find a high rate of concordance between the two methods. Overall, they were able to reclassify over 65% of the variants tested, with far greater efficiency than traditional methods. While this method will not work for all genes and phenotypes, the authors have demonstrated an efficient method for functional interrogation of variants. Which may greatly accelerate discovery and conditions such as Long QT or other congenital arrhythmias. The next paper, Nocturnal Atrial Fibrillation Caused by Mutations in KCND2 Encoding Poor Forming Alpha Subunit of the Cardiac KV 4.2 Potassium Channel, comes from Max Drabkin, Ohad Birk, and colleagues at Soroka University Medical Center in Israel. This paper also focuses on cardiac ion channels and the role of mutations in atrial fibrillation. In a family with early-onset peroxisomal AF across three generations, whole XM sequencing revealed a variant in KCND2 encoding the KV 4.2 Potassium Channel, which segregated consistent with autosomal dominant heredity. This variant resulted in a replacement of a conserved [inaudible] residue with an arginine. To investigate functional consequences of this novel variant, they conducted experiments in xenopos laevis oocytes and found that there is decreased voltage depended channel and activation and impaired formation of the KV 4.2 Homotetramer and the KV 4.2, KV 4.3 Heterotetramer. Overall, this study shows that a novel mutation in a conserved Protein kinase C Phosphorylation site within the KV 4.2 Potassium Channel underlies the phenotypes observed in a family of peroxisomal atrial fibrillation. The targeting Atrial KV 4.2 might be an effective therapeutic avenue. Next up, Michael Levin and Scott Damrauer and colleagues from the University of Pennsylvania published an article entitled, Genomic Risks Stratification Predicts All-Cause Mortality After Cardiac Catheterization. They were interested in understanding the utility of polygenic risk scores for disease prediction. They constructed a genome Y genetic risk score for CAD and applied it to individuals from the Penn Medicine Bio-bank who had undergone Coronary angiography and genotyping. They included over 139,000 variants for the 1,500 ancestry subjects who were included and classified them as high or low polygenic risk. Individuals who were classified as high polygenic risk were shown to have higher risk of All-Cause mortality than low polygenic risk individuals despite no differences in traditional risk factor profiles. This was particularly evident in individuals with high genetic risk but no evidence of angiographic CAD. Adding the polygenic risk score to a traditional risk assessment model was able to improve prediction of five year All-Cause mortality. Highlighting the utility of a polygenic score and underscoring traditional risk factors do not yet fully capture mortality risk. The next article entitled, "Bio-marker Glycoprotein Acetyls is Associated with the Risk of A Wide Spectrum of Incident Diseases and Stratifies Mortality Risk in Angiography Patients" comes from Johannes Kettunen, Scott Ritchie, Peter Würtz and colleagues from the University of Oulu Finland. GlycA is a circulating biomarker that reflects the amount of Glycated proteins in the circulation. It has been associated with cardiovascular disease, Type 2 Diabetes, and all-cause mortality. In this paper, the authors used electronic health record data from over 11,000 adults from the finish general population previously included in the "FINRISK" and "Dilgom" studies and they tested for a associations between GlycA and 468 different health outcomes over an 8-12 year follow up. They report new associations between GlycA and multiple conditions including incident alcoholic liver disease, chronic renal failure, glomerular diseases, chronic obstructive pulmonary disease, inflammatory polyarthric disease and hypertension. These associations held true even after adjusting for CRP suggesting that GlycA represents an independent biological contributor to inflammation and disease. Their findings highlight potential utility for GlycA as a biomarker of many diseases and underscore the importance future functional and mechanistic studies to understand how GlycA is linked to disease risk. Our last original research article entitled, "Tissue Specific Differential Expression of Novel Jeans and Long Intergenic Non-coding RNAs in Humans with Extreme Response to Endotoxic glycemia comes from Jane Ferguson, Murdock Riley, and colleagues from Vanderbilt University, Columbia University, and the University of Pennsylvania. That first author is none other than me, so I'm not unbiased reader of this particular manuscript, but I'd like to tell you a little bit about it anyway. We were interested in understanding the transcriptional changes that occur in tissues during acute inflammation. As part of the genetics of evoked responses to Niacin and Endotoxemia, or gene study, we recruited healthy individuals and performed an inpatient endotoxin challenge where we administered a low dose of LPS and looked at the systemic inflammatory response. Individuals vary greatly in the degree of their inflammatory response to LPS and we identified high and low responders, men and women, of African and European ancestry, who had responses in the top or bottom 10% for cytokines and fever. We conducted RNA seek and adipose tissue in 25 individuals and CD-14 positive monosites for 15 individuals in pre and two or four hours post LPS samples. We found that the differences in transcriptional response between high or low responders are mostly explained by magnitude rather than discrete sets of genes. So some core genes were altered similarly, in both groups, but overall the high responders mounted a large transcription of response to LPS or low responders rather than mounting an anti-inflammatory response actually just barely responded on the transcription level. We saw clear tissue specificity between manosites and adipose tissue we identified several long non-coding RNAs that were up or down regulated in response to LPS and validated these independent samples one of these link RNAs which we have now named Monosite LPs induced link RNA regulator vile six or Mahler Isle six, with highly regulated by LPs and monosites but not in adipose tissue. We [inaudible] THP-1 monosites and find a significant effect on iOS six expression suggesting that this is a novel link RNA that regulates Isle six expression in manosites potentially through a cd-86 dependent pathway. Overall our data revealed tissue specific transcriptional of changes that correlate with clinical inflammatory responses and highlight the role of specifically incarnate and inflammatory response. Next up is a research letter entitled "Reduced Sodium Current in Native Cardiomyocytes of a Regatta Syndrome Patient Associated with Beta Two Central Mutation" published by Constance Schmidt, Felix Wiedmann, Ibrahim El-Battrawy, Dierk Thomas, and co-authors from University Hospital Heidelberg. They obtained cardiomyocytes from a patient with Regatta Syndrome previous whole XM sequencing had implicated a variant in the Beta Two Syntrophin or "SNTB2" gene as potentially causal in this individual. Expression analysis showed lower SNTB2 expression and atrial tissue of the affected individual compared with controls. They performed electrophysiology on the Microcytes and found reduced peak sodium density and reduced late sodium current. They co-express wild type or mutant SNTB2 in heck 293 T cells and [inaudible] with the cardiac sodium channel NAV-1.5 and found a significant effect on binding which adversely affected sodium currents. This study nicely demonstrates the functional effect of this SNTB2 mutation underlying Regatta Syndrome in this patient. A second research letter comes from A.T. van den Hoven and Jolien Roos- Hesselink and colleagues from Erasmus University Medical Center in the Netherlands and is entitled "Aortic Dimensions and Clinical Outcome in Patients with SMAD three mutations, they were interested in understanding how the Aortic dilation comment individuals with SMAD three mutations compared to individuals with other syndrome and causes of Aortic dilation. In 28 patients with SMAD three mutations, there were significant growth in the Sinotubular Junction the ascending Aorta on the diaphragm over an average of 10 years of follow up at reads far higher population averages but lower than might be seen in other syndromes, such as [inaudible]. Intensive management and preventive surgery and many of the patients prevented any mortality in this group. Rounding out this issue is a clinical letter entitled "Concealed Arrhythmogenic Right Ventricular Cardiomyopathy in Sudden unexplained Cardiac Death events from Jodie Ingles, Chris Semsarian, and colleagues from the University of Sydney, Australia. They report on for clinical cases where individuals presented in early adulthood with unexplained cardiac arrest, which was later found to be attributable to mutations in the PKP2 gene. PKP2 or, Plakophilin 2, encodes an integral component of the Desmosome, which is important and Cell-Cell adhesion. Further PKP2 is involved in transcriptional activation of genes controlling intracellular calcium cycling. This gene has been implicated arrhythmogenic right ventricular cardiomyopathy in individuals with cardiac structural abnormalities. These four cases where unrelated individuals were all fans to have loss of function variants and PKP2 underlying sudden cardiac death or events, despite structurally normal hearts. This prompts questions on the clinical management of such cases of concealed ARVC. That's all from us for November, thanks to all of you out there listening. We'll be back in December for the final episode of 2018. This podcast was brought to you by Circulation Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2018.

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Pediheart Podcast # 47: ICD's In Young Athletes

Play Episode Listen Later Dec 21, 2018 41:36

This week we review the notion of sports participation in athletes who have ICD's. Is this a safe approach? How do the athletes fare? How do the devices stand up to sport? What are the subtleties of discussing this important topic with a family and how does shared decision making work in this process? We review this serious and complex topic with Dr. Rachel Lampert, Professor of Medicine at Yale University and Dr. Elizabeth Saarel, Professor of Pediatrics - The Cleveland Clinic. Both experts have much to share about their experience in this important work on how to potentially improve the quality of life for our ICD patients. doi: 10.1161/CIRCEP.118.006305

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Pediheart Podcast # 47: ICD's In Young Athletes

Play Episode Listen Later Dec 21, 2018 41:36

professor medicine decisions yale university pediatrics cardiology sudden death young athletes icd hcm qol arvc lqts arvd

Pediheart Podcast # 43: Novel Biomarker To Identify ARVC

Play Episode Listen Later Nov 23, 2018 30:38

This week we explore the topics of cardiomyopathy, electrophysiology and sudden death and delve into the world of arrhythmogenic right ventricular cardiomyopathy (ARVC). What role might autoimmune disease play in this disorder? Can a biomarker potentially allow us to identify the vast majority of individuals with this disease with high sensitivity and specificity? Can this biomarker identify 'pre-clinical' disease? Can immunological therapies possibly be used to change the course of this disorder? We explore all of these issues and more with Professor Robert Hamilton, University of Toronto, this week on the podcast. This is groundbreaking research that represents a paradigm shift in our understanding of this potentially lethal disorder. doi: 10.1093/eurheartj/ehy567

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Pediheart Podcast # 43: Novel Biomarker To Identify ARVC

Play Episode Listen Later Nov 23, 2018 30:38

university children toronto childhood identify pediatrics pediatric cardiology immunology sudden death biomarker scd cardiologia cardiomyopathy arvc arvd

Circulation September 18, 2018 Issue

Play Episode Listen Later Sep 18, 2018 18:56

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. This week's journal features two papers that deal with genetic testing in young athletes and for sudden arrhythmic death, and with findings that may surprise you. They really show the complexities of this era of genetic testing and cardiovascular medicine, and in fact are discussed as growing pains in cardiovascular genetics. You must listen to our feature discussion, which is coming right up after these summaries. The first original paper this week suggests that targeting fibronectin polymerization may be a new therapeutic strategy for treating cardiac fibrosis. Fibronectin polymerization is necessary for collagen matrix deposition and is a key contributor to increased abundance of cardiac myofibroblast following cardiac injury. In today's paper, first author Dr Valiente-Alandi, corresponding author Dr Blaxall from University of Cincinnati College of Medicine and Heart Institute, and their colleagues hypothesized that interfering with fibronectin polymerization, or its genetic ablation and fibroblasts, would attenuate myocardial fibrosis and improve cardiac function following ischemia reperfusion injury. Using mouse and human cardiac myofibroblasts, authors found that the fibronectin polymerization inhibitor pUR4 attenuated the pathological phenotype exhibited by mouse and human myofibroblasts by decreasing fibronectin polymerization and collagen deposition into the extracellular matrix as well as by myofibroblast proliferation and migration. Inhibiting fibronectin matrix deposition by pUR4 treatment or by deleting fibronectin gene expression in cardiac fibroblasts confirmed cardioprotection against ischemia reperfusion-induced injury by attenuating at first left ventricular remodeling and cardiac fibrosis, thus preserving cardiac function. In summary, interfering with fibronectin polymerization may be a new therapeutic strategy for treating cardiac fibrosis and heart failure. The Insulin Resistance Intervention after Stroke, or IRIS trial, demonstrated that pioglitazone reduced the risk of both cardiovascular events and diabetes in insulin-resistant patients. However, concern remains that pioglitazone may increase the risk of heart failure in susceptible individuals. To address this, Dr Young from Yale Cardiovascular Research Center and the IRIS investigators performed a secondary analysis of the IRIS trial. They found that older age, atrial fibrillation, hypertension, obesity, edema, high CRP, and smoking were risk factors for heart failure. Pioglitazone did not increase the risk of incident heart failure, and the effect of pioglitazone did not differ across levels of baseline risk. It should however be noted that in the IRIS trial, the study drug dose could be reduced for symptoms of edema or excessive weight gain, which occurred more often in the pioglitazone arm. Overall, pioglitazone reduced the composite outcome of stroke, MI, or hospitalized heart failure in the IRIS trial. The next study highlights the importance of genetic variation in cardiac fibrosis and suggests that while fibroblast activation is a response that parallels the extent of scar formation, proliferation may not necessarily correlate with levels of fibrosis. In this paper from co-first authors Dr Park and Ranjbarvaziri, corresponding author Dr Ardehali, from David Geffen School of Medicine, University of California, Los Angeles, the authors utilized a novel multiple-strain approach known as the Hybrid Mouse Diversity Panel to characterize the contributions of cardiac fibroblasts to the formation of isoproterenol-induced cardiac fibrosis in three strains of mice. They found that isolated cardiac fibroblasts treated with isoproterenol exhibited strain-specific increases in the levels of activation, but showed comparable levels of proliferation. Similar results were found in vivo with fibroblast activation but not proliferation correlating with the differential levels of cardiac fibrosis after isoproterenol treatment. RNA sequencing revealed that cardiac fibroblasts from each strain exhibited unique gene expression changes in response to isoproterenol. The authors further identified LTBP2 as a commonly upregulated gene after isoproterenol treatment. Expression of LTBP2 was elevated and specifically localized in the fibrotic regions of the myocardium after injury in mice and in human heart failure, suggesting that it may be a potential therapeutic target. That brings us to the end of our summaries. Now for our feature discussion. We all know that t-wave inversion is common in patients with cardiomyopathy, however up to a quarter of athletes of African descent, and five percent of white athletes also have t-wave inversion on ECG, but with unclear clinical significance despite comprehensive clinical evaluation. Now, what is the role in diagnostic use of genetic testing beyond clinical evaluation when we investigate these athletes with t-wave inversion? Well we're about to get some answers in today's feature paper, and I'm so pleased to have the corresponding author of the paper, Dr Sanjay Sharma from St. George's University of London, as well as our associate editor Dr Mark Link from UT Southwestern. Sanjay, please let us know what you did and what you found. Dr Sanjay Sharma: Well as you rightly say, that up to 25% of black athletes have t-wave inversion, as do three to five percent of white athletes. And these t-wave inversions often overlap with the sort of patterns that you see in patients with hypertrophic cardiomyopathy and arrhythmogenic cardiomyopathy. For example, 80% of people with hypertrophic cardiomyopathy have t-wave inversion as do 60% of patients with ARVC. Now we know that some ECG patterns, t-wave inversions in V1 to V4 are benign in black patients, but the significance of other ECG patterns is unknown. Cascade screening in family members with cardiomyopathy have shown that t-wave inversion may be the only manifestation of gene inheritance, and there are reports to suggest that some athletes with t-wave inversion do go on to develop overt cardiomyopathy. Now when we investigate the vast majority of our patients with t-wave inversion, these are our athlete patients, we don't actually find anything. But over the past decade, also, these has been major advance in next generation sequencing that allows us to perform genetic testing in a large number of genes that can cause diseases, capable of causing sudden death. And so, we thought we'd investigate the role of this gene testing in athletes with t-wave inversion. We looked at a hundred, 50 black athletes and 50 white athletes who had t-wave inversion, and we investigated them comprehensively with clinical tests. But we also added in a gene panel looking at 311 genes implicated in six cardiac diseases, notably hypertrophic cardiac myopathy, arrhythmogenic cardiomyopathy, dilated cardiomyopathy, left ventricular non-compaction, long QT syndrome, and the brugada syndrome. We found that 21% of our athletes were then diagnosed with a cardiac disorder capable of causing sudden death, and the vast majority of these people had hypertrophic cardiomyopathy. And this diagnosis was based on clinical evaluation. When we looked at gene testing, we found that gene testing only picked up a problem in 10%. So, the diagnostic yield of gene testing was half that of comprehensive clinical investigation. When we actually looked at athletes who had nothing wrong with them in clinical investigation, and actually had a gene mutation, we found that only 2.5% of athletes who had t-wave inversion but clinically normal tests, actually had something wrong with them. And our conclusions were that gene testing picks up only half the athletes that clinical testing does, and gene testing is only responsible for identifying 2.5% of athletes with t-wave inversion, where clinical tests are negative. That was the summary of our study in short. We did find that black athletes were less likely to have a positive diagnosis of cardiac myopathy than white athletes, and black athletes are also less likely to have a genetic mutation capable of causing a cardiomyopathy than white athletes. Dr Carolyn Lam: First and foremost, congratulations on such a beautiful paper, and so wonderfully summarized as well. It really seems to fly in the face, doesn't it? Of the way we've been discussing personalized medicine and saying that we're going to start whole genome sequencing everyone and that's going to provide all the answers for future disease risks. I mean, if I'm not wrong, what your paper is trying to tell us is that at this moment we don't have good examples where genetic testing may trump clinical diagnoses, and in fact we should be still focusing on a comprehensive clinical evaluation of patients and in the absence of a genotype we should learn to question what we're doing in genetic testing. Do you agree with that? Dr Sanjay Sharma: You couldn't have said that more precisely. As I've said, the diagnostic yield of clinical testing was 21% versus only 10% with genetic testing. The diagnostic yield of pure genetic testing in people with otherwise completely normal findings clinically was only 2.5%. And the other thing that I forgot to tell you was that genetic testing, if we included genetic testing in addition to comprehensive assessment, cost us three times as much as clinical investigation on its own, and had we relied solely on genetics, and nothing else, it would have cost us ten times more than clinical testing. So our cost per making a diagnosis using genetics only would have amounted to $30,000 per condition. Dr Carolyn Lam: Wow, what a great wake up call. Mark, you've thought a lot about this and in fact there was another paper in this week’s journal that has very complimentary messages. In fact you invited an editorial by Dan Roden, and I really loved his title of it, "Growing Pains in Cardiovascular Genetics." Would you maybe add your thoughts in relation to the other paper, as well as overall? Dr Mark Link: Sure. Circulation was very interested in these papers. These are really ... Now, as Dan Roden says, "Growing pains." Twenty years ago when genetics came out it was looked upon as it was going to completely change our clinical medicine and precision medicine is really relying a lot on genetics. And while ultimately that may be the case, we are in a stage now where the honeymoon is over. And the other paper that was in this same issue was a paper by Hosseini and colleagues, and it was the Clin Gen paper looking at the Brugada Syndrome abnormalities. Now the Clin Gen is an NIH sponsored group that takes individuals from a number of different institutions and actually gene testing, and tries to provide an independent assessment of the abnormality of genes. Previously is was companies that did this. A company would gene test ... They would look for gene abnormalities, try to link it with clinical disease, and they could basically then do just on their patients. But Clin Gen now is trying to tie all those companies together to get a broad consortion and to look at genetic abnormalities and whether they're truly pathologic, where there's areas of unknown significance, or whether they're truly not pathologic. So as an example, they took Brugada Syndrome, and they took the different gene abnormalities that have been described from basically different companies and different labs and different institutions, and they looked at the evidence behind the fact that they were truly pathologic, 'cause all 21 genes were defined as pathologic. They found in their independent assessment that only one ended up to be truly pathologic, and the others ones were disputed. And sort of another wakeup call that just because a single company calls a gene pathologic or Brugada Syndrome, does not make it pathologic necessarily. So we all thought these were two very important papers that looked at some of the limitations of genetic testing. We asked Dan Roden, who is really a very accomplished scholar in this field, to provide perspective on this. And I agree, I loved his title, "Growing Pains in Cardiovascular Genetics." And what he did is reviewed the history of genetic testing, and he actually starts before genetic testing and starts with Mendelian genetics, and [inaudible] genetics. And then 23 years ago they started linking that Mendelian genetics to gene abnormalities, especially in diseases such as long QT syndrome and hypertrophic cardiomyopathy. We've come a tremendous way in diagnosing gene abnormalities and associating them with these underlying cardiac myopathies and hind channel abnormalities. So no one doubts we've come a tremendous way, but there's a long way to go in terms of getting better diagnostic accuracy and really defining where these genetic testing are ultimately going to play out in clinical medicine. So everyone's excited about it, but I think these two papers are two cautionary tales that we do have to remember that genetic testing in 2018 is not the end all and be all. Dr Carolyn Lam: I love that, cautionary tales. So important. But where do we go from here? What's the take home message for clinicians listening to this today in 2018? I mean is it that perhaps when we do these things we now need to include medical geneticists and genetic counselors as vital partners as we look at this all? Perhaps we need to not forget the primacy of clinical evaluation. What do you think, Sanjay? Dr Sanjay Shar: Well, there are guidelines from the American Medical Genetics side as to what one defines as a disease-causing mutation. But I agree that we need to be using certified laboratories that can actually interpret the genetic mutations. For example, in our study of athletes, 63% actually had variance of undetermined significance. So they had spinning mistakes in their genes which probably didn't account to anything at all, but had these mutations, or these so called variance of undetermined mutations been interpreted by someone who didn't really know much about this, these could have resulted in false positive results which could cause absolute chaos for an athletes career. So I do think this type of testing has to be governed very, very carefully and needs to be performed in very specialized and certified laboratories. Dr Carolyn Lam: Indeed. Not just to the athlete, but to their families too, isn't it? Mark, what do you think is the take home message [inaudible 00:16:18]? Dr Mark Link: I think one of the big take home messages that I took away from these papers is that clinical medicine is not dead. In fact, clinical medicine in this day and age is still the prime way of taking care of patients. Genetic testing is still in its infancy. It doesn't help clinically in too many situations yet. It will in the future. It helps in the diagnosis, it's not as useful in the treatment. So we have a long ways to go with genetics. I like your comment that going forward we're going to need more genetic counselors to make sense of these results. Clinicians are going to have a hard time making sense of these results. I do think that there is plenty of role once a disease causing mutation has been defined, and in that situation it's invaluable in cascade screening in identifying other family members who may be affected, but outside that I do believe and I agree completely with both of you, that clinical medicine is not dead. And clinical evaluation should be number one and should enjoy it's prime time because that's where we still are at. And genetics is still in its infancy and so is cardiology. Dr Carolyn Lam: Perhaps in selective settings ... We're not talking here about, for example, hypercholesteremia variance, we're not talking about cancer gene variance for which screening may be a little bit more advanced, and we may understand the gene phenotype associations that are perhaps- Dr Mark Link: I think that understanding gene phenotype associations are going to be critically important in the future. I think, as Sanjay said, the real use of genetic screening now is cascade screening for the family, and there it's invaluable. That you can tell if you've got a co-band with the disease, and with a defined pathological mutation. You can test siblings, sons and daughters, parents to see if any of them have the gene. I think that's where it should be used for sure in 2018. Dr Carolyn Lam: Thank you so much Mark and Sanjay. So some precautions, some hope. Very, very balanced discussion. So much more we could discuss, so I really want to highly encourage our audience. Pick up this issue. You have to read these amazing papers and the editorials. Dr Carolyn Lam: So, here's a podcast with all your colleagues, and don't forget to tune in next week.

university california los angeles young medicine african park run singapore twenty similar expression stroke genetic growing pains nih university of london clinicians rna cascade sanjay circulation qt ecg crp v1 david geffen school v4 ut southwestern cincinnati college mendelian hosseini inhibiting heart institute duke national university sanjay sharma arvc carolyn lam pioglitazone brugada syndrome fibronectin dan roden

Update on the Clinical Diagnosis and Genetics of ARVC/D

Circulation: Arrhythmia and Electrophysiology On the Beat

Play Episode Listen Later Aug 6, 2018 28:48

Commentary by Dr. Valentin Fuster

commentary diagnosis clinical genetics arvc valentin fuster

Circulation: Arrhythmia and Electrophysiology On the Beat February 2018

Play Episode Listen Later Feb 20, 2018 54:25

Dr Wong: Welcome to the monthly podcast, "On The Beat, for Circulation: Arrhythmia, and Electrophysiology." I'm doctor Paul Wong, editor in chief, with some of the key highlights from this month's issue. We'll also here from Dr. Suraj Kapa reporting on new research from the latest journal articles in the field. In our first article, Mathew Daly and associates examine whether a high-resolution, 9 French, infrared thermography catheter can continuously image esophageal temperatures during atrial fibrillation catheter ablation. The infrared temperature catheter was inserted nasally or orally into the esophagus, adjacent to the left atrium. Endoscopy was performed within 24 hours to document esophageal injury. Thermal imaging showed that 10 out of 16 patients experienced one or more events where the peak esophageal temperature was greater than 40 degrees centigrade. Three patients experienced temperatures greater than 50 degrees centigrade and one experienced greater than 60 degrees centigrade. Analysis of temperature data from each subject's maximal thermal event revealed high radius, 2.3 degrees centigrade per millimeter and rates of change 1.5 degrees centigrade per second, with an average length of esophageal involvement of 11.0 millimeters. Endoscopy identified three distinct thermal lesions, all in patients with temperatures greater than 50 degrees centigrade, all resolving within two weeks. The authors concluded that infrared thermography, high-resolution mapping of esophageal temperatures during catheter ablation may be performed. Esophageal thermal injury occurs with temperatures greater than 50 degrees centigrade, and was associated with large spacial-temporal gradients. In our next article, Nitesh Sood and associates reported on the real-world incidence and predictors of perioperative complications in transvenous lead extractions involving ICD leads in the NCDR ICD registry. Lead extraction was defined as removal of leads implanted for greater than one year. Predictors of major perioperative complication for all extraction procedures, 11,304, and for high voltage leads, 8,362, or 74% across 762 centers were analyzed, using univariate and multivariate logistic regression. Major complications occurred in 258, or 2.3% of the extraction procedures. Of these, 258 procedures with a complication, 41 or 16% required urgent cardiac surgery. Of these, 14 or 34% died during surgery. Among the total 98, or 0.9% deaths reported, 18 or 0.16% of the total occurred during extraction. In multivariate, logistic regression analysis of all extractions, female sex, admission other than electively for the procedure, three or more leads extracted, longer implant duration, dislodgement of other leads, patients' clinical status, requiring lead extraction, such as infection or perforation, were associated with increased risk of complications. For high voltage leads, smaller lead diameter, a flat versus round coil shape, in greater proximal surface coil area, were multivariate predictors of major perioperative complications. The rate of major complications and mortality with transvenous lead extraction is similar in the real world compared to single center studies from high volume centers. There remains a significant risk of urgent cardiac surgery with a very high mortality, and planning for appropriate cardiothoracic surgical backup is imperative. In our next paper, Bence Hegyi and associates, have reported on the repolarization reserve in failing rabbit ventricular myocytes, and the role of calcium and beta-adrenergic effects on delayed and inward rectifier potassium currents. The authors measured the major potassium currents, IKr, IKs, IK1, and their calcium and beta-adrenergic dependence in rabbit ventricular myocytes, in chronic pressure, in volume overload, induced heart failure, and compared them to age-matched controls. The authors made a number of observations. One, action potential duration was significantly prolonged only at lower pacing rates, 0.2 to 1 Hertz, in heart failure under physiological ionic conditions and temperature. Two, beat to beat variability of action potential duration was also significantly increased in heart failure. Three, both IKr and IKs were significantly regulated in heart failure under action potential clamp but only when cytosolic calcium was not buffered. Four, CaMKII inhibition abolished IKs upregulation in heart failure, but did not affect IKr. Five, IKs response to beta-adrenergic stimulation was also significantly diminished in heart failure, and, six, IK1 was also decreased in heart failure regardless of calcium buffering, CaMKII inhibition or beta-adrenergic stimulation. These observations changed when cytosolic calcium was buffered. The action potential prolongation in heart failure was also significant in higher pacing rates. The authors concluded that in heart failure, calcium dependent up regulation of IKr and IKs counter-balances the reduced IK1, maintaining the repolarization reserve, especially at higher heart rates. In physiologic conditions, unlike conditions of strong cytosolic calcium buffering. Under beta-adrenergic stimulation, reduced IKs responsiveness, severely limits the integrated repolarizing potassium current in repolarization reserve in heart failure, increasing the arrhythmia propensity. In the next paper, Christopher Piorkowski and associates report on the feasibility of a combined endo-epicardial catheter approach for mapping the ablation of atrial fibrillation. The authors studied 59 patients with permanents pulmonary veins isolation and had further symptomatic recurrences of paroxysmal atrial fibrillation, persistent atrial fibrillation, or atrial tachycardia. These patients underwent repeat ablation using bi-atrial endo- and epicardial mapping and ablation. Identification of arrhythmia substrates and selection of ablation strategy were based on sinus rhythm voltage mapping. In all patients, endo-epicardial mapping ablation were feasible using standard technologies of catheter access, three dimensional mapping, and radiofrequency ablation. Epicardial mapping and ablation did not add procedural risk. Exclusively, epicardial low voltage substrate were found in 14% of patients. For the first time, novel epicardial conduction abnormalities located in the epicardial fiber network were described in human patients, 19% of the cohort. Epicardial ablation was needed in 80% of the patients. Over 23 months of follow up, freedom from arrhythmia recurrence was 73%. The authors used continuous monitoring and three months blanking period. Freedom from ATR of greater than two minutes was defined as the primary end-point. The authors concluded that endo-epicardial mapping ablation was feasible and safe. Epicardial ablation increases transient mortality of ablation lesions. Further studies will be needed to demonstrate reproducibility and long-term outcomes, and how the technique compares to other methods. In the next article, Michael Wolf and associates examined the long-term results of substrate modification for ablation of ventricular tachycardia using substrate elimination, targeting local, abnormal ventricular activities, or LAVA, post-myocardial infarction. They reported on 159 consecutive patients undergoing first ablation, age 65, 92% with ICDs, 54% with storms, and 73% with appropriate shocks. LAVA were identified in 92% and VT was inducible in 73%. Complete LAVA elimination after ablation was achieved in 64% and non-inducibility was achieved in 85%. During a median follow-up of 47 months, single procedure, ventricular free survival was 55%, 10% storms, and 19% shocks. The ventricular arrhythmia free survival was 73% after one year and 49% after five years. Complete LAVA elimination was associated with improved outcomes, ventricular arrhythmia free survival of 82% at one year and 61% at five years. The subgroup treated with multi-electrode mapping and real-time image integration had improved ventricular arrhythmia free survival, 86% at one year and 65% at four years. Repeat procedures were also performed in 18% of patients. The outcomes improved, 69% ventricular arrhythmia free survival during a median follow-up of 46 months. In a single center study, substrate modification, targeting LAVA for post myocardial infarction ventricular tachycardia resulted in a substantial reduction in ventricular tachycardia storm and ICDs shocks with up to 49% of patients free of arrhythmias at five years after a single procedure. Complete LAVA elimination, multi-electrode mapping, and real-time integration were associated with improved ventricular arrhythmia free survival. In the next paper, Jean-Baptiste Gourraud and associates examined the safety and feasibility of transvenous lead extraction in adults with congenital heart disease over a 20 year period at a single center. The authors reported on 71 transvenous lead extraction procedures in 49 patients with adult congenital heart disease, mean age 38 years in which a total of 121 leads were extracted. The primary indication for extraction were infection in 48%, lead failure in 31%. A laser sheath was required in 46% and a femoral approach in 8%. Complete transvenous lead extraction was achieved in 92% of the leads. 49% of the patients had transposition of the great arteries. In multivariate analysis, lead duration was predictive of transvenous lead extraction failure. No perioperative death or pericardial effusion was observed. Subpulmonary, atrioventricular valve regurgitation increased in eight patients, five of whom had TGA and were independently associated with ICD leak or valvular vegetation. After a median of 54 months of follow up after the first lead extraction, three deaths occurred independently from lead management. The authors concluded that despite complex anatomical issues, transvenous lead extraction can be achieved successfully in most adult congenital heart disease patients using advanced extraction techniques. Subpulmonary AV valve regurgitation is a prevalent complication, particularly in patients with transposition of the great arteries. In the next paper, Gabriela Orgeron and associates examined the incidence of ventricular arrhythmias and follow-up in ARVC patients grouped by the level of indication for ICD placement, based on the 2015 International Task Force Consensus Statement Risk Stratification Algorithms for ICD Placement in arrhythmogenic right ventricular dysplasia/cardiomyopathy. In 365 of arrhythmogenic right ventricular dysplasia/cardiomyopathy patients, the authors found that the algorithm accurately differentiates survival from any sustained VT/VF among the four risk groups, p < 0.001. Patients with a Class I indication had significantly worst survival from VT/VF than patients with a Class IIa indication or a Class IIb. However, the algorithm did not differentiate survival free from VF or V flutter between patients with Class I and Class II indications. Adding Colter results, less than 100 PVCs per 24 hours to the classification, helps differentiate the risk. Patients with a high PVCs burden, greater than 1000 PCVs per 24 hours had a poor survival from both VT/VF and VF and V flutter. In the next paper, Takeshi Kitamura and associates studied eight patients that had bi-atrial tachycardia, a rare form of atrial macroreentrant tachycardia, in which both atria form a critical part of the circuit and were mapped using an automatic, high resolution, mapping system. 708 patients had a history of persistent atrial fibrillation, including septal or anterior left atrial ablation before developing bi-atrial tachycardia. One of the patients had a history of atrial septal path closure with a massively enlarged right atrium. The authors found that 9 atrial tachycardias, with a median cycle length of 334 milliseconds had three different types. Three were peri-mitral and peri-tricuspid reentrant circuit, three utilized the right atrial septum in a peri-mitral circuit, and three utilized only the left atrium and the left right atrial septum. Catheter ablation successfully terminated eight of the nine bi-atrial tachycardias. The authors found that all patients who developed bi-atrial tachycardia had an electrical obstacle on the intraseptal left atrium, primarily from prior ablation lesions. In our next paper, Kwang-No Lee and associates randomized 500 patients with paroxysmal atrial fibrillation to one of two strategies after pulmonary vein isolation. One, elimination of non-PV triggers in 250 patients, group A, or, two, step-wise substrate modification using complex fractionated atrial electrogram or linear ablation until non-inducibility of atrial tachyarrhythmias was achieved, 250 patients in group B. Recurrence of atrial tachyarrhythmias was higher in group B compared to group A. 32% of patients in group A experienced at least one episode of recurrent atrial tachyarrhythmia after the single procedure, compared to 43.8% in group B. P-value of 0.012 after a median follow-up of 26 months. Competing risk analysis showed that the cumulative incidence of atrial tachycardia was significantly higher in group B compared to group A (p= 0.007). The authors concluded that elimination triggers as the end-point of ablation in paroxysmal atrial fibrillation patients decreased long-term recurrence of atrial tachyarrhythmias compare to non-inducibility approach achieved by additional empiric ablation. In our final paper of the month, Roland Tilz and associates reported on 10 year outcome after circumferential pulmonary vein isolation using a double lasso and three dimensional electro anatomic mapping technique. From 2003 to 2004, 161 patients with symptomatic drug refractory paroxysmal atrial fibrillation underwent electro-anatomical mapping guided circumferential pulmonary vein isolation. The procedure end-point was absence of pulmonary vein spikes thirty minutes after isolation, after a single procedure and a median follow up of 129 months, stable sinus rhythm was present in 32.9% of patients based on Holter-ECGs and telephonic interviews. After multiple procedures, mean 1.73 and median follow up of 123.4 months, stable sinus rhythm was seen in 62.7% of patients. Progression towards persistent atrial fibrillation was observed in 6.2%. The authors concluded that although the 10-year single procedure outcome in patients with paroxysmal atrial fibrillation was low, 32.9%, it increased to 62.7% after multiple procedures and the progression rate to persistent atrial fibrillation was remarkably low. That's it for this month but keep listening. Suraj Kapa will be surveying all journals for the latest topics of interest in our field. Remember to download the podcast, "On the beat." Take it away Suraj. Dr Kapa: Thank you Paul, and welcome back everybody to Circulation’s “On the Beat”, where we'll be discussing hard hitting articles across the electrophysiology literature. Today, we'll be reviewing 22 separate articles of particular interest, published in January 2018. The new year saw plenty of articles that are of particular interest either for the future of our field of for present management of our patients. First, within the realm of atrial fibrillation, we'll review several articles within the realm of anticoagulation and left atrial appendage occlusion. The first article we'll review is by Yong et al in the American Heart Journal, volume 195, entitled "Association of insurance type with receipt of oral anticoagulation in insured patients with atrial fibrillation: A report from the American College of Cardiology NCDR PINNACLE registry." In this publication, the author sought to evaluate the effect of insurance type on the appropriate receipt of anticoagulant therapy, specifically looking at warfarin versus NOACs. They reviewed retrospectively over 360,000 patients and found significant differences in appropriate prescription of anticoagulants, irrespective of which anticoagulant was considered. Medicaid patients received less appropriate anticoagulant prescription than those who were privately insured on Medicare or military insured. Furthermore, those on military or private insurances had a higher rate of NOAC prescription than those with Medicare. Furthermore, there was an even wider disparity in NOAC use than warfarin use amongst differently insured patients. These data are important in that they highlight potential variability in appropriate management of patients based on insurance type. Of course, there are many issues that might impact this, such as health care access or available pharmacy coverage of specific medications. Furthermore, the authors do not dive into the impact on outcomes based on the therapy availability. The next article we'll review is by Jazayeri et al, entitled "Safety profiles of percutaneous left atrial appendage closure and lysis: An analysis of the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database from 2009 to 2016" published in the Journal of Cardiovascular Electrophysiology in volume 29 issue 1. Here, the authors sought to evaluate the overall safety profiles of procedures performed with different percutaneous left atrial appendage occlusion devices, including LARIAT and WATCHMAN. They review 356 unique reports and compared outcomes pre- and post- approval of the WATCHMAN device. The look at the specific composite outcome of stroke, TIA, pericardiocentesis, cardiac surgery, and death. They noted that this composite outcome occurred more frequently with WATCHMAN than with LARIATs, and this is irrespective of pre- or post- approval status. These findings highlight the importance of postoperative monitoring in evaluation of overall outcomes. The reason by which there was more frequent negative outcomes in the WATCHMAN than LARIATs need to be considered. Obviously there's several limitations in the MAUDE database, similar with all large databases. However, it does highlight the importance of considering the mechanisms or sure decision making necessary, not just amongst patients and their providers but amongst operators of the staff or amongst physicians and industry executives. To determine how to optimize devices going forward. Speak of left atrial appendage occlusion devices and the potential future of these, we next review an article by Robinson et al, entitled "Patient-specific design of a soft occluder for the left atrial appendage" published in nature biomedical engineering, in volume two in the year 2018. Robinson et al used 3D printing to create a soft, immunocompatible, biocompatible, endocardial implant to occlude the left atrial appendage. They use the individual CT of an in vivo pig to three D print using a specialized material, a left atrial appendage occlusion device, and demonstrated feasibility of achieving adequate occlusion. This paper is important and is one of the initial [inaudible 00:22:03] to how three D printing may be used to optimize patient care. In fact, three D printing has the potential to overturn medical manufacturing and device development. Anatomy tends to be more often patient-specific than not. That's one size fits all implant designs may not be optimal, and resulting exclusion or inadequate occlusion amongst many patients. Decide of three D printable patient specific rapidly prototype soft devices that are biocompatible and hemocompatible, holds the potential to revolutionize the occlusion. Staying in the field of left atrial appendage occlusion, we next review an article by Lakkireddy et al entitled "left atrial appendage closure and systemic homeostasis: The LAA homeostasis study" published in JACC. The authors sought to evaluate the effect of epicardial-versus endocardial left atrial appendage occlusion on systemic homeostasis, including effects on neuro-hormonal profiles of patients. They performed a prospective, single center, observational study, including 77 patients, about half of whom received endocardial versus epicardial device. Interestingly, they noted that the epicardial left atrial appendage occlusion cohort exhibited significant decrease in blood adrenaline, noradrenaline and aldosterone levels. Those are not seen with endocardial devices. Internal epicardial devices are associated with increases in adiponectin and insulin levels as well as a decrease in free fatty acids and consistently lower systemic blood pressure. These data suggest a significant difference in the effect of epicardial versus endocardial closure left atrial appendage on neurohormonal profile. The authors propose several mechanisms for these findings but not the exact mechanisms as yet unclear. Several factors potentially could lead to these findings. One is that epicardial ligation may result in more total ischemia of the left atrial appendage than endocardial closure. Another potential mechanism maybe that the presence for material in the pericardial space versus in the bloodstream may have different effects on neuro-hormonal profile. However, these significant differences in outcomes highlight the importance of considering whether all approaches of left atrial appendage occlusion are considered equal. Many flaws of this study is that it's observational and not randomized. Does it possible those receiving epicardial closure may have been perceived to be lower risk for epicardial puncture, in this, as result, had better long-term outcomes. Changing gears now but staying within the realm of atrial fibrillation, we next review elements for cardiac mapping and ablation. The first article we review is one that has received significant press, published by Marrouche et al entitled "Catheter ablation for atrial fibrillation with heart failure" in the New England Journal of Medicine, volume 378. It is well recognized that morbidity and mortality are higher in heart failure patients who also have atrial fibrillation. Marrouche et al published the results of the CASTLE-AF trial, which attempted to determine if catheter ablation [inaudible 00:24:46] better outcomes among patients with heart failure and atrial fibrillation. They randomized 179 patients to ablation and 184 to medical therapy, which consisted of either rate or rhythm control. Inclusion criteria were those with NYHA class II to IV heart failure, LVEF of 35% or less, and an ICD. The primary endpoint was a composite where the death from many causes or hospitalizations for worsening heart failure. They noted over a median of three as a follow up, the end-point was reached in 28.5% of the ablation group and 44.6% of the medical therapy group, accounting for a significant hazard ratio of 0.62. Furthermore, fewer patients that in the ablation group died from any cause, were hospitalized for worsening heart failure, or died from cardiac causes. These data made a big splash because they're highly supportive of the premise that catheter ablation may be beneficial in some patients with atrial fibrillation and heart failure, often beyond that of medical therapy alone. One major strength of this paper is that the actual AF burden was tracked by the ICD, so we know for sure whether or not the procedure was successful and how controlled the atrial fibrillation was. One thing to note however, is that subgroup analysis suggest that those with more symptomatic heart failure, namely NYHA class III to IV, not benefit as much from ablation. Furthermore, it's also important to note that the five years expected mortality in patients was higher than predicted in the CASTLE-AF trial, however overall these trials highly suggest that the potential benefit that ablation may hold over conventional medical therapy. Extrapolation to comparison with the utility of interventions such as biventricular pace with AV node ablation, however, remains to be considered. Next, we review an article by Chugh et al entitled "Spectrum of atrial arrhythmias using ligament of Marshall in patients with atrial fibrillation" published in Heart Rhythm volume 15, issue 1. They reviewed the spectrum of presentations associated with arrhythmogenesis attributed to the ligament of Marshall, amongst patients with atrial fibrillation. They demonstrate that nearly a third of those patients, ligament of Marshall associated arrhythmias had a pulmonary vein ligament connection, that variously required ablation, the left lateral ridge, the mitral annulus, or alcohol ablation. In addition, they noted about a quarter of patients had atrial tachycardia attributable to the ligament, and the remaining had periatrial reentry requiring either ablation or alcohol injection of the ligament to attain a conduction block. The relevance of this publication, albeit it is of a small number of patients and a small center, lies in highlighting on the right mechanisms by which the ligament of Marshall may contribute to arrhythmogenesis. Namely, can include direct venous connections, inhibition to inaudibility to attain mitral block, and directly attributed atrial arrhythmias. Recognition of the various ways and situations under which the ligament of Marshall may play a role in arrhythmogenesis in atrial fibrillation patients, may optimize physician decisions to look for identify and target the ligaments. What is not as well understood however is the frequency with which ligament of Marshall plays a significant role in arrhythmogenesis in atrial fibrillation. Moving gears, we next review an article by Pathik et al entitled "Transient rotor activity during prolonged three-dimensional phase mapping in human persistent atrial fibrillation" published in a special issue of JACC Clinical Electrophysiology, that focus on atrial fibrillation specifically, in volume 4 issue 1. Pathik et al sought to validate three-dimensional phase mapping system for persistent atrial fibrillation. Commercially available rotor mapping systems project the heart into two dimensions based on a three-dimensional catheter. Instead, Pathik et al used a combination of basket catheters along with the non-left atrial surface geometry to construct three D representations of phase progression. Amongst 9 out of 14 patients, they identified 34 rotors, with all these rotors being transients. Of particular interest, the rotors were only seen in areas of high electric density, where internal electric distances were shorter. They also noted the single wave front is also the most common propagation pattern. The importance of this publication lies in considering two things. First is the three dimensional representation of rotor position and the feasibility of this, and the second is really the high electro-density necessary to observe for others. This has been one of the main problems in rotor analysis, namely what the spacial and temporal density is, that is required to identify rotors, especially given how transient they often are. The presence of rotors does not necessarily mean they're ablation targets in all patients. However, the question still remains regarding the optimal approach to mapping rotors, it needs to be remembered that rotors actually are meant to represent three dimensional scrollway phenomena, that cannot necessarily always be reflected in traditional two D mapping schema. Furthermore, to be remembered that when we claim three-dimensional mapping, this just reflects a two-dimensional surface being wrapped in three dimensions to reflect overall internal surface geometry but it does not take into account transmural activation. Thus, taking into account all these elements it should be remembered as sometimes, it is possible that a rotor might exist but it's just not evident based on the two-dimensional representation or a two-dimensional representation that looks like a rotor may in fact not be a rotor when you consider it in a three-dimensional media. Our last article within the realm of cardiac mapping and ablation we will consider is by Zghaib et al, entitled "Multimodal examination of atrial fibrillation substrate: Correlation of left atrial bipolar voltage using multielectrode fast automated mapping, point by point mapping, and magnetic resonance imaging intensity ratio", published in JACC Clinical Electrophysiology, in the same volume as the previous article. The authors sought to compare fast automated mapping with multiple electrodes versus point by point mapping and correlate with weighed gadolinium enhancement as seen by MRI, termed the image intensity ratio. We all recognize that bipolar voltage is critical to recognizing and evaluating substrate. It's traditionally used in decay regions of substrate in both the atrium and ventricles. However, whether a newer automated approach used to characterize substrate perform equally well in comparison with traditional point to point mapping is still unknown. Thus, the authors in 26 patients perform cardiac MRI and mapping endocardial using both voltage mapping techniques. They noted that for each unit increase in image intensity ratio on MRI, in other words, increasing late enhancement, there was 57% reduction of bipolar voltage. They also noted that the bipolar voltage using other fast elevating mapping or point by point was significantly related with actual differences in calculated voltage, becoming more dissimilar in the extreme of high and low voltage areas. The relevance of this publication is highlight in the potential utility of fast automated mapping in creating accurate voltage maps. The correlation of voltage values with image-intensity ratios suggest the utility of either approach. In turn, correlation with MRI suggest a pathologic correlate for all of these findings. However, whether substrate characterization guide ablation carries incremental benefit remains to be seen. Changing gears but staying in the realm of atrial fibrillation, we next review elements of risk stratification and management. The first article we review is by Friedman et al, entitled "Association of left atrial appendage occlusion and readmission for thromboembolism amongst patients with atrial fibrillation undergoing concomitant cardiac surgery", published in JAMA, volume 319, issue four. Friedman et al sought to evaluate whether surgical left atrial appendage occlusion let to a reduction in long-term thromboembolic risk in a large database of Medicare recipients. They included the primary outcome as readmission for thromboembolism, including stroke, TIA, or systemic embolism, in up to three years of follow-up. With secondary end-points including hemorrhagic stroke, all-cause mortality, and a composite end-point of all outcomes. Amongst more than 10,000 patients, there were almost 4,000 patients receiving surgical occlusion of left atrial appendage. Surgical occlusion was associated with a reduction in thromboembolic risk, OR of 6%, all cause mortality, 17 versus 24%, and the composite end-point, 21 versus 29%. However, interestingly, surgical occlusion was only associated with reduction in thromboembolic risk compared with no occlusion amongst those discharged without anticoagulation and those discharge with it. Namely, the thromboembolic risk reduction was primarily seen in those where the surgical occlusion, those who were sent home without any sort of anticoagulation. These data suggest that surgical occlusion leads to reduction of thromboembolic risk overall. As any large database based study, there are massive flaws in the database itself. Namely, we're relying on the coding of hospitals and operators. To know exactly what was done and what happens latter. However, these data are hypothesis generating. One key element is the fact that surgical left atrial appendage occlusion was only superior in reducing thromboembolic risk amongst those discharged without anticoagulation. This raises the question as why. Was left atrial appendage completely closed in these patients? In which case, they may be at further increased risk or that the operators felt that there is a high risk for other reasons that cannot be cleaned from an administrative datasets? While the data support consideration of the benefit of left atrial appendage occlusion in a surgical manner, a kin to what has been seen in papers on WATCHMEN and other approaches, and how is the critical nature of randomized trials in this regard. We next review an article published in JAMA Cardiology, volume three issue one by Inohara et al, entitled "Association of atrial fibrillation clinical phenotypes with treatment patterns and outcomes: A multicenter registry study." Traditionally classification of AF has depended largely on factors such as the nature of AF, paroxysmal versus persistent, LA size, and other factors such as extend of the late enhancement. Inohara et al sought to evaluate whether cluster analysis could better define heterogeneity of AF in the population. They included an observational cohort of almost 10,000 patients admitted to 124 sites in the United States in the ORBIT-AF registry. Outcome was a composite major address cardiovascular and neurological events or major bleeding. Amongst these patients, they identified four clusters, including one those with lower rates of risk factors and comorbidities than other clusters, two, those with AF at younger ages and with comorbid behavior disorders. Three, those with AF with tachycardia-bradycardia type syndromes and had devices for sinus node dysfunction, and four, those with AF with other risk factors such as a coronary disease. Those in the first cluster had significantly lower risks of major events. All clusters were noted to have symptom dissociation to specific clinical outcomes. These data are interesting and highlight the highly heterogeneous nature of classifying risk attributable to atrial fibrillation. When broad datasets associated atrial fibrillation with specific outcomes. Maybe suggest an attribution to all patients with atrial fibrillation. However, this single relationship was specific to the outcomes suggest the limitation of applying outcome as approach to understand atrial fibrillation impacts and outcomes, namely depending on clusters that may take into account patient age or comorbidities, it may be irrelevant in discriminating patient outcomes than the traditional paradigm in the same paroxysmal versus persistent or depending on the left atrial size. These data also highlight the importance of considering the inclusion criteria in randomized trials of atrial fibrillation before stripling real world outcomes to patients who don't fit within that trial. Next, we will be reviewing an article by Chou et al entitled "Relationship of aging and incident comorbidities to stroke risk in patients with atrial fibrillation," published in JACC, volume 71 issue two. Chou et al sought to evaluate the effect of aging and evolving instant comorbidities to stroke risk in patients with atrial fibrillation. Many large database studies or trials where added baseline CHADSVASC score and the then ensuing follow up period to define risk over time of ischemic stroke. The authors hypothesized that as patients age, develop new comorbidities that would change the score, may be more predictable of long-term outcomes than the score itself. They included over 31,000 patients who do not have comorbidities to CHADSVASC aside from age and sex but had atrial fibrillation. They didn't calculate a delta score defined as the difference between the baseline and follow up scores. The mean baseline score was 1.29 with an increase in 2.3 during follow up, with an average delta of one. The score may not change over follow up in 41% of patients. Interestingly, significantly more patients had a delta CHADSVASC of one or more and develop ischemic stroke than non-ischemic stroke. The delta CHADSVASC was shown to better predictor of ischemic stroke than either baseline or follow up CHADSVASC score. This data suggest that additive shifts in the CHADSVASC score over time may be more predictive of stroke risk than the actual score itself. These findings are thoughtful and logical. They indicate the potential impact of continued aging or acquisition identification of new comorbidities. In some patients, potential discovery or new comorbidities or follow-up; for example, hypertension and coronary artery disease may lead to reclassification of stroke risk. That is important to maintain close follow up of atrial fibrillation patients, and not to show a continued need or lack of need of anticoagulation on the basis of a baseline evaluation. This also holds relevance single center long-term outcomes in patients specific scores. Whether is acquisition of new comorbidities or presence of baseline comorbidities or predict a long-term score, should we consider when assessing the need for anticoagulation, particularly in perceived initially low risk cohorts who go on to develop ischemic stroke. Lastly, within the realm of atrial fibrillation, we review an article by Hussain et al, entitled "Impact of cardiorespiratory fitness on frequency of atrial fibrillation, stroke, and all-cause mortality" published in the American Journal of Cardiology, volume 121 issue one. Hussain et al review the effect of cardiorespiratory fitness on overall outcomes and incidence of atrial fibrillation and outcomes amongst patients with atrial fibrillation. Amongst over 12,000 individuals prospectively followed up after treadmill exercise test, they noted 1,222 had a incidence of AF, 1,128 developed stroke, and 1,580 died. For every 10% increase in functional layover capacity, there was a 7% decrease in risk of incident AF, stroke, or death. Similarly, in those who developed AF, stroke was lower in those with higher functional aerobic capacity. These findings support the notion known to other areas of cardiovascular disease that better cardiorespiratory fitness is associated with better outcomes, in this case to stroke, incident AF, or mortality. Furthermore, even on the presence of AF, those with better functional capacity had a lower risk of stroke. These data highlight the continued importance of counseling patients on the benefits of physical fitness even in the setting of already present AF. Moving on to a different area of electrophysiology, we review the realm of ICD pacemakers and the CRT. The first article review is by Sze et al entitled "Impaired recovery of left ventricular function in patients with cardiomyopathy and left bundle branch block" published in JACC volume 71 issue 3. Patients with left bundle branch block and cardiomyopathy are known to respond to CRT therapy. Thus the investigators sought to evaluate whether guideline medical therapy in patients with reduced LVEF and left bundle branch block, afford a beneficial first line approach therapy. The reason for this currently guidelines suggest waiting at least three months before consideration of CRT has had as some patients may recover on guideline directed medical therapy without the need for device implantation. They review patients with a LVEF of less or equal than 35% and baseline ECG showing left bundle branch block. In evaluating left ventricular ejection fraction at follow up of three to six months. They excluded patients with severe valvular disease, and already present cardiac device, an LVAD, or heart transplant. Among 659 patients meeting criteria, they notice 74% had a narrow QRS duration of less than 120 whereas 17% had QRS duration greater than 120, and the remainder had a QRS duration greater 120 but was not left bundle branch block. The mean increase in the left ventricular ejection fraction on guideline directed medical therapy was in those with a narrow QRS duration and least in those with left bundle branch block, 8.2%. Furthermore, when comparing mean LVEF improvement, those with on versus non-on guideline directed medical therapy, there was virtually no difference in rates of recovery. Furthermore, composite end-point of heart failure hospitalization mortality was highest in those with left bundle branch block. These data suggest that those with bundle branch block and cardiomyopathy received less overall benefit from guideline directed medical therapy over the three to six months follow up period. Whether this is due to already more severe myopathic process to start with or due to the CRT is unclear. However, it may suggest that in some patients, left bundle branch block may benefit from inclusion of CRT early in their disease course as known the significant number of patients up to three to six months guideline directed medical therapy with insufficient DF recovery may then benefit from CRT. As well as intervening earlier may result in better outcomes, especially knowing the high and term raise mortality in heart failure hospitalization remains to be seen. A trial studying early implantation of CRT on these patients may be relevant. The next article review is by Gierula et al entitle "Rate-response programming tailored to the force-frequency relationship improves exercise tolerance in chronic heart failure" published in JACC Heart Failure, in volume six, issue two. The authors sought to evaluate whether tailored rate-response programming improved exercise tolerance in chronic heart failure. The double blinded, randomized, control, crossover study, they compared the effects of tailored programming on the basis of calculated force-frequency relationship, defined as including critical heart rate, peak contractility, and the slope, multidimensional programming and exercise time and maximal oxygen consumption. They demonstrate amongst 98 enrolled patients that rate-response settings limiting heart rate raise to below the critical heart rate led to create exercise timing and higher peak oxygen consumption. These data suggest that personalizing rate-response therapies may improve exercise time and oxygen consumption values in patients with heart failure and pacing devices. The main limitation of the study is that the number of patients was small, 90, and then the number of patients crossing over was even smaller, 52. However, highlights the potential of working closely between device programmers and consideration of individual's characteristics and their exercise needs in determining optimal programming strategy. Finally, within the realm of devices, we review an article by Hawkins et al, entitled "Long-term complications, reoperations, and survival following cardioverter defibrillator implant" published in Heart, volume 104 issue three. Hawkins et al sought to evaluate the long-term complications and risk of reoperation associated with defibrillator implantations in a large [inaudible 00:41:56] population of 300,410 patients, they noted over a 30-month follow up period there was a 12% reoperation rate within the year of implant. This is most prominent for CRT devices, with a risk of 18% in one year post-implant. Furthermore, CRT had the highest rate of early complications, with device complexity, age, or the presence of atrial fibrillation being significantly associated with complication risk. Mortality also increased over time from 5% within the first year to nearly a third after five years. However, younger patients exhibited five years survival similar to the general population with a progressive decline of this as older patients were considered. These findings highlight several critical issues. First, they report a high one year reoperation rate for a variety of reasons. This finding highlights the importance of considering protocols to minimize the need for reoperation. Furthermore, they note the higher rate amongst CRT patients, with seems logical given the likely longer associated procedural risk and need for more leads. Finally, the impact of age on expectant survival are to be taken into consideration with the device and the life-saving potential of the defibrillator. Moving on to cellular electrophysiology, review one article by Zhang et al, entitled "Reduced N-type calcium channels in atrioventricular ganglion neuron are involved in ventricular arrhythmogenesis" published at the journal of the American Heart Association, in volume seven issue two. Zhang et al reported a rat model of ventricular arrhythmogenesis and characterized the role of atrioventricular ganglion neurons in risk of arrhythmogenesis as well as the mechanism for this risk this model relates in humans to the attenuated cardiac vagal activity in heart failure patients, which is known to relate to their arrhythmic risk. The demonstrated reduced N-type calcium channel in these AV ganglion neurons, which project innervating systems to the myocardium, resulting in increased risk of PVCs, and increased susceptibility to induction of ventricular arrhythmias with programmed stimulation. The relevance of the intrinsic cardiac nervous system arrhythmogenesis has become increasingly prominent as methods to study it have improved. Understanding the direct and most relevant inputs may facilitate better understanding of risk of arrhythmias in patients. In the case of this study by Zhang et al, the critical finding is that disorder of the atrioventricular ganglion neurons may lead to increased susceptibility for ventricular arrhythmogenesis. Clinical relevance includes consideration of effects on this specific ganglion when performing ablation on for other conditions, and potential long-term effect on arrhythmogenic risk, as well as potentially relevant functional explanations for arrhythmogenesis. Moving on to the genetic channelop, these are considered two separate articles. The first one by Bilmayer et al, entitled "ExomeChip-Wide analysis of 95,626 individuals identified ten novel loci associated QT and JT intervals" published in Circulation: Genomic and Precision Medicine, in volume 11 issue 1. This whole exome study reviewed several novel loci that modified the QT and JT intervals. They include over 100,000 individuals and identified ten novel loci not previously reported in the literature. This increases the number of known loci that impact from ventricular portal adjacent by nearly one third. These loci appear to be responsible for myocyte and channel structure and interconnections that internally impact the ventricular repolarization. While long QT syndrome be characterized amongst the known genes in 75% of affected individuals, that also means one fourth long QT syndrome cannot be characterized based on known genes impacting ventricular repolarization. The identification of novel loci or novel that may be affect repolarization kinetics to unique means are critical to define novel therapies as well as in genetic counseling the patients in potential effects on family members when screening them for potential disease risk. These findings should assess an opportunity for further studying the mechanisms by which these loci modulate QT and JT intervals and the potential contribution to phenotypic risk. The second paper within this realm we review is by Zumhagen et al, entitled "Impact of presynaptic sympathetic imbalance on long QT syndrome by positron emission tomography" published in Heart, volume 104. The authors sought to evaluate by a PET scan the impact of sympathetic heterogeneity on long-QT syndrome risk. Amongst 25 patients with long-QT syndrome, including long-QT type I and II, and 20 ostensibly healthy controls, they noted that regional retention in disease were similar between affected patients and controls. However, regional washout rates were higher in the lateral left ventricles in patients with long-QT syndrome. Internal global washout rates were associated with greater frequency of clinical symptoms. That's there seem to be some relationship between regional and global sympathetic heterogeneity, particularly during washout, with overall risk in long-QT syndrome patients. These findings report the notion for sympathetic imbalance, partly mediating the risk attributable to long-QT syndrome. The findings on PET suggest regional imbalance of presynaptic cathecholamine and reuptake and release, being one mechanisms. This was most prominent in long-QT I patients who also often drive most benefit from left sided sympathectomy. The novelty of these findings is in the potential role of imaging to determine basic contributors to congenital long-QT syndrome in given patients. The larger prospect of size would really need to be evaluated this further. Moving on to the realm of ventricular arrhythmias, we review three different articles. The first one, by Hamon et al, entitled "Circadian variability patterns predict and guide premature ventricular contraction ablation, procedural disability, and outcomes" published in Heart Rhythm, volume 15 issue one. Hamon et al sought to evaluate whether circadian variability of PVC frequency can predict optimal drug response intraprocedurally during PVC ablation. One of the main problems of PVC ablation is when PVC are infrequent and tend to disappear during the procedure, achieving procedural success or attaining sufficient frequencies of PVCs to map becomes very difficult. Next, they use Holter monitoring in the ambulatory stripe to define three groups. Those of higher PVC burden during faster heart rates, those with higher PVC burden during slower heart rates, and those with no correlation between their PVCs burden and their heart rate. More than half the one hundred and one patients included a high burden of PVCs at fast rate while 40% had no correlation between the two and 10% had higher burden in slower heart rates. Almost one third of patients taken for ablation have infrequent PVCs during a procedure, while the best predictor of this being a low ambulatory PVC burden of less than 120 per hour. Isoproterenol infusion was only useful in lessening PVCs in those with PVCs associated with fast heart rates. The isoproterenol washout or phenylephrine where used with those associated with slower heart rates. Interestingly, not a single drug was effective in inducing PVCs in those with infrequent PVCs that have not heart rate correlation in the ambulatory stages. They noted that outcomes ablates were similar amongst those with higher heart rate associated PVCs and non-heart rate correlated PVCs previously responded to a drug. But, [inaudible 00:48:08] noted only a 15% success rate from ablation in infrequent PVCs in patients who lacked correlation between PVC burden and heart rate and who were unresponsive to drug previously. These data are important highlighting the potential for further defining idiopathic PVC ablation needs and likelihood of success based on ambulatory data, by correlating PVC burden with heart rate and their circadian variability, it's possible to predict likelihood specific intraoperative drugs working when dealing with infrequent intraprocedural PVCs. Furthermore, the finding of lack of correlation with slower or fast heart rate in terms of PVC burden is associated with the poor success rate unless those PVCs are drug responsive. Highlights the potential benefit of performing preoperative antiarrhythmic drug testing to get likelihood of ablation success in this patients. The next article we review is by Lee et al, entitled "Incidence and significance of the lesions encountered during epicardial mapping and ablation of ventricular tachycardia in patients with no history of prior cardiac surgery or pericarditis" published in Heart Rhythm, volume 15 issue one. Lee et al sought to determine the frequency of pericardial lesions, impeding mapping in patients without prior surgery, operative procedure, or pericarditis, in other words virgin hearts. Amongst 155 first time attempts of access, 8% had pericardial lesions. The only clinical predictor was the presence of severe renal impairment. In addition, no patients with supposedly normal hearts had a lesions. Notably, those with a lesion had more frequent impairment in mapping and lower overall success rates; there were similar complication rates as those without the lesions. These data are relevant in highlighting the ease of mapping of pericardial access may not always be present, even when dealing with inversion of pericardial space. A lesion may be present in patients, particularly with severe renal disease. Advising patients of this possibility prior to the procedure and considering that epicardial access may be impaired in a fair number of patients, even the absence of prior history of surgery, epicardial access or pericarditis isn't important. The final article we'll review within the realm of ventricular arrhythmias is by Kumar et al, published in Journal of Cardiovascular Electrophysiology, volume 29 issue one, entitled "Right ventricular scar-related ventricular tachycardia in nonischemic cardiomyopathy: Electrophysiological characteristics, mapping, and ablation underlying heart disease." Kumar et al sought to evaluate the substrate and outcomes associated with right ventricle scar related ventricular tachycardia ablation in nonischemic patients at large, but particularly in those with neither stroke or coronary artery disease as potential explanations for this scar. They reviewed 100 patients consecutively over half of whom had ARVC and the remainder was sarcoid or RV scar of unclear origin. Those with RV scar of unknown origin tend to be older compared to the ARVC patients, and had more severe LV dysfunction compared with saroid patients. However, the scar distribution extend was similar within all these groups. Furthermore VT/VF survival was higher in those with RV scar of unknown origin. The velocity of survival free or death or cardiac transplant and VT/VF survival seen in sarcoid patients. These data suggest that close to one third of patients, RV scar related VT may have VT of unknown cause. Total outcome was superior overall to those with defined myopathic processes. What's most interesting is, over follow up, none of those with RV scar of unknown origin develop any further findings to reclassify them as sarcoid or ARVC. It is possible this group reflects some mild form of either disease however. Again, the exact pathophysiologic process remains unclear. These findings may help in counseling patients who are in long-term expected outcomes from ablation intervention. The final article we'll review this month is within the realm of other EP concepts that may be broadly applicable, published by van Es et al, entitled "Novel methods for electrotissue contact measurement with multielectrode catheters", published in Europace, volume 20 issue one. In this publication, the authors sought to evaluate the potential utility of a novel measure on evaluating electro tissue contact. With multielectrode catheters it is known that one of the problems with assessing contact is a contact force that cannot be used. Electro with coupling index is often used but even this has fragile problems, especially when you get into high impedance areas, that can be affected by surrounding ion impedance structures. Due to the fact that measuring contacts forces challenging in such multielectrode catheters, the authors measure electric interface resistance by applying a low level electrical field, pushing neighboring electrodes. They compared the effectiveness of assessing contact by this approach without using contact force in a poor side model. They know that this measure was directly correlated with contact force in measuring tissue contacts. These findings support a role for aversion of an active electrode location and determining tissue proximity and contact-based on the coupling between the electrodes on multipolar catheters in the tissue. These findings may be highly useful when there is a variety of catheters where contact force cannot be implemented. Further studies on the methods and cutoff to establish tissue proximity on the end of contact will be also needed. To summarize, however, as a term was brilliant here that was not well explained, active electrical location is actually a phenomenon that occurs in nature. This is seen in deep sea fish, which actually have multiple electrodes oriented around its body. They emit a small electrical field that results in a general impedance field surrounding the fish. This essentially is the way of visualizing the world around them. Perturbations based on proximity to different structures, whether they are live or death, and based on whether they are live or death, results in changes in the perturbations of this resistive fields, resulting in proximity determination by the fish. Several individuals are looking into potential applications of this to understanding tissue proximity when using catheters in the body. This consideration of impedance is fundamentally different than the traditional measure impedance were used by traditional generator. I appreciate everyone's attention to this key and hardening articles that we've just focus on or this past month of cardiac electrophysiology across literature. Thanks for listening. Now back to Paul. Dr Wong: Thanks Suraj, you did a terrific job surveying all journals for the latest articles on topics of interesting in our field. There's not an easier way of staying in touch with the latest advances. These summaries and the list of all major articles in our field for month can be downloaded from the Circulation: Arrhythmia and Electrophysiology website. We hope that you find the journal to be the go to place for everyone interested in the field. See you next month.

united states relationships freedom moving french food heart medicine speak staying safety impact 3d journal patients inclusion decide robinson anatomy iv internal analysis rv medicare clinical spectrum af competing recognition outcome repeat watchmen wong electro av hawkins progression medicaid mri american colleges traditionally mortality friedman notably kumar lava crt identification zhang tia surgical vt american heart association hertz jama cardiology correlation american journal watchman exclusively lv atr pv advising circulation new england journal hussain thermal df qt predictors pvc chou precision medicine ecg circadian yong incidence tga icd transient impaired vf recurrence multimodal hamon commercially suraj catheter endoscopy esophageal holter laa noac sze michael wolf electrophysiology lvad kapa qrs class ii lariat extrapolation chugh jacc heart rhythm icds pvcs ikr noacs iks lvef arvc jama cardiology paul wong nyha on the beat american heart journal camkii chadsvasc epicardial isoproterenol circulation arrhythmia circulation genomic jacc clinical electrophysiology

HRS Feature: Andrew Landstrom; Anneline te Riele; Ernesto Fernandez; David Tester

Circulation: Arrhythmia and Electrophysiology On the Beat

Play Episode Listen Later Sep 27, 2017 43:17

Jane Ferguson: Hi, everyone. Welcome to Episode Four of Getting Personal: -Omics of the Heart." I'm Jane Ferguson, an assistant professor at Vanderbilt University Medical Center. This month, we have a special feature from early career member, Andrew Landstrom, who went to the Heart Rhythm Scientific Sessions in Chicago earlier this month and talked to some of the scientists who presented their research. So listen on for interviews Andrews conducted with Anneline te Riele, discussing the challenges and opportunities related to incidental findings in genetic testing, with Ernesto Fernandez, describing his research into whole exome sequencing and Long QT syndrome, and with David Tester, discussing novel variance and pathway analysis in Sudden Infant Death Syndrome. Andrew : My name is Andrew Landstrom and I am from the Baylor College of Medicine Department of Pediatrics' section on Cardiovascular Disease. I'm here at the 2017 Heart Rhythm Society Scientific Sessions. Anneline, will you tell us a little bit more about yourself, and what brought you to HRS? Anneline: Sure. So my name is Anneline Te Riele, I am a physician from The Netherlands. I finished my medical training in 2012 basically, in The Netherlands, and I started doing a PhD on ARVC in a combined project of our Netherlands patient as well as a group at Hopkins. So what brought me to HRS? I think of course the science. There's a lot of very good science. Actually, I think it's the best meeting for my purposes. Andrew : Absolutely. So will you just start by telling us a little bit about the spectrum of genetic testing in the clinic and about both the opportunities and the challenges that it brings? Anneline: Sure. So what we do in clinic, and I think this is really the challenge that we're facing currently, is we have moved from just testing on gene or one small panel of genes to bigger panels and then to whole exome or even whole genome sequencing. And I think the good part of that is that in certain cases, certain well-selected cases, you'll get a higher change of actually finding that gene that is responsible for disease. On the contrary, it also leads to a lot of incidental findings. So findings that you were not expecting based on the phenotype of the patient and then you need to deal with those abnormalities that you've found and that brings on a lot of challenges as well for the family but also for us as physicians. Do we then need to screen those families, what do we do with this patient, do we treat them with medical therapies or drugs or do we give them ICDs? That kinds of question. So that I think is a virtually important part of what we're currently dealing with in clinical practice. Andrew : It does seem to be a very widespread problem. And here in the US of course we have the American College of Medical Genetics guidelines about reporting a variance. How do you think that that plays into the increased genetic uncertainty here in the US at least? Anneline: So that's a great questions. In 2013, the ACMG produced a guideline on which genes to report if you find these incidental findings. So 24 of these genes, and that's actually a big number, 24 of these genes are cardiovascular genes and that's mainly because changes in cardiovascular genes may detrimental effects down the line and really cause death or certain morbidities that are really important for the patient so we do need to deal with that. And the problem with the ACMG guidelines and especially the pathogenicity guidelines is that they require two aspects. They basically require first that the variant was seen before in other cardiomyopathies or in this case other patients with disease. And that's really difficult for cardiomyopathy genes because these are large genes, they have a lot of novel or private mutations in there, so it's really hard to fulfill that requirement of having been seen before. And the second thing is that the ACMG guidelines require functional studies as another proof of evidence of pathogenicity and of course, I think we would all like to do that in all of our patients, but it's just not feasible for financial purposes and all that. So that's a problem that we're facing. There are options and solutions but I think we'll talk about that later, but yeah, I think that's a problem that we're facing. Andrew : So on the one hand you have the ability to make a diagnostic decision based on a clear finding, but oftentimes the threshold to calling it a clearly pathologic variant is very high and oftentimes it never rises to that so it becomes more genetic uncertainty. Anneline: Yeah. I think that's basically right. And of course in an ideal world, we'll have certainty and say this is likely or this is definitely pathogenic, and this is likely or definitely benign, but in the real world, really, I think maybe even 80, 90% of the cases were in that gray zone in between and we need to deal with that. Andrew : Yeah, yeah. And you had some great resources that both scientists and clinicians alike can apply to these unknown, uncertain variants that might clarify things at least a little bit, and what are these tools? Anneline: So of course, from a traditional perspective, we have always looked at in silico predictive programs, we'll look at segregation data, and I think they're all very important, but they all have limitations, so for example, in silico predictive programs, they likely overcall mutations deleterious and segregation data is nothing more than evidence of pathogenicity of a locus to a disorder, not necessarily that variant, so the new things that are on the horizon, and a thing that could be the future of [inaudible 00:06:04] interpretation is collaborative project so really we should be collaborating, we should not be having our own little islands. The collaboration is the key here. And collaborative efforts in the US have been for example, ClinVar and NHLBI funded effort, as well as ClinGen and ClinGen, or Clinical Genome, is perhaps the, at least it claims to be, the authoritative central resource to go back to that curates variants as being pathogenic yes or no. And I think these databases, ClinVar finally has a database entry, so the variants will be in ClinVar, but ClinGen provides an expert panel of individuals who will curate these variants as being pathogenic yes or no. I think that is a central resource that we should all be aware of. I know these are not the only ones, there are other collaborative efforts out there. I mean, there are ways to connect clinicians, so for example, Match Maker Exchange is a website that you could use to enter your variant and the phenotype of the patient and you submit your own information and then you'll get matches in other databases, but not only your own match shows up. So if, say, two years later, another physician comes up and looks for the same variant, you'll get a pop up, which will actually be very nice for these clinicians to get in touch. So that's, I think, the feature ... future of variant interpretation is collaboration. That's basically my, I think my main important message here. Andrew : I think that's absolutely right. I think this has become sort of a big data question that requires many perspectives, and a lot of resources to be able to curate accurately. What are some of the limitations of these tools that you've seen that kind of, you have to keep in mind in terms of trying to determine whether a variant is truly pathologic or not with a patient that you have sitting in front of you? Anneline: So that is, I mean, of course, there's many limitations in the things that we currently do because there's so much that we don't know. But for example, to give you an example, ClinVar I think, is one central resource that we should all be aware of and if you go to ClinVar, there is actually data from two years ago, and I'm sure the numbers are high if we would look now, but if we look in ClinVar two years ago, we already saw that of the, say 120,000 variants that were in the database, 21% of these variants were called VUSes but if you look at these variants, 17% of the cases, the labs or the individual submitters of ClinVar didn't agree on the actual classification of that variant. So the limitations that we all should be aware of is that there is not one single solution and you should look for evidence and really research your variants. So look at Popmap, look at what is out there, look the patient of course, look at the clinical phenotype, does it match what you think the gene should be doing or not, or is it completely unrelated? And then of course search these databases but be aware of the fact that there may be errors there. Another thing I want to highlight too is that we typically go to population databases, so Exome Variant Server, ExAC, I think these are very popular databases that we use to look at the frequency of variants in a selected population. But really these databases may have sub-clinical disease patients, so I know ExAC has three NYBPC-3 mutations that are known to cause HCM, so this is something to keep in mind. There's not a gold standard truth if you open these databases, but you should have multiple pieces of information when interpreting your variant. Andrew : And that's a good point. I think with a lot of these cardiomyopathies and channelopathies, particularly some of the more frequent ones, when you have a database of 60,000 people, at least a couple of them are going to have disease. Anneline: Yeah. I think that is part of the problem. I mean HCM is pretty prevalent, I mean one in 500 individuals likely, I mean these are recent numbers, has the disease. So I think the cutoff of a minor allele frequency of five percent, which is in the ACMG guidelines, I think is way too high for this disease. So this is what the cardiovascular expert panel of ClinGen has done, so they ... This is, ClinGen, as you might know, Clinical Genome, is a one-on-one team of curators that know the framework of ClinGen and then there is disease experts that are very well accustomed with the disease and the genes associated with it. So they provide teams and these teams work together, and the cardiovascular expert group has recently published a modified, or customized, ACMG guidelines on how to deal with the intricacies of the cardiomyopathies and for example, NYH-7 which is the first genotype deposed in ClinGen or in ClinVar finally. So they modify that cutoff, the minor allele frequency of five percent, which is the BA-1 ACMG guideline cutoff, they changed that to 0.1% and I think that's exactly what you were saying, that is important to keep in mind, some of the cardiomyopathies are way more prevalent so you should not consider that if you see it in a population database that you think that it's, then it's normal, it's not necessarily the case because this is a prevalent disease. Andrew : Yeah, and particularly when commercial genetic testing companies all can't agree that a variant is bad, and we all can't agree that a healthy variant may or may not be good, there is definitely a lot of genetic uncertainty there. Anneline: Exactly, exactly. Andrew : Now, whole-exome sequencing certainly has its role clinically, even with that genetic uncertainty that we spoke about, but it has a clear role in genetic discovery as well. Anneline: Sure. Andrew : And you were part of a very recent paper, and you led a very long list of authors, speaking more about your collaborative approach to genetics research that evaluated a novel substrate for ARVC, is that correct? Anneline: Yes. So this is something I'm actually pretty proud of. As you said, it's a collaborative effort, so it literally take a village to do these kind of studies and we're lucky enough to collaborate with a lot of people who are interested in the same topic. So what we did ... and I metnioned to you in the beginning, I come from the ARVC field ... So what we did is we had one ARVC patient that was discovered by whole-exome sequencing to carry an SCN5A variant and we, in and of itself, found that that was very interesting, because SCN5A, as you know, has been associated with Brugada syndrome predominantly but many other cardiomyopathies as well, so DCM, even ACM. There's been a lot of controversy about SCN5A in that matter. So the computational data, the population data, it all pointed to the fact that this variant may be pathogenic, but we weren't really able to connect those dots just yet. So we then collaborated with the group in NYU with Mario Delmar, who did, first of all, functional studies on the sodium channel, but what was nice is that he was able to use his novel method of super-resolution microscopy which is a way in which we can look at the nano-scale structure of the cardiomyocytes, or really the small, small levels of molecules that you see in these cells. And what we did is we found that not only NAV1.5 which is the gene product of SCN5A but also [inaudible 00:13:53] which is an adherence structure molecule, which links the cells together was actually less present in our ARVC patient compared to the control. And this was in the IPS so cardiomyocyte molecule, which we corrected using CRISPR-Cas9 technology so I think at least in current practice, on of the best pieces of evidence that we can get. So I think this shows that our SCN5A variant, I mean, in this case, probably really was pathogenic, but also in a pathophysiological standpoint, explains to us how SCN5A mutations, which are typically thought to be only affecting the sodium channel, can also lead to cardiomyopathy phenotype which has implications beyond the ARVC world, but also in DCM I think this is a nice finding of collaboration that I think ... I hope more people will look into this. Andrew : Absolutely I think the trouble with SCN5A is exactly like you were saying, it's been implicated in Long QT, Brugada Syndrome, SIDS, [inaudible 00:14:57], now ARVC, and even nodal disease, like sinus syndrome and things like that. So the ability to show sort of mechanistically, that while you have a change in your sodium channel gating that you also have a change in the way that the cells can connect with each other and form contractile force is, I guess, key to your study. Anneline: Yeah, yeah. I think this really, I mean, I'm hoping at least, it was also finally published in a journal that looks more into functional studies, so not necessarily only genetics, and I think we need to work closely not only on the genetic side, but look closely at the pathophysiological standpoint for gene discovery purposes because this will really explain to us why one gene is implicated in one disease, and also it points to possible directions to perhaps stop the disease process and treat these patients, which I think is vital in our clinical practice. Andrew : So are SCN5A mutations in ARVC a common finding or are they rare? Anneline: So they are pretty rare. I mean, we do find them every now and then and maybe they're modifiers. So what we did to follow up on that one individual, we check 281 ARVD patients who were screened just by regular screening, not by whole-exome but we did a targeted screening of SCN5A and we found five variants in these 281 patients, so that's two percent. I mean, it's still rare, but it is as rare as any other minor gene causing ARVC, but it is a rare feature, so I mean, I think it could be a player. And interestingly, the phenotype didn't change much. It wasn't really different from the ARVC patients without an SCN5A mutation which is reassuring. What we also saw is that the prevalence of mutations in those with desmosomal mutations. So ARVC is, as you know, typically associated with diseases or mutations in the desmosome. It was more often seen in those without a desmosomal mutation. That was almost double as frequent as in those with a desmosomal mutation. So it does give us some direction to the fact that this may be a player out there. I mean of course it's not Plakophilin-2 which is the major player, I think, in ARVC, but I think it may cause a, at least a certain form of cardiomyopathy of arrhythmogenic cardiomyopathy that we need to be aware of. Andrew : And how do you think your new discovery of SCN5A being associated with ARVC, how do you think that plays into the bigger discussion we were having about expansive genetic testing and what that may mean for a patient as far as diagnostic utility but also limitations of variant interpretation? Anneline: That's a great question. So I think we should be cautious of saying this gene causes only this disease, and I think this is a common feature not only in ARVC but in a lot of cardiomyopathies and even in channelopathies. I think the concept of one gene causes one disease is outdated. We know that multiple genes have multiple effects and this SCN5A, of course the gene product is NAV1.5 which is the major alpha subunit of the sodium channels so it is really not the canonical function of SCN5A or NAV1.5 that causes cardiomyopathy here but it's a non-canonical function so I think we should be aware of the fact that gene products have different functions and that there can be overlap of the cardiomyopathies. So of course I think we should be screwing SCN5A in our ARVC patients and I'm hoping a lot of labs and a lot of physicians are already doing that, but it's really not the only thing that is associated with ARVC. So that's important to keep in mind. Andrew : What do you think the next steps are for sort of broadening the implication of your finding? Anneline: So what we are doing currently, and is a little bit of a sneak peek, because this data is not really out there yet, but we have, in this cohort, we found these five variants in 281 individuals, and we're currently working on one of these individuals to get another IPSO cardiomyocyte cell line and look into the functional components to that. And interestingly, this variant, that exact variant in that ARVC patient was also found in a Brugada Syndrome patient. So wouldn't it be nice to actually set them side by side and see what the differences are? Of course this is a little bit of a future music, if you know what I'm saying, like this is something that we don't have just yet, but I think what we need to figure out is how epigenetic or environmental factors play into this field and to explain how one gene or one variant, even, can cause opposite functional effects in different phenotypes. Andrew : What do you think is needed to help clarify some of the genetic uncertainty you see clinically? Anneline: I think a lot of collaboration, a lot of money, quite frankly. I think we need to ... I mean, the functional data is really helping us not only for understanding that single variant, but also for gene discovery, and as I said, for treatment down the line, that is necessary, and I think the variant of uncertain significance, I mean, if we all live on our little islands and only do our little practices, then we're not going to go a lot further. So we need to work together to understand what your patient has in this variant, my patient had in that variant, and this is our phenotype, so we need to connect those dots to be able to make certain conclusions. Andrew : Well, I'm all for collaboration, as well as additional money, that's good. Anneline: Good. Andrew : Well, thank you so much for spending time with us. Anneline: Sure. Andrew : And again, congratulations on a wonderful presentation. Anneline: Thank you very much. Andrew : I'm joined by Dr. Ernesto Fernandez from the Baylor College of Medicine to talk about his research project. Ernesto, I'm wondering if we can just start by introducing yourself and what your project is. Ernesto: I am a second-year pediatric resident, I'm applying to a cardiology fellowship right now and I'm interested in, obviously, all aspects of pediatric cardiology. We're trying to figure out whether testing for Long QT genes or Long QT syndrome is actually warranted in otherwise healthy individuals. We're trying to see what the yield is on these testings, specifically whole-exome sequencing. Andrew : And I think this project really hits on an important point, whereby, because we've been able to interrogate the genome more comprehensively with clinical testing, that we've run into more incidentally identified variants. And these variants can pop up in genes, like the genes responsible for Long QT syndrome. Talk a little bit more about these variants, what the implication is of finding these variants incidentally, and what your project hoped to target as far as the diagnostic value of these variants. Ernesto: Yeah. So I guess the answer to your first question is that we are coming up with these marvelous new techniques of analyzing the genome and now we're using whole-exome sequence testing to look up is someone has any exome that's abnormal and this has caused a huge problem whereby we're now finding all these variants that we don't really know what they mean. We call them variants of undetermined significance. Our study is basically premised by the fact that if you have no underlying suspicion for any arrhythmic disease, there's really no need or no indication to be referred for whole-exome sequencing testing, given that the most likely result is a variant that we don't really know what it means. And it's probably going to be benign. Andrew : So on the one hand, you have a well-established gene panel that's being used for diagnostic purposes with you index of suspicion being high for Long QT syndrome versus something like a whole-exome gene screen where somebody may not be thinking about Long QT syndrome as a diagnosis and have low pre-test suspicion but then comes back with a variant found in these genes sort of incidentally. Is that sort of the dichotomy you're drawing? Ernesto: Yeah. I think the best way of explaining it is through Bay's Theorem whereby if you have someone with a high index of suspicion when you start off to have sudden cardiac death, a family history of an arrhythmic disease, and you get a test for it, such as a gene panel for Long QT syndrome, and they come up with a positive test result, then you're going to say, "Oh. I should probably evaluate this further," whereas if you have someone who has some dysmorphism, they have delay, they might have seizures, but there's no family history of sudden cardiac death, no personal history of syncope, then there's really no need to send off this big gun, the whole-exome sequence, because you're likely to either get a normal variant or you're likely to get a variant that we don't know what to make of. Andrew : So I think, Ernesto, that nicely summarizes the clinical question that you had in mind. What was your hypothesis going into the study, and how did you seek to approach that hypothesis, sort of experimentally? Ernesto: So we came up with the hypothesis that if you have an incidentally identified variant within the whole-exome sequencing tests without any other clinical suspicion, it's likely to represent a benign finding. We went about by analyzing the data from the Baylor Miraca labs on the whole-exome sequencing data that they achieved, and we looked specifically at individuals who had gotten these tests and found to have a variant of undetermined significance, or had a pathologic variant for either one or all 17 of the genes for Long QT syndrome. We compared them to individuals who had known Long QT syndrome that had undergone genotype testing, and we [inaudible 00:25:21] these individuals from the literature. And we wanted to compare the whole-exome sequencing cohort to individuals who were otherwise healthy and had obtained a whole-exome sequence. So these are patients or individuals from the well-established ExAC database that are believed to be ostensibly healthy individuals. Andrew : So if I understand you correctly, you're comparing this unknown cohort, that being the rare variants found in whole-exome sequencing, against a positive control cohort of pathologic cases versus a negative control cohort of healthy individuals derived from the ExAC database to look for whether those west variants are more similar to the cases or the controls. With regards to the west cohort, what was the prevalence of individuals with these incidentally identified variants, how many did you find? Ernesto: So we actually found just about 49% of individuals had some variant in Long QT syndrome gene, and noted that about 12% of them had a mutation in the major causes of Long QT syndrome, and just over a third, or 36% had a mutation in the more rare causes of long QT syndrome. Andrew : That's a pretty surprising finding. So you're saying that one in two individuals who get whole-exome sequencing sent for whatever reason, have a variant in a Long QT-associated gene? Ernesto: That's what the data suggests. Andrew : And where did you go from here? Ernesto: So from there, we went onto compare the variant frequency between the case's cohort, those individuals with known Long QT syndrome, those individuals in our west cohort from the Baylor Miraca labs, and those individuals from the ExAC database who are otherwise healthy. So we noted that in our west cohort, there was about 13% of individuals who had a positive variant in the Long QT syndrome one through three genes, the major causes of Long QT syndrome. When we compare that to the ostensibly healthy individuals from the ExAC database, it was 12% in that study that had some variant in Long QT syndrome genes that are major causes of Long QT syndrome itself. This was statistically similar, it was indistinguishable. And then when we compared it to the pathologic cases, it was actually about 50% of those cases who had a positive variant in a Long QT syndrome gene one through three. Andrew : So there was a relatively low frequency of individuals who had variants in one of the big three Long QT genes in both controls and the west cohort, and was obviously much higher among individuals with a diagnosis of Long QT syndrome. Ernesto: Yep. That's exactly what we found. Andrew : And where did you go from here? Ernesto: And then from there, we had a good idea that there was probably a big difference between cases and west, but we wanted to make sure, gene by gene, that there was no difference between our west cases and the ExAC database, the control cases. So we mapped each variant frequency by gene for the major causes of Long QT syndrome. There was no statistically significant difference between the west and the controls. Andrew : So the gene frequencies between the controls and the west were indistinguishable and very much different, both of them, it would seem, to the pathologic cases. Ernesto: Correct. Andrew : And you then looked at the position of these variants, the actual amino acid residues, correct? Ernesto: Yeah. So we looked at, for KCNQ1, KCNH2, and SCM5A, the three major causes of Long QT syndrome, one, two, three respectively, and we mapped out the amino acid positions where there was actually a mutation for each individuals. So the cases, controls, and pathologic cohorts. We determined the percent overlap between the west cohort and the controls and the percent overlap between the west cohort and the cases and noticed that for all three, there is a huge preference for west and control versus west and cases. Andrew : So if you're a west variant you're more likely to reside in the residue also occupied by a healthy individual variant as opposed to a pathologic variant? Ernesto: Yeah. Exactly. Andrew : And so what did you do next? You retrospectively looked at some of the charts of the patients who were seen at Texas Children's Hospital, correct? Ernesto: Mm-hmm (affirmative). So then we had 223 total individuals that had an incidentally identified variant within one of the major three genes, the Long QT syndrome genes. We looked at the reasons for their referrals and noticed that the vast majority of individuals were referred for some developmental delay, for some dysmorphism, for a non-cardiac cause, and then it was only about 23% of these individuals that actually had a reason for referral that was cardiac in nature. And less than on percent of individuals were referred for a solely cardiovascular reason. And we concluded that it's unlikely that these individuals were referred for a cardiac reason, as the data suggests, and that as a result, the index of suspicion for an arrhythmia is likely lower in these individuals. Andrew : And what did you find when you looked at the charts of those individuals? Ernesto: We had EKG data for a good number of them, and we excluded individuals who obviously had no EKG data, and we excluded individuals who had some congenital abnormality and then anyone with any other arrhythmia that would make the QTC interpretation more difficult, such as interventricular conduction defects. We ended up with 62 individuals and 61 of them had a normal QTC, so there was no evidence of QT prolongation at all. There was one individual who was left who had borderline elevated QTC of 460, which was our cutoff for borderline elevation and this individual had actually been seen by pediatric cardiology at Texas Children's Hospital and found to have ... a history of syncope and it was found to be non-cardiogenic in nature. Andrew : So matching the variant data which suggested that you had likely found background variation in the west, you found no evidence of Long QT syndrome in these individuals who had variants in Long QT genes. Ernesto: That's correct. So, the overall percent was very similar between the healthy individuals and the west individuals. The variant frequencies were almost indistinguishable, and then the variant co-mapping for all, for both the west and the controls, was preferential to the western cases. So that kind of matched what we found in our study, that there was no clinical suspicion or clinical diagnosis of Long QT syndrome in these individuals who had been found incidentally. Andrew : Well that sounds to me to be a pretty big finding. Ernesto: Yeah. I think it's pretty important to get this information out there. Andrew : So what do you think the take home message for your study is? Ernesto: I think the take home message is if you don't have a suspicion of Long QT syndrome or of an arrhythmia, there's low likelihood that such a big gun test as the whole-exome sequence is likely going to change your mind. Andrew : So Ernesto, what would you advise a cardiologist who maybe gets a patient in clinic with a chief complaint of a VUS in a Long QT associated gene picked up on west, what would you advise based on your study findings? Ernesto: They're going to have to determine their own pre-test suspicion. They're going to have to get a good history and physical, probably get a baseline EKG to determine what the QTC intervals are, and if there's really no other clinical suspicion for Long QT syndrome, they're likely to be able to provide reassurance at that point in time. Andrew : Ernesto, what do you think the next steps are for this project, and what do you think still needs to be done in the field to reinforce your conclusions? Ernesto: I think my study is one of the early studies of this field, so getting more studies like this and other channelopathies, getting not just looking at Long QT one through three but looking at all of them, and in patients who've been evaluated at Texas Children's or any other institution would be helpful. And then moving forward to give more credence to the idea that if you have history that's reassuring and physical exam that's reassuring, then you probably don't need to have further testing. Andrew : What do you recommend if your index of suspicion is high for Long QT syndrome, so maybe a QTC in the low 480s, maybe a family history of syncope or seizures, do you think whole-exome sequencing is the way to go? Ernesto: Right now, that's probably not the best test, given all these incidental findings that we don't really know what to do with. There's other tests that are more high-tailored for those specific diseases, like Long QT syndrome panel among others, that are probably more likely to give you a positive post-test probability. Andrew : So testing for the disease you're suspicious for as opposed to testing indiscriminately? Ernesto: Yeah. Andrew : So Ernesto, thank you so much for taking the time our of your day to speak with us. Ernesto: Thank you, Andrew. Andrew : I'm here with David Tester, senior research technologist working with Mike Ackerman at Mayo Clinic, and he just gave a wonderful talk on whole-exome sequencing and next-generation sequencing as an unbiased look to determine underlying causes of Sudden Infant Death Syndrome, or SIDS. So David, I'm wondering if you can introduce yourself and talk a little bit about your project. Dave: Sure. I'm Dave Tester and I'm at the Mayo Clinic, again with Mike Ackerman. Dr. Ackerman and I have been together for about 18 years now, with a real focus on genetics of sudden cardiac death disorders. So this latest study was looking at whole-exome sequencing in a population of SIDS cases in collaboration with Dr. Elijah Behr at St. George's University in London. And really the approach, what we were aiming for is really kind of two-fold. First we were looking to determine what is the yield of ultra-rare variance within genes that have been implicated in cardiovascular disorders? These would be the cardiac channelopathies and some of the cardiomyopathies such as ACM or ARVC, for example. And the second thing that we were wanting to look at was can we use this to search for sort of novel candidate genes for Sudden Infant Death Syndrome susceptibility? And so we took that aim and really the main result was to show that about 14% of our SIDS cases had what we term potentially informative variants. And those are going to be variants that were within sort of the major channelopathy genes that are implicated in Long QT syndrome or CPVT as well as loss of function variants within the 90 ICC genes that we had examined. Using the ACMG guidelines for determining the pathogenicity of variants, about 4.3% of our SIDS cases hosted an ACMG guideline predicated likely pathogenic to pathogenic variant. And most of those variants represent either a frame shift or splice site error variance really in minor cardiomyopathy genes and channelopathy genes. So there's still a lot of work that needs to be done in terms of looking at specifically missense variance within channel genes and that sort of thing, and really kind of functionally characterizing those to determine whether or not they truly are pathogenic or if they should remain variants of uncertain significance. Andrew : And so you took a very complex disease like SIDS with probably a number of differens ideologies and found a pretty good percentage have suspicious variants, that 14% or so, and then 4% had variants that were so suspicious they would meet American College of Medical Genetics guidelines for being a possible or likely pathologic variant. Where do you think this study lies in sort of the continuum of identifying the genetic ideology of SIDS, and what do you think these findings sort of add to that overall picture? Dave: Well I think these findings in general really just kind of show the complexity of SIDS. Whether or not SIDS is really truly genetic or not, or perhaps it just, if it's not monogenic, perhaps it's polygenic, and so those are some things that we should be considering and looking at. Now some of those questions might be able to be answer through our whole-exome sequencing data set that we have, and I think those are really going to be kind of the next phases. We can also take and do some pathway analyses of the exome sequencing data, for example, and see our variance kind of lining up on certain pathways that may contribute to certain pathologies that could contribute to SIDS. Andrew : And in your study, you had a few genes where the number of variants that were found in SIDS cases were higher than in your controls. Can you speak some more about what those genes may tell you in the context of pathway analysis for SIDS? Dave: Yes. So there was ... There were not genes that came out with sort of a genome-wide significance level. But there were at least 400 genes that had a p-value of 0.05 over representation in SIDS versus our ethnic match controls and 17 of those genes have a p-value of 0.005 and we're really kind of focused on some of those that have a little bit higher p-value for us to assess. A few of those genes may represent biologically plausible candidate genes for SIDS and we were kind of actually going through and considering which ones we'd like to follow up on in terms of function. Some of these genes do play a role in, say, cardiorespiratory system and function of the heart as well as in the brain. Andrew : So then given all these findings, and the fact that you may have some candidate genes and candidate pathways that might be interesting to look at further, what are the next steps that you think would help this project move forward, and what do you think the field of Sudden Infant Death Syndrome and Sudden Unexplained Death Syndrome needs to kind of move forward? Dave: Well I think from a genetic standpoint, the study that we just complete was really on a large set of unrelated infants that had died suddenly. We did not have access to parental DNA and so moving forward in terms of the genetics, I think incorporating sort of a trio analysis I think would get at the question of sort of [inaudible 00:42:01] variance for example. The other things, in terms of genetic standpoint is perhaps looking at different genetic mechanisms. Whether these are copy number variance that may be missed by exome sequencing, perhaps some of the SIDS could be due to epigenetic abnormalities or even small chromosomal abnormalities that perhaps may not be detected on certain arrays on there being used. So I think going forward, kind of taking those approaches to look for sort of unique genetic variation. Andrew : Well Dave, thank you so much for taking the time to speak with me and congratulations on a great project. Dave: All right, great, thank you. Jane Ferguson: Thanks to Andrew for highlighting the interesting precision medicine research presented at HRS and thanks to you all for listening. We'll be back with more next month.

chicago talk phd heart dna medicine netherlands nyu feature andrews correct baylor hopkins american colleges mm fernandez mayo clinic icc ips tester ackerman qt cardiovascular diseases baylor college hrs episode four acm sids ekg crispr cas9 texas children hcm vanderbilt university medical center dcm sudden infant death syndrome medical genetics vus brugada medicine department ipso qtc jane ferguson nhlbi landstrom arvc acmg texas children's hospital long qt nav1 brugada syndrome scn5a arvd cpvt kcnq1 kcnh2

Circulation: Arrhythmia and Electrophysiology On the Beat August 2017

Play Episode Listen Later Aug 15, 2017 50:36

Dr. Wang: Welcome to the monthly podcast On The Beat for Circulation, Arrhythmia and Electrophysiology. I'm Dr. Paul Wang, editor-in-chief, with some of the key highlights from this month's issue. We'll also hear from Dr. Suraj Kapa, reporting on new research from the latest journal articles in the field. This month's issue of Circulation: Arrhythmia and Electrophysiology has a number of fascinating and important articles. Let's start with the first article by Philip Halbfass and Associates, which describes the use of esophageal endoscopy in patients undergoing atrial fibrillation ablation. Of 1,802 patients undergoing afib ablation, 832 underwent post-procedural esophageal endoscopy. All patients were ablated using a single tip re-circular ablation catheter. Category one lesions described as erythema erosion were seen in 98 out of these 295 patients, while in 52 out of the 295 patients, ulceration was seen. In three of the 832 patients, esophageal perforation occurred, and in two of the 832 patients, atrial-esophageal fistula occurred. Esophageal perforation only occurred in patients with category two lesions with an absolute risk of 9.6%. The authors concluded that post-ablation esophageal endoscopy is able to identify patients with high-risk lesions. One out of 10 patients with post-ablation esophageal ulcers progressed to perforation, while no patients without esophageal ulcers showed evidence of perforating complications. In the next article by Christian Sohns and Associates describes the relationship between atrial fibrosis identified with magnetic resonance imaging and atrial rotor activity identified by noninvasive electrophysiological mapping. Ten patients underwent pulmonary vein isolation for persistent atrial fibrillation. Late gadolinium enhancement using magnetic resonance imaging, which projected onto the anatomy used for noninvasive electrophysiologic mapping. The noninvasive electrophysiologic mapping identified 410 rotors evenly distributed between the left atrium and the right atrium. This study found that there was no statistically significant association between the presence of late gadolinium enhancement and the presence of rotors. In the next article written by Jereon Venlet examines the endocardial unipolar voltage that best identifies abnormal epicardial electrograms. Thirty-three patients underwent endocardial epicardial right ventricular electro-anatomical mapping in ablation of right ventricular scar-related ventricular tachycardia. Eighty-six percent of abnormal epicardial electrograms had corresponding endocardial sites with bipolar electrogram less than 1.5 millivolts. The remaining abnormal epicardial electrograms could be identified by endocardial unipolar voltages of less than 3.7 millivolts. The authors concluded that this use of endocardial unipolar voltage cut off at normal bipolar voltage sites improves the identification of all abnormal epicardial electrograms where there is less than 1 millimeter of fat. The next article by Alan Bulava and Associates examines the outcomes of hybrid epicardial and endocardial radial frequency ablation, a persistent atrial fibrillation. Seventy patients underwent the epicardial thoracoscopic procedure followed by endocardial mapping ablation two to three months later. At the time of catheter ablation, 76% of patients were in sinus rhythm. All four pulmonary veins were found to be isolated in 69% of the patients and the left atrial posterior wall was isolated in 23% of the patients. In the 12 months after the catheter ablation, 77% were arrhythmia-free, off antirrhythmic drugs. The majority of arrhythmia occurrences occur during the first 12 months following catheter ablation. Using previously ineffective antiarrythmics drugs and re-ablation procedures, arrhythmia-free survival increased to 97% during a mean followup of 936 days. Left atrial volume greater than 165 milliliters, the absence of sinus rhythm before catheter ablation and induce-ability of any sustained tachyarrhythmia at the end of catheter ablation predicted atrial fibrillation recurrence. The authors concluded that the majority of patients after epicardial ablation required endocardial catheter ablation to complete the linear ablation or pulmonary vein isolation lesion sets. In the next article, Jason Roberts and Associates studied the clinical phenotype of Type 6 Long QT Syndrome, stemming from mutations in the KCNE2 encoded voltage gated channel beta subunit. The authors examined individuals reported pathogenic KCNE2 mutations collected from inherited arrhythmia clinics in the Rochester LQTS registry as well as previously reported LQT6 cases identified through a med-line database search. Of 44 probands studied, 16 probands had resting QTC intervals and only developed QT prolongation and malignant arrhythmias following exposure to QT prolonging stressors. Ten had other Long QT pathogenic mutations and 10 did not have a Long QT phenotype, with the remaining eight subjects having a Long QT phenotype, but with evidence suggesting that the KCNE2 variant was not the underlying culprit. The authors noted that the collective frequency of KCNE2 variance implicated in Long QT6 syndrome in the exome aggregation consortium database was 1.4%, in comparison with the 0.0005% estimated clinical prevalence of LQT6 syndrome. Thus, the authors concluded that based on clinical phenotype, the high allelic frequencies of LQT6 mutations in the exome consortium database, in absence of prior documentation of genotype phenotype segregation, many KCNE2 variants, and perhaps all have been erroneously designated as long QT syndrome causative mutations. Instead, KCNE2 variants may confer pro-arrhythmic susceptibility when provoked by additional environmental acquired or genetic factors. In the next article, Alexander Quinn and Associates examine how mechanically-induced ectopy may cause ventricular fibrillation, the mechanism of commotio cordis. It is known that the block of stretched sensitive ATP inactivated potassium channels limits ventricular fibrillation occurrence in a porcine model of commotio cordis. In isolated rabbit heart preparations using optical voltage mapping combined with pharmacological block of potassium ATP or stretch activated cation nonselective channels, the authors showed that the mechanical stimulation reliably triggers premature ventricular excitation at the contact site with induce-ability predicted by local tissue indentation. Mechanically-induced premature ventricular excitation induction is decreased by stretch activated cation nonselective channel block. The authors also found that mechanically-induced premature ventricular excitation resulted in ventricular fibrillation only if the mechanical stimulation site overlaps the re-polarization wave edge in hearts where T-waves involve a well-defined re-polarization edge traversing the epicardium. This defines a narrow subject-specific vulnerable window for commotio cordis-induced ventricular fibrillation in both time and space. In the next article Matthias Seidl and Associates examine the gene expression required for development of atrial fibrillation in a transgenic mouse model. Recent studies showed that atrial fibrillation susceptibility is associated with down regularization of target genes of the CREB/CREM family of transcription factors. CREB/CREM refers to cyclic and P-response element binding protein modulator. Short CREM repressor isoforms like CREM-IbΔC-X bind to cyclical A&P responsive elements preventing transcriptional activation. Messenger RNA for CREM-IbΔC-X is up-regulated in atrial biopsies from patients with paroxysmal or chronic atrial fibrillation. The authors examined transgenic mice expressing CREM-IbΔC-X, which spontaneously developed atrial fibrillation proceeding to permanent fibrillation with age. The authors found that the most prominent alterations of the gene program linked to CREM-induced atria modeling were identified in expression of genes related to structure, metabolism, contractility and electrical activity regulation. In the next article by Takumi Yamada and Associates electrophysiologic characteristics of the idiopathic ventricular arrhythmias originating from the parietal band, one of the muscle bands of the right ventricle, were examined. Of 294 consecutive patients with right ventricular origins, 14 patients had ventricular arrhythmia origins in the parietal band. All patients have left bundle block pattern with 12 inferior and two superior axis. All patients had the notch in the middle of the curess in all cases. Seven patients had precordial transition before lead V3 and four patients had a slow curess onset. Far field ventricular electrogram with an early activation was always recorded in His bundle region regardless of the location of the ventricular arrhythmia origin. During the catheter ablation, a mean number of 10.4 radio frequency of applications with a mean duration of 1,099 seconds were delivered. Catheter ablation was successful in 10 patients and ventricular arrhythmias recurred in four with a mean followup of 41 months. In the Advances in Arrhythmia and Electrophysiology section, the Buza and Associates have reviewed cancer treatment-induced arrhythmias. The authors describe ECD advances in arrhythmias associated with individual cancer chemotherapeutic agents. Now here with a review of the highlights from the articles from journals throughout the world in the past month, is Dr. Suraj Kapa. Dr. Kapa: Hello. Today we're going to be going over several hard hitting articles we have identified that seem to stand out in the electrophysiological literature from the month of July 2017. The first area we will be delving into is that of atrial fibrillation. Specifically related to cardiac mapping and ablation. The first article in this area that we've chosen was published by Samuel et al. in the Journal of Cardiovascular Electrophysiology entitled Catheter Ablation for the Treatment of Atrial Fibrillation Is Associated with a Reduction in Healthcare Resource Utilization. Samuel et al. reviewed data from a large population base cohort in Quebec, Canada including over 1,500 patients undergoing cardiac ablation for atrial fibrillation. They demonstrated that healthcare resource utilization including hospitalizations, emergency room visits and cardioversions were significantly reduced both 12 months as well as 24 months after the next ablation. These findings seem to suggest that catheter ablation has a sustained overall impact on resource utilization amongst patients with atrial fibrillation. While the study was not randomized and was a retrospective evaluation of outcomes, these findings are provocative. Certainly as we wait for the results of the Cabana trial in about one year we hope to see whether or not cardiac ablation carries the weight of potential beneficial impacts both in terms of long-term care as well as long-term outcomes. Of course being a retrospective evaluation, one question that lies with regards to these findings is whether or not the reduction in resource utilization might be a byproduct of improved ambulatory care of these patients or whether it's a byproduct of patients understanding their disease process better, and thus perhaps not seeking emergency room care or hospitalization as frequently. The next publication we'll focus on was published by Anselmino et al. in The International Journal of Cardiology entitled Conduction Recovery Following Catheter Ablation in Patients with Recurrent Atrial Fibrillation and Heart Failure. This publication synergizes with several other publications that have come out in the month of July. Focusing on the publication by Anselmino et al., they reviewed retrospectively patients undergoing redo atrial fibrillation ablation in the setting of underlying heart failure. What they demonstrated was that nearly a third of patients had no pulmonary vein reconnection, but tended to have more persistent forms of atrial fibrillation suggesting more extensive atrial substraights. This study is complimentary to a publication by [inaudible 00:15:23] et al., published in JACC EP. this past month where they evaluated the longterm outcomes of patients who, when presenting for redo atrial fibrillation ablation had persistent pulmonary vein isolation. In that article, they found that nearly 17% of patients presenting for redo ablation had persistent pulmonary vein isolation. Moreover, these patients tended to perform significantly worse in terms of longterm outcomes than those who presented with PV reconnection, with about a 56% freedom from affiliate swipe after we do ablation in the setting of persistent pulmonary vein isolation as opposed to 76% when there was PV reconnection seen. So the question becomes if we see this greater atrial substraight, should we automatically be doing more ablation? Of course as we all know, there have been many studies performed trying to tease out whether additional ablation in patients who might have more significant atrial substraight carries benefits. In this regard, Fink et al. in last month's edition of Circulation, Arrhythmia and Electrophysiology demonstrated that in fact as an index procedure of performing a stepwise concomitant café plus linear ablation on top of pulmonary vein isolation in persistent and long standing persistent atrial fibrillation patients did not necessarily confer an increased likelihood of longterm success over pulmonary vein isolation alone. Thus, the jury continues to still be out as far as what the right strategy is in many of these patients. However, these studies highlight the importance of continued evaluation and understanding of how we can use information about atrial substraight to guide our ablation procedures more successfully. Changing gears, we'll move on the pathophysiology mechanisms of disease within atrial fibrillation. The article we will choose to focus on here was published by Die et al. in The Journal of Cardiovascular Electrophysiology entitled The Effects of Extrinsic Cardiac Nerve Stimulation on Atrial Fibrillation Induce-ability: The Regulatory Role of the Spinal Cord. Over the course of the last several years many investigators have sought to show that modulation of the autonomic nervous system can successfully alter cardiac electrophysiology and provide antiarrythmic benefits. However, when subject to prospective trials such as the recently published Defeat HF Trial, they have not necessarily found clear benefit. Thus, a critical question becomes how we translate our animal models into human treatment. The interesting results from Die et al. lie in the fact that they looked at the effects of spinal cord stimulation and spinal cord block in addition to concomitant stimulation of other centers such as the venous nerve, the stellate ganglion and ganglionated plexi. They demonstrated that spinal cord stimulation enhanced the effects of venial nerve stimulation while attenuating the effects of stimulating the left stellate ganglion or ganglionated plexus. In turn, the combinations of these different levels of stimulation had different effects on affiliate swipe induce-ability, whether significantly increasing or decreasing the potential. The reason this article is important is it highlights the extensive cross linking and synergy that exists within the autonomic nervous system and that attention paid to only a single center of autonomic innovation may not be sufficient for certain paradigms of care. This past month there were also two reviews summarizing the role of the autonomic nervous system and modulation of that nervous system and the treatment of arrhythmias. The first was by Witt et al. and Europace. The other by Schwartz et al. in the International Journal of Cardiology. These articles help the reader understand the extensive crosslinking and cross communication that might occur, that might sometimes defeat our efforts to use a single element of the autonomic nervous system to modulate cardiac arrhythmias. Changing gears yet again, we'll move on to risk stratification and management for atrial fibrillation. Perino et al. in last month's edition of The Journal of the American College of Cardiology published an article entitled Treating Specialty in Outcomes in Newly Diagnosed Atrial Fibrillation from the Treat AF Study. They present data based on a very large cohort of over 180,000 veterans regarding the effect of treating specialty on atrial fibrillation outcome. Interestingly they demonstrated that when a cardiologist was involved in the care of the patient, there was an overall decrease in stroke and mortality. Albeit with a concomitant increase in hospitalization for AF. The stroke reduction seen was also seen to be secondary to better anticoagulation prescription within 90 days of diagnosis when those patients were seen by a cardiologist as compared with a general internist. This earlier prescription anticoagulation however did not mediate the mortality reduction. These data presented by a Perino et al. are provocative in this era of rising healthcare costs. The question is, as atrial fibrillation rates rise, as the general population ages, how quickly and how aggressively we should engage specialty care early on in patient evaluation. The data by Perino et al. suggests that maybe this engagement should occur earlier. Part of the reasons for this might be improved understanding of current evidence regarding treatment of such patients or better systems of care that allow for providers to identify patients who might need alterations and care faster. However, if anything this is hypothesis-generating. Why anticoagulation prescriptions are delayed when patients are not seen by a specialist or why there would be a difference in mortality are important factors to review further. In this past month Hernandez et al. in Stroke published an article discussing the large degree of geographic variation that exists with regards to appropriate anticoagulation prescription in patients with atrial fibrillation. They demonstrated that there's extensive inhomogeneity across the United States in terms of how and in whom anticoagulation gets prescribed. Thus, how much of these outcomes are specialist-driven, geographically-driven or based on elements of access to care or other issues are going to be important features that have to be evaluated. The next article in risk stratification was published by Mostofsky et al. in Heart, entitle Chocolate Intake and Risk of Clinically Apparent Atrial Fibrillation: The Danish Diet, Cancer and Heart Study. In this study they demonstrated in a population of over 55,000 patients that when accounting for as many variables as they could, higher chocolate intake, more than once per month, was associated with a decreased atrial fibrillation risk when compared with those consuming less chocolate than once per month. Of course, they note that despite these attempts to account for multiple confounding variables, residuary confounders cannot be accounted for. The relevance of this article lies in the question of lifestyle choices patients are asked to make when thinking about how to either prevent themselves from having atrial fibrillation or trying to even treat their atrial fibrillation risk. Chocolate has been shown to have multiple potential beneficial effects in multiple areas of cardiology, however, how to counsel patients with data like these becomes very difficult. The questions lies in how chocolate might mediate arrhythmia risk and how it might also modulate other potential risks such as weight gain or other factors. Thus while important to consider this in light of patients often asking what they can and cannot have, it is important to further consider that we don't understand the full story. The other key element to understand is that really when they say that chocolate intake reduces risk of clinically apparent atrial fibrillation they are speaking about moderate chocolate intake and not necessarily having it for three meals a day. Changing gears away from atrial fibrillation, we will next focus on the area of ICDs pacemakers and CRT. Aberi et al. in Nature's Scientific Reports published regarding inductively power wireless pacing via miniature pacemaker and remote stimulation control system. Their approach provides potential novel opportunities beyond currently available both lead-based and leadless pacemakers and improving battery and allowing for further miniaturization of such devices. They noted by creating a very novel inductive power supply they're able to miniaturize the pacing components and also significantly reduce the power requirements. In fact, they suggested that they could create a leadless device that could be as small as being delivered out of the anterior ventricular vein. This is the first report of such an inductively powered miniaturized pacing system with low enough power consumption that may prove viable for ambulatory human use. The desire to create improved pacing and fibrillation systems is further highlighted by an article published by [Kalu 00:25:41] et al. in JACC Clinical Electrophysiology this past month where they demonstrated initial results of percutaneous epicardially delivered partially insulated defibrillator lead. Work like these holds the potential to improve options for patients and in traditional vascular access is not desired, or an identifying new ways of delivering pacing therapy that exists outside the traditional lead base or even somewhat miniaturized leadless approaches. We'll next focus on the area of sudden death and cardiac arrest. The first article we'll focus on was published by Stecker et al. in The Journal of The American Heart Association entitled Health Insurance Expansion and Incidence of Out of Hospital Cardiac Arrest: A Pilot Study in the US Metropolitan Community. This article looked at the results of The Affordable Care Act, mainly health insurance expansion, on the rate of out of hospital cardiac arrest in a large US metropolitan community of over 600,000 people. They separately studied a middle aged population that might have been affected by healthcare expansion versus an older population, above 65, who would have had relatively stable insurance plans having been covered by Medicare both prior to and after this change in healthcare plans. They demonstrated that there was a significant decrease in overall out of hospital cardiac arrests amongst middle age people without any significant change amongst the more elderly Medicare population in the same time period. The time period studied was relatively short, nearly less than a decade. Of course, whether there were other events that might have occurred to alter this risk such as improvements in care beyond the combination of availability and mandates plus carrying health insurance, it remains to be seen. However, the data is very suggestive. Further evaluation at the national level in varying communities however would be useful, as well as consideration of population level cost benefit analysis. The next article published by Shen et al. in the New England Journal of Medicine entitled Declining Risk of Sudden Death in Heart Failure. They presented data across 40,000 patients from multiple clinical trials over two decades regarding the changing rates of sudden death amongst heart failure patients. Interestingly they noted there was an overall 44% reduction in sudden death rates across these trials over time dating from the 1990s to 2014. In the earliest trials considered, the mortality rate within 90 days after randomization was as high as 2.4% while the most recent trials suggest that that rate is more like 1.0%. This profound decline was attributed to improved usage and prescription of medications early on in the heart failure course, which may modulate outcomes. The relevance of these findings lies in trials that have been published recently and met analysis that we've discussed regarding utility of defibrillators in nonischemic cardiomyopathy or even ischemic cardiomyopathy. The recently published Danish study suggested that ICDs might not confer an equivalent mortality risk as what would have been expected years ago. However, this publication by Shen et al. is particularly provocative because it calls into question whether the same mortality benefit we anticipated from earlier heart failure trials should still be the rubric by which current defibrillator trials are powered. Namely, if we consider that Danish saw the 25% difference in mortality, with a 44% overall reduction in sudden death seen in trials over time for heart failure, seeking a 25% reduction might be excessive. Thus, this highlights the need to potentially power trials for ICDs and the benefit of such ICDs better. This importance of better stratifying better heart failure patients for sudden death risk has been raised in multiple articles this month, including in a review by Holiday et al. in Circulation and in the series of reviews published in Volume 237 of The International Journal of Cardiology. The last article we choose to focus on in the role of sudden death and cardiac arrest was published by Vehmeijer in Circulation: Arrhythmia and Electrophysiology entitled Prevention of Sudden Cardiac Death in Adults with Congenital Heart Disease: Do the Guidelines Fall Short? They reviewed outcomes amongst 26,000 adults with congenital heart disease in light of existing guidelines for risk prediction and prevention of sudden death. They demonstrated that less than half of the patients with sudden cardiac death actually had a guideline basis recommendation for an ICD on the basis of either the 2014 consensus statement on arrhythmias or the 2015 European Society of Cardiology Guidelines. These findings are very provocative in suggesting that we don't really understand who requires treatment amongst adults with congenital heart disease. With improved care paradigms, both with improvements in surgical outcomes as well as ambulatory care of these patients and recognition of need for interventions, arrhythmias are becoming a greater and greater problem amongst patients with adult congenital heart disease. However, large scale studies are limited in stratifying overall risk of arrhythmias. The risk is certainly present as many of these patients have ventricular scar often attributable to cardiac surgeries or have hemodynamic insults that may result in progressive fibrosis of the ventricles. In addition, the basal abnormalities of cardiac formation itself may lend itself to a sudden increased risk of arrhythmias. Thus, the question remains as how to best risk stratify these patients in order to reduce these overall sudden death rates. Changing gears yet again, we'll focus on two articles within the realm of cellular electrophysiology. The first article was published by Cerrone et al. in Nature Communications entitled Plakophilin-2 is Required for Transcription of Genes that Control Calcium Cycling and Cardiac Rhythm. They demonstrated that plakophilin-2, or PKP2, which is known to mediate arrhythmogenic right ventricular cardiomyopathy due to abnormalities in the desmosomes actually has other direct electrical effects independent of substraight effects that are seen. Specifically PKP2 plays a significant role in maintaining gene transcription for several genes that mediate normal electrophysiologic activity, such as the ryanodine receptor, calsequestrin and others. They demonstrated that this reduced expression of other genes secondary to PKP2 absence or abnormality leads to increased isoproterenol or adrenaline-induced arrhythmias that in turn can be suppressed with Flecainide. These findings are provocative in the fact that they suggest that it is possible for patients to have abnormalities of genes such as PKP2 that result in electrical abnormalities independent of the structural abnormalities. Furthermore, it suggests that manifestation of the disease such as catecholaminergic polymorphic ventricular tachycardia may be immediate upstream of typical channels associated with the disease. For example, if PKP2 reduces expression of the ryanodine receptor, this might result in manifestations similar to CPTB in some patients. Along the same lines, Hewitt et al. published in Science Advances regarding deregulated calcium cycling underlies the development of arrhythmia and heart disease due to mutant obscurin. Obscurins are a relatively growing area of interest as these are cytoskeletal proteins that have be associated with both hypertrophic and dilated cardiomyopathy. Similar to the story we just told about PKP2 however, they demonstrated that obscurins, likely through circa 2 and pentameric phospholamban can cause abnormal calcium handling. In fact, they demonstrated that the principle phenotype associated with obscurin abnormalities is one of an electrical abnormality, namely frequent PVCs. In turn, mechanical phenotypes such as cardiomyopathy result in the setting of chronic pathologic stress such as increased afterload, thus these findings demonstrate that genes such as obscurin or PKP2, which are commonly associated with structural or mechanical myopathic processes might have direct independent electrical effects. The story with obscurin raises further question into how this may apply to conditions of PVC-related cardiomyopathy or other such conditions. The other key point about these two areas of interest lie in the fact that it is possible as these genetic abnormalities mediate not just direct substraight elements, but arrhythmogenesis via abnormal channel expression, whether in all patients presenting with such specific genetic abnormalities substraight-based ablation alone will result in reduction of arrhythmia tendency. Of course this remains to be seen and is primarily hypothesis-generating. Next we'll focus on three articles within the area of genetic channelopathies. The first paper was published by Rohatgi et al. in The Journal of the American College of Cardiology entitled Contemporary Outcomes in Patients With Long QT Syndrome. In a large single center practice, they reviewed the results of over 600 patients predominantly affected by LQT1 or LQT2 and demonstrated that after initial evaluation along with treatment based on the individual, done at a highly skilled center, 92% of patients did not experience any breakthrough cardiac events over longterm followup. It was noted however, that the incidence of breakthrough cardiovascular events over longterm followup were far more common in patients who were symptomatic prior to their first evaluation than asymptomatic. In other words, if you were symptomatic prior to your first evaluation, the likelihood of a breakthrough cardiovascular event over longterm followup was as high as 25%, but if you were asymptomatic it was as low as 2%. These data suggest that our overall care of the Long QT patient is improving. However, it also supports that further improvements in care are needed as breakthrough cardiovascular events can continue to occur. It also highlights the importance of close followup of that symptomatic patient in the modern era. The second article was published by Kannenkeril et al. in JAMA Cardiology entitled the Efficacy of Flecainide in the Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia. Flecainide currently carries a class 2A indication according to both the 2015 ENC guidelines and 2013 HRS AHRA APHRS consensus statement for treatment of patients with CPVT who fail max dose beta blockers. A lot of this evaluation however, has been based on retrospective evaluations. Kannenkeril reviewed in a prospective single blind placebo controlled crossover trial the effect of Flecainide on exercise associated arrhythmias in CPTV patients who were already on max tolerated beta blockers and had an ICD. Amongst the 14 patients included of whom 13 completed the study, they showed there was a significant reduction in median ventricular arrhythmia score during exercise and in fact there was complete suppression with Flecainide compared to the placebo of 85%. These findings thus add to the existing literature in terms the potential incremental value of Flecainide in achieving adequate arrhythmia suppression when used in conjunction with maximal tolerated beta blockers. The last article within the realm of genetic channelopathies we'll focus on was published by Yang et al. in The Journal of Physiology entitled A Multi-Scale Computational Modeling Approach Predicts Mechanisms of Female Sex Risk in the Setting of Arousal-Induced Arrhythmias. It is recognized that female gender can increase the risk of Torsades in the setting of both inherited and acquired prolonged QT syndromes. In a combination of experimental and computational approaches, Yang et al. demonstrated that hormone concentrations can partly mediate this risk, specifically as it relates to her-related mutations. They demonstrated testosterone and high progesterone levels provide a protective effect against Torsades. However, estrogen can enhance Torsadogenic potential, particularly in the setting sympathetic stress. They also demonstrated the mechanism by which this likely occurs is due to interaction of estrogen with pore loop or intracavity binding site of the her channel. In fact, on top of this they demonstrated that combined treatment with both estrogen and Dofetilide can simultaneously blockade the pore channel of her. These findings are provocative and hypothesis-generating. In terms of potential future research to further clarify risk for patients, particularly as it may apply to menstruating females who might have varying levels of estrogen, especially when being treated with concomitant QT prolonging agents such as Defetilide. Next we will focus on three articles within the realm of ventricular arrhythmias. The first article was published by Sapp et al. in JACC Clinical Electrophysiology entitled Real Time Localization of Ventricular Tachycardia Origin from the Twelve Lead Electrocardiogram. They presented a methodology for rapidly determining in real time the approximate origin of a ventricular tachycardia using the 12 lead during cardiac ablation. In 38 patients they used a variety of methods that involved multiple linear regression learning methods and demonstrated that a patient-specific regression method using at least 10 training set pacing sites in the individual patient can provide a localization accuracy of the exit site for VT of as much as five millimeters. Furthermore, with additional pacing sites that accuracy could improve further. These findings support the continued utility of the standard 12 lead ECG in localizing the exit site of ventricular tachycardia. Furthermore, it points out the importance of considering that the electrocardiogram can be patient-specific. By using multiple pacing sites, this helps an algorithm learn how a patient-specific heart exists in terms of its electrical propagation potential. Further informing based on a 12 lead of a specific VT approximately where it should be exiting from. The next article we will focus on was published by Muser et al. in again, JACC Clinical Electrophysiology entitled Longterm Outcomes of Catheter Ablation of Electrical Storm in Nonischemic Dilated Cardiomyopathy COMpared with Ischemic Cardiomyopathy. The summary point to this article is in a single center, large volume group of patients including about 267 total, the longterm outcomes of VT recurrence or mortality was no different between nonischemic and ischemic patients. This is important to note as most prospective studies and in fact retrospective studies of the role of ventricular tachycardia ablation have focused on ischemic patients where the substraight is relatively predicable. These findings highlight that ablation may provide a reasonably effective therapy irrespective of the cause of the myopathy. Finally, changing gears within the realm of ventricular arrhythmias, we'll focus on a translational article by Motloch et al. in JACC Basic to Translational Science entitled Increased Afterload Following Myocardial Infarction Promotes Conduction-Dependent Arrhythmias That Are Unmasked by Hypokalemia. They studied the role of increased afterload after myocardial infarction in a listing arrhythmias in a porcine infarct model. They demonstrated that in the setting of increased afterload there was increased widespread interstitial fibrosis. Interestingly, pacing -induced arrhythmias induced by a rapid burst pacing were mediated by hypokalemia associated conduction abnormalities rather than repolarization abnormalities. The reason these findings are potentially important lie in the fact that arrhythmias in the early stages after myocardial infarction, especially in a setting of increased afterload, might be considered to be secondary to either repolarization abnormalities or depolarization abnormalities. These findings suggest that in the setting of concomitant hypertension the primary problem really lies in hypokalemia associated conduction abnormalities. Thus, treatments that impair cardiac excitability, for example, even sodium channel blockade, may similarly confer an increased risk of ventricular arrhythmias when in the presence of increased afterload and myocardial infarction. It also calls into question whether interventions such as antitachycardia pacing in patients with hypertension, in other words increased afterload, might be more prone to acceleration of the ventricular arrhythmias than patients who are relatively better managed as far as afterload. Changing gears yet again, we will focus on EP relevant myopathies. [inaudible 00:44:19] et al. published in JACC Clinical Electrophysiology regarding use of the 12 lead electrocardiogram to localize regions of abnormal electron atomic substraight in arrhythmogenic ventricular cardiomyopathy. There were really two major articles in this regard that have been published both in the same month. The other article was published by Andrews et al. in Circulation, Arrhythmia and Electrophysiology entitled Electrical and Structural Substraight of Arrhythmogenic Right Ventricular Cardiomyopathy Determined Using Noninvasive Electrocardiographic Imaging and Late Gadolinium Magnetic Resonance Imaging. The relevance of both of these articles lies in their statements about the potential utility of noninvasive approaches essentially using electrocardiograms to determine the distribution of substraight in arrhythmogenic right ventricular cardiomyopathy. The article by [inaudible 00:45:16] et al. specifically focused on fractionation of the QRS. They showed that patients with evidence of fractionation in the QRS on a 12 lead ECG had more extensive substraight. Furthermore, distribution of fractionation to specific leads such as inferior, anterior or basal superior leads, was 100% specific, but veritably sensitive for identifying substraight as it localizes to specific cardiac regions. In turn, the publication by Andrews et al. in Circulation, Arrhythmia and Electrophysiology reviewed how the addition of multiple leads by a noninvasive electrocardiographic imaging could be used to even more specifically hone in on the relevant substraights. Their further benefit was in the suggestion that repolarization abnormalities in fact co-localized with origination sites for ventricular ectopy in these patients. In combination, these sites highlight the utility of simple, noninvasive methods of electrocardiographic imaging in identifying and defining the arrhythmogenic substraight in the NRVC. The next article we will review was by Sommariva et al. in Nature's Scientific Reports published just this past month entitled MIR 320A as a Potential Novel Circulating Biomarker of Arrhythmogenic Cardiomyopathy. They did micro RNA analysis on 53 healthy controls, 21 idiopathic VT patients and 36 arrhythmogenic cardiomyopathy patients and demonstrated that the circulating micro RNA 320A was significantly higher in arrhythmogenic cardiomyopathy than in either other cohorts. It is recognized that some patients with idiopathic VT, especially right ventricular [inaudible 00:47:09] VT might reflect a cohort that might have what we call "concealed ARVC." The question thus becomes how to define why a patient has a specific manifestation of disease because longterm outcomes, if there is some underlying ARVC might be worse if the ARVC is not recognized and if cure is assumed based on treatment of the initial presenting rhythm. Thus identifying novel ways of defining the presence of a disease even in the absence of obvious structural abnormalities carries benefit in terms of suggestions on longterm followup. Complimentary to the previously discussed article on the role of PKP2 mutations on mediating electrical instability in the heart, the study by [inaudible 00:48:01] et al. does in fact suggest that there might be methods of distinguishing arrhythmogenic cardiomyopathy from whether it be controls or truly idiopathic ventricular tachycardia using a very specific circulating biomarker. On a completely different route, we'll finish our podcast today with a discussion of Bruner et al. published in European Heart Journal entitled Alcohol Consumption, Sinus Tachycardia and Cardiac Arrhythmias at the Munich Oktoberfest: Results from the Munich Beer-Related Electrocardiogram Workup Study or Munich Brew. Bruner et al. studied over 3,000 voluntary participants with a combination of breath alcohol concentration measurements and electrocardiographic recordings via smartphone throughout the Munich Oktoberfest. In addition, they sought to evaluate chronic alcohol consumption effects on arrhythmias in a separate cord of over 4,000 patients from the Cora S4 study. In the study regarding acute alcohol effects, they demonstrated that in line with increasing BAC, there was a greater occurrence of arrhythmias in particular sinus tachycardia in almost a third of patients. What was even further interesting was that respiratory sinus arrhythmia over the course of higher BAC is from baseline was reduced in the setting of alcohol use. Similarly, with chronic alcohol consumption there was an apparent significant association with the occurrence of sinus tachycardia. The reason these findings are important is in their suggestive element that the effects of alcohol intake in terms of whether it be acute or chronic arrhythmogenesis might somewhat lie in their effects on the basal autonomic states. As demonstrated by the reduction in overall sinus arrhythmia. These findings serve to further elucidate mechanisms by which alcohol may mediate arrhythmias in a large real world patient sample. Thank you for joining us on this edition of On The Beat. Tune in next month again for more articles that might be of interest to the general electrophysiologic community all summarized in a single location.

united states canada work holiday heart left medicine risk cancer journal patients focusing treatments effects chocolate prevention adults similar medicare danish required associates outcomes quebec thirty andrews af hernandez yang stroke genes wang advances schwartz american colleges reduction physiology electrical seventy crt affordable care act atp rna vt american heart association efficacy international journal fink cardiology eighty witt 2a transcription pv hewitt circulation new england journal bac shen qt pvc heart failure complimentary sudden death ecg cabana cerrone incidence icd albeit european society sapp stecker alcohol consumption enc bruner v3 nature communications spinal cord arrhythmia catheter science advances jason roberts kalu ecd esophageal electrophysiology kapa mechanically translational science qrs sudden cardiac death crem european heart journal perino buza messenger rna qtc icds pvcs hypokalemia i'm dr muser torsades arvc catheter ablation jama cardiology long qt syndrome on the beat long qt cptv paul wang cpvt circulation arrhythmia jacc clinical electrophysiology kcne2

Circulation: Arrhythmia and Electrophysiology On the Beat July 2017

Circulation: Arrhythmia and Electrophysiology On the Beat

Play Episode Listen Later Jul 18, 2017 39:06

Dr. Paul Wang: Welcome to the monthly podcast, On The Beat for Circulation: Arrhythmia, and Electrophysiology. I'm Dr. Paul Wang, Editor in Chief, with some of the key highlights from this month's issue. We'll also hear from Dr. Suraj Kapa, reporting on new research from the latest journal articles in the field. This month's issue of Circulation: Arrhythmia, and Electrophysiology has a number of groundbreaking and fascinating articles. Let's start with the first article by Christopher Andrews and Associates on the novel use of noninvasive electrocardiographic imaging in patients with arrhythmogenic right ventricular cardiomyopathy. The authors compared 20 genotyped arrhythmogenic right ventricular cardiomyopathy patients to 20 control patients using electrocardiographic imaging, ECGI, a method for noninvasive cardiac electrophysiology mapping. They found that ARVC patients had a longer ventricular activation duration, with a mean of 52 milliseconds versus 42 milliseconds with a p-value of 0.007, as well as a prolonged mean epicardial activation recovery interval, a surrogate for local action potential duration with a median of 275 milliseconds versus 240 milliseconds with a p-value of 0.014. In addition, the authors observed abnormal epicardial activation breakthrough locations with regions of nonuniform conduction and fractionated electrograms. These abnormal activation patterns correlated with late gadolinium enhancement using cardiac magnetic resonance scar imaging. This study suggests that electrocardiographic imaging may be a promising tool for the diagnosis and follow-up of patients with ARVC. In the next article, Thomas Fink and Associates report the results of the prospective randomized Alster-Lost AF trial, comparing ablation strategies in patients with symptomatic persistent or long-standing persistent atrial fibrillation. The study compared standalone pulmonary vein isolation, the PVI-only approach, with a stepwise approach of PVI followed by complex fractionated atrial CFAE ablation and linear ablation, the substrate modification approach. Patients were randomized one-to-one to each study group. The primary study endpoint was freedom from recurrence of any atrial tachyarrhythmia at 12 months after a 90-day blanking period. 118 of 124 enrolled patients were analyzed. 61 in the p-value only group and 57 in the substrate modification group. The pulmonary vein isolation only group had a one-year freedom from arrhythmia recurrence of 54%, which was similar to the 57% recurrence rate in the substrate modification group, p = 0.86. Thus, this study confirms in a population of persistent and long-standing persistent atrial fibrillation that there is no significant benefit to the addition of CFAE ablation to pulmonary vein isolation only. In the next paper, John Papagiannis and associates studied AV nodal reentrant tachycardia in patients with congenital heart disease. In this multi-centered, retrospective study, the authors compared catheter ablation of AV nodal reentrant tachycardia in 51 patients with complex congenital heart disease, with 58 patients with simple congenital heart disease. There was no significant difference between the groups in terms of growth parameters, the use of 3D imaging, or type of ablation, radio frequency versus cryoablation. The procedure times, fluoroscopy times were longer in the complex group compared to the simple group. There were also significant differences between the groups in terms of acute success of ablation, 82% versus 97%; the risk of AV block, 14% versus 0%; and the need for chronic pacing, all significant in favor of the simple congenital heart disease group. There were no permanent AV block observed in patients who underwent cryoablation. After a mean, 3.2 years of follow up, the long-term success was 86% in the complex group, and 100% in the simple group, p = 0.004. Thus, the authors concluded that the complexity of congenital heart disease affects the outcome of AV nodal reentrant tachycardia catheter ablation. In the next paper, Moloy Das and associates studied whether the presence of abnormal intra-QRS peaks would indicate altered activation and might predict ventricular arrhythmias in cardiomyopathy patients. The authors examined the 99 patients with ischemic or nonischemic cardiomyopathy undergoing primary prevention ICD implantation, with a mean left ventricular ejection fraction of 27%. After a median follow up of 24 months, 20% of patients had arrhythmic events. Using a multivariate, Cox regression model that included age, left ventricular ejection fraction, QRS duration, and QRS peaks, only QRS peaks was an independent predictor of arrhythmic events with a hazard ration of 2.1. ROC analysis revealed that a QRS peak value of greater than or equal to 2.25 identified arrhythmic events with a greater sensitivity than QRS duration, 100% versus 70%, with p < 0.05, and a negative predictive value of 100%, compared to 89% for QRS duration, p < 0.05. Thus, the authors concluded that this novel QRS morphology index may be a promising additional tool in sudden death risk stratification. In our next paper, Yoshiyasu Aizawa and associates studied J wave changes during atrial pacing in patients with and without idiopathic ventricular fibrillation. In eight patients with idiopathic ventricular fibrillation, and 17 patients without idiopathic ventricular fibrillation, having J waves, the J wave amplitude was measured before, during and after atrial pacing. All of the patients with ventricular fibrillation did not have any structural heart disease. The idiopathic ventricular fibrillation patients were younger than the non-idiopathic ventricular fibrillation patients, and had larger J waves with more extensive distribution. The J wave amplitude decreased from 0.35 millivolts to 0.22 millivolts when the R-R intervals shortened, a decrease of greater than, equal to 0.005 millivolts in the J wave amplitude was observed in six of eight idiopathic ventricular fibrillation patients while the J wave amplitudes were augmented in nine out of 17 non-idiopathic ventricular fibrillation subjects. The authors therefore concluded that the different response patterns of J waves to rapid pacing suggested different mechanisms that is early repolarization in idiopathic ventricular fibrillation patients, and conduction delay in non-idiopathic ventricular fibrillation patients. Our final paper of the month was written by Jim T. Vehmeijer and colleagues, who examined the utility of recent guidelines and consensus documents for ICD implantation for sudden death protection in adults with congenital heart disease. The authors examined an international, multi-center registry, having 25,790 adult congenital heart disease patients, and identified all sudden cardiac death cases, which were then matched to living controls by age, gender, congenital defect and surgical repair. They used conditional logistic regression models to calculate odds ratios, and receiver operating characteristic curves. In their first analysis, they identified 124 cases and 230 controls. In total, 41% of sudden cardiac death cases, and 17% of controls had an ICD recommendation based on the 2014 consensus statement on arrhythmias in adult congenital heart disease, with an odds ratio of 5.9. A similar analysis of the 2015 European Society of Cardiology guidelines showed that 35% of cases and 14% of controls had an ICD recommendation, respectively with an odds ratio of 4.8. The authors concluded that a minority of sudden cardiac death cases had an ICD recommendation according to these guidelines, while the majority of sudden cardiac death victims remained under-recognized, emphasizing the need for continued critical, clinical reasoning when deciding on ICD implantation in adult congenital heart disease patients. And now, here with the review of the highlights from the articles from journals throughout the world, in the past month is Dr. Suraj Kapa. Dr. Suraj Kapa: Thank you, Paul. Today we'll be discussing hard-hitting articles that have been published within the last month across the electrophysiologic literature. First, we'll be focusing on the topical area of atrial fibrillation, with an initial foray into the realm of anticoagulation. The first article we will be focusing on was published by Yao, et al., in the Journal of the American College of Cardiology in volume 69, entitled Non-Vitamin K Antagonist Oral Anticoagulant Dosing in Patients with Atrial Fibrillation and Renal Dysfunction. In the study, Yao, et al, demonstrated that the dosing of direct oral anticoagulants in a real world patient sample, with preexisting renal dysfunction was inappropriately dosed in as many as 43% of patients. Specifically, in these patients, there was overdosing of the direct oral anticoagulants. Moreover, as many as 13% of patients were underdosed. The overdosing of these patients led to increased bleeding risks, without an incremental stroke benefit compared with cohorts that were appropriately dosed. In turn, underdosing led to increased stroke risk without an incremental reduction in bleeding risk. These results are provocative in that they indicate, in a real life sample of patients, frequent inappropriate dosing of direct oral anticoagulants. This identifies the need for better guidelines, or better adherence to guidelines, in management of these patients to improve clinical outcomes. In another article with the realm of anticoagulation management of atrial fibrillation patients, was published by Labovitz, et al. in Stroke, in volume 48, entitled Using Artificial Intelligence to Reduce the Risk of Nonadherence in Patients on Anticoagulation Therapy. They demonstrated in a small randomized study that a smart phone based artificial intelligence program could be used to monitor anticoagulation adherence, and in fact, improve it. The program utilized features available on all smart phones to identify the patient, the medication, and active ingestion of the medication by the patient in real time. With this approach, they noted the plasma drug concentration levels indicated 100% adherence in the intervention group, namely those using the artificial intelligence program, while in the control group, only 50% of patients had adherence to the medications. Overall, there was an absolute improvement in adherence amongst patients on direct oral anticoagulants by as many as 67%. These findings are provocative given data suggestive of the lack of appropriate adherence to anticoagulant therapy amongst patients. Changing paths from anticoagulation management, the next article we choose to focus on was published within the realm of cardiac mapping in ablation for atrial fibrillation. It was published by Das, et al. in JACC: Clinical Electrophysiology in volume three, entitled Pulmonary Vein Re-Isolation as a Routine Strategy Regardless of Symptoms, The PRESSURE Randomized Controlled Trial. In this randomized trial, Das, et al, demonstrated that aggressive reevaluation of patients undergoing pulmonary vein isolation after index ablation for pulmonary vein reconnection, with the intent to re-ablate, significantly reduced arrhythmia recurrence. In addition, there was a commented improvement in quality of life. It has been well-recognized that even in the absence of clinical recurrence, a large number of patients, after index pulmonary vein isolation, may have pulmonary vein reconnection. However, it has always been unclear whether aggressive reevaluation and re-isolation of reconnected veins holds value, has been unclear. Further study is needed to evaluate the cost effectiveness and the risk-benefit ratio of such an invasive approach to reevaluate pulmonary vein isolation, irrespective of the evidence of clinical atrial fibrillation recurrence, however. Changing gears, with the realm of atrial fibrillation, we will now focus on risk stratification and management. Pathik, et al, in JACC: Clinical Electrophysiology, published in volume three, have progressed to complement their work on the role of risk stratification, and risk factor management in patients with atrial fibrillation, to evaluate the cost-effectiveness and clinical effectiveness of such risk factor management clinics in atrial fibrillation, that they termed the SENSE Study. They demonstrated that there was significant cost and clinical benefits to aggressive risk factor targeting clinics for patients with atrial fibrillation, specifically, utilizing supervised approaches to weight-loss, improvements in fitness and reduction in other clinical risk factors such as diabetes, hypertension, or other risks. The patients had a significantly decreased risk of arrhythmia occurrence. In addition to this, there was an actual incremental cost benefit of $62,000 for quality adjusted life year saved. These findings suggest that such an aggressive risk factor mediated approach to management of patients with atrial fibrillation holds significant promise, not just in the reduction of arrhythmia occurrence, but also in potential healthcare cost savings. Our next article within the realm of risk stratification and management relates to identification of patients with atrial fibrillation, in otherwise normal population-wide cohorts. Krivoshei, et al, in Europace volume 19, studied algorithms applied to information gathered on pulse-wave signals via smartphone-based LED light/camera lens. They demonstrated that using such a tool on patients, atrial fibrillation can be discriminated from sinus rhythm with sensitivity specificity of above 95%. We recognize the critical importance of early detection of atrial fibrillation, particularly in high-risk cohorts for stroke. Early identification of patients may identify those patients for initiation of anticoagulation, even if asymptomatic or minimally symptomatic. Our so-termed subclinical atrial fibrillation patients, which we identify by prior clinical trials, have an increased risk of stroke. However, the main hurdle to implementation of such technology has been the high cost, applied to traditional medical interventions. However, use of ever-advancing ambulatory technologies, such as smartphones or in the future, smart watches, may held the promise to identify atrial fibrillation via cheaper mechanisms. The last article within the realm of atrial fibrillation risk stratification and management that we'll choose to focus on is that by Gaeta, et al, published in Europace in volume 19. They performed a systematic review and meta-analysis of existing trials, regarding whether epicardial fat depot was associated with atrial fibrillation. They demonstrated via their meta-analysis that there is, in fact, a significant association between epicardial fat and atrial fibrillation risk, with more epicardial fat being associated with more persistent, rather than paroxysmal forms of atrial fibrillation, as well as any atrial fibrillation versus none. However, the role of epicardial fat in arrhythmogenesis remains unclear. While many studies suggest an association, causation remains to be proven. A recent review, however, published by Antonopoulos, et al, in the Journal of Physiology in June 2017, has multiple suggestive pathways by which paracrine effects of epicardial fat on the heart and vice versa, may lead to alterations in normal cardiac function. Thus, while this remains an association, there are evolving principles that might further support causation. Changing topics, we'll next focus on four major articles within the realm of ICDs, pacemakers, and CRT managements. Lyons, et al, in JACC: Heart Failure, volume five, studied the impact of current versus previous cardiac resynchronization therapy guidelines on the proportion of patients with heart failure eligible for therapy. They evaluated the effect of changing guidelines based on increased bodies of evidence, related to indications for resynchronization therapy on real world patient samples. They demonstrated that these further refined guidelines would decrease by as many as 15% those patients eligible for cardiac resynchronization therapy. However, while their study demonstrates that fewer patients may qualify, as far as receiving benefit from resynchronization therapy, at least two studies published in the same month have demonstrated that even amongst patients who meet guidelines, there is severe under-utilization/under-referral for such devices. These studies by Marzec, et al, in JAMA Cardiology, as well as by Randolph, et al, in American Heart Journal, demonstrated that there's frequent under-utilization and under-referral of patients meetings indications for resynchronization therapy. Keeping on the same topic in resynchronization therapy, Barra, et al, in Heart, volume 103, looked at sex-specific outcomes with addition of defibrillation to resynchronization therapy in patients with heart failure. They demonstrated in a multi-central observational cohort study that the addition of defibrillator resynchronization therapy in patients meeting primary prevention indications for device implant, primarily conferred benefit in men, rather than women. In the same month, Randolph, et al, in the American Heart Journal, demonstrated that resynchronization therapy offered potential greater benefits in women over men. Interestingly, this study by Barra, et al, conversely demonstrates that the concomitant addition of defibrillator therapy does not necessarily further improve outcomes on women, with the primary benefit being conferred to men. Whether this differential is effected by relative rates of arrhythmogenic myopathy is in men versus women remains unclear. However, the findings are provocative. Keeping within the realm of appropriateness of defibrillator therapies, Luni, et al, performed a meta-analysis of randomized controlled trials published in the Journal of Cardiovascular Physiology, in volume 28, on the mortality effect of ICDs in primary prevention in nonischemic cardiomyopathies, including six studies that met criteria. They found that while there was an overall significant survival benefit in patients receiving ICDs in the setting of nonischemic cardiomyopathy. Once accounting for those on adequate beta-blockade, and ACE or ARP 00:22:56 therapy, there was no statistical difference conferred by primary prevention ICD use. This complements an article published by Al-Khatib, et al, in JAMA Cardiology, in the same month, which also suggested that the overall mortality benefit was present in nonischemic patients, though in their case, they did not evaluate the granularity of appropriateness based on current management at the time of ICD implant. These findings further previous findings from a Danish study that the survival benefit of primary prevention ICD in nonischemic cardiomyopathy might not be anywhere near the same as those conferred with ischemic cardiomyopathy. However, the perceived lower relative mortality benefit, compared to earlier clinical trials, namely partly due to improvements in the clinical and pharmacologic management of such patients. The final paper we'll choose to focus on within the realm of device therapies was published by Doppalapudi, in the Journal of Cardiovascular Electrophysiology, in volume 28. They looked at the significant discrepancy between estimated and actual longevity in St. Jude Medical implantable cardioverter defibrillators. While amongst a small number of patients of only 40, they demonstrated that up to 74% of these patients had a significant discrepancy between actual and estimated battery life, specifically amongst current or promotes defibrillator devices. This discrepancy was most significant in the 18 months prior to reaching electrical replacement medication. These findings suggest the need for more frequent monitoring of such devices to look for rapid battery depletion. Switching topics away from device therapies, we next focus on the realm of sudden death in cardiac arrest. The first paper we'll focus on was published in Circulation, in volume 135, by Halliday, et al, and focused on the association between mid-wall late gadolinium enhancements, and sudden cardiac death in patients with dilated cardiomyopathy in mild and moderate left ventricular systolic dysfunction. In his publication, Halliday demonstrated that the presence of mid-wall late gadolinium enhancements on MRI identified patients at risk of sudden cardiac death, with a hazard ratio up to 35.9 for border sudden cardiac death, amongst dilated cardiomyopathy patients with such mid-wall dilated enhancements. The incremental value of MRI is evolving in the risk stratification of patients, though it has not quite met inclusion in guidelines for decision making regarding those who most benefit from ICDs. However, studies like this are provocative in the sense of identifying those patients most at risk. Within the realm of cardiac arrest, we next focus on the role of out-of-hospital cardiac arrest, and how to improve management of these patients. Boutilier, et al, published in Circulation, in volume 135, optimization of drone networks to deliver automated external defibrillators. They demonstrated via simulation model that using a drone network system to deliver AEDs to patients suffering sudden cardiac arrest could decrease the time to response by as much as six minutes and 43 seconds compared to traditional approaches, such as 911 in urban areas, or as much as 10 minutes and 34 seconds in rural areas. These findings are highly provocative. However, they need to be applied to clinical real world situations. The first attempt at such was actually published this month as well, by Claesson, et al, in the Journal of the American Medical Association, and demonstrated the feasibility of implementing a drone network within real world case example, and the efficacy of the same. These disruptive technologies have the potential to improve emergency care, and out of hospital cardiac arrest survival. Next, we move on to studies in electrophysiology. The first article we will focus on is by De Jesus, et al, published in Heart Rhythm, volume 14, on antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction. De Jesus, et al, in this study, demonstrated that the use of anakinra and interleukin 1 beta antagonist would improve conduction velocity, calcium handling, spontaneous and inducible ventricular arrhythmias, and action potential duration dispersion, in canine models. These findings of potential antiarrhythmic effects were due to increased expression of connexin 43, and sarcoplasmic reticulum calcium ATPase. While in isolation, this might seem a general article, it complements multiple recent studies that suggest a significant role for targeting inflammatory pathways, not just in infarct pathogenesis, but in arrhythmogenesis. Lazzerini, et al, this month as well, demonstrated in the European Heart Journal, the link between systemic inflammation and arrhythmic risk based on a review of the existing literature. In addition, Yucel, et al, demonstrated in Nature Scientific Reports the relationship between lipopolysaccharides and electrophysiology dysfunction in stem cell direct cardiomyocytes, which they felt partly may be mediated through interleukin pathways. Finally, though as of yet unpublished, a clinically available interleukin 1 beta inhibitor, canakinumab, has been shown in preliminary data to reduce major cardiovascular events in a randomized, double-blind, placebo-controlled trial, when combined with optimal medical therapy in patients with post myocardial infarction. These potential clinical benefits complement translational benefits seen to date. However, whether these are conferred by primary inflammatory pathways, arrhythmogenic pathways, or interactions between both remains to be seen. The next article we will focus on is by Chauveau, et al, published in Circulation: Arrhythmia Electrophysiology, volume 10. They looked at induced pluripotent stem cells derived cardiomyocytes in producing in vivo biological pacemaker function. They demonstrated that in canines with atrioventricular block, injection of such derived cardiomyocytes into the epicardial surface of the heart, demonstrated inherent pacemaker activity with global cardiac activation. In fact, this activation in pacemaker activity increased over time, up to four weeks of maturation, and also demonstrated responsiveness to epinephrine and alterations with day and night variation. However, the intrinsic rates tend to be quite low, in the 50 to 60 beat per minute range. The potential to restore pacemaker activity in patients with severe conduction disease, holds the potential to dynamically progress options in care for patients with electrophysiologic disease. However, even though these findings are promising, significant remaining questions include ensuring the robustness of the heart rate conferred by these biologic pacemakers, the durability of pacemaker activity, and the arrhythmogenic potential of such interventions. Within the realm of cellular electrophysiology, the final article we will choose to focus on was published by Barbic, et al, in American Journal of Physiology, heart and Circulatory Physiology, in volume 312, entitled Detachable Glass Microelectrodes for Recording Action Potentials in Active Moving Organs. They demonstrated that a new glass microelectrode could allow for determinational cellular actional potential duration in actively moving organs. This is a profound potential advance in the physiologic evaluation of both in vitro and in vivo translational cellular models of cardiac activation. Traditional patch clamping action potential studies required immobilization of cells being studied, whether by mechanical or pharmacologic means. However, directed efforts to immobilize cells can alter electrophysiologic parameters. The ability to record cellular action potentials in actively moving cells, for example the beating heart, may offer studies of cellular electrophysiology, that more closely approximate real world physiology. Our next area of focus will be on genetic channelopathies, including long QT syndrome, Brugada, catecholaminergic polymorphic ventricular tachycardia and others. The article we choose to focus on this month, within this realm, was published by Pappone, et al, in Circulation: Arrhythmia and Electrophysiology, volume 10. They focus on electrical substrate elimination in 135 consecutive patients with Brugada syndrome. They demonstrated in this large cohort of patients that the arrhythmogenic electrical substrate associated with the Brugada syndrome primarily localized to the right ventricular epicardium, and an ablation of such region led to normalization of electrocardiogram and non-inducibility ventricular arrhythmias acutely in all patients, and over a long term in all but two patients. These findings complement prior work by Nademanee and others that support a role for targeting substrate in the region of the right ventricular epicardium, in preventing recurrent ventricular arrhythmias in patients with Brugada syndrome, and in normalizing the electrocardiographic Brugada pattern. At the translational level, prior work has demonstrated that the same SCN mutations associated with Brugada syndrome confer accentuated transmittal gradients within the realm of the right ventricle, along with preferential prolongations of action potentials in the right ventricular epicardial myocytes. However, it remains to be seen whether the specific genetic cause of individual patient's Brugada pattern or Brugada syndrome is associated with discreet pathologic and inter-ablation findings and success rates. Next, moving on to the realm of ventricular arrhythmias, we focus on three major articles published in the past month. The first article is published by Vaseghi, et al, in the Journal of the American College of Cardiology, volume 69, entitled Cardiac Sympathetic Denervation for Refractory Ventricular Arrhythmias. They demonstrated that cardiac sympathetic denervation may be an effective therapy in many patients with intractable ventricular arrhythmias, with a greater than 50% reduction in sustained VT, ICD shock, transplant or death over one year follow-up. Not only this but nearly one third of patients no longer required antiarrhythmics. However, bilateral sympathectomy is far superior over left sided only sympathectomy. Furthermore, advanced heart failure and VT cycle length were associated with poor outcomes. These findings suggest a role for bilateral sympathectomy in management of patients presenting with intractable ventricular arrhythmias. However, patient identification and selection in terms of the ideal cohorts for such therapy, and how to identify such cohorts remains to be seen. Our next article regards advances in attaining epicardial access. Di Biase, et al, published in Heart Rhythm, volume 14, the initial international multi-centered human experience with the novel epicardial access needle embedded with a real time pressure frequency monitor to facilitate epicardial access. They looked specifically at feasibility and safety of this novel approach. While in only 25 patients, they did demonstrate that epicardial access can be successfully obtained with only one complication of a delayed pericardial effusion. With evolving indications for epicardial access, including for left atrial appendage occlusion, epicardial ganglia modulation, and ventricular arrhythmia mapping and ablation, development of novel tools to minimize the risks associated with epicardial ablation, particularly in individuals who do not perform it routinely, is critical. However, whether these variable approaches hold significant advances in randomized trials, beyond traditional approaches, remains to be seen. Within the realm of ventricular arrhythmias, the last article we will choose to focus on was published by Acosta, et al, in Europace, volume 19. They looked at the long-term benefit of first line peri-implantable cardioverter-defibrillator implant ventricular tachycardia substrate ablation in secondary prevention patients. This study complemented prior data from SMASH-VT supporting a role for early ablation to reduce future arrhythmia events in patients receiving defibrillators. In their study, they demonstrated that early ablation was associated with a decreased recurrence of ventricular arrhythmias and defibrillary shocks over an average of almost four years. However, it addressed patients with lower ejection fractions, namely less than 35%, received less benefit. Though this was mostly conferred by while having similar frequency of VT recurrence, having an overall lower burden compared to those who did not have ablation. Practice patterns continue to vary in the decision making with regards to performing early ablation in such patients. Furthermore, whether or not a mortality benefit exists with early ablation remains relatively unclear and unproven. However, there's an evolving body of evidence to support the notion that aggressive, early intervention with invasive procedures in patients receiving ICDs, and at high risk for ventricular arrhythmias, may make sense. The final article we will focus on that has been published in the past month, is published by Turagam, et al, in the International Journal of Cardiology, volume 236, entitled Practice Variation in the Re-initiation of Dofetilide: an Observational Study. Turagam, et al, surveyed 347 providers in the U.S. and worldwide, and demonstrate significant practice variability when re-initiating dofetilide. They know that up to 21% of providers always admit patients to the hospital for dofetilide re-initiation, while 37% of physician admit patients less than 10% of the time. Interestingly, the duration off of dofetilide ranging anywhere from three days to more than a year, did not necessarily significantly affect the rate of decision to re-initiate dofetilide, after prior cessation. One key finding of this was the 4% of physicians reporting major adverse events with drug re-initiation in patients. This was despite the vast majority of these patients tolerating de novo initiation. Given the prolific effects of antiarrhythmetic drugs, strategies to reduce those potential risks are critical. In fact, multiple groups such as the Cardiac Safety Research Consortium, within the same month, had sought to publish recommendations for long-term electrocardiographic monitoring, in drug developments. It must be realized the consideration of the impact of antiarhythmetic drug managements may not always be well outlined by existing protocols. And thus, further study is likely required to inform current clinical practice. It was my pleasure to introduce to you some of the major heart hitting articles published in the part month across the electrophysiologic literature. While none of this is really touching on every single major advance, we hope to identify those that hold potential, measure immediate clinical potential, or those that hold potential for future advancements within our field. Thank you. Dr. Paul Wang: I hope you enjoyed this month's podcast On the Beat, Circulation: Arrhythmia and Electrophysiology. We've had a number of groundbreaking and fascinating studies. See you next month.

practice heart risk chief 3d journal patients traditional reduce symptoms led switching danish associates stroke av mri american colleges roc lyons physiology crt cox dejesus acosta rr vt international journal randolph cardiology american journal barra american medical association circulation qt icd arp halliday atrial fibrillation european society using artificial intelligence yao gaeta scn aeds luni electrophysiology marzec antonopoulos observational studies brugada claesson qrs european heart journal heart rhythm icds atpase pvi i'm dr boutilier nature scientific reports arvc jama cardiology cardiovascular physiology on the beat nonadherence american heart journal jim t paul wang circulation arrhythmia jacc clinical electrophysiology

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Commentary by Dr. Valentin Fuster

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Right Ventricular Strain Signatures in ARVC

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