Podcasts about nhlbi

Uranium Mining in Northern Saskatchewan: What You Need To Know Part 3―Health Impacts of Uranium Mining on Indigenous Bodies  Join host Beverly Andrews, Dr. Dale Dewar, and Professor Douglas Brugge for a deeper dive into information on the human health impacts of uranium mining.  Dr. Dale Dewar is a co-author with Florian Oelck of From Hiroshima to Fukushima to You. She is an associate professor in the Department of Family Medicine at the University of Saskatchewan, an active member of the International Committee of the Society of Rural Physicians of Canada, a two-term member of the Canadian Friends Service Committee, and the former Executive Director of Physicians for Global Survival. An anti-nuclear activist since the 1980s, she has published articles and spoken at conferences about nuclear proliferation. Douglas Brugge, Professor & Chair at the Department of Public Health Sciences at the University of Connecticut School of Medicine - Doug Brugge has a Ph.D. in cellular and developmental biology from Harvard University and an MS in industrial hygiene from the Harvard School of Public Health.  He is Professor and Chair of the Department of Public Health Sciences at the University of Connecticut School of Medicine.  For over a decade, he has directed the Community Assessment of Freeway Exposure and Health, a series of community-based participatory research projects funded by NIEHS, NHLBI, NLM, EPA, HUD and the Kresge Foundation.  CAFEH has about 200 publications, including over 50 on traffic-related ultrafine particle pollution and their association with health.  He has worked in community collaborations with many neighbourhoods. This podcast episode was edited and produced by Beverly Andrews. This podcast was created from a live-stream webinar previously broadcast on Keepers of the Water's YouTube and Facebook channels on February 27th, 2024

A person with rheumatoid arthritis and lupus develops new back pain in her mid-upper left side. It feels like “it's coming from under my ribs,” she says. First, it's diagnosed as arthritis, but interventions don't seem to make a difference. Finally, a year into this unremitting pain, a rheumatologist asks about her breathing and discovers she has developed a complication called pulmonary thrombosis, probably related to her autoimmune diseases. They start treatment and voilà, her back pain is gone. This is a good example of a case in which massage therapy was definitely NOT the best choice.   Resources: Dsouza, K.G. et al. (2023) ‘Management of interstitial lung disease in patients with autoimmune disease-related interstitial lung disease', Multidisciplinary Respiratory Medicine, 18(1), p. 890. Available at: https://doi.org/10.4081/mrm.2023.890.   Fibrosis as an autoimmune disease (no date) CPC - M. Available at: https://www.cpc-munich.de/en/research-projects/fibrosis-as-an-autoimmune-disease/index.html, https://www.cpc-munich.de/en/research-projects/fibrosis-as-an-autoimmune-disease/index.html (Accessed: 3 May 2024).   3. Gole, S. and Bankole, A. (2024) ‘Nintedanib', in StatPearls. Treasure Island (FL): StatPearls Publishing. Available at: http://www.ncbi.nlm.nih.gov/books/NBK585049/ (Accessed: 8 May 2024).   Interstitial Lung Diseases - What Are Interstitial Lung Diseases? | NHLBI, NIH (2022). Available at: https://www.nhlbi.nih.gov/health/interstitial-lung-diseases (Accessed: 8 May 2024).   5. Kašiković Lečić, S. et al. (2022) ‘Management of musculoskeletal pain in patients with idiopathic pulmonary fibrosis: a review', Upsala Journal of Medical Sciences, 127, p. 10.48101/ujms.v127.8739. Available at: https://doi.org/10.48101/ujms.v127.8739.   6. Massage & Bodywork - MAY | JUNE 2021 (no date). Available at: https://www.massageandbodyworkdigital.com/i/1358392-may-june-     Host:   Ruth Werner is a former massage therapist, a writer, and an NCBTMB-approved continuing education provider. She wrote A Massage Therapist's Guide to Pathology, now in its seventh edition, which is used in massage schools worldwide. Werner is also a long-time Massage & Bodywork columnist, most notably of the Pathology Perspectives column. Werner is also ABMP's partner on Pocket Pathology, a web-based app and quick reference program that puts key information for nearly 200 common pathologies at your fingertips. Werner's books are available at www.booksofdiscovery.com. And more information about her is available at www.ruthwerner.com.        Sponsors:   Anatomy Trains: www.anatomytrains.com    Elements Massage: www.elementsmassage.com/abmp   Earthlite: www.earthlite.com  

-For more information about heart health and to find free educational resources and tips to prevent heart disease, visit the NHLBI website at www.nhlbi.nih.gov and The Heart Truth® program at www.hearttruth.gov-If you are interested in QPR training, visit: https://www.agrisafe.org/QPR/Sign up for the AgriSafe newsletter: https://www.agrisafe.org/newsletter/View upcoming webinars: https://www.agrisafe.org/events/-Directed by Laura SiegelHosted by Linda EmanuelEdited by Matt McKenney for ProPodcastingServices.comSpecial Guests: Dr. Eric Shiroma and Dr. David Schopfer

In this must-listen episode of The Safety Guru, we're focusing on the critical yet often overlooked topic of lone worker safety. While they have fewer interactions with leaders and coworkers, their decisions are still shaped by the safety climate and priorities set by their organization. Join us to dive deeper into this topic with Dr. Ryan Olson, who will share his invaluable insights, groundbreaking research, and profound strategies for lone worker safety. Tune in! About the Guest: Dr. Olson is a Professor in Occupational Health Psychology at the Rocky Mountain Center for Occupational and Environmental Health at the University of Utah. His research has focused on safety, health, and well-being interventions for isolated or “lone” workers. Dr. Olson leads an internationally recognized safety and health intervention research program with commercial drivers funded by NHLBI and has also designed impactful supportive group interventions for home care workers with funding from CDC/NIOSH. His interventions have improved a range of outcomes for workers, including safety, diet, exercise, sleep, stress, and job satisfaction. For more information: http://bit.ly/r-olson Learn more about your ad choices. Visit megaphone.fm/adchoices

This week, Dr. Victoria Sanchez of the University of South Florida, and Dr. Shannon Basham of Phonak, join host Amyn Amlani to discuss the ACHIEVE study, a multi-year randomized controlled trial examining the effects of best-practice hearing care interventions on cognitive decline in older adults. The study results found that for those at higher risk of cognitive decline, providing hearing aids and counseling slowed cognitive decline by 48% over 3 years compared to a control group. The hearing intervention utilized comprehensive audiological evaluations, evidence-based device fitting, and patient education and support. While additional analyses continue, these significant findings demonstrate the potential impact optimized hearing care can have on supporting long-term cognitive health. The panelists emphasize that complex research like ACHIEVE requires interdisciplinary expertise and collaboration. As the field increasingly focuses on the connections between hearing and cognition, audiologists will need to take a more holistic approach in managing patients while partnering closely with physicians, researchers and others. Resources like Phonak's upcoming ECHHO training program will help clinicians translate recent research on hearing and cognitive health into effective patient care and communication. With cognitive decline emerging as a major health issue, audiology has an opportunity to play a central role in providing interventions that support cognitive health in aging adults. More information about the ECHHO program can be found here: https://www.sonova.com/en/media/phonak-introduces-echho-program-enhance-understanding-link-between-hearing-loss-and-cognitive General acknowledgements and funding for ACHIEVE Parent Study: Members of the ACHIEVE Collaborative Research Group are listed at achievestudy.org. The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) Study is supported by the National Institute on Aging (NIA) R01AG055426 and R01AG060502 with previous pilot study support from the NIA R34AG046548 and the Eleanor Schwartz Charitable Foundation, in collaboration with the Atherosclerosis Risk in Communities (ARIC) Study, supported by National Heart, Lung, and Blood Institute contracts (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I). Neurocognitive data are collected by 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917 from the NIH (NHLBI, NINDS, NIA and NIDCD), and with previous brain MRI examinations funded by R01HL70825 from the NHLBI. The funder of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit for publication.  The investigators thank the staff and participants of the ACHIEVE and ARIC studies for their important contributions and dedication to the study, Sonova / Phonak for in-kind donation of hearing technologies and training support of audiologists for the ACHIEVE study, and the members of the ACHIEVE DSMB (Doug Galasko, Julie Buring, Judy Dubno, Tom Greene, and Larry Lustig) for their guidance and insights during the course of the study. ACHIEVE Hearing Intervention Follow-up Study (ACHIEVE – HIFU) The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) Hearing Intervention Follow-Up Study (ACHIEVE – HIFU) is supported by the National Institute on Deafness and Other Communication Disorders (NIDCD) R01DC019408. ACHIEVE Brain Health Follow-up Study (ACHIEVE – BHFU) The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) Brain Health Follow-Up Study (ACHIEVE – BHFU) is supported by the National Institute on Aging (NIA) R01AG076518. The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) Hearing Intervention Follow-Up Study (ACHIEVE – HIFU) is supported by the National Institute on Deafness and Other Communication Disorders (NIDCD) R01DC019408.

Title: Cardiology Grand Rounds: Lessons Learned from DOAC's and the New Factor XI Anti-thrombotic Therapies Being Studied Speaker: Manesh R. Patel, MD Chief, Division of Cardiology Co-Director, Duke Heart Center Duke Clinical Research Institute Duke University, Durham, NC Disclosures: Research Grants: PACIFIC-AF: Bayer, Janssen, Heartflow, Idorsia, NHLBI, Novartis Advisory Board/Consulting: Bayer, Janssen, Heartflow, Medscape Objectives: •Understand the Net-Benefit of Warfarin and then NOACs in AFib •Understand the use of NOACs and limitations •Understand the Factor XI therapy and promise in A. Fib

Credits: 0.25 AMA PRA Category 1 Credit™   CME/CE Information and Claim Credit: https://www.pri-med.com/online-cme-ce/podcast/nhlbi-cystic-fibrosis  Overview: “Cystic Fibrosis: The Primary care Provider's Role in Case Finding and Referral” is a CME podcast episode produced by Pri-Med in partnership with Learn More Breathe Better®, a program of the National Heart, Lung, and Blood Institute of the National Institutes of Health. In this episode, we are joined by Dr. Marrah Lachowicz-Scroggins, Program Director with NHLBI's Division of Lung Diseases, and Dr. Deepika Polineni, director of the Cystic Fibrosis Center, Washington University School of Medicine in St. Louis. We'll be discussing what general practitioners should know about cystic fibrosis, including the factors that contribute to delayed or missed diagnosis, and the similarities and differences with primary ciliary dyskinesia, or PCD. 

Credits: 0.25 AMA PRA Category 1 Credit™   CME/CE Information and Claim Credit: https://www.pri-med.com/online-cme-ce/podcast/nhlbi-breathe-better-pulmonary-fibrosis   Overview: “Pulmonary Fibrosis: What Primary Care Providers Need to Know” is a CME podcast episode produced by Pri-Med in partnership with Learn More Breathe Better®, a program of the National Heart, Lung, and Blood Institute of the National Institutes of Health. In this episode, we are joined by Dr. Matt Craig, Chief of the Lung Biology and Disease Branch with NHLBI's Division of Lung Diseases, and Dr. Fernando J. Martinez, Chief of the Pulmonary and Critical Care Medicine Division at Weill Cornell Medicine. Today we'll be discussing pulmonary fibrosis and the role of primary care providers, including signs to look out for, diagnosis, and treatment options.

This month on Episode 47 of Discover CircRes, host Cynthia St. Hilaire highlights three original research articles featured in the March 31 issue of Circulation Research. We'll also provide an overview of the Compendium on Increased Risk of Cardiovascular Complications in Chronic Kidney Disease published in the April 14 issue. Finally, this episode features an interview with Dr Elizabeth Tarling and Dr Bethan Clifford from UCLA regarding their study, RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels.   Article highlights:   Shi, et al. LncRNAs Regulate SMC Phenotypic Transition   Chen, et al. Bilirubin Stabilizes Atherosclerotic Plaque   Subramaniam, et al. Mapping Non-Obvious cAMP Nanodomains by Proteomics   Compendium on Increased Risk of Cardiovascular Complications in Chronic Kidney Disease   Cindy St. Hilaire:              Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to share three articles selected from our March 31st issue of Circulation Research and give you a quick summary of our April 14th Compendium. I'm also excited to speak with Dr Elizabeth Tarling and Dr Bethan Clifford from UCLA regarding their study, RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels.   So first the highlights. The first article we're going to discuss is Discovery of Transacting Long Noncoding RNAs that Regulates Smooth Muscle Cell Phenotype. This article's coming from Stanford University and the laboratory of Dr Thomas Quertermous. Smooth muscle cells are the major cell type contributing to atherosclerotic plaques. And in plaque pathogenesis, the cells can undergo a phenotypic transition whereby a contractile smooth muscle cell can trans differentiate into other cell types found within the plaque, such as macrophage-like cells, osteoblast-like cells and fibroblast-like cells. These transitions are regulated by a network of genetic and epigenetic mechanisms, and these mechanisms govern the risk of disease.   The involvement of long non-coding RNAs, or Lnc RNAs as they're called, has been increasingly identified in cardiovascular disease. However, smooth muscle cell Lnc RNAs have not been comprehensively characterized and the regulatory role in the smooth muscle cell state transition is not thoroughly understood. To address this gap, Shi and colleagues created a discovery pipeline and applied it to deeply strand-specific RNA sequencing from human coronary artery smooth muscle cells that were stressed with different disease related stimuli. Subsequently, the functional relevancy of a few novel Lnc RNAs was verified in vitro.   From this pipeline, they identified over 4,500 known and over 13,000 unknown or previously unknown Lnc RNAs in human coronary artery smooth muscle cells. The genomic location of these long noncoding RNAs was enriched near coronary artery disease related transcription factor and genetic loci. They were also found to be gene regulators of smooth muscle cell identity. Two novel Lnc RNAs, ZEB-interacting suppressor or ZIPPOR and TNS1-antisense or TNS1-AS2, were identified by the screen, and this group discovered that the coronary artery disease gene, ZEB2, which is a transcription factor in the TGF beta signaling pathway, is a target for these Lnc RNAs. These data suggest a critical role for long noncoding RNAs in smooth muscle cell phenotypic transition and in human atherosclerotic disease.   Cindy St. Hilaire:              The second article I want to share is titled Destabilization of Atherosclerotic Plaque by Bilirubin Deficiency. This article is coming from the Heart Research Institute and the corresponding author is Roland Stocker. The rupture of atherosclerotic plaque contributes significantly to cardiovascular disease. Plasma concentrations of bilirubin, a byproduct of heme catabolism, is inversely associated with risk of cardiovascular disease, but the link between bilirubin and atherosclerosis is unknown.   Chen et el addressed this gap by crossing a bilirubin knockout mice to a atherosclerosis prone APOe knockout mouse. Chen et el addressed this gap by crossing the bilirubin knockout mouse to the atherosclerosis-prone APOE knockout mouse, and used the tandem stenosis model of plaque instability to address this question. Compared with their litter mate controls, bilirubin-APOE double knockouts showed signs of increased systemic oxidative stress, endothelial dysfunction, as well as hyperlipidemia. And they had higher atherosclerotic plaque burden.   Hemeatabolism was increased in unstable plaques compared with stable plaques in both of these groups as well as in human coronary arteries. In mice, the bilirubin deletion selectively destabilized unstable plaques and this was characterized by positive arterial remodeling and increased cap thinning, intra plaque hemorrhage, infiltration of neutrophils and MPO activity. Subsequent proteomics analysis confirmed bilirubin deletion enhanced extracellular matrix degradation, recruitment and activation of neutrophils and associated oxidative stress in the unstable plaque. Thus, bilirubin deficiency generates a pro atherogenic phenotype and selectively enhances neutrophil-mediated inflammation and destabilization of unstable plaques, thereby providing a link between bilirubin and cardiovascular disease risk.   Cindy St. Hilaire:              The third article I want to share is titled Integrated Proteomics Unveils Regulation of Cardiac Monocyte Hypertrophic Growth by a Nuclear Cyclic AMP Nano Domain under the Control of PDE3A. This study is coming from the University of Oxford in the lab of Manuela Zaccolo. Cyclic AMP is a critically important secondary messenger downstream from a myriad of signaling receptors on the cell surface. Signaling by cyclic AMP is organized in multiple distinct subcellular nano domains, regulated by cyclic AMP hydrolyzing phosphodiesterases or PDEs.   The cardiac beta adrenergic signaling has served as the prototypical system to elucidate this very complex cyclic AMP compartmentalization. Although studies in cardiac monocytes have provided an understanding of the location and the properties of a handful of these subcellular domains, an overview of the cellular landscape of the cyclic AMP nano domains is missing.   To understand the nanodynamics, Subramanian et al combined an integrated phospho proteomics approach that took advantage of the unique role that individual phosphodiesterases play in the control of local cyclic AMP. They combined this with network analysis to identify previously unrecognized cyclic AMP nano domains associated with beta adrenergic stimulation. They found that indeed this integrated phospho proteomics approach could successfully pinpoint the location of these signaling domains and it provided crucial cues to determine the function of previously unknown cyclic AMP nano domains.   The group characterized one such cellular compartment in detail and they showed that the phosphodiesterase PDE3A2 isoform operates in a nuclear nano domain that involves SMAD4 and HDAC1. Inhibition of PDE3 resulted in an increased HDAC1 phosphorylation, which led to an inhibition of its deacetylase activity, and thus derepression of gene transcription and cardiac monocyte hypertrophic growth. These findings reveal a very unique mechanism that explains the negative long-term consequences observed in patients with heart failure treated with PDE3 inhibitors.   Cindy St. Hilaire:              The April 14th issue is our compendium on Increased Risk of Cardiovascular Complications in Chronic Kidney Disease. Dr Heidi Noels from the University of Aachen is our guest editor of the 11 articles in this issue. Chronic kidney disease is defined by kidney damage or a reduced kidney filtration function. Chronic kidney disease is a highly prevalent condition affecting over 13% of the population worldwide and its progressive nature has devastating effects on patient health. At the end stage of kidney disease, patients depend on dialysis or kidney transplantation for survival. However, less than 1% of CKD patients will reach this end stage of chronic kidney disease. Instead, most of them with moderate to advanced chronic kidney disease will prematurely die and most often they die from cardiovascular disease. And this highlights the extreme cardiovascular burden patients with CKD have.   The titles of the articles in this compendium are the Cardio Kidney Patient Epidemiology, Clinical Characteristics, and Therapy by Nicholas Marx, the Innate Immunity System in Patients with Cardiovascular and Kidney Disease by Carmine Zoccali et al. NETs Induced Thrombosis Impacts on Cardiovascular and Chronic Kidney disease by Yvonne Doering et al. Accelerated Vascular Aging and Chronic Kidney Disease, The Potential for Novel Therapies by Peter Stenvinkel et al. Endothelial Cell Dysfunction and Increased Cardiovascular Risk in Patients with Chronic Kidney Disease by Heidi Noels et al. Cardiovascular Calcification Heterogeneity in Chronic Kidney Disease by Claudia Goettsch et al. Fibrosis in Pathobiology of Heart and Kidney From Deep RNA Sequencing to Novel Molecular Targets by Raphael Kramann et al. Cardiac Metabolism and Heart Failure and Implications for Uremic Cardiomyopathy by P. Christian Schulze et al. Hypertension as Cardiovascular Risk Factor in Chronic Kidney Disease by Michael Burnier et al. Role of the Microbiome in Gut, Heart, Kidney crosstalk by Griet Glorieux et al, and Use of Computation Ecosystems to Analyze the Kidney Heart Crosstalk by Joachim Jankowski et al.   These reviews were written by leading investigators in the field, and the editors of Circulation Research hope that this comprehensive undertaking stimulates further research into the path flow of physiological kidney-heart crosstalk, and on comorbidities and intra organ crosstalk in general.   Cindy St. Hilaire:              So for our interview portion of the episode I have with me Dr Elizabeth Tarling and Dr Bethan Clifford. And Dr Tarling is an associate professor in the Department of Medicine in cardiology at UCLA, and Dr Clifford is a postdoctoral fellow with the Tarling lab. And today we're going to be discussing their manuscript that's titled, RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels. So thank you both so much for joining me today.   Elizabeth Tarling:             Thank you for having us.   Bethan Clifford:               Yeah, thanks for having us. This is exciting.   Cindy St. Hilaire:              I guess first, Liz, how did you get into this line of research? I guess, before we get into that, I should disclose. Liz, we are friends and we've worked together in the ATVB Women's Leadership Committee. So full disclosure here, that being said, the editorial board votes on these articles, so it's not just me picking my friends. But it is great to have you here. So how did you enter this field, I guess, briefly?   Elizabeth Tarling:             Yeah, well briefly, I mean my training right from doing my PhD in the United Kingdom in the University of Nottingham has always been on lipid metabolism, lipoprotein biology with an interest in liver and cardiovascular disease. So broadly we've always been interested in this area and this line of research. And my postdoctoral research was on atherosclerosis and lipoprotein metabolism. And this project came about through a number of different unique avenues, but really because we were looking for regulators of LDL biology and plasma LDL cholesterol, that's sort of where the interest of the lab lies.   Cindy St. Hilaire:              Excellent. And Bethan, you came to UCLA from the UK. Was this a topic you were kind of dabbling in before or was it all new for you?   Bethan Clifford:               It was actually all completely new for me. So yeah, I did my PhD at the same university as Liz and when I started looking for postdocs, I was honestly pretty adamant that I wanted to stay clear away from lipids and lipid strategy. And then it wasn't until I started interviewing and meeting people and I spoke to Liz and she really sort of convinced me of the excitement and that the interest and all the possibilities of working with lipids and well now I won't go back, to be honest.   Cindy St. Hilaire:              And now here you are. Well-   Bethan Clifford:               Exactly.   Cindy St. Hilaire:              ... congrats on a wonderful study. So LDLR, so low density lipoprotein receptor, it's a major determinant of plasmid LDL cholesterol levels. And hopefully most of us know and appreciate that that is really a major contributor and a major risk for the development of atherosclerosis and coronary artery disease. And I think one thing people may not really appreciate, which your study kind of introduces and talks about nicely, is the role of the liver, right? And the role of receptor mediated endocytosis in regulating plasma cholesterol levels. And so before we kind of chat about the nitty-gritty of your study, could you just give us a brief summary of these key parts between plasma LDL, the LDL receptor and where it goes in your body?   Elizabeth Tarling:             Yeah. So the liver expresses 70% to 80% of the body's LDL receptor. So it's the major determinant of plasma lipoprotein plasma LDL cholesterol levels. And through groundbreaking work by Mike Brown and Joe Goldstein at the University of Texas, they really define this receptor mediated endocytosis by the liver and the LDL receptor by looking at patients with familial hypercholesterolemia. So those patients have mutations in the LDL receptor and they either express one functional copy or no functional copies of the LDL receptor and they have very, very large changes in plasma LDL cholesterol. And they have severe increases in cardiovascular disease risk and occurrence and diseases associated with elevated levels of cholesterol within the blood and within different tissues. And so that's sort of how the liver really controls plasma LDL cholesterol is through this receptor mediated endocytosis of the lipoprotein particle.   Cindy St. Hilaire:              There's several drugs now that can help regulate our cholesterol levels. So there's statins which block that rate limiting step of cholesterol biosynthesis, but there's this new generation of therapies, the PCSK9 inhibitors. And can you just give us a summary or a quick rundown of what are those key differences really? What is the key mechanism of action that these therapies are going after and is there room for more improvement?   Bethan Clifford:               Yeah, sure. So I mean I think you've touched on something that's really key about the LDR receptor is that it's regulated at so many different levels. So we have medications available that target the production of cholesterol and then as you mentioned this newer generation of things like PCSK9 inhibitors that sort of try and target LDL at the point of clearance from the plasma.   And in response to your question of is there room for more regulation, I would say that given the sort of continual rate of increased cholesterol in the general population and the huge risks associated with elevated cholesterol, there's always capacity for more to improve that and sort of generally improve the health of the population. And what we sort of found particularly exciting about RNF130 is that it's a distinct pathway from any of these regulatory mechanisms. So it doesn't regulate the level of transcription, it doesn't regulate PCSK9. Or in response to PCSK9, it's a completely independent pathway that could sort of improve or add to changes in cholesterol.   Cindy St. Hilaire:              So your study, it's focusing on the E3 ligase, RNF130. What is an E3 ligase, and why was this particular one of interest to you? How did you come across it?   Elizabeth Tarling:             is predTates Bethan joining the lab. This is, I think, again for the listeners and those people in training, I think it's really important to note this project has been going in the lab for a number of years and has really... Bethan was the one who came in and really took charge and helped us round it out. But it wasn't a quick find or a quick story. It had a lot of nuances to it. But we were interested in looking for new regulators of LDL cholesterol and actually through completely independent pathways we had found the RNF130 locus as being associated with LDL cholesterol in animals. And then it came out in a very specific genome-wide association study in the African American care study, the NHLBI care study. And so really what we started looking at, we didn't even know what it was.   Elizabeth Tarling:             So we asked ourselves, well what is this gene? What is this protein? And it's RNF, so that's ring finger containing protein 130 and ring stands for really interesting new gene. Somebody came up with the glorious name. But proteins that contain this ring domain are very characteristic and they are E3 ubiquitin ligases. And so they conjugate the addition of ubiquitin to a target protein and that signals for that protein to either be internalized and/or degraded through different decorative pathways within the cell. And so we didn't land on it because we were looking at E3 ligases, we really came at it from an LDL cholesterol perspective. And it was something that we hadn't worked on before and the study sort of blossomed from there.   Cindy St. Hilaire:              That's amazing and a beautiful, but also, I'm sure, heartbreaking story because these long projects are just... They're bears. So what does this RNF130 do to LDLR? What'd you guys find?   Bethan Clifford:               As Liz said, this is a long process, but one of the key factors of RNF130 is it's structurally characteristically looked like E3 ligase. So the first thing that Liz did and then I followed up with in the lab is to see is this E3 ligase ubiquitinating in vitro. And if it is going to ubiquitinate, what's it likely to regulate that might cause changes in plasma cholesterol that would explain these human genetic links that we saw published at the same time.   And so because the LDL cholesterol is predominantly regulated by the LDL receptor and the levels of it at the surface of the parasites in the liver, the first question we wanted to see is does RNF130 interact in any way with that pathway? And I'm giving you the brief view here of the LDL receptor. We obviously tested lots of different receptors. We tested lots of different endocytose receptors and lipid regulators, but the LDL receptor is the one that we saw could be ubiquitinated by RNF130 in vitro. And so then we wanted to sort of go on from there and establish, okay, if this E3 ubiquitin ligase, is it regulating LDL receptor? What does that mean in an animal context in terms of regulating LDL cholesterol?   Cindy St. Hilaire:              Yeah, and I guess we should also explain, ubiquitination, in terms of this receptor, and I guess related to Goldstein and Brown and receptor mediated endocytosis, like what does that actually mean for the liver cell and the cholesterol in the LDLR that is binding the receptor?   Bethan Clifford:               So yes, ubiquitination is a really common regulatory mechanism actually across all sorts of different cells, all sorts of different receptors and proteins. And basically what it does is it signals for degradation of a protein. So a ubiquitin molecule is conjugated to its target such as in our case the LDL receptor and that ubiquitin tells the cell that this protein is ready for proteasomal degradation. And that's just one of the many things ubiquitination can do. It can also signal for a trafficking event, it can signal for a protein to protein interaction, but it's most commonly associated with the proteasomal degradation.     Cindy St. Hilaire:              So in terms of... I guess I'm thinking in terms of PCSK9, right? So those drugs are stemming from observations in humans, right? There were humans with gain and loss of function mutations, which caused either more or less of this LDLR receptor internalization. How is this RNF130 pathway different from the PCSK9 activities?   Elizabeth Tarling:             Yeah, so PCSK9 is a secreted protein, so it's made by hepatocyte and actually other cells in the body and it's secreted and it binds to the LDL particle, LDL receptor complex, and signals for its internalization and degradation in the proteasome. So this is not ubiquitination event, this is a completely different trafficking event. And so the RNF130, actually what Bethan showed, is it directly ubiquitinates the LDL receptor itself, signaling for an internalization event and then ultimately degradation of the LDR receptor through a decorative pathway, which we also define in the study.   So these are two unique mechanisms and actually some key studies that we did in the paper were to modulate RNF130 in animals that do not have PCSK9. And so in that system where in the absence of PCSK9 you have a lot of LDR receptor in the liver that's internalizing cholesterol. What happens when you overexpress RNF130? Do you still regulate at the LDL receptor? And you absolutely do. And so that again suggests that they're two distinct mechanisms and two distinct pathways.   Cindy St. Hilaire:              That was one thing I really loved about your paper is every kind of figure or section, the question that would pop up in my head, even ones that didn't pop in my head were beautifully answered with some of these really nice animal models, which is never an easy thing, right? And so one of the things that you brought up was difficulty in making one of the animal models. And so I'm wondering if you could share a little bit for that challenge. I think one thing that we always tend to hide is just science is hard and a lot of what we do doesn't work. And I really think especially for the trainees and really everyone out there, if we kind of share these things more, it's better. So what was one of the most challenging things in this study? And I guess I'm thinking about that floxed animal.   Elizabeth Tarling:             Yeah, so I'll speak a bit about that and then I'll let Bethan address because she was really the one on the ground doing a lot of the struggles. But again, we actually weren't going to include this information in the paper. And upon discussion and actually prompted by the reviewers of the paper and some of the questions that they asked us, we realized, you know what? It's actually really important to show this and show that this happens and that there are ways around it.   And so the first story is before Bethan even arrived in the lab, we had purchased embryonic stem cells that were knockout first condition already. And so this is a knockout strategy in which the exon of interest is flanked with lots of P sites so that you can create a flox animal, but also so you can create a whole body knockout just by the insertion of this knockout first cassette.   Elizabeth Tarling:             And so we got those mice actually in the first year of Bethan joining the lab. We finally got the chimeric mice and we were able to stop reading those mice. And at the same time we tried to generate our flox animals so that we could move on to do tissue-specific studies. And Bethan can talk about the pain associated with this. But over two years of breeding, we never got the right genotypes from the different crosses that you need to do to generate the flox animal.   And it was actually in discussions with Bethan where we decided we need to go back. We need to go back to those ESLs that we purchased five years ago and we need to figure out if all of the elements that the quality control step had told us were in place are actually present. And so Bethan went back and sequenced the whole locus and the cassette to figure out what pieces were present and we found that one of the essential locks P sites that's required for every single cross from the initial animal was absent and therefore we could actually never make the mouse we wanted to make.   And so that's sort of just a lesson for people going down that route and making these tools that we need in the lab to answer these questions is that despite paying extra money and getting all of the sort of QCs that you can get before you receive the ESLs, we should have gone back and done our own housekeeping and sort of a long journey told us when we went back that we didn't have what we thought we had at the beginning. And that was a real sticking point as Bethan can-   Cindy St. Hilaire:              Yeah. And so you know you're not alone. My very first postdoc that I did, I went with a mouse that they had also bought and were guaranteed that it was a knockout and it was not. And it is a painful lesson, but it is critical to... You get over it.   So Bethan, maybe you can also tell us a little bit about what are the other kind of next things you tried? You pivoted and you pivoted beautifully because all the models you used I thought were quite elegant in terms of exactly asking the question you wanted to ask in the right cells. So can you maybe explain some of the in vivo models you used for this study?   Bethan Clifford:               Sure, there are definitely a lot. So I mean I think Liz sort of encapsulated the trouble we have with the knockout really succinctly, but actually I want to just take this moment to sort of shout out to another postdoc in the Tarling lab, Kelsey Jarrett, who was really instrumental in the pivoting to a different model. So for the knockouts when we sort of established we didn't have exactly what we thought we did and then to compound that we also weren't getting the DeLiAn ratios breeding this whole body knockout.   We wanted to sort of look at a more transient knockout model. And that's where Kelsey really stepped in and sort of led the way and she generated AAV-CRISPR for us to target RNF130 specifically in the liver. And that had the added beauty of, one, not requiring breeding to get over this hurdle of the knockout being somewhat detrimental to breeding. But it also allowed us to ask the question of what RNF130 is doing specifically in the liver where the liver regulates LDL receptor and LDL cholesterol.   And so that was one of the key models that really, really helped get this paper over the finish line. But we did a whole barrage of experiments, as you've seen. We wanted to make sure... One of the key facets of the Tarling lab is whenever you do anything, no matter what you show Liz, it will always be, "Okay, you showed it to me one way, now show it to me a different way." Can you get the same result coming at it from different ways? And if you can't, why is that? What is the regulation behind that? And so that's really what the paper is doing is asking the same question in as many ways as we can accurately and appropriately probe what RNF130 does to the LDR receptor.   So we tried gain of function studies without adenovirus overexpression. We tried transient knockdown with antisense oligonucleotides, and then we did, as I said, the AAV-CRISPR knockdown with the help of Kelsey and our whole body knockout. And then we also repeated some of these studies such as the adenovirus and the ASO in specific genetic backgrounds. So in the absence of PCSK9, can we still regulate the LDL receptor? And then we also, just to really confirm this, in the absence of the LDL receptor, do we see a difference? And the answer is no, because this effect was really dependent on that LDL receptor being present. So there was a big combination.   Cindy St. Hilaire:              It was really nice, really a beautiful step-wise progression of how to solidly answer this question. But a lot of, I think, almost all you did was in mice. And so what is the genetic evidence for relevancy in humans? Can you discuss a little bit about those databases that you then went to to investigate, is this relevant in humans?   Bethan Clifford:               I think Liz might be better off answering that question.   Elizabeth Tarling:             And I think this sort of pivots on what Bethan was saying. So when we had struggles in the lab, it was a team environment and a collaboration between people in the lab that allowed us to make that leap and make those next experiments possible to then really answer that question. And to be able to include the antisense oligonucleotides required a collaboration with industry. We were very lucky to have a longstanding collaboration with Ionis, who provided the antisense oligonucleotides.   And for the human genetics side of things, that also was a collaboration with Marcus Seldin, who was a former postdoc with Jake Lusis and is now our PI at UC Irvine. And what he helped us do is dive into those summary level databases and ask from that initial study in the NHLBI care population, do we see associations of RNF130 expression in humans with LDL cholesterol with cardiovascular outcomes. And so one database which I would recommend everybody use, it's publicly available, is the StarNet database. And it's in the paper and the website is there. And that allowed us to search for RNF130.   Elizabeth Tarling:             And what it does is it asks how RNF130 expression in different tissues is associated with cardiometabolic outcomes and actual in CAD cases and controls, so people with and without heart disease. And we found that expression of RNF130 in the liver was extremely strongly correlated with the occurrence of cardiovascular disease in people with CAD. So in cases versus controls. And then we were also able to find many other polymorphisms in the RNF130 locus that were associated with LDL cholesterol in multiple different studies.   And I think the other message from this paper is this, unlike PCSK9 and unlike LDR receptor itself, which are single gene mutations that cause cardiovascular disease, there are many sub genome-wide significant loci that contribute to this multifactorial disease, which is extremely complex. And I think RNF130 falls within that bracket that those sort of just on the borderline of being genome-wide significant still play significant biological roles in regulating these processes. And they don't come up as a single gene hit for a disease, but combinatorialy they are associated with increased risk of disease and they have a molecular mechanism that's associated with the disease. And so that's what Marcus helped us do in terms of the human genetics is really understand that and get down to that level of data.   Cindy St. Hilaire:              Yeah. Yeah, it really makes you want to go back and look at those. Everyone always focuses on that really high peak and those analyses, but what are all those other ones above the noise, right? So it's really important.   Elizabeth Tarling:             I think it's really hard to do that. I think that's one where people... Again, it comes down to team science and the group of people that we brought together allowed us to ask that molecular question about how that signal was associated with the phenotype. I think by ourselves we wouldn't have been able to do it.   Cindy St. Hilaire:              Yeah. So your antisense oligonucleotide experiments, they were really nice. They showed, I think it was a four-week therapy, they showed that when you injected them expression of RNF130 went down by 90%. I think cholesterol in the animals was lowered by 50 points or so. Is this kind of a next viable option? And I guess related to that, cholesterol's extremely important for everything, right? Cell membrane integrity, our neurons, all sorts of things. Is it possible with something that is perhaps really as powerful as this to make cholesterol too low?   Elizabeth Tarling:             I think that what we know from PCSK9 gain and loss of function mutations is that you can drop your plasma cholesterol to very low levels and still be okay because there are people walking around with mutations that do that. I think RNF130 is a little different in that it's clearly regulatory in a homeostatic function in that it's ubiquitously expressed and it has this role in the liver to regulate LDL receptor availability, but there are no homozygous loss of function mutants people walking around, which tells us something else about how important it is in potentially other tissues and in other pathways. And we've only just begun to uncover what those roles might be.   So I think that as a therapy, it has great potential. We need to do a lot more studies to sort of move from rodent models into more preclinical models. But I do think that the human data tell us that it's really important in other places too. And so yeah, we need to think about how best it might work as a therapy. If it's combinatorial, if it's dosed. Those are the types of things that we need to think about.   Cindy St. Hilaire:              Yeah, it's really exciting. Do you know, are there other protein targets of RNF130? Is that related to my next question of what is next?   Elizabeth Tarling:             I mean, so I should point out, so Bethan unfortunately left the lab last year for a position at Amgen where she's working on obesity and metabolic disease. But before she left, she did two very, very cool experiments searching for new targets or additional targets of RNF130. Starting in the liver, but hopefully we'll move those into other tissues. And so she did gain of function RNF130 versus what loss of function we have of RNF130, and she did specific mass spec analysis of proteins that are ubiquitinated in those different conditions. And by overlaying those data sets, we're hoping to carve out new additional targets of RNF130. And there are some, and they're in interesting pathways, which we have yet to completely test, but definitely there are additional pathways, at least when you overexpress and reduce expression. Now, whether they turn out to be, again, bonafide in vivo, actual targets that are biologically meaningful is sort of the next step.   Cindy St. Hilaire:              Yeah. Well, I'm sure with your very rigorous approach, you are going to find out and hopefully we'll see it here in the future. Dr Elizabeth Tarling and Dr Bethan Clifford, thank you so much for joining me today. I really enjoyed this paper. It's a beautiful study. I think it's a beautiful example, especially for trainees about kind of thoroughly and rigorously going through and trying to test your hypothesis. So thanks again.   Elizabeth Tarling:             Thank you.   Bethan Clifford:               Thank you very much.   Cindy St. Hilaire:              That's it for the highlights from the March 31st and April 14th issues of Circulation Research. Thank you for listening. Please check out the Circulation Research Facebook page and follow us on Twitter and Instagram with the handle @CircRes, and #DiscoverCircRes. Thank you to our guests, Dr Liz Tarling and Dr Bethan Clifford.   This podcast is produced by Ishara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, you're on-the-go source for the most exciting discoveries in basic cardiovascular research.   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 information, visit ahajournals.org.  

This week, please join author Amil Shah and Associate Editor Ntobeko Ntusi as they discuss the article "Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities 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, associate editor, Director at the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature, very interesting. Many times in older individuals we understand how to manage severe valvular heart disease, for example, severe aortic stenosis. But do we really know how to manage individuals with mild valvular heart disease, for example, mild mitral regurgitation or aortic valve sclerosis? Well, our feature today will address that issue. And so, listeners, grab a cup of coffee. We're going to go through some of the other articles in the issue first, and then we'll get to that really interesting, very practical feature discussion. Well Carolyn, now that I've got my cup of coffee, this paper's from your group. And I'm going to ask you, Carolyn, as if it was a feature discussion, what was the background information that went into this and what was the hypothesis that you wanted to address? Dr. Carolyn Lam: Oh, it's great because it's at least not a Carolyn quiz, so I'm very happy to talk to you about it. Sex differences, as you know, it's a passion of mine. And in response to heart failure pharmacotherapies, in particular, we know that there are sex differences, wherein women appear to benefit from newer hormonal modulators across a wider heart failure ejection fraction range compared to men. And this was particularly evident in the Paragon heart failure trial of Arne versus Valsartan. However, whether these considerations also apply to the sodium-glucose Cotransporter 2 inhibitors or SGLT 2 inhibitors, remains unclear. So along with the groups from the DAPA-HF and DELIVER trial, we therefore examine and assess the impact of sex on the efficacy and safety of dapagliflozin in a pre-specified pooled analysis of these trials. Dr. Greg Hundley: Very interesting, Carolyn. So, differences between men and women and evaluation of efficacy of SGLT 2 inhibitors. So what did you find? Dr. Carolyn Lam: In essence, women and men derived similar benefits from dapagliflozin for both the primary outcome of worsening heart failure or cardiovascular death. And for secondary outcomes, including improvement in health status across the full spectrum of ejection fraction in heart failure. Dapagliflozin was also safe and well tolerated in both sexes. So these findings are consistent with other SGLT 2 inhibitors and suggest a class effect. And in fact, this is very, very nicely discussed in an accompanying editorial by Dr. Ileana Piña. Dr. Greg Hundley: Ah, very nice, Carolyn. Well, my first study here comes from the world of preclinical science. And Carolyn, this study assesses the role of epsins in modulating endothelial to mesenchymal transition in atherosclerosis. So Carolyn, you may ask what are epsins? Well, epsins are ubiquitously expressed adapter proteins involved in the regulation of endocytosis. And then Carolyn, there's a second process addressed in this study. And Carolyn, it is known that chronic vascular inflammation, a hallmark of atherosclerosis, induces a process called endothelial to mesenchymal transition. And during endothelial to mesenchymal transition, the transition of non-smooth muscle cell-derived cells that are capable of maintaining indices of atherosclerotic lesion stability are lost. And this allows atherosclerosis to progress to a more advanced stage. So Carolyn, in this study led by Dr. Hong Chen, from Boston Children's Hospital, these authors wanted to know if impacting epsins could reduce endocytosis and thereby modify endothelial to mesenchymal transition and attenuate atherosclerosis progression. Dr. Carolyn Lam: Sounds like an important concept to address in the progression of atherosclerosis. So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So the authors found that epsins are required for endothelial to mesenchymal transition, and that the loss of these proteins in the endothelium reduces endothelial to mesenchymal transition by permitting sustained fibroblast growth factor receptor-1 protein, FGRF1, signaling by inhibiting the degradation of this receptor complex. They also demonstrate the efficacy of blocking epsin FGRF1 interactions specifically in atheromas using systemic administration of a targeted epsin UIM containing peptide to inhibit endothelial to mesenchymal transition and atherosclerosis progression in APO deficient and PCSK9 mutant viral induced atherosclerotic models. So Carolyn, in summary, these authors show that blocking these epsin FGRF1 interactions could provide a new approach to combat atherosclerosis progression. Dr. Carolyn Lam: Wow, Greg, thanks. Well, this next paper is an important preclinical paper showing that agents that induce senescence in cells of pulmonary vasculature can unexpectedly worsen rather than ameliorate pulmonary hypertension. So this paper is from Professor Serge Adnot and colleagues from Hospital Henri-Mondor in France. And they began by showing that in human lung tissues from pulmonary hypertension patients, about 30% of lung endothelial and smooth muscle cells have elevated P16, an observation recently also reported by others, as further evidence of senescence. Many of the cells with elevated P16 also had an increase in unrepaired DNA damage. They then used multiple senolytic strategies in several animal models to remove senescent cells and then found unexpectedly that eliminating senescent cells aggravated rather than suppressed pulmonary hypertension development. As models of pulmonary hypertension, the authors examined a number of animal models of pulmonary hypertension. That included rats exposed to chronic hypoxia, rats injected with the toxin monocrotaline, and rats injected with a VEGF receptor blocker prior to exposure to chronic hypoxia. As well as mice over-expressing the serotonin transporter in smooth muscle cells. And mice with P16 over-expression that develop pulmonary hypertension with age. So lots of animal models were tested and these animals also received the senolytic ABT 263 or FOX04-DRI, that would be expected to remove senolytic cells with equivalent results. Dr. Greg Hundley: Wow, Carolyn, so multiple animal models highlighting that senescent cells in the pulmonary vasculature can worsen rather than attenuate pulmonary hypertension. So what are the clinical implications of these models? Dr. Carolyn Lam: Well, this is discussed in a beautiful editorial by Dr. Rabinovitch that accompanies this paper. And quoting from that editorial, "The study is therefore extremely important in pointing out the potential overkill of senolytics in promoting rather than reversing pulmonary hypertension. The study also has particularly important translational implications as it indicates that the potential efficacy of an emerging therapy relies on the underlying disease mechanism and animal model use, the cell specificity dose, and root of administration." So lots of translational implications of this paper. Dr. Greg Hundley: Wow, Carolyn, so we've got some other articles in this issue and it looks like you've got a great review of those to describe. Dr. Carolyn Lam: Sure, I'd love to tell you about them. First there's a letter from Dr. Liao regarding the article, "Association Between Device Measured Physical Activity and Incident Heart Failure: A Prospective Cohort Study of the UK Biobank Participants." There's also a Cardiovascular Case Series by Dr. Ostrominski on "Pulling Out All The Stops: A Case of Progressive Dyspnea." In Cardiology News by Tracy Hampton, there's a story of scientists creating spatial map of cardiac remodeling after myocardial infarction, published in Nature. Loss of Y chromosome in myeloid cells promoting cardiac fibrosis, published in Science. And details behind the DNMT3A and TET2 mutations linking atherosclerosis. And that's published in Immunity. There's also a Perspective piece by Dr. Somers on “Whom to Screen and How to Screen for Obstructive Sleep Apnea in The Cardiology Clinic?” And a Research Letter by Dr. Felker on the clinical implications of negatively adjudicated heart failure events, data from the Victoria study. Dr. Greg Hundley: Wow, Carolyn, this issue, it's just packed with information. Well, how about we get on to that feature discussion? Dr. Carolyn Lam: Let's go. Thanks. Dr. Greg Hundley: Welcome listeners, to this feature discussion on this February 21, where we're going to delve into the world of valvular heart disease. And we have with us today Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our own associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa. Welcome gentlemen. Well Amil, we'll start with you. Could you describe for us some of the background information that really went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Amil Shah: Well, thanks very much, Greg, and let me start by thanking you and the circulation team for the interest in this paper and the opportunity to discuss it with you today. So I think in terms of background, we know that the prevalence and incidence of valvular heart disease increases with age, and that severe valvular heart disease is associated with substantial morbidity and mortality. Sub-severe valvular heart disease is, of course, even more common and has also been associated with worse cardiovascular outcomes. So I'm thinking of earlier studies that have associated even aortic sclerosis in the absence of stenosis with worse outcomes. Acknowledging the progressive nature of valvular heart disease, the ACCHA valve guidelines adopted this framework of valvular heart disease stages, where stage A was really defined as at risk for valvular dysfunction based on valve morphology in the absence of hemodynamic perturbation. Stage B is progressive valve dysfunctions. This is commonly what we would clinically consider mild or moderate valvular lesions. And then stage C, severe asymptomatic valve dysfunction. Stage D, severe symptomatic valve dysfunction. And we believe that looking at valvular heart disease in the context of these stages, as opposed to just as the hemodynamic severity of the lesion, can provide important insights into the burden of valvular heart disease. And especially sub-severe valvular heart disease in at-risk individuals, and in particular in older individuals. But the prevalence of these stages in the community and their progression over time really prior to this, to our knowledge, hasn't been described. And so really our aims and our hypotheses in this paper was to understand the prevalence of valvular heart stages amongst older adults. And really what we anticipate is that a large proportion of individuals in late life would have at least stage A, if not stage B, valvular heart disease. To describe the prognostic relevance of these stages, and particularly the sub-severe stages, and we anticipated that even stage A or stage B relative to no stage would be associated with worse outcomes, based on the prior literature. And finally, to characterize the rate of progression in late life. Dr. Greg Hundley: So rather than just the hemodynamic significance, it sounds like we're going to investigate the stages of valvular heart disease in an elderly population and associate that with prognosis. So how did we do that? What was your study design and can you describe for us also your study population? Dr. Amil Shah: Sure, of course. So we ended up using longitudinal data from a large cohort of older adults who are participating in the Atherosclerosis Risk in Communities, or ARIC study. So ARIC is an NHLBI funded longitudinal epidemiologic cohort. It's actually been following participants from four communities in the US since 1986. So Maryland, Mississippi, North Carolina, and Minnesota. Echocardiography was performed in just over 6,000. So 6,118 individuals are participants in 2011 to 2013. And at that time the mean age was 76. Just under 3,000 of those individuals underwent a repeat echocardiogram in 2018 to 2019. So that's a time elapse of about six and a half years, at which time the mean age was 81. So we're really looking at how things are changing between the ages of 76 to 81 years of age. We really focused on the mitral and aortic valves and determined or ascertained the stage of regurgitation or stenosis in those valves using a combination of quantitative and qualitative criteria based on the study echocardiograms, which are all read and interpreted centrally. And of course, each valve gets its own stage. And so for the purposes of this paper, we classified individuals as an overall valvular heart disease stage based on whichever valve had the highest grade lesion. Dr. Greg Hundley: Very nice. So using the ARIC study and then following the stages. So describe for us, Amil, what were your study results? Dr. Amil Shah: So at the first assessment, so amongst these approximately 6,000 individuals who had imaging in 2011 and 2013, the prevalence of stage A valvular heart disease was about 39% of individuals. Stage B, which again would be progressive, was about 17% of individuals. And stage C or D, which is really severe valvular heart disease, which was just over 1% in this community based population. And again, another 1% had previously undergone valve replacement or repair. And not surprisingly, even amongst this older cohort, older age was associated with a higher prevalence of each one of these stages. Then over a median follow up of about six and a half years, we looked at the association of each one of these stages with incident cardiovascular events relative to that group of individuals who were free of valvular heart disease stage in this cohort. And in each one of these stages, including stage A, was associated with a higher risk of incident heart failure, incident atrial fibrillation, coronary heart disease, which is largely MI, and then all-cause mortality. And that was true after accounting for many of common cardiovascular risk factors we usually think about as being related to risk for these outcomes. Interestingly, there was not an association with incident stroke in this study, although I will say our numbers for incident events were modest. Dr. Greg Hundley: Now, did you find similar results for men and for women? Dr. Amil Shah: So these results were fairly consistent for men, for women. And then the other demographic subgroup we looked at is... One of the unique features of ARIC is that it is a biracial cohort. And so when we looked at demographic subgroups based on both gender and race group, these trends were similar. Dr. Greg Hundley: And I know, Amil, right at the beginning you were discussing the importance of the stages versus the hemodynamic consequences. Did you do any comparisons, for many of us that are following patients, for example, with aortic stenosis? Did you find a discrepancy between using the stage as the defining term for a patient as opposed to the hemodynamic significance of one of these valve lesions? Dr. Amil Shah: Yeah, that's an excellent question. And so I think the first point to make is the valvular heart disease stages, of course, that we are assigning are based on the highest stage lesion, and so, of the four lesions we assessed. And part of this is a little nuanced, I guess, based on how the guidelines have defined these stages. So interestingly, if you look at stage A valvular heart disease, the majority of those individuals are getting in due to mild mitral regurgitation, because mild mitral regurgitation is considered stage A. In contrast, if you look at stage B, the majority of those individuals are getting in because of mild aortic regurgitation, because mild AR is considered stage B. And then stage C/D is really driven by aortic stenosis, probably not surprisingly. So what we can do is look not only overall, but also by stage within lesion. And certainly for aortic stenosis and mitral regurgitation, which are the most common valvular lesions we encountered, we saw similar findings. For mitral stenosis we had very few cases. So I don't think we can really comment on that based on this study. And for aortic regurgitation, we largely had individuals with no regurgitation or mild regurgitation, only a few with moderate. So again, we're a little bit limited in commenting on that. Dr. Greg Hundley: Very nice. Well, thank you so much, Amil. And listeners, now we're going to turn to our associate editor, Dr. Ntobeko Ntusi from Cape Town, South Africa. Ntobeko, you have many papers that come across your desk. What intrigued you about this particular paper? Dr. Ntobeko Ntusi: Thanks, Greg. I'd like to start by congratulating Amil and his co-authors on this paper, which as an associate editor was an absolute pleasure to handle. And the reason why we liked it are two-fold. Firstly, it's a large study, simple science of over 6,000 people. Very well characterized cohort clinically. We also liked its prospective design, as well as the protocolized nature of the echocardiograms. We liked that there was a central facility for core reading of all of these echocardiograms. And the use of a well-validated system of categorizing valvular heart disease. And importantly, we also liked the fact that it is a very representative study in terms of ethnicity and sex. And for me, there were three important takeaway messages from this study which advance our concepts of valvular heart disease. The first is that we've known for a long time that most severe valvular heart disease is associated with poor outcomes. But for the first time, this study provides us with data that shows a clear created association between the valve stage and outcomes related to mortality incident at fila and incident AF. So this is a new contribution. The second important novel contribution from the study is the data they provided on disease progression between stages of valvular heart disease. And then thirdly, I really liked the figures, in particular figure three and figure four, which I think are going to be highly cited and used in many presentations. So figure three demonstrates the Kaplan-Meier curves and shows survival rates dependent on the stage of valvular heart disease. And figure four, beautiful alluvial plot showing disease progression. And for these reasons we thought this was a piece that we would like to include in Circulation. Thanks, Greg. Dr. Greg Hundley: Thanks so much, Ntobeko. Well Amil, based on all this work, where are you going next? What do you see as the next study to really be performed in this sphere of research? Dr. Amil Shah: So two major findings I think that may have downstream consequences for future studies, first relate to identifying a subgroup A. That these valvular heart disease stages progress fairly substantially over fairly limited periods of time in late life. And really identify older individuals with certainly stage B, but even stage A valvular heart disease as a group, not only that we should screen with follow up, as recommended by the guidelines when we do detect sub-severe valvular lesions. But also potentially for therapeutics to prevent progression as those become increasingly available. And so I think one place where this data may be very helpful is in thinking about at-risk groups to evaluate therapeutics in. I think the second place is this relationship of even stage A valvular heart disease with adverse outcomes, which I think suggests that when we see valve deformation on imaging, that is likely a marker of risks that we're not fully capturing using our other traditional cardiovascular risk factors. And potentially could begin to become incorporated into how we think about risk stratifying our patients. Dr. Greg Hundley: Very nice. Ntobeko, do you have anything to add? Dr. Ntobeko Ntusi: Indeed. So I think in terms of future directions, there are probably three questions that I think would be important in taking this work forward. The first one is that this is clearly a descriptive epidemiological study. And for me it would be interesting to look at some of the mechanisms that underlie the adverse clinical outcomes associated with different stages of valvular heart disease. Two, the follow-up is relatively short and I think that it will be interesting as these individuals continue to be followed up long term, to see how these observations are either strengthened or evolve over time. And then finally, which is probably not going to be possible with the ARIC cohort. I think it would be useful to also look at rates of disease progression, but also the associations with outcomes in a younger cohort. And so for me, those would be interesting future ways of taking this work forward in the future. Thank you, Greg. Dr. Greg Hundley: Very nice. Well, listeners, we're going to wrap up and we want to thank Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa, for bringing us this study highlighting that subclinical valvular heart disease is common in older adults with 39% at risk for stage A, and 17% with progressive valvular heart disease, or stage B. And they are independently associated with the risk of incident cardiovascular events. Well, on behalf of Peder, 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 2023. 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.

Hear from Victoria Pemberton, RNC, MS, CCRC, project officer for the National Heart, Lung and Blood Institute (NHLBI), as she discusses the importance of heart health literacy and highlights ways nurse practitioners can effectively engage with patients to reduce heart disease risk. February is American Heart Month — the ideal time to remind your patients about the importance of making heart-healthy lifestyle changes. New resources from the NHLBI's The Heart Truth® program can help you empower patients to achieve their cardiovascular health goals.   The American Association of Nurse Practitioners® (AANP) offers continuing education (CE), tools and resources to support nurse practitioners (NPs) working to reduce the risk of heart disease. Members may opt to join the AANP Cardiology Community, complete AANP CE Center activities, attend sessions at the 2023 AANP National Conference in New Orleans June 20-25, download clinical practice briefs or access a variety of cardiology-related resources.   Additional Resources American Heart Month Outreach Toolkit. High Blood Pressure and Women. Pregnancy and Your Heart Health. Heart Disease Prevention.  Heart Smart Basics: What to Know to Keep Yours Healthy. My Heart Health Tracker.

Credits: 0.25 AMA PRA Category 1 Credit™   CME/CE Information and Claim Credit: https://www.pri-med.com/online-cme-ce/podcast/copd-patient-cases-reduced-lung-function  Overview: “Lung Health Updates for Primary Care Providers: Conversations with NHLBI” is a series of CME podcast episodes produced by Pri-Med in partnership with Learn More Breathe Better®, a program of the National Heart, Lung, and Blood Institute of the National Institutes of Health. In this episode looking at case studies of patients with reduced lung function, we are joined by Dr. Mihaela Stefan, a Program Officer with NHLBI's Division of Lung Diseases, and Dr. Elizabeth Oelsner, general internist and Irving Assistant Professor of Medicine at Columbia University Department of Medicine Division of General Medicine. We'll be discussing profiles of three patients with reduced lung function, including an asymptomatic smoker, a smoker with respiratory symptoms but without spirometric evidence of COPD, and a COPD patient with history suggestive of AAT deficiency. So let's begin.

In September 2022, the Biden administration convened a Conference on Hunger, Nutrition, and Health to unpack and address food and nutrition insecurity across the country. Food insecurity is a deeply cross-cutting challenge to take on, so we're bringing you a two-part episode examining the science of nutrition insecurity and policies looking to address it. In part 1, we talk with Dr. Alison Brown, a program director at NHLBI, about health inequities and scientific research behind food insecurity.

What is a clinical trial? When should a patient consider participating? Olga Rios, RN, at the NHLBI at the National Institutes of Health, answers these questions.

Enduring CME will expire on 11/2/2024. The presentation is originating from Northeast Georgia Medical Center Gainesville. Objectives: 1. To review sex differences in ischemic heart disease prevalence and outcomes 2. To understand new data regarding sex-specific ischemic heart disease pathophysiology in women 3. To evaluate sex-specific diagnosis and treatment strategies for ischemic heart disease in women Disclosures: Grant support*: NHLBI, Louis B Mayer Foundation, NIH-CTSI, CMDRP-DoD, NIH-Caladrius, California Institute for Precision Medicine (CIAPM), Sanofi-Vascular Consulting: Medscape*, Sanofi-Vascular*, NIH CSR and NIH ORWHAB*, iRhythm Honorarium*: Abbott Diagnostics Stocks: None Accreditation and Designation: The Northeast Georgia Medical Center & Health System, Inc. is accredited by the Medical Association of Georgia to provide continuing medical education for physicians. The Northeast Georgia Medical Center & Health System, Inc. designates this live activity for a maximum of 1 AMA PRA Category 1 Credit(s) TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Credits: 0.25 AMA PRA Category 1 Credit™ CME/CE Information and Claim Credit: https://www.pri-med.com/online-education/Podcast/identifying-and-testing-for-copd Overview: “Lung Health Updates for Primary Care Providers: Conversations with NHLBI” is a series of CME podcast episodes produced by Pri-Med in partnership with Learn More Breathe Better®, a program of the National Heart, Lung, and Blood Institute of the National Institutes of Health. In this episode on identifying and testing for COPD in primary care, we are joined by Dr. Antonello Punturieri, a Program Officer with NHLBI's Division of Lung Diseases, and Dr. Byron Thomashow, Professor Emeritus at Columbia University Medical Center and Co-founder and Chief Medical Officer of the COPD Foundation. We'll be discussing why primary care providers play such a crucial role in finding COPD cases among patients, the tools to help identify these cases, and the diagnostic criteria that points to starting appropriate treatments. 

Credits: 0.25 AMA PRA Category 1 Credit™ CME/CE Information and Claim Credit: https://www.pri-med.com/online-education/Podcast/copd-treatment-for-primary-care-providers Overview: “Lung Health Updates for Primary Care Providers: Conversations with NHLBI” is a series of CME podcast episodes produced by Pri-Med in partnership with Learn More Breathe Better®, a program of the National Heart, Lung, and Blood Institute of the National Institutes of Health. In this episode on COPD treatment for primary care providers, we are joined by Dr. Mihaela Stefan, a Program Officer with NHLBI's Division of Lung Diseases, and Dr. MeiLan Han, Professor of Medicine and Chief of the Division of Pulmonary and Critical Care at the University of Michigan. We'll be discussing the range of treatments for patients diagnosed with COPD using spirometry, including lifestyle interventions, pulmonary rehabilitation, medications, and non-medication COPD treatments. 

This week, please join authors Jonas Oldgren and Signild Åsberg as they discuss the article "Early Versus Delayed Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority 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, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Today's featured paper is a very important discussion, and in fact, the first study to compare early versus delayed NOACs after acute ischemic stroke in patients with atrial fibrillation. The timing study. You're not going to want to miss this, but you're going to have to wait for it, because we're going to discuss all the papers in today's issue. Can I start, Greg? Because I want to start, or is it too early to start with a Greg quiz? With the quiz question being, what is cell-free DNA? Dr. Greg Hundley: Oh, thank you Dr. Lam. I really appreciate your wonderment into the world of preclinical science. So something maybe short DNA fragments, but I'm not sure. Dr. Carolyn Lam: Aw, you're absolutely right. It's circulating DNA fragments predominantly from mononuclear zones that represent cell injury and/or turnover. So what we know is elevated total cell-free DNA concentration has been associated with worse prognosis in a variety of conditions such as sepsis, trauma, malignancy. In addition, and this may be where a lot of us have heard of cell-free DNA, it's become clinically relevant as a noninvasive marker of solid organ transplant rejection as well as a tool for genotyping and surveillance in oncology. However, in today's paper, given the parallels in the pathogenesis of pulmonary artery hypertension, two of the diseases I've talked about before that are characterized by increased cell proliferation and turnover, like the cancers and inflammatory mediated tissue injury. Now this particular study sought to determine if plasma cell-free DNA concentrations were elevated in pulmonary artery hypertension, and if those levels would correlate with disease severity or predict outcomes. Dr. Greg Hundley: Oh wow, Carolyn, this sounds really informative. So what did they find? Dr. Carolyn Lam: Well, this study from corresponding authors, Dr. Solomon from NIH Clinical Center and Dr. Agbor-Enoh from NHLBI in Bethesda and their team found that circulating cell-free DNA is elevated in patients with pulmonary arterial hypertension compared to healthy controls. In two independent PAH patient cohorts, cell-free DNA concentrations increased with severity of disease and predicted transplant free survival in the larger of the two cohorts. Interestingly, methylation patterns revealed increased cell-free DNA originating from biologically plausible sites including erythrocyte progenator and myeloid lineage inflammatory cells, vascular endothelium, and cardiac myocytes. So the implications are that in pulmonary arterial hypertension, cell-free DNA concentrations could serve as a non-invasive biomarker of underlying disease activity, may add prognostic value to currently use risk scores, and may provide a unique noninvasive window into its pathogenesis. Dr. Greg Hundley: Wow, Carolyn. So another interesting technique and pathophysiologic study highlighting the utility of circulating cell-free DNA. Wow. Well, Carolyn, how about I start in with my first study and it comes to us from the world of clinical science and refers to the paradise MI echocardiographic substudy. So Carolyn, the prospective RNE versus ACE inhibitor trial to determine superiority in reducing heart failure events after myocardial infarction. So the Paradise MI echo study tested the effect of Sacubitril/Valsartan compared to Ramipril on LV function and adverse remodeling following high risk acute myocardial infarction. So this substudy included 544 Paradise MI participants that underwent echocardiography at randomization, and then again later at eight months. Patients were randomized within a half to seven days of their presentation with their index, myocardial infarction, to receive a target dose of Sacubitril/Valsartan of 200 milligrams or Ramipril five milligrams twice daily. Dr. Carolyn Lam: All right. So the Paradise MI echo substudy, what did they find? Dr. Greg Hundley: Right Carolyn, so treatment with Sacubitril/Valsartan compared to Ramipril following acute myocardial infarction did not result in changes in left ventricular ejection fraction or left atrial volume at eight months. Patients randomized to Sacubitril/Valsartan had less LV enlargement and greater improvement in filling pressure, and thus there are new insights here in that treatment with Sacubitril/Valsartan compared to Ramipril early following acute myocardial infarction may beneficially impact LV size and diastolic properties possibly due to reductions in LV filling pressure. Dr. Carolyn Lam: Oh, very nice, Greg. Thank you. Another clinical study here, and this time a paper aimed to evaluate the influence of sex on the effects of empagliflozin in patients with HFpEF enrolled in the Emperor Preserved trial. Dr. Greg Hundley: Ah, Carolyn, two of your favorite things, sex differences and SGLT2 inhibitors. So Carolyn, remind us, what did Emperor Preserved show us? Dr. Carolyn Lam: Ah, so Emperor Preserved studied the sodium glucose cotransporter 2 or SGLT2 inhibitor empagliflozin in patients with HFpEF, which is an ejection fraction above 40%, and showed a significant reduction in the risk of cardiovascular death or heart failure hospitalization. In the current paper, corresponding author Dr. Javed Butler from University of Mississippi Medical Center and colleagues found that empagliflozin reduced the risk of the primary outcome of cardiovascular death or hospitalization for heart failure to a similar degree in both women and men with HFpEF irrespective of baseline left ventricular ejection fraction. Empagliflozin produced comparable benefits for the pre-specified secondary outcomes of total heart failure hospitalizations, cardiovascular death, and all-cause mortality, as well as physiologic measures and health status. The pattern of the effects of empagliflozin and HFpEF in both sexes in EMPEROR- Preserved stands in contrast to the influence of sex on the response to neprilysin inhibition. So very interesting paper. I encourage everyone to pick it up, of course, because it's two of my favorite topics. Dr. Greg Hundley: Very nice, Carolyn. Well, my next paper comes to us from the world of pre-clinical science, and it's from Dr. Chunyu Zeng from Diping Hospital, the third military medical university. Carolyn, adverse environmental exposure during the prenatal period can lead to diseases in offspring, including hypertension. Now whether or not the hypertensive phenotype can be trans-generationally transmitted is really not new. Dr. Carolyn Lam: Wow, that's interesting. So what did this paper find? Dr. Greg Hundley: Carolyn, this was really interesting. So these authors in a rat model, they found that prenatal lipopolysaccharide exposure can impair the ability to excrete a salt load and induce hypertension from the first to the third generations, with the fourth and fifth generations inducing salt-sensitive hypertension. And Carolyn, really interestingly, and based on these findings, they treated lipopolysaccharide exposed pregnant rats with the reactive oxygen species scavenger temple, which successfully prevented hypertension in the first-generation offspring and the transgenerational inheritance of hypertension. So Carolyn, these findings show that adverse prenatal exposure induces transgenerational hypertension through an epigenetic regulated mechanism. And these findings identify potentially preventive and therapeutic strategies for this form of generationally transmitted hypertension. Really interesting. Dr. Carolyn Lam: Wow, that sounds wild. Very, very interesting. Well, let's go through the other things that are in today's issue. There's a research letter by Dr. Moayedi on anteroposterior pacer pad position is more likely to capture than anterolateral for transcutaneous cardiac pacing. Dr. Greg Hundley: Great, Carolyn. And I've got a research letter from Professor Porrello entitled, “Defining the Fetal Gene Program at Single Cell Resolution in Pediatric Dilated Cardiomyopathy.” And then lastly, there's an ECG Challenge from Dr. Chen entitled, “A Shark Thin Electric Cardiogram in the Intensive Care Unit.” Well Carolyn, how about we get onto that featured discussion and learn more about non-vitamin K antagonists after acute ischemic stroke? Dr. Carolyn Lam: Yep. In patients with EF, here we go. Today's feature discussion is all about atrial fibrillation, how it's a risk factor for stroke, but also about how we've never known really how soon after an acute stroke can we start oral anticoagulation to prevent recurrent strokes? Today we're going to talk about the timing study. It's the first randomized controlled study to evaluate the efficacy and safety of initiation of treatment with NOACs within 10 days of acute ischemic stroke in patients with atrial fibrillation. Wow. What an exciting study, and also how exciting that we have two co-first authors. We have Dr. Jonas Oldgren and Dr. Signild Åsberg from Uppsala University in Sweden, and this represents a partnership between neurology and cardiology. I mean really unique in many aspects as well as the way this study was performed, which is truly, truly a feat in itself. May I ask you both please to tell me the story of how this study came to be in the first place? Dr. Signild Åsberg: Well, we like to mention the late Professor Gesteruen student who actually was the first to bring this question to the table. Together we talked with the cardiology department and Jonas Oldgren to see if we can collaborate to solve this important question for us that works with stroke patient, because it's on a weekly or even a daily basis, troublesome question. Dr. Jonas Oldgren: My background is as a cardiologist and professor of coagulation research. I've been very interested in anticoagulants, antithrombotic treatments, and had the pleasure and privilege to be part of the development of the novel oral anticoagulants. And in all those pivotal trials, we excluded patients with a recent stroke at least seven days from the stroke, sometimes even 30 days from the acute stroke we excluded them from the studies. So when we found the exciting results with at least as good efficacy as warfarin and at least as good safety as warfarin and the tremendous reduction in intracerebral or intracranial bleeds, that was a finding which was not evaluated in acute stroke patients with atrial fibrillation. And when Signild approached me with this idea, I said, "Well this is absolutely a very important question and why hasn't it been resolved earlier?" And the problem is, of course, that these are patients who are in a sensible setting earlier after the acute ischemic stroke, and when are we able to safely start an effective treatment? Dr. Carolyn Lam: Oh, I couldn't agree more with you about how important that is. I mean, when we have an acute stroke patient, we just don't know whether we should start the NOAC early or delay it and we definitely need that evidence gap filled. But I'm also so intrigued with the way you did it with the Swedish Stroke Register. I mean, what a powerful way to look at important questions like this. Could you tell us a bit more about the method used? Dr. Jonas Oldgren: Yeah, so in cardiology we started rather early by using our national health registries for doing randomized controlled trials. We did a lot of observational studies in our registries, both in stroke and in cardiovascular medicine, otherwise in every other area of medicine. But in the end we realized that we could at best be hypothesis generating, but we still needed to add randomized controlled studies to have the last piece of the puzzle to provide good evidence. And then we ran a lot of studies in cardiologists, especially in myocardial infarction patients, by just adding to simplify, by adding a randomization module, and then follow the patients in the registries because we know that we have high quality data in the registry. For instance, in the stroke registry. So we anyway collect every important data on each and every patient in the register. So by adding a randomization module, we can facilitate the conduct of a clinical study. Dr. Carolyn Lam: Wow. The way you say it, you make it sound so simple, but I can tell you what you have there in Sweden is like the envy of the whole world, and everybody's thinking about how to do a registry based trial like that. So maybe after you tell us the results, you could also share a little bit of how difficult and challenging it can be as well. But would either of you like to share the results? Dr. Signild Åsberg: Well, the major result from our trial is that initiating NOAC within four days is non-inferior to starting in a delayed phase of up to 10 days. So that's our key finding. But equally important is that we didn't have any patients explaining as symptomatic and terrible hemorrhage, and that is extremely good news for us who worked with these patients. Dr. Carolyn Lam: That is such an important message. The early initiation was non-inferior. Could you expand on non-inferior in terms of what primary outcome? Dr. Jonas Oldgren: Yeah, so the primary outcome was really a clinically important outcome we think, both from the cardiac perspective but also from stroke specialists. So we had a combination composite of symptomatic intracerebral hemorrhages, ischemic strokes and death. And this is what matters to patients and to doctors. We would like to avoid strokes, and it doesn't matter if it's an ischemic stroke or if it's a hemorrhagic stroke. We would like to avoid them. And of course we would not like to have an increased mortality as well. So it's a relevant endpoint. And when we designed the study, the main drug used was warfarin, and there we knew that there was a lot of hemorrhagic transformations and a lot of intracerebral hemorrhages. So we designed the trial to look at these three endpoints to prevent ischemic strokes, but to avoid hemorrhagic strokes. And that is why we choose to have a non-inferiority design, because we also have the advantage of starting early if we can make the decision to start with the stroke specialists sometimes in collaboration with the cardiologist, and then we can have the patient step down unit earlier if the treatment is already started. So that was the choice of a non-inferiority design. We of course also tested for superiority, but unfortunately we didn't meet that superiority testing endpoint. But as Signal mentioned, I think thrilling results is to have no symptomatic intracerebral hemorrhage in any of the groups. That really speaks in favor of the safety of this drug or these drugs that we used, but also the concept to start early. We can also note that we had some ... I mean there were numerically lower rates of both ischemic strokes and deaths in the early group, albeit not meeting the significance for superiority, but it's important. And as we see also the events tend to occur very early. So we really gain with treating our patients earlier with this intervention. Dr. Carolyn Lam: Oh indeed. And to all the listeners, do pick up the paper because if you look at the Kaplan-Meier curves, they're really impressive, exactly like you said, numerical differences, although the trial did demonstrate non-inferiority and could not demonstrate the superiority. But have a look at those figures. And if I could just clarify the comparator arm, notice that we've been saying NOACs, not a particular NOACs. So could you expand on that a bit? Dr. Signild Åsberg: We used all the four NOACs that we have in Sweden, so that was to the physician's discretion to choose between them. So that was not a part of the randomization. So we only randomized the timing to the early phase or the delayed phase. Dr. Carolyn Lam: I love that. And then if you could please educate the cardiologist in me, please. There are symptomatic intracerebral hemorrhages, and then there are all kinds of little things that you can pick up if you image the brain and hemorrhagic transformation and microbleeds and all these things. So I think one of the things here was their systematic imaging and does it matter? Could you teach us a little bit more about these different types of bleeds? Dr. Signild Åsberg: We did not have a systematic imaging, but in Sweden that is performed mostly by CT on admission. So that was for all patients. And then on events, the imaging was performed and reported through the registry. And yes, there were hemorrhagic transformation actually in three patients, two in the early phase, and one in the delayed phase, but only one before day 10. So all blood that was seen on imaging was reported, but we used symptomatic criteria from the stroke severity scale. Dr. Carolyn Lam: Thank you. That's a good clarification. And then the study aimed for a larger number, and here perhaps if either of you could tell us the story, the struggles, and how you ended up with these beautiful results. Dr. Signild Åsberg: Yeah, struggle is the word. It was troublesome and we had long talks. So why was this happening? Why didn't science recruit more? But I think one issue might have been that NOACs had been on the market for a while once we started, and even the stroke physicians were getting used to it and had trouble not to start. Before the timing study started, we did a observational pre-timing study just to see how we were doing in Sweden at this stage. Because we didn't really know that. We know that a lot of patients were discharged with oral anticoagulation, but we didn't really know when they started. And so by that study we could see that in median time to initiation was five days, already before the timing study. So one thought was that this was for some physicians then had to delay their start. They were getting used to start early. So that could have been one explanation. Dr. Jonas Oldgren: And of course there has been a lot of observational studies looking at the safety of NOACs or other oral anticoagulants in the early setting after acute ischemic stroke in patients with atrial fibrillation. And of course with the evidence from such studies, albeit observational doctors felt perhaps more confident starting very early despite the lack of evidence from randomized control trials. So we had the opportunity to follow those patients as well in the stroke registry. Every patient with an acute stroke in Sweden attending a stroke unit is registered. So we have in the supplement of the paper in circulation, we have observational data from the centers participating in stroke, but patients not randomized in the timing study. And we also have observational data from all stroke centers in Sweden. So we can see that many start very earlier with NOACs based on observational data, based on experiences. And perhaps we're more and more reluctant to randomize the patient in the study because as Signal says, that means there is a 50% chance of delayed treatment by randomization. And when we started this study, there were no evidence from randomized controlled trials within the first 14 days. But while running the study for a couple of years, you start to believe that there seemed to be safety because no one saw any symptomatic intracerebral hemorrhage. And we discussed that, of course, at investigative meetings that this seemed to be a very good treatment, which is bad for running a clinical study, but it's of course good for the patients. Dr. Carolyn Lam: Interesting. So echo points kind of may have shifted a little bit even during the course of the trial. So just thank you so much all the more. Thank you for seeing this to completion in the sense of a beautiful manuscript with very meaningful results. If I could ask you both to each summarize just very quickly what the take home message is for clinical practice from neurologist's point of view and cardiologist's point of view? Dr. Signild Åsberg: Yeah, what I would say, it seems both safe and reasonable to initiate NOAC earlier after an acute ischemic stroke. So I think that's the key take home message that really to consider the acute secondary prevention. Dr. Jonas Oldgren: I may bring that from another perspective. I think when there's lack of data in collaboration, we can do a lot. So in this case, we had a great collaboration in the student committee, cardiologist and stroke specialists collaborating to run such a study. And we are extremely grateful for all the sites and all the investigators at the sites participating in the study. And then of course grateful to circulation for publishing it because we are very proud of this study. Dr. Carolyn Lam: And we are proud to be publishing this. So ladies and gentlemen, you heard it right here in Circulation On The Run. Remember this is about early versus delayed initiation of NOACs in patients after an acute stroke who also have atrial fibrillation. And this is a very, very, I think, important study that fills an important evidence gap. We're so grateful to both of you for being here to discuss it, and to the audience for listening today. You've been listening to Circulation On The Run. And don't forget to tune in again next week. 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.

A new research paper was published in Aging (listed as "Aging (Albany NY)" by Medline/PubMed and "Aging-US" by Web of Science) Volume 14, Issue 17, entitled, “Aging, prevalence and risk factors of MRI-visible enlarged perivascular spaces.” Cerebral small vessel disease (CSVD) increases with age and is associated with stroke and cognitive decline. Enlarged Perivascular Spaces (ePVS) is an emerging marker of CSVD, but its prevalence over the life span remains unclear. In a new study, researchers Frances Rodriguez Lara, Ashlea Lynn Scruton, Adlin Pinheiro, Serkalem Demissie, Pedram Parva, Andreas Charidimou, Michael Francis, Jayandra J. Himali, Charles DeCarli, Alexa Beiser, Sudha Seshadri, and Jose R. Romero from Boston University School of Medicine, Boston University School of Public Health, NHLBI's Framingham Heart Study, Veterans Affairs Boston Health System, University of Texas Health Sciences Center, and University of California at Davis characterized the age and sex-specific prevalence of ePVS and its relation to age-specific risk factors in a large community-based sample. “In this report we aim to describe 1) the age and sex specific prevalence of ePVS in a large sample of asymptomatic, community dwelling individuals, and contrast ePVS prevalence with the prevalence of vascular risk factors in the same age groups, and 2) study the association of vascular risk factors with burden of ePVS by brain region. This knowledge will help support the increasing number of studies of ePVS as a biomarker of aging and age related adverse neurological outcomes.” Full Press Release - https://aging-us.net/2022/09/22/aging-aging-prevalence-and-risk-factors-of-mri-visible-enlarged-perivascular-spaces/ DOI: https://doi.org/10.18632/aging.204181 Corresponding Author: Jose R. Romero - Email: joromero@bu.edu Keywords: neurological markers, aging, disease marker, perivascular spaces Sign up for free Altmetric alerts about this article: https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204181 About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/agingus​ LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Lenora Johnson, DrPH, MPH directs the science policy, engagement, health education, and public-facing communication initiatives of the National Heart, Lung, and Blood Institute (NHLBI) at the National Institute of Health (NIH). This office supports and coordinates the public facing messaging and information delivery channels on behalf of NHLBI. One of the many projects Dr. Johnson works with […] The post Building Trust with Each Audience (HLOL #226) appeared first on Health Literacy Out Loud Podcast.

This week, please join author Ambarish Pandey and Editorialist Linda Peterson as they discuss the article "Frailty Status Modifies the Efficacy of Exercise Training Among Patients with Chronic Heart Failure and Reduced Ejection Fraction: An Analysis from the HF-ACTION Trial" and the editorial "Heart Failure With Reduced Ejection Fraction (HFrEF): ‘The Importance of Being Frail.'" Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature article, Heart Failure Reduced Ejection Fraction in Evaluating the Efficacy of Exercise Training. But guess what? It appears it may be more efficacious in those that have high Frailty Index scores, as opposed to those that may not. But before we get to our feature discussion, let's grab a cup of coffee and go through some of the other articles in the issue. Would you like to go first? Dr. Carolyn Lam: I would love to, and this first paper is one that defines epigenetic biomarkers of lifelong cardiovascular health exposure and really contributes to our understanding of their roles in cardiovascular disease development. First though, a little quiz for Greg. So, Greg, what does DNA methylation mean to you? Dr. Greg Hundley: Well, Carolyn, DNA methylation. So, what I understand is these methyl groups get involved with our DNA and actually affect change over time that leads to phenotypic expression of, maybe, new traits. But I don't know. Maybe I'm not quite up to date. Dr. Carolyn Lam: Oh, you're perfect. Indeed, DNA methylation is a widely characterized epigenetic modification, which means exactly as you said. It's a regulatory modification to our DNA induced by environmental exposures and can affect gene expression. And this is the topic of today's paper by Doctors Zheng, Hou, and Lloyd-Jones from Northwestern University Feinberg School of Medicine and their colleagues. So, what they did is they studied blood DNA methylation at over 840,000 methylation markers measured twice over five years in participants of the CARDIA study. Epigenome-wide association analyses on a clinical cumulative cardiovascular health score were then performed in both CARDIA and compared in the Framingham Heart Study. Dr. Carolyn Lam: The authors identified 45 midlife DNA methylation markers associated with clinical cardiovascular health metrics, such as body mass index, blood pressure, blood glucose, and total cholesterol longitudinally measured since young adulthood. The methylation markers were located in genes involved in lipid metabolism, insulin secretion, and cytokine production, which could not be fully attributed to genetic factors. So, they proposed and validated in summary a methylation-based risk score to promote a personalized cardiovascular disease risk evaluation beyond traditional cardiovascular risk factors. Dr. Greg Hundley: Oh, wow, Carolyn. Interesting, a methylation-based risk score to promote personalized cardiovascular disease risk evaluation. Wow! That's really exciting. Dr. Greg Hundley: Well, I'm going to go to the world of preclinical science, and just like last week where we had a really nice article on myocardial regeneration, this week, we've got another. And so, Carolyn, early neonates of both large and small mammals are able to regenerate the myocardium through cardiomyocyte proliferation for only a very short period after birth. This myocardial regenerative capacity declines in parallel with withdrawal of cardiomyocytes from the cell cycle in the first few postnatal days. No mammalian species examined to date has been found capable of a meaningful regenerative response to myocardial injury later than one week after birth. Dr. Carolyn Lam: Interesting. Now, I see that these investigators worked with possums. Could you tell me why they did that, and what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So, this work was led by Dr. Wataru Kimura from the RIKEN Center for Biosystems Dynamic Research and their colleagues. The reason they studied possums, so the marsupial possum maintains cardiomyocyte proliferation and a capacity for myocardial regeneration for at least two weeks after birth. Remember we stated before, all the other mammalian species, it's only one week after birth. So, this appears to be the longest postnatal duration of such a capacity among mammals examined to date, and AMP kinase signaling was implicated as an evolutionary conserved regulator of mammalian postnatal cardiomyocyte proliferation. Dr. Greg Hundley: And they additionally found that in a separate mouse experiment, the authors noted that the pharmacological inhibition of AMP kinase signaling was sufficient to extend the postnatal window of cardiomyocyte proliferation in neonatal mice, so really exciting work in the area of cardiomyocyte regeneration. Dr. Carolyn Lam: Wow, indeed! And I've learned now about possums. Thank you, Greg. Dr. Carolyn Lam: So, Greg, have you ever asked yourself, what is the frequency, penetrance, and variable expressivity of dilated cardiomyopathy-associated gene variants in the general population? Well, guess what? This next paper addresses just that in more than 18,600 UK Biobank participants who had undergone whole-genome sequencing, ECG, and cardiovascular magnetic resonance imaging. Dr. Greg Hundley: Wow, Carolyn, another really interesting study from the UK Biobank. So, what did they find? Dr. Carolyn Lam: So, this study is from Dr. Chahal from the Center for Inherited Cardiovascular Diseases Wellspan Health in Lancaster, Pennsylvania and colleagues, and they found that approximately one in six of adults with putative pathogenic variants in dilated cardiomyopathy genes exhibited early dilated cardiomyopathy features potentially associated with the genotype. And it's most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction. Dr. Carolyn Lam: Among individuals with putative pathogenic dilated cardiomyopathy gene variants, ECG or CMR-detected early features were nearly four times more common than clinically manifest dilated cardiomyopathy or early features. Over 90% of subjects with these gene variants in dilated cardiomyopathy-associated genes did not have a prior history of dilated cardiomyopathy, and the overall clinical or subclinical penetrance of dilated cardiomyopathy-associated single pathogenic variants was highly variable between genes ranging from zero to 67%. And so, in conclusion, a genotype-first screening approach for dilated cardiomyopathy using a large genetic panel is currently not suitable in the general population due to incomplete understanding of the genetic architecture and reduced penetrance of the associated genes. Dr. Greg Hundley: Very nicely said, Carolyn. Wow! Well, let's take a look and see what's in the mailbag. And first, there's a Research Letter from Professor Huguenard entitled, “Frequency of Screening Detected Intracranial Aneurysms in Patients With Loeys-Dietz Syndrome.” And our own Bridget Kuehn has a really nice piece on Cardiology News. Dr. Carolyn Lam: Nice. There's also an On My Mind paper by Dr. Sattar, McGuire, and Gill entitled, “High-Circulating Triglycerides Are Most Commonly a Marker of Ectopic Fat Accumulation: Connecting the Clues to Advanced Lifestyle Interventions,” and an exchange of letters between Dr. Groothof and myself, Dr. Lam, regarding my article on “Efpeglenatide and Clinical Outcomes With and Without Concomitant SGLT-2 Inhibition in Type 2 Diabetes: An Exploratory Analysis of the AMPLITUDE-O Trial.” Dr. Carolyn Lam: Ah, that was awesome. Well, thanks, Greg. I am so excited to get to the future discussion that you queued us on so well, frailty in heart failure with reduced ejection fraction. Here we go. Dr. Greg Hundley: You bet. Dr. Greg Hundley: Welcome, listeners, to this July 12th, 2022 feature discussion. And we have with us today, Dr. Ambarish Pandey from University of Texas Southwestern Medical Center in Dallas, Texas, and Dr. Linda Peterson, an editorialist for this article from Washington University in St. Louis. Welcome to you both. Well, Ambarish, We're going to start with you. Could you describe for us basically the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address? Dr. Ambarish Pandey: Thanks, Greg, for having me on this, and thanks to Circulation for publishing our article. Yeah, I think the premise for this study stems from the longstanding known benefit of exercise training in patients with heart failure with reduced ejection fraction. Now, that was shown in the HF-ACTION trial, where individuals with chronic stable heart failure with reduced ejection fraction underwent exercise training, and there was demonstrated benefit in quality of life and adjusted analyses. There was a protocol-specified adjusted analysis that did demonstrate improvement in some of the key primary endpoint. Dr. Ambarish Pandey: Based on these results, CMS has approved exercise training and cardiac rehabilitation in patients with chronic stable heart failure with reduced ejection fraction. However, despite this mandate from CMS and generally well-accepted benefits of exercise training in heart failure with reduced ejection fraction, the uptake of exercise training has been pretty low, and there's a lot of heterogeneity in the improvement in outcomes that is associated with exercise training. Dr. Ambarish Pandey: So, we wanted to see whether frailty, which is a well-characterized syndrome of reduced physiologic reserve and impaired homeostatic tolerance to stressors and is common in patients with HFrEF, we wanted to see how frailty modifies the beneficial effects of exercise training in HFrEF. And based on the existing literature and some of the prior works we have done, we hypothesized that individuals who are frail and who have more functional impairments are going to have more targets for improvement in their functional status and thus would be more likely to benefit from exercise training. And we looked at this in the HF-ACTION trial itself and using the Rockwood Frailty Index and the difference in primary outcome and treatment effect of exercise among frail and non-frail individuals. Dr. Greg Hundley: Very interesting, so really sort of a look back in HF-ACTION data. Describe a little bit more for us that study design, and then specifically, what was the study population that you used to test your hypothesis? Dr. Ambarish Pandey: Right. So HF-ACTION was a randomized control trial multi-centered that was sponsored by NHLBI and was conducted in the early 2000s and basically focused on chronic stable patients with heart failure with reduced ejection fraction who have not had a hospitalization in the past six weeks and have ejection fraction less than 35% and class II to IV. And these participants were randomized in one-to-one fashion to getting aerobic exercise training followed by some home-based exercise versus the usual care. Dr. Ambarish Pandey: And in our study, what we looked at was we looked at the effect modification by baseline frailty status on the treatment effect of exercise training. So, we calculated the frailty index, which is a well-established measure of frailty using a Rockwood Index Model, and we stratified patients by frail versus non-frail status based on a Frailty Index cut-off of 0.21, such that higher index identifies more frail participants. And then, we looked at how the treatment benefit of exercise training on different outcomes was differential across the frail and non-frail strata. We looked at qualitative interaction, and we also looked at the Frailty Index, so the continuous variable to assess the benefits of exercise across the spectrum of frailty in the study population. Dr. Greg Hundley: And so, before we get to your study results, how many patients were in your study? Give us an idea of what was the range in age, and then also the composition of sex? How many men? How many women? Dr. Ambarish Pandey: Right, so this is really important because that's addressed to the generalizability of the study. So, the study included around a little over 2,100 participants. The mean age was 59 years. 28% were women, and 32% were self-reported black individuals with chronic stable heart failure. That was the demographic distribution. The age was slightly younger than what you've commonly see in observational studies with heart failure, and that is largely because the study recruited patients who were able to do exercise training and were able to do exercise tests with peak VO2 and peak VO2 peak excess capacity assessment at baseline and follow-up. So, that kind of selected for a slightly younger population. Dr. Greg Hundley: Very nice. And so, what were your study results? Dr. Ambarish Pandey: So our study results are, indeed, pretty interesting. We identified that around 60% of patients with chronic stable heart failure with reduced ejection fraction who were in the trial were actually frail based on the Rockwood Frailty Index Model. And we observed that among the study participants, the exercise training was associated with significant improvement in the primary composite endpoint of all-cause hospitalization or death in frail participants, but not in the non-frail or less fail participants. And there was a significant treatment interaction, such that baseline frailty modified the treatment effect of exercise training for the primary composite endpoint. Dr. Ambarish Pandey: Now, this was largely driven by a significant reduction in all-cause hospitalization among frail individuals who underwent exercise training, and not so much by an effect on mortality. And we did not see a significant difference in the mortality component of the primary composite endpoint across frail versus non-frail status participants. So, in a nutshell, baseline frailty did modify the treatment effect, largely driven by substantial reduction in the risk of all-cause hospitalization among frail participants more than non-frail participants. Dr. Greg Hundley: And before we get to Linda in her interpretation of your study, Ambarish, did you see the same effects in frail men, in frail women? And also, what about in individuals that might be a little older versus those that were perhaps younger? Dr. Ambarish Pandey: That's a really important question, and we were a little bit limited to do further subgroups because we are dealing with around, I think, 2,000 participants and we had frail, non-frail, and we did not do a further subgroup stratification by sex or by age. The age range was rather narrow. It's 58 years plus/minus 13 years, so we didn't really have a lot of older individuals above 75, something like what REHAB-HF Trial has shown in the news, a recent trial. Dr. Ambarish Pandey: We couldn't address the question of whether the effect modification was further modified by sex or age, so I think that's the two-level interaction. But I think that is something that would be interesting to test perhaps in a pool analysis of multiple exercise training studies, which is something we are considering. Dr. Greg Hundley: Thank you. Well, listeners, now we're going to turn to our editorialist, Dr. Linda Peterson, from Washington University in St. Louis, and, Linda, very provocative results here, heart failure reduced ejection fraction. And certainly, we like to go to things like cardiac rehab, but we're hearing this it seemed to make a difference if you were frail versus not frail. Dr. Linda Peterson: Right, I think that's an important distinction here in this article as Ambarish has so eloquently put forth, and it's especially important because other articles have shown in looking at the PARADIGM-HF Study and ATMOSPHERE it appears that one out of two patients with HFrEF are actually frail. And so, the magnitude of these findings and the importance of these findings is highlighted by that study. And this frequency of frailty is roughly double that of community-dwelling adults who are over age 90, so we're thinking of frailty usually as much older adults, but in HF-ACTION, actually, the patients' average age was 60 in the patients with HFrEF. Dr. Linda Peterson: So, there's almost an accelerated aging phenotype we're seeing here in a large proportion of the patients who have HFrEF. I think this has an enormous impact on a lot of the patients that we're seeing with HFrEF, and we should be alerted to looking for frailty and potentially screening for frailty. And I think another highlight of this study is that it points out the importance of frailty because frail patients have a 50% higher risk of hospitalization and death, according to some other studies, particularly one by Faray and their group and also by Yang and their group. Dr. Linda Peterson: And so, it highlights the importance of getting patients who are frail with HFrEF into cardiac rehab or getting them some sort of aerobic exercise training. But paradoxically, frailty is also associated with a lower likelihood of those particular patients on getting into cardiac rehab and also getting on goal-directed medical therapy. And that was shown by Phil Ades and his group. So, I think the importance of these findings by Ambarish and his group are to be commended, and they're very important for a large proportion of our patients with HFrEF. Dr. Greg Hundley: Very nice. Well, let's turn back to Ambarish, and then follow up with Linda. Ambarish, what do you see as the next study that should be performed in follow-up to your study? Dr. Ambarish Pandey: I think that's a great question. And I think we are just beginning to realize the magnitude of impact that frailty has in the care of patients with heart failure. And this goes across the spectrum of ejection fraction, both HFpEF or heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. Indeed, the burden of frailty is higher in patients with heart failure with preserved ejection fraction, and they are more of the accelerated aging phenotype. Dr. Ambarish Pandey: And I think the next study basically should look at a targeted approach to exercise training or category of intervention among patients who are most likely to benefit from it, which would be patients who have a high frailty burden or patients who have HFpEF. I think they go hand in hand when it comes to frailty and HFpEF. So, I think that's the next study to do is to see to what extent we can actually identify and target exercise training in the highest risk individuals who are most likely to benefit from it because that subset of highest modifiable risk is indeed identified by frailty and when you look at other subtypes by HFpEF which has a lot of high frailty burden. Dr. Greg Hundley: And, Linda, from your perspective, what do you see as the next study to be performed in this sphere of research? Dr. Linda Peterson: Yeah, I think this study really provides a springboard for future studies in HFrEF, in particular. One, what hospital interventions can be done in patients to get them moving more, and really assess is there a possibility of different types of exercises to get patients less frail even while they're in the hospital when they're enroute to going home? And then also, how do we have different mechanisms by which we can get more patients into cardiac rehab? Clearly, our national average of getting patients who qualify for cardiac rehab, which is a class I indication is 20% at best, and the aim from the AHA is 70%. Dr. Linda Peterson: There's a big gap there, so interventions looking at implementation and getting patients to cardiac rehab or looking at other types of aerobic exercise training, such as home-based cardiac rehab for patients who don't have a cardiac rehab center next to them, I think the field is wide open for different studies to springboard off of these findings. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Ambarish Pandey from University of Texas Southwestern Medical Center in Dallas, Texas, and our editorialist, Dr. Linda Peterson, from Washington University in St. Louis, for bringing us this research study, highlighting that among patients with chronic stable heart failure and reduced ejection fraction, that baseline frailty modified the treatment effect of aerobic exercise training with a greater reduction in the risk of all-cause hospitalization. Dr. Greg Hundley: 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. 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.

In Episode 64 of the Sarc Fighter podcast Mary McGowan, CEO of the Foundation for Sarcoidosis Research and Tricha Shivas, Chief Strategy Officer talk about an exciting new development that will make it easier to patients to find the right doctor, and for doctors to find the right methods to treat Sarcoidosis.    Show notes The New FSR Initiative https://www.stopsarcoidosis.org/foundation-for-sarcoidosis-research-launches-groundbreaking-global-rare-disease-initiative/ Learn about the clinical trial from Novartis: https://bit.ly/3o9LXKk The FSR Summit: https://www.stopsarcoidosis.org/events/fsrs-third-annual-virtual-sarcoidosis-education-summit-unveiling-possibilities/ The Mayo Clinic article: https://www.mayoclinic.org/healthy-lifestyle/stress-management/in-depth/how-to-be-happy/art-20045714 Calvin Harris Blog: https://sarcoidosisnews.com/2022/05/19/im-grateful-that-despite-sacroidosis-i-can-run-my-own-race/ aTyr Pharma News Release: https://investors.atyrpharma.com/news-releases/news-release-details/atyr-pharma-presents-clinical-data-efzofitimod-atyr1923-american Merlin: https://merlin.allaboutbirds.org/ Universal Barriers Podcast:  https://www.stopsarcoidosis.org/sarc-fighter-podcast/ More on Universal Barriers https://www.stopsarcoidosis.org/events/universal-barriers-in-dealing-with-a-chronic-disease-a-sarcoidosis-perspective/ Ignore No More https://www.stopsarcoidosis.org/ignore-no-more-foundation-for-sarcoidosis-research-launches-african-american-women-sarcoidosis-campaign/ Sarcoidosis Awareness Film: https://www.purpledocumentary.com/ Nourish by Lindsey: https://www.nourishbylindsey.com/ Dr. Jinny Tavee's book, The Last Day of Suffering: https://www.amazon.com/Last-Day-Suffering-Health-Happiness/dp/0615542751 Read about the patient trial with aTyr 1923 https://investors.atyrpharma.com/news-releases/news-release-details/atyr-pharma-announces-positive-data-phase-1b2a-clinical-trial Also -- Note that investors also believe in the promise of aTyr 1923: https://investors.atyrpharma.com/news-releases/news-release-details/atyr-pharma-announces-closing-863-million-public-offering Yale University and sarcoidosis skin treatment | Dr. William Damsky: https://news.yale.edu/2018/12/26/yale-experts-treat-severe-disfiguring-sarcoidosis-novel-therapy Stanford University Clinical trial | Dr. Mathew Baker: https://med.stanford.edu/sarcoidosis/clinical-trial.html MORE FROM JOHN Cycling with Sarcoidosis http://carlinthecyclist.com/category/cycling-with-sarcoidosis/ Watch the Prednisone Town Hall on YouTube https://youtu.be/dNwbcBIyQhE More on aTyr Pharma: https://www.atyrpharma.com/ Do you like the official song for the Sarc Fighter podcast?  It's also an FSR fundraiser! If you would like to donate in honor of Mark Steier and the song, Zombie, Here is a link to his KISS account.  (Kick In to Stop Sarcoidosis)  100-percent of the money goes to the Foundation.  https://stopsarcoidosis.rallybound.org/MarkSteier The Foundation for Sarcoidosis Research https://www.stopsarcoidosis.org/ Donate to my KISS (Kick In to Stop Sarcoidosis) fund for FSR  https://stopsarcoidosis.rallybound.org/JohnCarlinVsSarcoidosis?fbclid=IwAR1g2ap1i1NCp6bQOYEFwOELdNEeclFmmLLcQQOQX_Awub1oe9bcEjK9P1E My story on Television https://www.stopsarcoidosis.org/news-anchor-sarcoidosis/ email me  carlinagency@gmail.com   The following is an Internet generated transcript of the interview.  Please excuse spelling and grammatical errors. John Carlin: welcome back to the Sarc Fighter podcast. I am so pleased today to have the people that make FSR absolutely run and operate here as guests today to talk about this new initiative. Our CEO, uh, Mary McGowan and Chief Strategy Officer Tricia Chivas are both here. Welcome to the podcast. Mary McGowan: Thank you, John. It's always a pleasure to be a guest on your podcast. Tricha Chivas: Thanks so much, John. We're excited to talk to you today. John Carlin: So the email went out this week, and we're talking late June. In 2022, FSR has a new program that deals with how FSR will be recognizing endorsing recommending clinics. Mary, tell me how all that works and tell me the gist of this new announcement. Mary McGowan: John, we're so excited this, week to have announced publicly this really exciting new initiative called the FSR Global Sarcodosis Clinic Alliance. The whole concept of this is to bring hospitals and Sarcodosis clinics together globally in the fight against Sarcodosis. So we were thrilled the very first presentation that we did was in March. We were, uh, hoping to launch this in January, but due to COVID, we couldn't for, um, obvious reasons, because the clinics were so engaged in taking care of COVID patients. And in relatively very short period of time, we are so thrilled that we had 22 esteemed founding members join us as they learned about this. Um, and we're continuing to accept founding, uh, members through September to continue to grow this and work with them as part of a leadership council. And, um, so anyway, this all developed because we, uh, saw this opportunity to be able to connect more closely with Sarcodosis clinics and hospitals. And after we had the vision for this, we actually sent out a survey to clinicians across the globe. Uh, and they, too, verified this opportunity and this need for bringing us all together to share best practices and to network both at the clinician and patient level. And that is why, uh, we decided to move forward with this extraordinary rare disease initiative. John Carlin: Yeah, that is a lot, and there's so many things I want to unbundle here. But let's start with what are the ways that patients will be supported by this alliance? If I've got psychodosis, how does this help me? Mary McGowan: Well, we want to ensure in every community across the globe that Sarcoidosis patients have access to the most up to date, uh, Sarcodosis information, education and support services. So what we're going to do is, through, uh, an application process, we're going to have Sarcoidosis patients apply to be peer led support group leaders. And we're going to host support group meetings monthly, uh, at institutions throughout the globe. In addition to that, some of the, uh, volunteers will receive training on how to be community educators and how to work with the media so that we can amplify, uh, the messaging about Sarcodosis about this rare disease throughout local communities, again, around the globe. So we're really excited to be recruiting for these leadership positions, and we're, uh, going to have ongoing trainings that are going to support these leaders and also provide opportunities for these leaders to network with each other. In other words, the, uh, other leaders across the globe in this effort to, uh, be able to provide these kinds of support services to patients. John Carlin: So these leaders will be patients? Mary McGowan: Yes, these leaders will be patients. We believe very strongly at FSR in the peer led leadership approach because it's, uh, really the patients who have the best understanding of what it's like living with Sarcodosis. And if we can empower them to, uh, be leaders of the support group sessions, then we believe that that has the strongest impact. John Carlin: And do you foresee in a post covered world of these support groups would meet in person? Mary McGowan: Yes, we do hope that they will be meeting shortly in person as the, uh, world hopefully continues to try to get back to normal and as we, uh, continue to fight Cobid and its forces, we do hope to have these in person. And up until the point when they can't be in person, we will be doing these virtually. John Carlin: And you did ring one of my bells when you said media training, how to deal with the media. Mary McGowan: Yes. John Carlin: Maybe I can help you with that. Mary McGowan: We, uh, would love that, John, of course, because, uh, we want to make sure that our volunteer leaders feel comfortable working with the media and, uh, have an opportunity, uh, to rehearse their talking points and again, empowering them so that they can empower others in their local communities. John Carlin: Got you. So there's 22 of these centers. That is center the right word? We're going to call somebody who's one of the 22. Mary McGowan: We're calling them founding members of the FSR, uh, Global Clinic Alliance. John Carlin: Alliance. Alliance members. Alliance members. Got it. And there's 22 alliance members. But that's all around the world right now, as you and I are speaking on June 24, 2022. Mary McGowan: Yeah. So right now, the 24 that have joined are from the United States. We are, uh, doing a webinar in July to invite all clinics globally, from around the world to the webinar about the alliance. And we're hoping, uh, at that point, that we will then have an opportunity to introduce this to International Sarcodosis, uh, Clinic Alliance potential members and have them join also as a founding member, I. John Carlin: Know because I've talked to so many doctors in other parts of the world through the podcast that FSR has got a long reach. So I don't anticipate that. I think, uh, it's going to be very popular in other parts of the world. Mary McGowan: We agree. And we're very excited to be working with our International Clinic, uh, future, uh, members. John Carlin: Right. I got you. So now, we talked a little bit about the patient side, but this has a big upside for the doctors, the researchers, the clinicians, I guess, is the proper term. Uh, what is the clinician facing program that the alliance offers? Mary McGowan: Well, there are several. I'll highlight a few. First of all, we believe, and we also confirmed again through the survey, that there's a real desire for these clinicians to have an opportunity for peer case review for, uh, cases that they have. Sorkidosis cases. So we're providing a platform for these peer case review sessions so, uh, that the clinicians can share the information and can get guidance, uh, and advice and input from other clinicians at other clinics, uh, worldwide. So that's one, the other one that we're really excited to be launching is a journal club, and we believe, uh, a, uh, Sarcoidosis specific journal club that's going to be supporting early career professionals and also encourages clinicians to stay up to date on Sarcodosis, um, medical literature, uh, is really going to be very effective. And again, an, uh, opportunity to bring these experts in these global clinics together to learn and talk about these journal articles. And then finally, we're also providing clinical, uh, engagement and education through, uh, our Clinic Engagement series. We just held our conference on June 15. We had, uh, I think, nine different countries that were represented over, uh, 100 registrants. And we had Dr. Menza from the NHLBI, who was, uh, the keynote speaker at this, um, really exciting conference. So we're going to be doing these quarterly, uh, and again, it's an opportunity to bring clinics together globally, to stay up to date on research and other topics around orchidosis care, education, research and support. John Carlin: I guess the end goal for all this, because when I'm talking to patients on the podcast, what they're saying is, I go to my local doctor and they've never heard of Sarcoidosis. This would be the beginning of a way to fix that, right? Mary McGowan: Correct. That's our belief as well. We do know, uh, that, again, uh, awareness is large, not only in the general population, so that if an individual does have psychedosis, uh, and has signs and symptoms of Sarchidosis, that they can bring that up to their doctor, hopefully for a shorter time period for an accurate diagnosis. But also to your point, John, from the clinician standpoint, again, there are, uh, so many rare diseases, and we want to make sure that Sarcodosis is front and center with clinicians, uh, and again, for the opportunity, uh, for a more timely, uh, accurate diagnosis, which, of course, can be lifesaving. And this is, um, critically important. And FSR beliefs strongly in making sure that we are working as hard as possible to bring this awareness to clinicians, uh, as well as to patients themselves. John Carlin: Basically, what this is infrastructure that's going to have doctors talking to each other more, sharing their research, sharing their best practices, sharing their success and failure stories, so that more doctors and more places are conversing about Sarcoidosis and understanding best practices, best paths forward, making patients have better outcomes. Mary McGowan: Absolutely. Beautifully said, John. Thank you. John Carlin: Okay. All right, well, that's my job. I like distilling stuff. First, I want to ask you, I know that FSR has been doing, uh, some stuff with the National Institutes of Health, and there really is some momentum now to get some federal backing for some of the things that FSR is doing and for Sarcodosis related research from the government, which we never have had before. Tricha Chivas: Yeah, thanks, John. We've been working really hard to grow relationships with the National Institutes of Health. And one of the ways that we've been doing that is to make sure that we are engaged in different institutes at the National Institutes of Health. So there's a lot of different institutes that have a particular focus. So Mary mentioned earlier that we had a session with Dr. George Menza, um, from the NHLBI, which is the National Heart and Lung and Blood Institute. And that is one of the, uh, areas, um, that has been a big focus for where Sarcodosis has been in the past. But we're also focusing in other areas, such as in the, um, environmental health studies area. So there's an institute that focuses on environmental impact, since we know there may be some environmental causes to Sarcodosis, um, and making sure we're part of that. We've been working with the organization that focuses on arthritis, um, and musculoskeletal disease and skin disease. Right. So we know there's different manifestations of psychosis, and we're having conversations now at all of these different spaces. In fact, this year in February, um, you may recall that FSR was able to participate in the NIH Rare Disease Day by having a panel, um, there. So really kind of activating and showing the NIH again, what we are doing and why the work that we're doing is so critically important in this space. And these are conversations that we're continuing. But in addition to the NH, we've also started working with the FDA on a number of different things in order to draw more attention from that federal level as well. John Carlin: And are we making some progress with respect to this work? Tricha Chivas: Yeah, so very excitingly. We just had a FDA patient listening session, uh, on pulmonary Sarcoidosis. This is a really, um, unique opportunity for FSR to get directly in front of the FDA and many, um, members of the FDA. We had 50 attendees at this session. It was a very well attended session, representing a lot of different institutes at the FDA. And for all of your listeners. I know everybody is a little, um, bit more familiar with the FDA now after cobid, but the FDA approves drugs, but they also, um, approve technologies that are being used for diagnosis. And they also, um, can help with the process, um, for repurposing drugs. So they have a number of different angles that we wanted to highlight that tie into the work and the needs of our patient population. And so what we did was we had this listening, um, session, which is a closed session, we weren't able to have that available to the public. That's the rules of the session itself. And then we had patients that came together, shared their stories. We had six patients, one caregiver. Mary shared a bit about things that we had learned from the community on this. And then, um, Dr. Lisa Meyer, who had provided the clinician perspective. And so that was our, uh, main goal was to get that information out. And these were really passionate stories that reflected what we heard from the community. John Carlin: So what would actually happen in a listening session? The doctors are listening to the patient's talk and see how Sarcidosis affects their lives. Tricha Chivas: Sure. Great question. So basically, it's an hour and a half long, um, meeting, and you have all of these different folks at the FDA who are making decisions about how drugs are approved or how technologies move forward. And we wanted to give them a chance. A lot of them are very scientific and don't necessarily have the chance to truly understand the patient experience. So, um, what this is, is a chance for them to understand how Sarcodosis is impacting individuals daily lives. What were the challenges that people faced with diagnosis, um, where did the technology, um, fail? And why do we need different technologies that might be able to do a better job, to do better at diagnosing? Understanding the drug, um, development process from the patient perspective would have been the barriers or challenges. So we raised issues there about diversity and, um, the challenges for diverse populations to be involved. We raise challenges for the drugs that are currently available, not adequately addressing the needs of, um, those living with Sarcodosis. So steroids is actually FDA approved in Sarcoidosis. And so that is oftentimes, um, a go to, as I know you've talked about many times on the podcast, a go to for clinicians as they're moving forward because it's cheaper there, um, are ways that it does work sometimes for some patients, but the cost was also something we reflected in those stories. So the stories were individual people sharing how all of those different things came to play. John Carlin: Um, if nothing else, Sarcodosis is on the FDA's radar now, right? Tricha Chivas: Yes. John Carlin: There's so many orphan diseases and everybody's clamoring to be recognized, but it sounds like, thanks to the work of FSR, that's happening now. Our voice is a little bit louder, 100%. Tricha Chivas: We are on the, um, radar, and we have some really exciting things that are going to be coming out as a result of that. And Mary, I don't know if you wanted to share some of the things that were coming out as a result of what we did with the listening session. Mary McGowan: Absolutely. So after the listening session took place, we started creating, uh, a white paper that have a little bit more details on the session. And we're going to be launching the white paper in mid July. In addition to that, we're going to be hosting a community webinar in August, because we're so grateful to the community. I think. You know, John, our approach at FSR is always about engaging the community in our efforts. So, in preparation for the FDA patient listening session, we sent a survey to our clinicians, to all of our patients, and to our industry partners, because we wanted to get, uh, what they thought was the important messaging to send to the FDA. And that's how we came up with our messages. That's how we came up with the patients who had those stories that, uh, reflected those messages. And so we want to give back to the community and share the results of the survey and share the details of this really milestone event for FSR that took place. In addition to that, we are, um, also now working on the possibility of hosting a patient focused drug development session sometime later next year. And these sessions are much larger. They are open to the public, and they are important for advancing clinical trials and drug development. So we're really excited about that. And at the same time, we're also exploring conducting additional patient listening sessions and other manifestations, such as neurosychotosis or cardiac sarcoidosis to deepen the FDA's understanding, uh, and needs of those living with this complex disease. John Carlin: Yeah, when you, uh, say neurosark, I'm so happy to hear that. I'm an orphan among orphans as the neurosark representative. So I'm, um, glad that that's getting spotlighted, uh, a little bit. Mary McGowan: Uh, absolutely. John Carlin: Yeah. All right, so now we got clinical trials, and it does seem like there's a lot more going on right now with clinical trials and trisha. Can you bring us up to speed on what's going on with that? I've talked to several different people, and I know there's a bunch of pharmaceutical companies out there, so can you kind of let us know where we are with that? Tricha Chivas: Yeah, 100%. So this is a really exciting time as far as clinical trials goes in sarcodosis. In the past, we've had, um, one clinical trial running at a time, or many times even no clinical trials running in our space. But right now, um, there is a lot of interest and engagement in the clinical, um, trial space. And as you know, SSR has done a lot of background work to try to make sure that this is really possible for pharmaceutical companies to come into this space. So what's important and what we have done is we've made it so that they understand there is an eager population that's interested in clinical trials that wants more and new drugs, and helping to do that education on the back end for them. And then, in addition, we have really worked very closely with pharmaceutical partners, getting them access to, um, some of the key opinion leaders in the space, some of those expert clinicians that are out there so that they could have really good conversations and understand a little bit more about how their drug might work, whether it's a good fit for the clinical practices that they're trying to meet. And then in addition to that, we've worked really closely with the patient, so we know that patients are, um, interested, so we want to make sure we're getting that in front of them. And so we put in place a system that allows for people to know about clinical trials that are going on. So we do a lot of marketing and advertising, um, for that, for patients, so they can get involved if they're interested in being part of that process. And I'm really excited to share with you that we have seven sponsored clinical trials underway right now. And so, remember, I said there was about one or two happening, staggering over in the past. And now, um, we have seven potential clinical trials that are starting off. And just to clarify for your audience very quickly, when we're talking clinical trials here, we're talking pharmaceutical sponsored or biotech sponsored clinical trials, which are the ones which will end up resulting ultimately in a new drug. And so we have the academic studies which are building all the background for that, and they continue. And those are very important, but these are the ones that are getting much closer to getting that new therapy available for patients. John Carlin: Seven. Tricha Chivas: Seven. John Carlin: That's amazing. Just in the time that we've been doing the Stark Fighter podcast, I think, like you said, one or two, and that was reason to celebrate. And now, a couple of years later, it's up to seven, potentially. And that could result in seven new drugs that patients could take. And the farther you can get those of us who are patients away from steroids, the happier we all will be. Tricha Chivas: Exactly. Yeah. So it is a really exciting time. If anybody does want to know more, um, about clinical trials, please reach out to us, how they work. We're happy to give more background information, but this is the moment where we hopefully can get more and more engagement and more excitement around this. And this is why partly, we're talking to the FDA as well, because it's very important for us to continue those conversations. John Carlin: So anything else happening that listeners should know about? Tricha Chivas: Sure, yeah, there's a lot going on in research right now. Um, thank you to everyone who has supported all the research efforts that we have. FSR has been taking our research funding worldwide. You may know that we have funded over, um, $6 million worth of Sarco Dosis specific research efforts. And last year, we gave out about $200,000, uh, in research grants to academic researchers. This year, we're poised to give out over $300,000 in research funding to our academic researchers. And so this is really an exciting time. We just, right now, are in the final wrap up stages for our fellow that's going to be coming out this year. So we have received those applications and are finalizing the announcement, so keep an eye out for that. And very excitingly, we have grants that just came, um, out, uh, specifically for, um, pilot grants, which are early background kind of information studies that can help make it possible for researchers to get bigger funding to move the needle forward, and a new grant, which we have not had up until this point specifically available for cardiac sarcidosis, and we had an incredible amount of engagement around that. John Carlin: Yeah, so let me ask you about that. How excited are the researchers, Mary, uh, for this opportunity? Mary McGowan: Really very exciting, and I think it builds off the momentum that Trisha has been talking about, just about the interest in clinical trials and in research in the sarcodosis space. Again, we received the most applications ever for our pilot grants, and we received a very high number of cardiac sarcodosis grants, by the way, which was made, uh, available through a very generous donor to FSR, and wanted us to be providing funding, uh, specifically for cardiac sarcodosis. So we are so grateful to donors who allow this type of, uh, funding for additional support and research for, uh, sarcodosis. But I think all of this combined, John, is really building on this tremendous momentum for sarcodosis. Again, we see it at the FDA, we see it through the Clinic Alliance, we see it through research, we see it through the patient engagement, and it's just such an exciting time to really be moving the needle forward for sarcoidosis. We have our upcoming Patient Summit, uh, and thank you for your leadership, uh, as part of the Patient Advisory Group. And you all coming up with the title of Unveiling Possibilities Moving forward. And really, this is just what is happening at foundation for Sarcoidosis and for sarcodosis globally. And it's most exciting. John Carlin: Yeah. Tricia, do you want to add anything to that? Tricha Chivas: I don't have much to add, uh, except to say that we are also very, very excited. I know that the, um, conference itself is something we're very excited about. There's a lot of opportunities for us to engage around the conference. If you have not attended, um, an FSR conference, this is virtual, it is available. Last year, we had many individuals from all over the world participating in this. There's opportunities for networking, there are opportunities for engaging with global experts. So, um, whether you're brand new or you've, uh, had sarcodosis for a little bit of awhile, we'll have different tracks that can help you learn a little bit more about what's happening in the disease or what you need to know. And then we also have these great tracks that came out of the wonderful theme that you came up with that's really focused specifically on things, um, like understanding your, um, finances, how to talk to your clinician, how to engage and learn, um, from others when you're trying to navigate the symptoms of your disease kind of life hacks, as it were, in order to think about things. So we're really excited about, um, that coming up and what that conference is going to be when we invite all of you to join us. John Carlin: Yes, the summits are wonderful, and I hope we get back to a point where they're in person again. Hopefully, we, uh, can get the pandemic behind us, and that's just my thought, just thinking, um, out loud, the networking opportunities, I think, are as good as they are virtually. I'm hoping that eventually we um, can all kind of meet in person. Because every time I've been for work to an event, you learned, uh, as much having a beer after the day, sitting around with your fellow conference as you do in the conferences themselves. Mary McGowan: Right? Tricha Chivas: And I think that's one of the things that will be another benefit coming from the Clinic Alliance is that um, opportunity for um, more local level engagement, uh, with others. And that is definitely something we want to be focusing in on as we move things forward there. John Carlin: Got you. So let me shift gears a little bit, Mary. Last year, early this year, there was some really exciting programming, uh, focused on increasing diversity. I was involved in some of that and inclusion with respect to uh, sarca dosis. How will FSR be continuing that work? Mary McGowan: Uh, John, this is such an important area for FSR. We believe so strongly in diversity and inclusion in everything that we do at FSR. But we were so thrilled, uh, with the very successful results, uh, of the Ignore No More Campaign. This campaign was focused on African American women and sarcoidosis. It was just an incredible reach with over 500,000 media impressions. We were so thrilled to have Gerald Prescott Galen, who's an actress of AMC's Walking, uh, Dead, and Bets All the Queen's Men. She's been living with sarcodosis for many years, but most recently was diagnosed with cardiac sarcodosis. She's been an amazing PSA for us that got over 1000 views in just one month and really helping to amplify our uh, messaging about this really critically important, uh, work. As you know, African American women have the highest prevalence of sarcodosis and by far the worst outcomes. And so it's important that the African American, uh, community understand this and also that clinicians understand this. And so that's what this was really uh, all about. This campaign. We're um, really excited as part two, we've just gotten uh, funding for uh, a part two campaign that's, uh, going to be called Ignore No More Act. Now act stands for Advanced Clinical Trials, Equity in Sarcodosis. And this is really going to be taking a deeper dive into how we um, can support and encourage clinical trial participation, uh, among all African Americans. Um, and our goal is to really learn from the community and to create strategies that can be captured in white paper, uh, and will be helpful tool for, again, both academic as well as, uh, industry sponsored trials. And we're really excited to be, as part of this campaign, hosting a congressional briefing to drive change at the federal level. So I hope listeners stay tuned for this really exciting expansion of this national campaign, and thank you for asking that question. We also have a Chance Zuckerberg initiative going on. I'll turn it over to tricia. She's been working very closely with the Chan Zuckerberg group, uh, on this exciting diversity campaign as, um, well, yeah, so. Tricha Chivas: The Chanceuckaberg Initiative, I think it's really important to say, for the community. So everyone knows this has been not just a grant and then the work that comes, uh, out of that, but this has really afforded FSR a lot of other opportunities for advancing and growing the skill sets of the staff, for reaching out and understanding from others that are in the network, um, best practices that they're using that we can, uh, then bring back to our community. So this has really afforded us a lot of opportunities in order to expand and grow and move things forward for those living with Sarcoidosis, which is our ultimate goal. The actual grant itself will be looking to work with clinics. So, um, members of the alliance, or, um, others that will be working with those clinics and helping to improve the diagnostic, um, and what we'll call the referral pathway. And what I mean by that is the ways that you get from your local doctor, your, um, local pulmonologist, or your local generalist to those more expert, uh, care. And what is that pathway? Um, and how do we really define that so that we can, again, reduce the amount of time for diagnosis and improve the pathway for treatment, especially if someone's living more rurally and they don't have that kind of connection to a more urban center that might be more, um, advanced in this space? John Carlin: I've never heard of that term before, the referral pathway. And you, um, guys are so good at sort of finding terms because you see this stuff all the time. The individual patient that lives in the middle of north or South Dakota or some rural area, in fact, not too far from where I live here in Virginia. That's what they talk about. They say my doctor had never heard of sarcle dosis before. Um, I'm not in a real large urban area, but we do have a large clinic here. People drive 4 hours to get to where I am in Roanoke, Virginia, for care, because we're the big medical center in this part of the world, right, serving the western half of the state of Virginia. But even here, there are very few Sarca doses patients. I might have been one of six for my Rheumatologist doctor, which is not the same as, um, going to Cleveland Clinic, which is what I ultimately decided to do, where I'm dealing with a center where that's all the doctor sees. So that's not so. That term is a referral pathway, and you're trying to sort of take that from being a rural road to an interstate to get you to that doctor quicker. Tricha Chivas: That's all right. I think for us, what we're trying to do is help to identify those areas where patients are being seen and create a kind of a conversation both ways from, um, the major centers to some of those more local level individuals that are, um, supporting individuals living with Sarcodosis, and then, um, also allowing an opportunity for them to have that conversation back. And because a lot of times, even as you're going to Cleveland Clinic, John, you still have the local doctor that you're going to want to talk to, and giving that kind of conversation, allowing them to get the kind of education they need. And then when a case is more complex or they need more support, they can have that support that way. And that's what we're trying to build. John Carlin: Awesome. So, so many exciting things. Mary, what else can listeners look forward to as we move forward over the next few months? Mary McGowan: Well, we have so many exciting things that we've been talking about going on at FSR. Tricia and I are continuing to speak internationally at different conferences. As a matter of fact, in just two weeks, we're headed to Boston. We're both going to be speaking at the World, uh, Orphan Drug Congress, which is really exciting. It's a very large conference, and it's wonderful to have Sarcoidosis being represented, uh, there at that conference. So we're really looking forward to that. Uh, I think also the viewers, if they want to stay in touch with us in terms of the Clinic Alliance and its growth, if, uh, anybody is being treated at the center or alliance that is not on our web page and would like to share contact information, please, uh, let us know, because we want to ensure that we are reaching out, uh, to everybody to offer this opportunity to bring them into this really extraordinary, uh, unique effort. And also, please sign up for our patient conference, um, July 30 and 31st. It's going to be so exciting this year. Last year, we had over 300 attendees from around the world, so we're really looking forward to a really exciting conference this year as well. So those are just a couple of other events. We have some other events on our web page that are coming up. Uh, we have a couple of, uh, painting sessions, so I would encourage anybody who's listening to please join FSR if you have not, all you, uh, simply do is fill out a quick form with your email and that helps you stay up to date on all of our different events and activities. John Carlin: Okay, so I've got a note here to ask you about life, uh, hacks and living with Sarquoidosis. So how will patients be able to take advantage of those or find out what those are? Tricha Chivas: Sure, I'll jump in if that's okay. Mary. Mary McGowan: Great. Tricha Chivas: The life hacks things that we're trying to do here is learn from folks like you, John. Like, what do you do when the fatigue is overwhelming? Or what do you do when you're just having a really painful day? Or what are those things that you're doing? Life hacks are the tips and tricks that people have used in their own daily lives to navigate the disease and learning from individuals that are living with the disease to, um, do that. So this is going to be one of the exciting kinds of sessions that we're having this year are, um, beyond all of our wonderful chat boards and we have a coffee break that's open and chatting. This session is a chance for people to talk back and forth with one another, um, and share how, um, they are managing their day to day. John Carlin: Got it. Life hacks. I love it. And so can people now sign up? Is there not a discount if you sign, uh, up early? How's that work? Early bird? Is that how that works? And how long is that available? Mary McGowan: Early bird registration right through the end of the month. So it's a great opportunity. And there's also, John's, scholarships that are available. So for people who want to attend the conference, uh, there is a registration fee, but we want to make sure that there are no barriers to anybody joining this conference. So if anybody needs financial assistance, there's information there as part of the registration as well. Uh, and so, please, we, uh, want to be able to ensure that everybody has access to attending this really important educational, global event as part of that. But, yes, please pay attention to, uh, the early bird registration, uh, as well. John Carlin: Got you. And if somebody can't afford it, but they want to be there, we'll find a way to make it happen. Mary McGowan: That's absolutely correct. We want to make sure that everybody has access again, uh, to support education, opportunity to ask questions, all the networking that takes place. We understand that this is critically important to bring people together, living with Sarcoid doses to support one another. And that's what this patient conference is all about. John Carlin: Uh, well, guys, look, we've covered a lot in a short amount of time. I'm just thrilled to have had both of you on. But more than that, thrilled to hear about all the momentum, uh, on all the different fronts. So congratulations on just really getting Sarcudos out there and advancing the cause you really deserve. Kudos. Mary McGowan: Well, thank you, John, and thank you for all that you're doing. These podcasts just really help, uh, to, again, amplify the messaging, the incredible interviews that you've done, the highlights of the campaigns that you continue to do. We are so grateful to you for doing this incredibly important work and sharing, uh, this information worldwide. And so you're, uh, part of the great success, uh, that we are all having, as well as all of the patients, the entire Sarcodosis community. It's everybody working, uh, together to spread the word, to spread the awareness, to engage in initiatives. And this is really the result of everybody's success in working together, um, building this momentum. And we're looking forward to the near future to continue to see great successes on the continuation of this momentum building so rapidly now. John Carlin: All right, well, thank you all very much. Tricha Chivas: Thank you so much. Mary McGowan: James on. Tricha Chivas: We appreciate it.    

Let's be honest, technology is not something our parents even thought about. There was a TV and that was it. In this week's episode we discuss all the different screens available and the effects it may or may not have on kids. Whitney and Britney are on two completely different sides when it comes to how much technology their kids are allowed to have. Bet you can't guess which one is rigid and which one is lax. Follow us at Instagram: https://www.instagram.com/slightlycrunchymomcast/ If listening on Apple Podcast please rate us, it helps us out! Questions? Comments. Topic ideas! Please feel free to contact us at: slightlycrunchymomcast@gmail.com. We would love to hear from you! Like what you hear? Buy us a beer to support the habit!!! Donate at https://www.buymeacoffee.com/slightlycrunchy. Donate 10 beers and you will get an original song in your honor! Resources: Reduce Screen Time, NHLBI, NIH Screen time and children: How to guide your child - Mayo Clinic Screen Time and Children (aacap.org) Tips for Reducing Screen Time, Reduce Screen Time, NHLBI, NIH Erikson-Institute-Technology-and-Young-Children-Survey.pdf The Negative Effects of Technology on Children and What You Can Do (nu.edu)

About Teonna Woolford and Sickle Cell Reproductive Education Directive: Teonna Woolford was born and raised in Baltimore Maryland. She has always been talkative, friendly, and full of life. She has Sickle Cell Anemia SS and has faced numerous health complications as a result. A true fighter at heart, she has recovered from numerous complications including bilateral hip replacements, a failed bone marrow transplant, many pain crises, and several other complications. She has a zeal for effecting change throughout the Sickle Cell community and understands the realities of those impacted by the disease. While sickle cell has been a huge part of Teonna's life, she does her best not to let sickle cell define who she is. Teonna has had opportunities to discuss sickle cell advocacy with world leaders including Former First Lady Michlle Obama and Congressman John Lewis. She has been blessed to sit at some incredible tables and contributed to publications and working committees with the American Society of Hematology and NHLBI. She is also the founder and CEO of a new nonprofit organization, The Sickle Cell Reproductive Health Education Directive. Sickle Cell Reproductive Education Directive (SC RED) was conceptualized in 2020 and established as a 501c3 nonprofit on April 8th, 2021. Our co-founder and CEO, Teonna Woolford sought to create the organization because she felt defeated by fertility struggles after a bone marrow transplant. When researching and seeking resources for fertility preservation, she found very little information about fertility and sickle cell and no resources to help pay for the costly procedure. Teonna reached out to Dr. Lydia Pecker, a pediatric hematologist, about starting an organization that could provide fertility preservation grants to sickle cell warriors undergoing curative therapies. Dr. Pecker, whose research areas include fertility and reproductive health of sickle cell patients, was excited to hear Teonna's vision and agreed much more needed to be done to improve both policies and health care practices. World-renowned hematologist Dr. Kim Smith-Whitley joined the cause after meeting Teonna at a conference where she presented on the reproductive health needs at different stages of life. Together these three powerful women founded an organization that advocates for high quality reproductive health care for individuals living with all types of sickle cell disease.

Dr. Stephen Johnston, Ph.D. (https://biodesign.asu.edu/stephen-johnston) is the Director for the Center for Innovations in Medicine, a Professor in the School of Life Sciences, and Director of the Biological Design Graduate Program at The Biodesign Institute at Arizona State University. Dr Johnston is also Founding CEO and Chairman of the Board Of Directors of Calviri (https://calviri.com/). The Center for Innovations in Medicine and Dr. Johnston's current work focuses on innovative solutions to fundamental problems in bio-medicine, and their organization brings together a unique group of interdisciplinary scientists to identify, analyze, and come up with inventive solutions for significant un-met medical needs. Current major translational sciences and technology development projects of Dr. Johnston include 1) Cancer Eradication: with a focus on developing a universal, preventative cancer vaccine, and 2) Health Futures: with an aim of producing a diagnostic system that allows continuous monitoring of the health status of healthy people - helping in the revolution to pre-symptomatic medicine. Dr. Johnston has broad experience in basic science, including cloning the Gal4 gene, showing that proteins have separable functional domains, and discovering the ATPases Associated proteins and their role in transcription. He was also co-inventor/innovator of pathogen derived resistance, organelle transformation, the gene gun, genetic immunization, Tobacco Etch Virus protease system, expression library immunization, linear expression elements, synbodies and immunosignaturing. Dr. Johnston is author of over 150 journal articles, has over 20 patents, and has garnered approximately $85M in grant support including large programs from DARPA, NIAID and NHLBI. Dr. Johnston has a B.S. in Molecular Biology and Ph.D. in Genetics and Plant Genetics/Plant Breeding, from the University of Wisconsin-Madison, and did Postdoctoral work in Biochemistry at Penn State University Medical Center.

  Episode description: We talk about sleep culture, why your body needs sleep, and what happens when you don't get enough sleep  Keywords: Sleep and weight loss, lack of sleep weight loss, lack of sleep effects, side effect of no sleep,  Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion - PMC (nih.gov)  In U.S., 40% Get Less Than Recommended Amount of Sleep (gallup.com)  Sleep Deprivation and Deficiency - What Are Sleep Deprivation and Deficiency? | NHLBI, NIH  Shechter A, Grandner MA, St-Onge MP. The role of sleep in the control of food intake. Am J Lifestyle Med. 2014;8(6):371-374. doi:10.1177/1559827614545315. St-Onge MP. The role of sleep duration in the regulation of energy balance: effects on energy intakes and expenditure. J Clin Sleep Med. 2013;9(1):73-80. doi:10.5664/jcsm.2348.  Find us at: Home - Tricia Stefankiewicz (triciard.com)   

In this episode, Ayesha shared insights she obtained from experts at NIH's National Heart, Lung and Blood Institute (NHLBI) about clinical trial diversity. The panel of experts outlined some of the challenges in recruiting participants from minority and disadvantaged socioeconomic backgrounds, and talked about an NHLBI initiative based on community outreach that helped recruit more participants from traditionally underrepresented groups for COVID-19 vaccine trials. The editorial team also talked about the theme of this year's World Health Day 2022, which is “our planet, our health.” The theme relates to new WHO data that shows most of the world is breathing polluted air. This is of great significance and concern as environmental causes are a leading cause of death worldwide. Learn about the initiatives and updated guidelines that the WHO has issued to help address the worsening quality of air globally, and hear our team's thoughts on how environmental responsibilities should be shared.Read the full articles here: Xtalks Voices: NIH Experts Share Insights on Increasing Clinical Trial DiversityWorld Health Day 2022: WHO Data Shows 99 Percent of People Breathe Poor Quality AirFor more life science and medical device content, visit the Xtalks Vitals homepage.Follow Us on Social MediaTwitter: @Xtalks Instagram: @Xtalks Facebook: https://www.facebook.com/Xtalks.Webinars/ LinkedIn: https://www.linkedin.com/company/xtalks-webconferences YouTube: https://www.youtube.com/c/XtalksWebinars/featured

Listen to Dr. Nehal Mehta, Senior Investigator at the NHLBI, discuss how psoriasis can affect cardiovascular disease risk

National Heart, Lung, and Blood Institute CIO Alastair Thomson returns to HealthCast to discuss updates on the new BioData Catalyst program — an open-data cloud platform where researchers can access and bring their own data in to advance research. Since the platform has gone live, Thomson shares how it is making a difference in biomedical research.

Welcome to PICU Doc On Call, a podcast dedicated to current and aspiring intensivists. My name is Pradip Kamat. And my name is Rahul Damania, we come to you from Children's Healthcare of Atlanta/Emory University School of Medicine. Today's episode is dedicated to Noninvasive and Invasive ventilation in children post-hematopoietic cell transplantation. We are delighted to be joined by Dr. Courtney Rowan, MD, MSCR, Associate Professor of Pediatrics, and the Director of the Pediatric Critical care Fellowship at Indiana University School of Medicine/Riley Children's Health. Dr. Rowan's research interest is in improving the outcomes of immunocompromised children with respiratory failure. She is active in this field of research and has led and participated in multi-centered studies. She is the co-chair of the committee of the hematopoietic cell transplantation subgroup of the Pediatric acute lung injury and sepsis investigators network. In our podcast today we will be asking Dr. Rowan about the findings of her recent study published in the journal-Frontiers in Oncology reporting on the risk factors for noninvasive ventilation failure in children post hematopoietic cell transplant. She is on twitter @CmRowan. Patient CaseI will turn it over to Rahul to start with our patient case... A 15-year-old female with a history of AML s/p Allogeneic hematopoietic stem cell transplantation T+15 days presents with tachypnea and a new O2 requirement. She has been on the BMT floor for 48 hrs after being admitted for respiratory distress and fevers. Her blood cultures are negative but she is febrile intermittently. Her CXR shows nonspecific haziness, no focal opacity, and underinflation. Her weight is up 2KG in the last 48 hours. She is found to have increased work of breathing and mild desaturations to 88%. She is placed on HFNC and continued on broad-spectrum antibiotics. A respiratory viral panel and Sars-CoV-2 PCR is sent. Transfer to the Pediatric ICU is initiated. Episode DialogueDr. Rowan, welcome to our PICU Doc on-call podcast. Dr. Rowan: Thanks Rahul & Pradip for having me. I am delighted to be here to discuss one of my favorite topics. I have no conflicts of interest but I have funding from the NHLBI. Today we will be discussing the up-to-date evidence for NIV (HFNC and NIPPV) use in children who have had BMT. Additionally, we will also be discussing the use of invasive MV strategies including HFOV in the pediatric BMT population. To start us off, Dr. Rowan, why is the BMT cohort different from other patients admitted to the PICU? There is an increase in the # of patients undergoing BMT as indications for BMT are being expanded to different disease processes. The Etiologies for lung disease in BMT patients can be infectious (common organisms as well as opportunistic organisms). They can have lung disease from non-infectious causes and even fluid overload from renal dysfunction/medications given and there is a constant threat of alloreactivity which can manifest as GVHD or engraftment syndrome. 75% of PICU admits of immunocompromised children come from the heme-onc inpatient services. BMT patients have a higher risk to progress to ARDS. Recent reports show the incidence of ARDS in the intubated BMT population reaching upwards of 92%. These patients are also at high risk for MODS and can have a mortality rate close to 60%.

Join us for the latest episode of The Hamilton Review Podcast! In this conversation, Dr. Bob sits down with Dr. Alice Kuo to discuss the COVID vaccine for children ages 5-11. Parents, caregivers and educators - this conversation is for you as the two doctors discuss the common questions and concerns about this important vaccine for children. A must listen episode. Enjoy this important conversation and share with a friend! Dr. Alice Kuo is Associate Professor of Internal Medicine, Pediatrics, and Psychiatry and Biobehavioral Sciences at the David Geffen School of Medicine at UCLA, and of Health Policy and Management in the UCLA Fielding School of Public Health. She is also the Chief of the Medicine-Pediatrics Section and Director of the Medicine-Pediatrics Comprehensive Care Center. Her research interests are mainly in early childhood, and she has published in the areas of developmental screening and services, early literacy practices, cognitive and language development in young minority children, hearing screening in early childhood, services for children with autism, and mental health services for children. In addition to her research, Dr. Kuo is heavily involved in educational programs at many levels, from high school to post-graduate fellows. As the co-director of the Training Core for the NHLBI-funded Center for Population Health and Health Disparities, she works with disadvantaged high school students in East Los Angeles, focusing on reduction of cardiovascular risk factors, community capacity-building and career mentoring. She is the Director of the Maternal and Child Health Bureau (MCHB)-funded Pathways for Students into Health Professions for disadvantaged undergraduate students interested in public health and health professional careers. She also teaches the Foundations of Maternal and Child Health course at the UCLA School of Public Health each year. In October 2012, Dr. Kuo joined the NICHD-funded Center for Autism Research and Treatment as its Director of Research Training and Education. In September 2020 she was named as the Project Investigator of the Autism Intervention Research Network on Physical Health, a multi-organizational network dedicated to improving health outcomes of autistic individuals. At the David Geffen School of Medicine, she is Director of the Systems of Care Pathway, a longitudinal program for medical students to learn about the intersection of health care systems and clinical practice. At the post-graduate level, Dr. Kuo is the Program Director of the UCLA Combined Internal Medicine and Pediatrics Residency Program. At the national level, Dr. Kuo is currently a member of the Executive Committee of the Council of Community Pediatrics in the American Academy of Pediatrics (AAP). She was the co-chair of the Community Pediatrics Training Initiative Program Advisory Committee at the AAP from 2005-20008. She was the co-chair of the Advocacy Training Special Interest Group in the Academic Pediatrics Association (APA) from 2004-2007, and Region Co-Chair of the APA from 2007-2010. Clinically, Dr. Kuo sees primary care patients at the Medicine-Pediatrics Comprehensive Care Center in Santa Monica, the first ambulatory practice at UCLA with extended hours in the evenings and on weekends and holidays. She also precepts residents and students at the Simms-Mann Health Center in Santa Monica. She also directs the School Function Program at the Venice Family Clinic, a primary care-based model for addressing learning issues and mental health problems in children. Dr. Kuo received a B.A. in biology from Harvard University, her M.D. from UCLA, and her Ph.D. in educational psychology with a focus on early childhood and special education from the Graduate School of Education and Information Studies at UCLA. How to contact Dr. Bob: YouTube: https://www.youtube.com/channel/UChztMVtPCLJkiXvv7H5tpDQ Instagram: https://www.instagram.com/drroberthamilton/ Facebook: https://www.facebook.com/bob.hamilton.1656 Seven Secrets Of The Newborn website: https://7secretsofthenewborn.com/ Website: https://roberthamiltonmd.com/ Pacific Ocean Pediatrics: http://www.pacificoceanpediatrics.com/ Share this episode with a friend and leave a rating + review on Apple Podcasts to help others find this content. Thanks so much!

Commentary by Dr. Emile Daoud

This month on Episode 29 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the September 17th and October 1st issues of Circulation Research. This episode also features conversations with BCVS Outstanding Early Career Investigator Award finalists, Dr Jiangbin Wu from the University of Rochester, Dr Chen Gao from UCLA, and Dr Chris Toepfer from Oxford University.   Article highlights:   Raftrey, et al. Dach1 Extends Arteries and Is Cardioprotective   Zhang, et al. Blood Inflammatory Exosomes and Stroke Outcome   Joyce, et al. Cardiovascular Health and Epigenetic Age   Liu, et al. Wls Suppresses Fibrosis in Heart Regeneration   Cindy St. Hilaire:        Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh. And today, I'll be highlighting articles presented in our September 17th and October 1st issues of Circulation Research. I also am going to speak with the BCVS Outstanding Early Career Investigator Award finalists, Dr Jiangbin Wu from the University of Rochester, Dr Chen Gao from UCLA, and Dr Chris Toepfer from Oxford University. Cindy St. Hilaire:        The first article I want to share is titled, Dach1 Extends Artery Networks and Protects Against Cardiac Injury. The first author is Brian Raftrey, and the corresponding author is Kristy Red-Horse from Stanford University. Coronary artery disease occurs when blood vessels supplying the heart develop atherosclerotic plaques that limit blood flow, which prevents oxygen and nutrients from reaching the cardiac tissue and often leads to a heart attack or cardiac arrest. The suggested strategy for treating coronary artery disease is to promote the growth of new blood vessels to compensate for the dysfunctional ones. Several factors are known to control coronary blood vessel development, including the transcription factor, DACH1. In mice lacking DACH1, embryonic coronary artery development is stunted. But whether increasing DACH1 protein levels boosts heart vessel development, and whether this would work in mirroring coronary arteries, were unanswered questions. Cindy St. Hilaire:        This group engineered inducible gain-of-function DACH1 mice and found that DACH1 over expression in the embryo boosted coronary artery development. The team then used the same model to induce DACH1 in adult mice for six weeks. While there was no apparent differences in the artery growth between the animals and the controls under normal conditions, after myocardial infarction, the mice over expressing DACH1 had better recovery and survival with increased artery growth and heart function. The results paved the way for studying the mechanisms of DACH1-mediated protection, and how they might be leveraged as potential coronary artery disease treatments. Cindy St. Hilaire:        The second article I want to share is titled Circulating Pro-Inflammatory Exosomes Worsen Stroke Outcomes in Aging. The first author is Hongxia Zhang, and the corresponding author is Kunlin Jin from University of North Texas Health Science Center. Aging is associated with declining tissue function and an assortment of health issues. But in rodents at least, certain factors, including the plasma of youthful animals and the exosomes of stem cells, can have rejuvenating effects on old animals. Exosomes are small membrane-bound particles containing cellular contents that circulate in the blood after they're released from cells. This group has shown that as rats age, the animals' serum exosomes accumulate pro-inflammatory mediators, such as C3a and C3b. Cindy St. Hilaire:        When these aged rats were subjected to stroke, and then injected with serum exosomes isolated from either old or young rats, those receiving youthful exosomes fared much better in terms of infarct size and sensory motor deficits, while those receiving aged exosomes fared worse. The team went on to show that injected exosomes accumulate at the site of stroke injury, but those from old donors caused more neuronal damage, as seen by reduced synaptic function. Preventing C3a activity on microglia reversed the effects of the old exosomes and improved stroke outcome, suggesting that such modulation of inflammatory molecules might be a treatment strategy for stroke. Cindy St. Hilaire:        The next article I want to share is titled Epigenetic Age Acceleration Reflects Long-Term Cardiovascular Health. The first author is Brian Joyce, and the corresponding author is Donald Lloyd-Jones. And they're from Northwestern University. DNA methylation is an epigenetic modification that regulates gene transcription. Studies of young and old individuals have shown that at certain locations in the genome, methylation status is highly correlated with age. These methylation patterns are also linked to measures of cardiovascular health, including blood pressure, cholesterol level and body mass index. This suggests that if a person has particularly good or particularly poor cardiovascular health, their DNA may appear younger or older than the individual's actual age. Cindy St. Hilaire:        This group tested the hypothesis that people with poor cardiovascular health exhibit methylation changes more commonly found in elderly individuals than those with good cardiovascular health. And if so, DNA methylation patterns might be useful for predicting future cardiovascular risk. Cindy St. Hilaire:        The team examined DNA methylation of over a thousand individuals enrolled in a prospective heart health cohort, testing them around age 40 and then again at around age 45. Changes in methylation status were then compared to individuals' cardiovascular health scores over a longer period. Sure enough, faster epigenetic changes did correlate with poor cardiovascular health later in life. Data from the second cohort of individuals supported the initial findings. This study indicates that DNA methylation status may be an early biomarker that signals cardiovascular issues, and may therefore allow for prompt implementation of treatment and prevention strategies. Cindy St. Hilaire:        The last article I want to share is titled, Yap Promotes Noncanonical Wnt Signaling from Cardiomyocytes for Heart Regeneration. The first author is Shijie Liu, and the corresponding author is James Martin. And they're from Baylor College of Medicine. After a heart attack, cardiomyocytes are destroyed and replaced with a fibrotic scar that interferes with the contractile function of the heart. While adult mouse and human hearts are similar in this regard, the hearts of newborn mice possess greater regenerative capacity, and this regeneration capacity persists for approximately one week. The transcription factor YAP is known to regulate regenerative processes in neonatal hearts of mice. And its deletion eliminates regeneration, and its over-activation in adult cardiomyocytes reduces fibrosis. Cindy St. Hilaire:        These experiments suggest cardiomyocytes transmit signals to cardiac fibroblasts. Wntless protein regulates the release of Wnt signaling molecules and also is a target of YAP. Mice that lack Wntless in their cardiomyocytes appear to have normal heart development and function. However, their neonatal regenerative capacity was impaired. In the weeks after heart injury, the mice that lack Wntless had reduced heart function, increased scar size and increased numbers of activated cardiac fibroblasts compared with that seen in controls. The study indicates that Wntless is critical to the regeneration of cardiac tissue, and may perhaps be leveraged to minimize scarring after heart attacks. Cindy St. Hilaire:        I'm really excited to have with me today the three finalists of the BCVS Outstanding Early Career Investigator Award. The first person I'm going to be speaking with is Jiangbin Wu, who is a research assistant professor at the Aab Cardiovascular Research Institute at the University of Rochester. Thank you so much for joining me today. Jiangbin Wu:               Thank you. Cindy St. Hilaire:        And congratulations, actually. I know this is a highly competitive award that gets a lot of applications, so congrats on becoming a finalist. Before we get to your abstract, which is related to mitochondria and calcium influx in cardiomyocytes, I was wondering if you could share a bit about yourself. Maybe what your research path was, and what brought you to study cardiomyocytes and the mitochondria that are within them? Jiangbin Wu:               Yeah. Right now, I'm an assitant professor at Cardiovascular Research Institute of University of Rochester. Previous, I was actually studying in the cancer field and also some kind of mitochondria work in some cancer cells. Although when I came to the University of Rochester and I switched to cardiovascular and then we are working on a kind of microRNA[at the initial. The way we screen for these is just by doing the RNA-Seq is target the microRNA. and then we start to study the function of these genes, and found that it's a mitochondria calcium channel regulator. Cindy St. Hilaire:        The title of your abstract is FAM210A Maintains Cardiac Mitochondrial Homeostasis Through Regulating LETM1-Dependent Calcium Efflux. So before we unpack what all those words in the abstract title mean, could you tell me how you ended up focusing on FAM210A? What does this protein do, and why'd you focus on it? Jiangbin Wu:               Yeah. As I mentioned that we just gathered this protein actually is by some kind of chance as a microRNA target. And this protein full name is family with similarity 210 A, actually is a family of proteins. This is just one of them. And the way discover is localized in mitochondria in the membrane. And also, there is some other people's report is in mitochondria. And we want to sort out its function inside the mitochondria and in the cardiac background. So we do some kind of omics or mass spec to get its interlocking interacting proteins. And then we found LETM1. It's a calcium channel inside the mitochondria in the membrane. So we figured out is, this FAM210 protein regulate LETM1 function in calcium, pump calcium is part of the mitochondria matrix. And I think this is a very important, because calcium overload is always happening in the very heart of the cardiomyocytes. Cindy St. Hilaire:        That's a perfect segue, because my next question was really what is the gap in knowledge that your study was trying to address? Were you really focused on just the function of this one protein, or what was the greater goal of this study? Jiangbin Wu:               Actually, the function this protein is the initial step. Our final aim is to use this protein, to over expression this protein in the heart failure patient or in some kind of heart failure models to do the, sort of do the work in some heart failure patients. Cindy St. Hilaire:        Maybe a gene therapy approach, or if there's a pharmacological way to up regulate this protein? Jiangbin Wu:               Yeah, because we've proposed that the self expression of this proteins will reduce the calcium overloading cardiomyocytes, which is a major cause for the cardiomyocytes death in heart failure process. So over expression will reduce this kind of process. And then it will make the cardiomyocytes survival in the failure heart. Cindy St. Hilaire:        That is interesting. I mean, obviously you were using a mouse knockout model, so you know what's driving the expression down in that case. But in humans, what do we know about the regulation of this protein? Is anything known, or any known causes that cause its reduction in expression? Jiangbin Wu:               Actually, we do. Its expression in heart failure is slightly increased in heart failure. So we feel it's a kind of some kind of compensating effect to try to save the heart from failing. Cindy St. Hilaire:        Interesting. It's just not turned on early enough, in that case then. Jiangbin Wu:               Yeah. And for the regulating protein for this one, I think we find microRNA can suppress its expression, but not too many other influences on these regulator proteins. Cindy St. Hilaire:        That is so interesting. So what's next? What are you going to do next on this project? Jiangbin Wu:               Yeah. I think currently, we are just at the start to do some kind of therapeutic effect that use to these proteins. I think we will do more deep in the therapeutic effects for over expression of these genes in... Currently, we are working on mouse models. Maybe in different heart failure models to prove that it's very benefiting to the heart failure patients. Cindy St. Hilaire:        Wonderful. Well, congratulations on an excellent study. Really looking forward to your presentation, which is coming up shortly, and really looking forward to your future research in this field. Jiangbin Wu:               Okay, thank you. Cindy St. Hilaire:        So I also have with me, Dr Chris Toepfer, who's another finalist for the BCVBS outstanding early career investigator award. He's a principal investigator from the University of Oxford, and his abstract is titled, Defining Diverse Disease Pathway Mechanisms Across Thick And Thin Filament, Hypertrophic Cardiomyopathy Variance. So congratulations, Chris, and thank you for joining me today. Chris Toepfer:             Thank you very much. It's great to be here. Cindy St. Hilaire:        Before we start to discuss your abstract, I was wondering if you could just share a little bit about yourself. Maybe your career path, and how you came to study hypertrophic cardiomyopathy? Chris Toepfer:             Yeah, sure. I guess this story gets longer and longer every time somebody asks it,right, in your career? Cindy St. Hilaire:        That's a good thing. Chris Toepfer:             Yeah. I started out as an undergraduate in London, and actually during the second year of my undergraduate degree, I fell into a lab kind of out of interest. It was starting to study cardiac muscle mechanics. And that was the lab of Professor Michael Ferenczy. And ended up, after I finished my undergraduate degree, I joined him for a PhD. I had a PhD program that also took me overseas to the NIH to work with Dr James Sellers, who was a muscle motor protein biochemist. And we really, I sort of really fell in love, with the idea of studying disease of multiple levels, and understanding how the heart would function from the basic molecule up to the entire organ and looking at different systems in between. Chris Toepfer:             And that's what led me to then, so my postdoctoral position to seek out a completely different direction in some ways, but something that could also extend how we could look at the heart. And that's where I moved to Boston to work with Christine and Jonathan Seidman. I'm looking at more of the genetic basis then of hypertrophic cardiomyopathy rather than just, sort of more diffusely the mechanisms underlying cardiac muscle contraction. And then two years ago, I moved back to the UK to Oxford to sets up my own group, which has been fun during the pandemic as you can imagine. Cindy St. Hilaire:        It's hard enough starting up a lab under normal times. I can't imagine doing it during a pandemic. Chris Toepfer:             And we are now completely focused on stem cell models and CRISPR CAS engineering, and trying to understand hypertrophic cardiomyopathy in a dish. Cindy St. Hilaire:        That's wonderful. And actually I looked at your CV. We actually overlapped a little bit. I was doing my postdoc at NIH in the NHLBI while you were there for your graduate school. So I too fell in love with kind of the starting with the human as the model path of research. So maybe you can  kind of fill in all the listeners in who aren't cardiomyopathy experts. So what is, I guess, in a nutshell, hypertrophic cardiomyopathy, and what gap in knowledge was your study specifically addressing? Chris Toepfer:             So in general, about one in 500 people have hypertrophic cardiomyopathy. And for those that are genetically linked, a lot of them are in the key contractile proteins of the heart, the drive muscle contraction. And what you often see in those people is they have thickened hearts. And what happens is actually the heart begins to be too hard, and it actually relaxes very poorly in between beats. Chris Toepfer:             So what we are really trying to understand in this disease and with this abstract was how are different forms of hypertrophic cardiomyopathy created? Because it can be a couple of different forms. There are different proteins involved that have very vastly different functional mechanisms within the cell. So would this, we went away, we generated some stem cell models where we could then differentiate into cardiomyocytes. Model the disease in a dish. And we made kind of a group of good methods to go and look at what was happening inside the cells. And then we could screen drugs against what's happening inside those cells, so that was kind of the idea of what we were looking at, at the time. And what's fallen out of all of that is a drug now called Melacamptin that's starting to get to the clinic, which addresses some of these underlying mechanisms we were beginning to study. So that's what I'll talk about a bit later on in our session today. Cindy St. Hilaire:        It's great. One of the things you focused on in the abstract is comparing these thick and thin filament variants. What are the implications of those, I guess, in the human disease state, but also in how you could design or use your stem cells as a model, and were any of the results that you found surprising? Chris Toepfer:             So I think what was the really key finding that we saw was that the thick filament variants seemed to be switching myosin, which is a molecular motor that drives cardiac muscle contraction very much to arm”ON”. And my sort of analogy to that is they're all very sort of bodybuilder like. Myosin switched on, ready to go to work causing way too much contraction. And the compound that we were using at the time Myocamptin, we could turn those off and resolve the disease. Whereas with the thin filament variants, they were operating through a completely different mechanism. And when we tried to treat them with the same compound, they wouldn't always salvage disease. So though the face of it, they look the same in the dish, in that they contracted too much, relaxed very poorly. You're clearly doing it via complete different mechanism. And that's what we're starting to dig into now. And that's what we'll be talking about. Cindy St. Hilaire:        Yeah. And that's actually kind of the question I was going to finish up with you. What are the, I guess translational implications? No, yes. You're using this drug. Is that only good for thick filament-like variants? And are you going to be able to screen patients to tell which variant they have, and therefore if this or that drug might be useful? Chris Toepfer:             So we're in a real golden age now for genomics where I guess patients can come into the clinic and they can be sequenced and you could maybe tell them now what might be the underlying cause of their disease. I am not a clinician, but what we, as a basic scientist can say is, well, we can go away and try and understand whether this variant you may have in your genome is causative of disease. And if it is what mechanism that may fall under, what may be causing them to have this phenotype? Chris Toepfer:             And I think what we can do is we can try and then bin the subpopulations of variants, and try and find novel drugs or novel pathways that we could try and find drugs for to treat the disease, and to differentiate them from each other. So I think it's too early to say whether Mylocamptin will be able to sort this for everybody, I guess we will find out in the next years. But I think already we can start thinking about, well, what would be the next step after this? We can bring precision medicine even further. And that's, I think the goal where we're heading towards. Cindy St. Hilaire:        Well, that's wonderful, and this is a wonderful abstract. I'm really looking forward to seeing the full study and your presentation later on. And thank you so much for joining. Chris Toepfer:             No. Yeah. Thank you for having me. I'm really looking forward to it later on. Cindy St. Hilaire:        Great. Dr Chen Gaol is the third finalist for the BCBS Outstanding Early Career Investigator Award. She's an assistant researcher at UCLA, and her abstract is titled, Functional Impact of RBFox1C in Cardiac, Pathological Remodeling through Targeted MRNA Stability Regulation. So congratulations, and thank you so much for joining me today. Chen Gal:                    Absolutely, thank you for having me. Cindy St. Hilaire:        Before we jump into your abstract, could you share with us a little bit about your career path, and how you came to study the role of RNA binding proteins, I guess specifically in pathological cardiac remodeling? Chen Gal:                    Yes, I think my research over the years has been into the very basic questions, which is I'm interested in looking at how the RNA is being regulated. For example, how the RNA is being spliced, is being ideated, and how the RNA is being degraded if it's ever been translated into protein. And the second half of my research is of course, physiological driven, because I'm interested in different type of cardiac disease, starting from the traditional heart attack to the now more emerging medical need, which is the cardiometabolic disease. So I was trained as a molecular biologist. I started in molecular biology Institute at UCLA. My PhD supervisor is Dr Yibin Wang, who first introduced me to understand there is actually a whole new world of R regulation at a post-transcription level. Chen Gal:                    So at that time we basically utilized the R sequencing. Just look for the easiest to heart, and try to understand how these RNA are differentially spliced in the heart. And I was so interested in understanding more about a cardiology. So I decided, even if I move out to my postdoc research I still want to continue working in the heart, although at a totally different angle. And that is when I started to really try to understand different aspects of RNA regulation. So now I am starting to be a junior faculty, establishing my own lab. And I really wanted to understand more how different steps of our metabolism is regulated. Cindy St. Hilaire:        Really timely research. And I really like how you are doing a great job combining extremely basic biochemical processes with advanced disease states. An extra, that's why this abstract made it as a finalist. So congrats on that. So your study was focused on the RNA binding protein, RB Fox one, which has several isoforms. And so can you tell us which isoform you were looking at, and why you were interested in that particular isoform? Chen Gal:                    Yes, actually I've studied about ISO form of RPFox1. It itself, is actually subject to alternative splicing, while generating one nuclear, and another simosolic isoform. Where I was a PhD student, I was very simple minded, just trying to screen for the R binding protein that actually is expressed in the diseased heart. So RBFox1 is at least at a transcriptional level, the only one that we identify to be to decreased in the fatal heart. The nuclear function, the nucelo ISO form of RPFox1 is mainly regulating alternative splicing. But it is when I was studying this nuclear function of the RBFox1, I identified there is actually another isoform where she is in the set ourselves based on the different of c terminal domains of the RFox1. So I was just wondering, apparently you shouldn't be regulating and splicing anymore. I just move on to another layer of RA regulation. And then what I found most interesting is these RBFox1 is regulating the R stability, which is something that we'll talking about later today. Cindy St. Hilaire:        That's great. So to do this study, you actually created a new knockout mouse model where you specifically deleted this one C isoform. What was kind of the baseline and maybe the disease state phenotypes that you saw in that mouse? Chen Gal:                    The result and phenotype so far is very striking. We utilize the CAS nine CRISPR technology simply because for, we were lucky the settle the Fox warehouse, one extra axon. So that does allow us to coach the lox P side, just blanking in that particular AXA. And in theory we could across it with different CRE, and to generate either cardiac or different tissue, specifically knock out. Even at a baseline we see a decreased cardiac function when we inactivate this isoform in the adult heart. And when we look at the gene expression profile is, I call mind-blowing type of experience, because turns out this gene not only is regulating some of the inflammatory genes, but also is helping involve protein translation and delivery metabolism, which I hope in the future will set us on the path to really understand the role of this RP Fox1. Not only into HFpEF, but also in the cardiometabolic disorder. Cindy St. Hilaire:        Yeah, that's great. It's so rewarding when you do this one really big kind of risky experiment, and it turns into not just one interesting path to study, but multiple. One of the things that you mentioned in the abstract is clip seek. I was wondering if you could tell us a little bit about this technology, and how you used it in your study? Chen Gal:                    Yeah. I think one of the rewarding parts for me focusing on the R metabolism is really driving different accounting and sequencing tools, and utilize that in the heart. So cardiomyocyte has been traditionally viewed now to be very easy to work with type of model comparing helo cells, right? And I think in the field, we are still so short of knowledge, what type of the cutting-edge tools that we can use in the heart. My research involved clip seek, which is to use UV crosslinking the RNA with the R binding protein. So that will allow us to understand which are the RNA targets that are directly interacting with the RNA binding protein. I'm also using great seek, which is to find dynamically label the recency size to RNA. And that will allow us to look forward to RA degradation profile at a global level in the baseline or under disease. So I thought those are really cool technologies, and that's something that makes me excited about my work on a daily basis. Cindy St. Hilaire:        Yeah, that's wonderful. So what's next? What are you going to do after this initial study? What's the next question you're going to go after? Chen Gal:                    Yeah, like I mentioned, I'm interested in, honestly, different type of heart disease, not just the stress induced heart failure, but also the recent years, I started to branch out a little bit to understand more of the biology of HFpEF. For example, how the R binding protein that we are studying right now is playing a role in the development of HFpEF. Or we actually understand very little about them, the micromechanism for HFpEF development, right. What are the RNA splicing profile in the cardio metabolic disorder on account? We also find differential regulation of R stability in the HfPEF compared to the HFpEF compared to the HFrEF. So I thought those are really interesting questions that I would like to pursue in the future. Cindy St. Hilaire:        That's great and best of luck in those future studies. Chen Gal:                    Thank you. Cindy St. Hilaire:        Before we leave, I was wondering if you could share with us any advice that you would give to a trainee, maybe something that you wish you knew ahead of time in this kind of early career stage. Chen Gal:                    I consider myself a really, really lucky person. And if I have one word to give to the younger people, younger than me, is to find great mentors for your career. And luckily our field has a lot of good mentors who are ready to help us every single step of our career. For example, my PhD supervisor, Dr Wang. And I have met a lot of good mentors inside and outside of UCLA. I'm pretty sure this is the same thing for Chris, who is trained by Dr Seidman, and everybody know how great a mentor she is. So I think having a great mentor will help you every step of your career development to making sure you're always on the right track. And that, that is also something that you will do when we have our own lab, because we want to be great mentors for our trainees as well. Cindy St. Hilaire:        I know. That's something I strive for too, is to emulate my amazing mentors that I've had. What do you think is a good quality for a good mentor? Like what's one of the, I guess key features that you look for in someone that you would like to be your mentor? Chen Gal:                    For me, I think my mentors are all cheerleaders. They never try to push me to move out one career path versus the other. They are good listeners, and they are also my role models. Cindy St. Hilaire:        That's wonderful. Chris, what's a piece of advice that you would like to share with trainees that your former self wish you knew of? Chris Toepfer:             I think it's very important to echo the message of a good mentorship, and a good lab environment that allows you to flourish and really helps you to grow yourself to the future. And also helps you understand the bits of you that you could actually grow as well, a little bit better. So you become a more rounded scientist. I think something that's really important or something that I've always found very infectious is to find mentorship and mentors that are also incredibly enthusiastic about you as an individual, as well as the science. I think that that can really drive you. And I think that's also an important thing to have in yourself, to have, to find that question for yourself that really drives you and you can be really enthusiastic about. Cindy St. Hilaire:        I totally agree. Well, thank you again for joining me today. Congratulations on being a finalist, and I wish everyone the best of luck in their presentations later on at BCBS. Chen Gal:                    Thank you so much. Jiangbin Wu:               Thank you. Chris Toepfer:             Thank you very much. Cindy St. Hilaire:        That's it for the highlights from the September 17th and October 1st issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page, and follow us on Twitter and Instagram with the handle  @CircRes and #Discover CircRes. Thank you to our guests, BCBS Outstanding Early Career Investigator Award Finalists, Dr Jaobing Wu, Dr Chen Gal, and Dr Chris Toepfer. And a special congratulations to Dr Toepfer who won this year's competition. This podcast is produced by Asahara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of circulation research. Some of the copy texts for highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire. And this is Discover CircRes, you're on the go source for the most exciting discoveries in basic cardiovascular research. 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 information, please visit AHAjournals.org  

In the latest episode of the Hamilton Review, Dr. Bob welcomes back Dr. Alice Kuo. Dr. Kuo shares her extensive knowledge and expertise on the Delta Variant of Covid 19, including why vaccinations are important, what to do if you are exposed to the infection, how schools are handing keeping children safe and much more. Don't miss this important conversation!  Dr. Alice Kuo is Associate Professor of Internal Medicine, Pediatrics, and Psychiatry and Biobehavioral Sciences at the David Geffen School of Medicine at UCLA, and of Health Policy and Management in the UCLA Fielding School of Public Health. She is also the Chief of the Medicine-Pediatrics Section and Director of the Medicine-Pediatrics Comprehensive Care Center. Her research interests are mainly in early childhood, and she has published in the areas of developmental screening and services, early literacy practices, cognitive and language development in young minority children, hearing screening in early childhood, services for children with autism, and mental health services for children. In addition to her research, Dr. Kuo is heavily involved in educational programs at many levels, from high school to post-graduate fellows. As the co-director of the Training Core for the NHLBI-funded Center for Population Health and Health Disparities, she works with disadvantaged high school students in East Los Angeles, focusing on reduction of cardiovascular risk factors, community capacity-building and career mentoring. She is the Director of the Maternal and Child Health Bureau (MCHB)-funded Pathways for Students into Health Professions for disadvantaged undergraduate students interested in public health and health professional careers. She also teaches the Foundations of Maternal and Child Health course at the UCLA School of Public Health each year. In October 2012, Dr. Kuo joined the NICHD-funded Center for Autism Research and Treatment as its Director of Research Training and Education. In September 2020 she was named as the Project Investigator of the Autism Intervention Research Network on Physical Health, a multi-organizational network dedicated to improving health outcomes of autistic individuals. At the David Geffen School of Medicine, she is Director of the Systems of Care Pathway, a longitudinal program for medical students to learn about the intersection of health care systems and clinical practice. At the post-graduate level, Dr. Kuo is the Program Director of the UCLA Combined Internal Medicine and Pediatrics Residency Program. At the national level, Dr. Kuo is currently a member of the Executive Committee of the Council of Community Pediatrics in the American Academy of Pediatrics (AAP). She was the co-chair of the Community Pediatrics Training Initiative Program Advisory Committee at the AAP from 2005-20008. She was the co-chair of the Advocacy Training Special Interest Group in the Academic Pediatrics Association (APA) from 2004-2007, and Region Co-Chair of the APA from 2007-2010. Clinically, Dr. Kuo sees primary care patients at the Medicine-Pediatrics Comprehensive Care Center in Santa Monica, the first ambulatory practice at UCLA with extended hours in the evenings and on weekends and holidays. She also precepts residents and students at the Simms-Mann Health Center in Santa Monica. She also directs the School Function Program at the Venice Family Clinic, a primary care-based model for addressing learning issues and mental health problems in children. Dr. Kuo received a B.A. in biology from Harvard University, her M.D. from UCLA, and her Ph.D. in educational psychology with a focus on early childhood and special education from the Graduate School of Education and Information Studies at UCLA. How to contact Dr. Bob: YouTube: https://www.youtube.com/channel/UChztMVtPCLJkiXvv7H5tpDQ Instagram: https://www.instagram.com/drroberthamilton/ Facebook: https://www.facebook.com/bob.hamilton.1656 Seven Secrets Of The Newborn website: https://7secretsofthenewborn.com/ Website: https://roberthamiltonmd.com/ Pacific Ocean Pediatrics: http://www.pacificoceanpediatrics.com/   Share this episode with a friend and leave a rating + review on Apple Podcasts to help others find this content. Thanks so much!

Matt Chia, Chris Audu, and Elizabeth Andraska sit down with Drs. Kevin Southerland, Karen Ho, and Andrea Obi for a panel discussion introducing basic science in vascular surgery and some tips on getting started and obtaining funding for your research. Dr. Kevin Southerland (@kwsoutherland) is an assistant professor of surgery at Duke.  He is a co-investigator of an NIH U01 grant to study the 4D nucleome of muscle regeneration in ischemia-induced damage and repair and was selected to be the 2021 Wylie Scholar to study transcriptional dynamics and heterogeneity of macrophages in CLTI. Dr. Karen Ho is the John Marquardt Clinical Research Professor of Vascular Surgery at Northwestern.  She was recently awarded an R01 grant from the NHLBI to study the meta-organismal pathways that impact susceptibility to arterial restenosis after vascular surgery. Dr. Andrea Obi (@AndreaObiMD) is an assistant professor of Vascular Surgery at the University of Michigan, a recipient of the 2019 Wylie Scholar award for young investigators in vascular surgery, an NIH K08 awardee and, most recently, the recipient of the SVS Foundation/ACS Mentored Clinical Scientist Research Development Award (a K08 matching grant) to study the role of myeloid epigenetic regulation on venous thrombus resolution.  Relevant Resources for Research and Funding: SVS Research Opportunities in Vascular Surgery AVAS award:  AVF/Jobst research grant AHA research grant VESS award SAAS award SUS award AAS award Vascular Cures/Wylie Scholar program NIH F32 Award Burroughs Wellcome Postdoctoral Grants HHMI Research Grants NIH RePORTER Host Introductions:  Dr. Chris Audu (@ChrisAuduMD) is in his fifth year of training in the integrated vascular surgery residency at the University of Michigan. His research studies the role of chromatin-modifying enzymes on wound healing pathways as well as learning the details of high throughput experimentation in discovering novel acid-amine organic reactions for vascular-focused, medicinal chemistry. He is currently F32 funded and was recently awarded the 2020 VESS Resident Research Award. Dr. Elizabeth Andraska (@eandraska) is in her fifth year of training in the integrated vascular surgery residency at the University of Pittsburgh.  She is T32 funded by the National Institutes of Health and is currently a Burroughs Wellcome Foundation fellow. She is studying the role of platelet-neutrophil complexes in immunothrombosis.  Dr. Matt Chia (@chia_md) is in his 6th of 7 years in the integrated vascular surgery program at Northwestern University. He obtained his medical degree from the University of Illinois College of Medicine and also holds a Master's in Health Services and Outcomes Research at Northwestern.  Follow us @audiblebleeding Learn more about us at https://www.audiblebleeding.com/about-1/ and #jointheconversation.

Podcast:  Updates in the Management of Asthma in the Pediatric Patient Evaluation and Credit:  https://www.surveymonkey.com/r/MedChat29 Target Audience             This activity is targeted toward primary care pediatric specialties.   Statement of Need Asthma is one of the most common chronic illnesses in children and in Kentucky approximately 10 - 12% of children have been diagnosed with asthma therefore it is critical for practitioners to understand the latest recommendations in the treatment of patients with asthma. In Dec. 2020, updated treatment guidelines were released for the management of patients with asthma.  This program will highlight these updates to the NHLBI asthma treatment guidelines as the standard of care for the treatment of pediatric asthma. Objectives At the conclusion of this offering, the participant will be able to: Review the common types of asthma in the pediatric patient. Discuss the new asthma treatment/management guidelines; highlighting the six focus areas. List the new recommendations for the diagnosis / screening of pediatric asthma. Moderator   Mark McDonald, MD, FAAP Pediatric Critical Care Specialist Medical Director, Norton Children's Hospital and Norton Children's Medical Center Professor Norton Children's Critical Care Affiliated with the UofL School of Medicine   Speakers Scott Bickel, M.D. Pediatric Pulmonologist Assistant Professor, Pediatrics Medical Director, Respiratory Therapy Norton Children's Pulmonology Affiliated with the UofL School of Medicine   Michael Orangias, M.D. Pediatric Pulmonologist Norton Children's Pulmonology Affiliated with the UofL School of Medicine   Moderator, Speaker and Planner Disclosures  The speakers, moderator and planners for this activity have no potential or actual conflicts of interest to disclose.   Commercial Support  There was no commercial support for this activity. Physician Credits  American Medical Association  Accreditation Norton Healthcare is accredited by the Kentucky Medical Association to provide continuing medical education for physicians.   Designation Norton Healthcare designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.   Date of Original Release |July 2021 Course Termination Date | July 2023 Contact Information | Center for Continuing Medical Education; (502) 446-5955 or cme@nortonhealthcare.org     Resources for Additional Study  Asthma Management Guidelines: Focused Updates 2020  https://www.nhlbi.nih.gov/health-topics/asthma-management-guidelines-2020-updates    2020 Focused Updates to the Asthma Management Guidelines: Clinician's Guide https://www.nhlbi.nih.gov/health-topics/all-publications-and-resources/clinician-guide-2020-focused-updates-asthma-management-guidelines   Updates to the Pediatrics Asthma Management Guidelines https://pubmed.ncbi.nlm.nih.gov/34096987/

While the numbers are constantly rising, more than 1 in 10 Americans – or more than 34 million people – live with diabetes already today. For many of them, nerve damage caused by diabetes – a condition called diabetic neuropathy – is a common complication that can cause painful shooting and stabbing sensations along with burning, tingling and numbness that affect the lower extremities. To understand more about the challenges patients face due to this condition, a new national survey reveals its findings on what it truly means to live with diabetic nerve pain. Here to discuss neuropathic pain associated with diabetic peripheral neuropathy – or diabetic nerve pain – and the survey findings is Dr. Rodica Pop-Busui, MD, PhD, Professor of Internal Medicine, Metabolism, Endocrinology and Diabetes and Vice Chair Clinical Research, Department of Internal Medicine at the University of Michigan, Ann Arbor and Lindsay Colbert, Executive Director of the Foundation for Peripheral Neuropathy. Rodica Pop-Busui, MD, PhD, is the Larry D. Soderquist Professor of Diabetes, a prominent diabetologist at Michigan Medicine and a recognized leader in the field of diabetes and diabetes complications. She is the Vice Chair for Clinical Research in the Department of Internal Medicine and the Associate Director of Clinical Research, Mentoring and Development of the Elizabeth Weiser Caswell Diabetes Institute at the University of Michigan. Her research interests involve chronic complications of diabetes, particularly diabetic peripheral and cardiovascular autonomic neuropathy, as well as diabetic foot complications, diabetic kidney disease and cardiovascular disease, and the design and conduct of traditional and pragmatic clinical trials for patients with diabetes. Dr. Pop-Busui has published more than 200 peer-reviewed manuscripts and book chapters, and received awards from the American Diabetes Association (ADA) and the University of Michigan. She has chaired the most recent American Diabetes Association Position Statement on Diabetic Neuropathy, and has served as Chair of the American Diabetes Association Scientific Research Review Clinical and Chair of the ADA Diabetes & Cardiovascular Disease Interest Group. She is also one of the principal investigators in the recently established NIDDK Diabetes Foot Consortium. She has led neuropathy studies in several of the most important national and international diabetes clinical trials to date including: the NHLBI-funded Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, the NIDDK funded Bypass Angioplasty Revascularization Diabetes 2 (BARI- 2D) and Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications. In addition, she designed and leads several investigator-initiated studies funded by NIDDK and Pharma to unveil disease modifying agents for diabetic neuropathy and other diabetes complications. Lindsay Colbert, MA, is Executive Director of the Foundation for Peripheral Neuropathy (FPN), a public charity organization based outside of Chicago, Illinois, that is dedicated to improving the lives of patients living with peripheral neuropathy. In her tenure with the organization, Colbert has lead FPN to increase awareness of peripheral neuropathy, prioritize research and funding in the field, and provide educational programs to patients throughout the world who are desperate for answers and hope. Colbert holds a Master of Arts degree in International Development and French from the University of Wisconsin-Madison. Prior to joining FPN in 2017, Colbert developed her marketing, fundraising and nonprofit management skills for over a decade at two Chicago-based institutions, namely Rotary International and Northwestern University. She resides in a Chicago suburb with her husband and two daughters. In her free time, Colbert enjoys traveling, cycling, gardening, and playing with her children.

COVID-19 led to closure of nearly all schools in the United States, affecting more than 55 million students. Efforts to continue children's education have been highly variable, ranging from remote learning, hybrid and modified in-person instructions. Return to school safely for children and staff is being implemented, again variably. Along with the safety concerns, there are significant concerns about the disruption to the learning process, mental health, nutrition and even safety. I'm in conversation with Dr Anita Gupta, DO, PharmD examining the challenges, risks and considerations in ensuring safe return to school of children nationwide.   Takeaways in This Episode Why it is important to weigh the risks, benefits and challenges to safe return to school.  Factors integral to ensuring safety of children, school staff and the community Who needs to be involved in the planning to ensure a safe and expeditious The CDC's policy to guide opening schools safely. What mitigation measures should be required What parents can do to support their children's physical and mental health. How parents can ensure a good learning experience for their children. Collective responsibilities to educate and ensure safety Who are the children at even higher risk even beyond the learning challenges.   Links Dr. Anita Gupta DO, PharmD JAMA article on Data & Policy to Guide Safe Opening of Schools FREE Clinicians' Pain Evaluation Toolkit   About the Guest Speaker Dr. Anita Gupta DO, PharmD Dr. Anita Gupta is a globally recognized leader, Hopkins anesthesiologist, pharmacist & policy expert. She's the first appointed woman physician anesthesiologist to pioneer the expansion of the only opioid overdose antidote, naloxone, at the U.S. FDA. Also, the first woman physician anesthesiologist to Co-Chair the American Society of Anesthesiologist Committee on Prescription Opioid Abuse. First woman anesthesiologist-pharmacist alumnae of both Princeton University School of Public and International Affairs and Harvard University School of Business. She is committed to addressing global public health, drug safety and policy.  She's been appointed as an advisor to the U.S Food and Drug Administration and the U.S. Department of Defense. Dr. Gupta has been featured on the cover of Philly Biz magazine as Top in Healthcare, international editor of three books by Oxford University Press. Featured as a recognized healthcare thought leader for the Washington Post, Forbes, CNN, on emerging threats including the Coronavirus crisis, the Opioid crisis, Zika crisis, catastrophic train crashes, and high profile expert medical cases involving: Tiger Woods, Bill Cosby, Jolie, Prince, Lady Gaga, Beyonce and others. She completed her pain fellowship from Johns Hopkins University, medical residency in anesthesiology at Georgetown University School of Medicine, and clinical physician scientist training during her medical residency at National Institutes of Health, NHLBI, doctorate in pharmacy at Rutgers University, medical school from Rowan University (formerly University of Medicine and Dentistry of New Jersey) and professional education from MIT in drug technology, masters in public policy and certificate in health policy from Princeton University and general management from Harvard Business School.

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

This week features Two Feature Discussions. In our first discussion, author Thomas Metkus and Guest Editor Allan Jaffe discuss the article "Myocardial Injury in Severe COVID-19 Compared to Non-COVID Acute Respiratory Distress Syndrome." Then in our second discussion, author Naveed Sattar and Guest Editor Ileana Piña discuss the article "Effect of Empagliflozin on Left Ventricular Volumes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction (SUGAR-DM-HF)." TRANSCRIPT BELOW Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: I'm Dr. Greg Hundley, Associate Editor, Director of the Pauly Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Guess what? Double feature again, this episode with the first talking about empagliflozin and its effect on left ventricular volumes in patients with type two diabetes, pre-diabetes, and HFrEF, and this is the sugar DM heart failure study. Dr. Greg Hundley: Carolyn, the second of our double feature Tuesday is a paper that involves myocardial injury in severe COVID-19 compared to non-COVID acute ARDS. Well, let's grab a cup of coffee and Carolyn this week, I'm going to jump into my first paper, which comes to us from Dr. Are Kalstad from the University of Oslo at the Oslo University Hospital. Carolyn, this study tested the hypothesis that the daily addition of 1.8 grams of N-3 PUFA to standard of care, secondary prophylaxis in elderly patients who have survived a acute MI would reduce the risk of subsequent cardiovascular events during two years of follow-up. Dr. Carolyn Lam: Interesting, Greg and a clinically important question. So what did they find? Dr. Greg Hundley: Yes, Carolyn. They enrolled 1,027 subjects who were randomized in this investigator initiated, multi-center randomized clinical trial of adding that 1.8 grams of n-3 PUFA, 930 milligrams of EPA, and 660 milligrams of DHA versus placebo, which was a corn oil supplement, daily to the standard of care in 70 to 82 year old patients with recent, so within two to eight weeks, acute myocardial infarction. The authors found that they could not detect reduction in clinical events in these elderly patients with the recent acute EMI treated with the 1.8 grams of n-3 PUFAs daily for two years. So, a negative study, Carolyn. Dr. Carolyn Lam: Surely, we'll add to that debate that's just so interesting surrounding the PUFAs. But let's go onto another paper I want to tell you about, it provides novel insights into the complex crosstalk between the cardiac endothelial cells and cardiomyocytes during cardiac repair after myocardial infarction. This paper is from Dr. Taleb and colleagues from Park Inserm in France. Their study suggested a deleterious role for endothelial indoleamine 2,30-dioxygenase-1, which I'm now going to abbreviate as IDO, which is an enzyme involved in tryptophan catabolism. They found that the specific deletion of IDO in endothelial cells enhanced cardiomyocytes survival and contractility leading to cardiac function improvement. The IDO dependent effects were mediated by endothelial cell production of kynurenine. The study in essence found that therapeutic strategies targeting cardiac IDO could, in fact, constitute an innovative approach to curb cardiac dysfunction following MI. This was followed by an editorial by Drs. Ma and Wang from Thomas Jefferson University. Dr. Greg Hundley: Very nice, Carolyn. Great studies again from the world of basic science. Well, my next paper comes to us from Professor Gerasimos Filippatos from the University of Athens Hospital. Carolyn, this was a sub-study of the FIDELO-DKD trial that evaluated the effect of the nonsteroidal selective mineralocorticoid receptor antagonists finerenone on kidney and cardiovascular outcomes in patients with chronic kidney disease and type two diabetes with optimized renin angiotensin system blockade. Compared with placebo, finerenone reduced the composite kidney and cardiovascular outcomes. Here the authors report the effect of the finerenone on individual cardiovascular outcomes and in patients with and without a history of atherosclerotic cardiovascular disease. Dr. Carolyn Lam: This is a much anticipated paper. Very excited for you to describe the findings, Greg. Dr. Greg Hundley: Thanks, Carolyn. Among patients with chronic kidney disease and type two diabetes, finerenone reduced the incidents of the composite cardiovascular outcome, that included time to cardiovascular death, myocardial infarction stroke, or hospitalization for heart failure. Additionally, there was no evidence of differences in treatment effect based on pre-existing cardiovascular disease status. Dr. Carolyn Lam: Emerging therapies. Isn't that awesome? Well, some other papers in this issue, there's a White Paper (Frontiers) about the therapy in patients with atrial fibrillation treated with oral anticoagulation undergoing PCI, a North American perspective, 2021 update by Dr. Angiolillo. There's a Research Letter on the gradient of risk and associations with cardiovascular efficacy of ertugliflozin by measures of kidney function, and these are observations from VERTIS-CV trial by Dr. Cherney. There's also a sub-study analysis from Explorer HCM, and that is entitled “Mavacamten Favorably Impacts Cardiac Structure in Obstructive Hypertrophic Cardiomyopathy.” This is by Dr. Saberi. There's another Research Letter on COVID-19 myocardial pathology evaluation in athletes with by CMR and that's by Dr. Clark. Dr. Greg Hundley: Very nice, Carolyn. I have an exchange of letters from Dr. Alkhalil and Kuzemczak, as well as Dr. Navarese regarding the article, “Comparative Efficacy and Safety of Oral P2Y12 Inhibitors in Acute Coronary Syndrome: A Network Meta-Analysis of 52,816 Patients From 12 Randomized Trials.” Next, there's another exchange of letters from Dr. Kastrati and Ferracane regarding the article, “Comparative Efficacy and Safety of the Same Oral P2Y12 Inhibitors in Acute Coronary Syndromes.” Dr. Karabinos has a nice ECG challenge. It's a bizarre down sloping ST segment elevation challenge. Finally, Carolyn, there's a Perspective piece from Dr. Okorodudu entitled, “Exposure to Cardiology as a Strategy to Increase Black Men Involvement in Medicine.” Well, Carolyn, how about we get on to those two feature discussions? Dr. Carolyn Lam: Oh, yes. Exciting. Let's go. Dr. Greg Hundley: Well, listeners, we are here for our first feature discussion today on this February 9th. We have with us Dr. Tom Metkus from Johns Hopkins and Dr. Allan Jaffe from Rochester. Tom, can you tell us what was the background that really framed this study and what hypothesis did you want to address? Dr. Thomas Metkus: This study really arose out of a time and a place in the COVID pandemic. If you can all turn your clocks back to late last spring, we were all enmeshed in the clinical care of many patients with COVID here in the United States, depending on your geography, and also reading an increasing number of reports from other centers that had been enmeshed in the pandemic for some time about myocardial injury, elevated troponin, different aspects of cardiac disease in patients with COVID-19. My background is as a cardiac intensivist, dual boarded in cardiology and critical care, and so this was of particular interest to me, specifically so in that my clinical practice at the time was in a COVID ICU. I spent much of the day every day taking care of these patients, so conceptualizing what myocardial injury meant, what's the pathogenesis, and what does it mean, was an open-ended question at the time. There are certainly many reasons to think that COVID-19 is particularly cardiotoxic. There's obviously the pro-thrombogenic nature of the illness. There's the inflammatory nature of the illness. Dr. Thomas Metkus: Yet, we also found that clinically, there was certainly many patients with COVID-19 who acted like they had myocardial injury from ARDS and pneumonia and we had investigated this in some prior studies prior to the pandemic. Really, the aim of the study was to clarify to the extent that we could and contribute to the growing body of knowledge about what is the prevalence and prognostic significance of myocardial injury in COVID-19. We felt that we had a unique lens on this because we also had a cohort of patients with generic ARDS who had cardiac biomarkers assessed, gave us a nice opportunity to do that. Dr. Thomas Metkus: Our hypothesis, that was really based on our clinical gestalt at the time from being in the ICU every day with COVID-19 patients, was that there are assuredly COVID-19 patients who have unique features of myocardial injury, myocarditis or malignant arrhythmias, or requiring mechanical support. But perhaps more, or at least a majority have myocardial injury that looks and acts an awful lot like it would in a sepsis patient, in an ARDS patient. We hypothesized that myocardial injury in COVID-19 would be more similar than different to the generic ARDS population. As such, we drew a population of patients with COVID-19 from our health system here across several hospitals, and did a bit of a comparison with our historical cohort of ARDS patients. Dr. Greg Hundley: Great description, Tom. Tell us a little more about that study population. You said there was going to be a comparison. What were some of the outcomes that you wanted to evaluate? Dr. Thomas Metkus: Right. This question alludes to an important point as we try to delve and do inference around the COVID literature in general, which is to say the pandemic is heterogeneous across geography and across time. In looking at this study, or indeed any study, and understanding of the study population where these ambulatory patients or intubated patients or patients on the ward, for example, as well as any comparison group are these sepsis patients, pneumonia patients, influenza patients, it's just imperative to do inference and to place the study in context. This study, we sought to look at only intubated patients, and that was partially driven by clinical interest, partially driven by the ability then to provide a comparison to our ARDS cohort. So, intubated patients with COVID-19. Dr. Thomas Metkus: The comparison group is from a study of acute respiratory distress syndrome patients. Primary lung injury patients that were drawn in turn from NHLBI sponsored areas, network clinical trials. That was a study that was a secondary analysis that we did where we checked troponin levels in everybody. A true cross sectional assessment. That's important in that there's a selection bias, isn't there, when you just look at patients who had troponin drawn in the context of clinical care? So, I think for this study in particular, it's important to note that the comparison group of ARDS patients was truly cross-sectional and that it was a population defined who had biomarkers assessed in the entirety; whereas our COVID-19 population was intubated patients who had troponin checked at the point of clinical care. Dr. Thomas Metkus: Now, to address some of the potential biases that are inherent in that assessment of exposure, we purposefully looked at only patients who had troponin assessed within 24 hours of intubation, really to sync up time zero in a sense. It's also important to note the time course of the pandemic. These patients were all in the late spring and very early summer. This was really before steroids, before the recovery trial, before steroids became standard of care. And really, health systems wonder a fair bit of duress at that time and indeed, as many of the listeners will know, the outcomes for hospitalized patients have improved since then for many reasons. But it's only to point out that this study was a place in geography and a place in time, and there are certainly implications about that that I'm sure we'll focus on subsequently. Dr. Greg Hundley: How many subjects did you enroll and what were your study results? Dr. Thomas Metkus: Our COVID-19 patient population here in the Johns Hopkins Hospital included 243 patients. All of them were intubated with COVID-19, so severe disease. Of those, we reported that just over half had clinical troponin levels greater than the upper limit of normal. We assessed the main clinical factors associated with elevated troponin in that patient population, which are largely similar to other reports and they include chronic kidney disease, lactate levels of the marker of malperfusion, ferritin fibrinogen levels as markers of systemic inflammation. We showed as have others that there's a graded increase in mortality with increasing amounts of myocardial injury. Then, probably what I would found the most interesting component of the study is that when we did covariate adjustment for features of critical illness, renal failure, lactate, how severe your hypoxemia was, vasopressor use, age, and sex. Age, sex, and multi-organ dysfunction in a sense. Dr. Thomas Metkus: The association of troponin with mortality attenuated quite significantly. That's similar to what we found in a general ARDS population and consistent with a paradigm of myocardial injury in the non-cardiac critically ill. I think the final finding that we would emphasize is that after you adjust for those mediating factors, the incidence of myocardial injury in COVID-19 was at least comparable to that in the general area's population. It gives an idea to place myocardial injury in context, in my view, as a function of critical illness in most COVID-19 patients. Surely, not all. There are patients with unique syndromes, but in many or most. Dr. Greg Hundley: Well, Alan, let's turn to you. Help us put these results that Tom has described for us really in the context of what we're learning about the heart and in patients with COVID-19. Dr. Allan Jaffe: Well, let me start by saying that as a cardiologist, too, at the Mayo Clinic in Rochester, Minnesota, we've studied previously patients with acute respiratory failure. In point of fact, although most of you are not quite as old and may not remember, when we first started seeing ARDS patients, many of the same issues that are here today for COVID, came up. For example, and people may not remember this, we actually did a randomized trial of anti-platelet therapy in patients with ARDS because we were convinced that thrombosis was ubiquitous and was a frequent contributor to the illness that we saw. So that if one thinks about it in another sense and says, "If you'll correct for modern day technology that gives us some additional insights, how different really is COVID ARDS from standard ARDS." I think what this paper has substantiated is that there are lots and lots of similarities that exist. I think that's important because it keeps us from chasing around and looking for some additional issues for us to try and take care of or treat additionally. Dr. Allan Jaffe: That said, I think the way to conceptualize it is some of the troponin elevations are because patients who have chronic heart disease get COVID and they may have those elevations right at admission. There's an acute component having to do with critical illness that is nicely described in this manuscript. Then, there are those unique clinical features, whether you think it's myocarditis, I'm not sure how common myocarditis, type 2 MI, ischemia, a variety of things, and maybe a new type of myocarditis that we're finding with some very peculiar cells that we see in interstitium with or without increases in troponin. But I think it puts it into the bucket of saying, treat these patients conventionally and look for the other complications. I think that's a terribly important message that I was attracted to when I read this paper. So, thank you, Tom. Dr. Greg Hundley: Very good. Well, Tom, what do you see as the next study really to be performed in this space? I'll ask you first and then come back and gather some of Allan's thoughts. Dr. Thomas Metkus: Absolutely. I love that framing about kind of COVID in the heart, which is to say that there are some things that are direct pathogenic related to COVID and there are some things that are secondary, and then there are some things related to patients with underlying heart disease coming to care. I think the next set of studies that can help us disentangle this are related to that paradigm in that more multimodal phenotyping, biomarker phenotyping, but also echo phenotyping and MRI phenotyping, we're starting to see those come down the pike to say, here's the biomarker evidence of myocardial injury, but what does that mean, functionally? What does that mean from an imaging perspective? The second important facet for the next series of studies will be the long-term follow-up. We know from the general critical care literature, that there is indeed a powerful and important entity of the post critical illness syndrome, and in COVID that's come to be called long COVID or the long hauling. We've known that even patients with general critical illness get that and to the extent that the heart plays a role in that, it implies one needs to follow these patients prospectively. Dr. Thomas Metkus: I think the other implication of this work for the next set of studies is that there are many biases that can be brought to bear when reviewing the pandemic literature and assuredly an editorial team sees the entire spectrum of them, but they would include, as I alluded to, careful selection of patients assuring meaningful classifications of exposure at a uniform time assuring adequate comparison groups. That's really going to be the key to doing good inference. Then, the final thing I'll add is that the next set of studies should and will integrate clinical research and clinical epidemiology with causal inference principles with using what we're learning from the basic science community, to have conceptual models about how has COVID affecting the heart at the cellular level, et cetera, et cetera, et cetera. In a sense, that community of researchers that you see coming together in this pandemic is why doing this work is very rewarding and I think meaningful. I think those are all features of the next set of studies that should include indeed epidemiologic analysis, randomized trials, and basic science analysis. Dr. Greg Hundley: Allan, do you have anything to add? Dr. Allan Jaffe: Well, I want to endorse the idea that one of the problems in this field is that patients present at different times with different clinical syndromes, because some of them have been at home, some of them have been hospitalized, some of them are recognized de novo late. One of the things that's necessary as a consistent repetitive approach so that we get consistent data, not only on each COVID patient sequentially, but also on the control group that is important. The other point I'll emphasize that Tom mentioned is that individuals who have elevated troponins who are critically ill with ARDS and most likely with COVID as well, have some sort of underlying cardiovascular disease. Often once those patients leave the hospital there, the troponin is out of sight and out of mind. COVID is reminding us by showing us the panoply of additional clinical syndromes that exist post-hospitalization. That as with ARDS, I would argue, that's a mistake. These patients need to have follow-up with cardiology to investigate what that underlying cardiovascular component is. Dr. Greg Hundley: Great. Well listeners, we want to thank Dr. Tom Metkus from Johns Hopkins om Johns Hopkins and Dr. Allan Jaffe from the Mayo Clinic in Rochester, Minnesota for bringing us this study regarding intubated patients with COVID-19, indicating that the myocardial injury shares many similarities to that experienced by patients with ARDS. Now listeners, we will turn to our second feature discussion on this February 9th. Dr. Greg Hundley: Well, listeners, welcome to our second feature discussion today. We have with us, Dr. Naveed Sattar from Glasgow, Scotland, and our guest editor, Dr. Ileana Pina from Detroit Medical Center. Welcome to you both. Naveed, we'll start with you. Could you describe some of the background that helped you formulate this study and what hypothesis did you want to address? Dr. Naveed Sattar: Yeah, thanks Greg. When I was watching the empirical outcomes study, I almost fell off my seat when I saw the results in heart failure, hospitalization. I actually, I sent a text to John McMurray who wasn't actually at the meeting and I sit next door to John McMurray who's obviously preeminent heart failure. I worked also with many of the fantastic heart failure colleagues, Mark Pietri, Cardic Joon and colleagues. At that time I felt, well, actually it wouldn't it be lovely, I was aware of MRI studies they've done on other drugs in heart failure and I thought, well, if this drug effects improves heart failure, well potentially, although we didn't have it amply reduced at the time or have heart failure, they've come subsequently. Perhaps it changes, lead to cardiac remodeling. Dr. Naveed Sattar: So we've designed the randomized placebo control trial of empirical fluorescent versus placebo and 105 patients who had heart failure with ejection fraction below 40%. We wanted big 4th ventricles as Professor McBuddy would tell me, we have lots of debates about these things to really give us adequate power follow-up for at least 36 weeks to see if we can see improvements in left ventricular installment volume or global longitudinal strain, which were our primary outcomes. Dr. Greg Hundley: Very nice. Great overview of the study design. Who did you enroll? I know patients with an ejection fraction less than 40%, but equal numbers of men and women, was this ischemic heart disease? Dr. Naveed Sattar: I think the majority of patients were male about two-thirds average age, 68, pretty much like the empirical reduced to that by half population. About 80% here had type two diabetes, about 20% had pre-diabetes. The other characteristics, the majority had class 2, NYHA Class IV heart failure, minority Class III. About a third were already on arnes. Also, the background theoretically was fantastically well. Dr. Naveed Sattar: The other critical thing we really did, we excluded people with atrial fibrillation because that really affects the quality of the MRI. Our group and it's a brilliant journey to be, I'm not a heart failure expert, but working with all these colleagues, they have brilliant experience in this. They know the mistakes to avoid, and one of them is, do not include people with atrial fibrillation because your MRIs will just not be readily interpretable. Also, it needs to be big enough. It needs to have big enough volumes to begin with to be able to see a change. It needs to be long enough to potentially see the remodeling. All that experience of John, Mark and Pandeep were put together in a really tight protocol. When the results came, I almost, again, fell off my seat because well, it worked. I guess, you're going to ask me about the results and what we find. Dr. Greg Hundley: Absolutely. Tell us about those results. We're waiting to hear. Dr. Naveed Sattar: Two primary outcomes were really what we saw was a reduction in the left ventricular and systolic volume index and by six mils per meter squared, and the diastolic volume index by 8.2 mils per meter squared. We didn't see a change in global longitudinal strain. We did not see changes in KCCQ or six minute walk test, but actually the reality is we now know the size of this chart is underpowered to see changes in six minute walk tests or KCCQ, in lieu of another trial that has some changes in that, but we didn't see them and I think our study was done ... I can tell you, Greg, the amount of work that went in this study, the quality control that people should look at the supplement when it comes out, the degree of attention to imaging protocols and quality control was, I think in my experience, unparalleled. Dr. Naveed Sattar: The team really pulled out all the stops to get this, but so the reductions in the volumes, that's probably the key thing. We think that this may reflect the reverse cardiac remodeling and that we think then fits in what you see with other drugs that benefit patients with heart failure. Because the bigger the volumes, the more people tend to die with heart failure or get readmitted. If you shrink the ventricles, that probably their contractility improves. What the actual mechanism is, I don't know, but I'm sure Ileana probably come in there in terms of discussing potential pathways. The final thing I should say is just for the internal validity or external validity, NT-proBNP did come down, suggesting less left ventricle wall stress. Schematic also went up. All the things that we've seen in the big trials was there so I think we've done a really strong, robust trial. Dr. Greg Hundley: Thank you, Naveed. Well, Ileana, as a guest editor, what attracted you to this paper? Then, how do you put the results from this study in the context with some of the other publications related to SGLT 2 inhibition in patients with heart failure? Dr. Ileana Piña: I think all of you know, that we, the heart failure community is pretty excited about these drugs and what they're doing. I also nearly fell off my chair when I saw the first EMPA-REG and I saw those curves splitting. Then, I further did that when the DAPA data came out and you see these curves split up almost immediately. What was attractive about this paper is that we really don't know how this happens. We think we do, but we really don't. We don't think necessarily that it's the glucose excretion, because that maybe happens in diabetics, but not necessarily in the non-diabetics. Yet the drugs seem to work in both. But remodeling is such a fascinating concept. I personally happen to love the concept of reverse remodeling. It's something that we in the heart failure community really believes that if we can reversely remodel the ventricle, then outcomes will get better.   Dr. Ileana Piña: We really link them. Your proBNPs were elevated but not huge. This wasn't a very sick debilitated population. This was primarily Class II. Pretty well-medicated in background, you didn't necessarily give the doses clearly, but pretty well with percentages of RAS inhibition and everything else. Now you see that the volumes are coming down and you say, "Wow, is that what's it doing?" If it happens that quickly, because remember, we've got to explain why the curves of heart failure, hospitalizations split up almost immediately. You did show in your time of follow-up that these changes occurred during that follow-up. I am actually not at all surprised that you didn't see anything in the KCCQ because we know that first of all, the patients weren't that sick to start with so it's hard to see improvement when you don't have a lot of sickness and a six- minute walk. This group, for a six-minute walk, is going to have a very wide standard deviation. A six-minute walk doesn't really distinguish the people who are doing well. To me, it's more for the sicker. Dr. Ileana Piña: The fact that neither of these things change doesn't bother me at all. But I think that the next step before Greg asked me, is what's the outcome. In other words, can you tie that reverse remodeling directly to an outcome, be it mortality, which is getting argued out there, whether all the drugs are the same? Or just even the heart failure hospitalization, which I think is a very important outcome in this population. You did it well, you did it carefully, you can tell the data's very clean. You did do a little bit better with the women, so I can't scold you for that as I usually do, because you've had about 30 some percent women, which is very similar to what the big EMPEROR trial has had. I'm always fighting to get more women in the trial. Dr. Ileana Piña: At some point you may want to examine the reverse remodeling by gender, by sex, actually and see, even though you have a small number, you have 105 patients, you may not have enough data. But I think in the future, because we do believe that women remodel differently and reversely remodeled differently. That would be very interesting to see if there's any differences. Dr. Greg Hundley: Thank you, Ileana. Naveed, do you have anything to add? Ileana's really laid out on a nice course to follow forward. Do you have anything to add to her comments? Dr. Naveed Sattar: No, I completely agree with all of them. I think the key thing is nice that this came out straight after EMEPEROR-reduced and a year after that, for heart failure with the team that, John and colleagues were led out. I was involved in the EMPEROR-reduced so that the mechanism helps. I think clinicians buy into this concept. It does what they think drugs do to improve heart failure outcomes. I think that helps and it might help prescribing, get people the confidence that these drugs do work in a mechanism that works. Dr. Naveed Sattar: The only thing that I think we would love to have done is if doing the MRIs even sooner, how quickly do these actual volumes change? We think it's reverse remodeling, but maybe we need another trial doing MRIs at one month, three months just to see how quickly these volumes do actually change. Because I still think that's a bit of doubt. But having said all that, I've loved this journey working with my fantastic Hatfield colleagues, a brilliant team in Glasgow. We're now thinking about the next trial. Let's see where we get to in terms of algorithms and trials, but the diabetes, heart failure, kidney disease fraternity coming together is fantastic. I'd loved being part of that journey. So great. Dr. Ileana Piña: There's another interesting observation in your data was a hematocrit. It's really tiny, but the signal is there, which to me has also been fascinating. We see a lot of anemia in this population. A benefit in the hematocrit, I think, is really important. The fact that you did this with MRI, I don't think this is a good echo study, to do this with echo. I think you need the reliability and the precision of an MRI.   Dr. Naveed Sattar: Yeah, I agree. We have other data coming up, Ileana, in terms of renal blood flow, because you've mentioned that as well at the same time, which we haven't yet analyzed. There's a lot more data which needs a good Biobank and pick some of these mechanisms. So, yeah, fantastic. Dr. Greg Hundley: Well listeners, this has been an excellent discussion and we want to thank Dr. Naveed Sattar from Glasgow and our guest editor, Dr. Ileana Pina from Detroit Medical Center, bringing us these results regarding the administration of empagliflozin and favorable changes in left ventricular volumes in patients with heart failure and a reduced ejection fraction. Dr. Greg Hundley: 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.  

Episode description:   This episode talks about the my-plate method of eating as well as what actually constitutes a portion size – it's smaller than you think, and some quick tips to help you visualize what you put into your mouth. Show Notes: MyPlate | U.S. Department of Agriculture Portion Distortion, Eat Right, NHLBI, NIH Thank you for listening.  Download my FREE Offer: 3 Ways to Eat Better When You Have A Busy Work Week: https://triciard.com/workbook/ If you found value in this podcast, please rate, review and subscribe on iTunes. Together we can create a safe space for taking imperfect action to create the whole health we desire and deserve. I'm truly grateful for your support in creating this community. Join the FREE FB community at:  www.facebook.com/groups/wholehealthempower/ Learn more and connect at WholeHealthEmpower.com https://www.instagram.com/wholehealthempower/ Are you interested in nutrition or accountability coaching sessions with me? My email is: info@triciaRD or head over to my website at wholehealthempower.com or triciaRD.com Are you Interested in sponsoring a show? How about having me as a guest on your podcast or in your community? Please contact me at:  info@triciaRD.com

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

CardioNerds (Carine Hamo, Amit Goyal, and Daniel Ambinder) discuss the obesity epidemic and how it relates to the cardiovascular system with Dr. Chiadi Ndumele, cardiologist and epidemiologist at The Johns Hopkins Hospital and chairs the obesity subcommittee of the American Heart Association (AHA). They cover obesity definitions, epidemiology, strengths and limitations of different biometrics, including BMI, impact on myocardial structure and function, and current pharmacologic & surgical options for weight loss. They also discuss the practical approach to addressing obesity with patients. This episode was produced by Dr. Carine Hamo. Show notes & references by Dr. Daniel Ambinder. Episode graphic by Dr. Carine Hamo Cardionerds Cardiovascular Prevention PageCardioNerds Episode PageSubscribe to our newsletter- The HeartbeatSupport our educational mission by becoming a Patron! Show notes Coming soon! Cardionerds Cardiovascular Prevention Series The Cardionerds CV prevention series  includes in-depth deep dives on so many prevention topics including the ABCs of prevention, approach to obesity, hypertension, diabetes mellitus and anti-diabetes agents, personalized risk and genetic risk assessments, hyperlipidemia, women’s cardiovascular prevention, coronary calcium scoring and so much more! We are truly honored to be producing the Cardionerds CVD Prevention Series in collaboration with the American Society for Preventive Cardiology! The ASPC is an incredible resource for learning, networking, and promoting the ideals of cardiovascular prevention! This series is kicked off by a message from Dr. Amit Khera, President of the American Society for Preventive Cardiology and President of the SouthWest Affiliate of the American Heart Association. Guest Profiles Dr. Chiadi Ndumele is an Assistant Professor in the Department of Medicine at Johns Hopkins University. Dr. Ndumele graduated from Harvard University School of Medicine. He completed his Internal Medicine training at Brigham and Women’s Hospital, where he also served as Chief Medical Resident. He was Chief Cardiology Fellow at Johns Hopkins University. During fellowship training, Dr. Ndumele received an MHS and Ph.D. in Epidemiology at Johns Hopkins Bloomberg School of Public Health. Dr. Ndumele’s research has been supported by career development awards from the NHLBI and Robert Wood Johnson Foundation, a Catalyst Award from Johns Hopkins, an R01 from the NHLBI and an AHA Strategically Focused Research Network Grant. He has received national recognition for his work, including a Young Physician-Scientist Award from the American Society of Clinical Investigation. He has national leadership roles including Chair of the Obesity Subcommittee of the American Heart Association (AHA) and Editorial Board membership on the journals Circulation and Circulation Research. Dr. Ndumele’s research focuses on mechanisms linking adiposity to CVD and strategies to improve prediction and prevention. References and Links Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: A report of the American College of cardiology/American Heart Association task force on practice guidelines and the obesity society. Circulation. 2014;129(25 SUPPL. 1):102-138. doi:10.1161/01.cir.0000437739.71477.ee Yu Z, Grams ME, Ndumele CE, et al. Association Between Midlife Obesity and Kidney Function Trajectories: The Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis. September 2020. doi:10.1053/j.ajkd.2020.07.025 Kaze AD, Musani SK, Bidulescu A, et al. Plasma Adipokines and Glycemic Progression Among African Americans: Findings from the Jackson Heart Study. Diabet Med. November 2020. doi:10.1111/dme.14465 Cohen LP, Vittinghoff E, Pletcher MJ, et al. Association of Midlife Cardiovascular Risk Factors with Risk of Heart Failure Subtypes Later in Life. J Card Fail. November 2020.

In this CME episode intended for allergists and other healthcare professionals, Michelle M. Cloutier, MD, Chair of the Expert Panel Working Group of the National Asthma Education and Prevention Program Coordinating Committee that is coordinated by the National Heart, Lung, and Blood Institute (NHLBI), discusses important aspects of the NHLBI’s newly released 2020 asthma guidelines during this in-depth and comprehensive interview. Listen now to learn more about what the guidelines do and do not address, as well as important perspective about how to put these recommendations into practice.

In this episode, the National Heart, Lung, and Blood Institute CIO Alastair Thomson explains how his agency is advancing international research related to COVID-19 with an expansive cloud-based ecosystem, called BioData Catalyst. Thomson also touches on how AI can improve patient health outcomes, the importance of diversity in research, agency funding opportunities and partnerships, and more.

Jane Ferguson:                  Hi, everyone. Welcome to episode 35 of Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine. I'm Jane Ferguson, an assistant professor of medicine at Vanderbilt University Medical Center, and an associate editor at Circulation: Genomic and Precision Medicine. This episode is first airing in December 2019. Let's see what we published this month.                                                 Our first paper is an “Integrated Multiomics Approach to Identify Genetic Underpinnings of Heart Failure and Its Echocardiographic Precursors: The Framingham Heart Study” from Charlotte Anderson, Ramachandran Vasan and colleagues from Herlev and Gentofte Hospital, Denmark and Boston University.                                                 In this paper, the team investigated the genomics of heart failure, combining GWAS with methylation and gene expression data, to prioritize candidate genes. They analyzed four heart failure related and eight echocardiography related phenotypes in several thousand individuals, and then identified SNPs, methylation markers, and differential gene expression associated with those phenotypes. They then created scores for each gene, based on the rank of statistical significance, aggregated across the different omics analysis.                                                 They examined the top ranked genes for evidence of pathway enrichment, and also looked up top SNPs for PheWAS associations in UK Biobank, and examined tissue specific expression in public data. While their data cannot definitively identify causal genes, they highlight several genes of potential relevance to heart failure pathogenesis, which may be promising candidates for future mechanistic studies.                                                 The next paper is “Genetic Determinants of Lipids and Cardiovascular Disease Outcomes: A Wide-Angled Mendelian Randomization Investigation” and comes from Elias Allara, Stephen Burgess and colleagues, from the University of Cambridge and the INVENT consortium. While it has been established, therapies to lower LDL cholesterol and triglycerides lead to lower risk of coronary artery disease, it remains less clear whether these lipid lowering efforts can also reduce risk for other cardiovascular outcomes. The team set out to address this question using Mendelian randomization. They generated genetic predictors of LDL cholesterol and triglycerides using data from the Global Lipids Genetics Consortium, and then assessed whether genetically predicted increased LDL and triglycerides associated with risk of cardiovascular phenotypes using UK Biobank data. Beyond CAD, they found that higher LDL was associated with abdominal aortic aneurysm and aortic valve stenosis. High triglyceride levels were positively associated with aortic valve stenosis and hypertension, but inversely associated with venous thromboembolism and hemorrhagic stroke.                                                 High LDL cholesterol and triglycerides were also associated with heart failure, which appeared to be mediated by CAD. Their data suggests that LDL lowering may have additional cardiovascular benefits in reducing aortic aneurism and aortic stenosis, while efforts to lower triglycerides may reduce the risk of aortic valve stenosis, but could result in increased thromboembolic risk.                                                 Next up is a paper from Steven Joffe, G.L. Splansky and colleagues, from the University of Pennsylvania and Boston University, on “Preferences for Return of Genetic Results Among Participants in the Jackson Heart Study and Framingham Heart Study”. There has been increasing discussion and concern about how to handle genetic data, and whether genetic results should be returned to participants, and under which circumstances. In this study, the teams that had to assess what participants themselves think. They query participants in the Jackson Heart Study, the Framingham Heart Study and the FHS Omni cohort, presenting them with potential scenarios that varied by five factors including phenotype severity, actionability, reproductive significance and relative of the absolute risk of the phenotype.                                                 Across all scenarios, 88 to 92% of respondents said that they would definitely or probably want to learn their result. In Jackson Heart Study respondents, factors increasing the desire for results included a positive attitude towards genetic testing, lower education, higher subjective numeracy, and younger age. The five pre-identified factors did not affect desire to receive results in Jackson Heart Study. Among Framingham Heart Study respondents, desire for results was associated with higher absolute risk, presentability, reproductive risk and positive attitudes towards genetic testing. Among FHS Omni respondents, desire for results was associated with positive attitudes towards genetic testing and younger age. Overall, these data show that across a variety of studies, there a high level of interest in receiving genetic results and that these are not necessarily linked to the phenotype or clinical significance of the results themselves.                                                 The next paper concerns “Peripheral Blood RNA Levels of QSOX1 and PLBD1 Are New Independent Predictors of Left Ventricular Dysfunction after Acute Myocardial Infarction” and this comes from Martin Vanhaverbeke, Peter Sinnaeve and colleagues, from University Hospital Leuven. They were interested in understanding whether they could identify subsequent left ventricular dysfunction in patients who suffered an acute myocardial infarction. They obtained blood and performed RNA-Seq at multiple time points in 143 individuals, following acute MI, to identify transcripts that were associated with subsequent LV dysfunction. They validated candidate gene transcripts in a validation sample of 449 individuals, confirming that expression of QSOX1 and PLBD1 at admission, were associated with LV dysfunction at follow-up. Adding QSOX1 to a model, consisting of clinical variables and cardiac biomarkers, including NT proBNP, had an incremental predictive value. They took their findings to a pig model and found that whole blood expression of both genes was associated with neutrophil infiltration in these ischemic myocardium. This study suggests that expression of QSOX1 and PLBD1 following MI, may have utility in predicting development of LV dysfunction and may be markers of cardiac inflammation.                                                 The next paper is a research letter from Hanna Hanania, Denver Sallee and Dianna Milewicz, from the University of Texas Health Science Center, and Emory University School of Medicine. Who set out to answer the question, “Do HCN4 Variants Predisposed to Thoracic Aortic Aneurysms and Dissections?” Previous work has suggested that rare variants in HCN4 associated with thoracic aortic disease, including ascending aortic dilation, left ventricular noncompaction cardiomyopathy, and sinus bradycardia. However, the evidence for disease segregation was relatively weak. The team set out to explore these potential associations using exome sequencing data from 521 individuals, from 347 unrelated families with heritable thoracic aortic disease, as well as 355 individuals with early onset sporadic aortic dissections, but no family history of disease. They identified a missense variant G482R, which segregated with disease in four unrelated families, was absent from the nomad database and was predicted to disrupt protein function and have deleterious effects. Their data support the evidence that HCN4 rare variants can cause heritable thoracic aortic disease with left ventricular noncompaction cardiomyopathy and bradycardia.                                                 Our final paper is a white paper from H. Li, X. J. Luo and colleagues, from the National Heart, Lung and Blood Institute at the NIH, and will likely interest anybody who applies for NIH grants, which I'm assuming is most of you listening to this podcast. Their paper on, “Portfolio Analysis of Research Grants in Data Science Funded by the National Heart, Lung, and Blood Institute”, delves into the type of data science research funded by NHLBI between fiscal year 2008 and fiscal year 2017. They identified 630 data science focused grants, funded by NHLBI, using keywords for bioinformatics and computational biology. They then analyzed the distribution of these grants across different disease areas and compared the results to data science grants funded by other NIH institutes or centers. Around 64% of funded grants were for cardiovascular disease with 22% in lung and airway disease, 12% in blood disease and 2% in sleep.                                                 NHLBI's investment in data science research grants averaged about 1% of its overall research grant investment, and this remained constant over the 10-year period. However, this proportion does not include other large scale investment by NHLBI in building data science platforms through other mechanisms. Of relevance to our listeners across all institutes, most funded data science research grants were related to genomics and other omics data. In this paper they include lots of graphs breaking down grant distributions across different categories, so it's worth a look as you plan your next grant application.                                                 That's all for December and the final episode of 2019. Thanks for listening and happy holidays to all who celebrate. I'm excited to be back in 2020, to kick off the next decade of exciting advances in genomic and precision cardiovascular medicine.                                                 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.  

Dr Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast soiree and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor for the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:            And I'm Greg Hundley, Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week we're going to talk about carotid stenosis, and you remember how we measure those a lot with ultrasound, and what that thickness is, and IMT? Well, we're going to talk about getting some thresholds and an update in that with our feature discussion today. But before we get there, how about grab a cup of coffee and we get started with other papers. Dr Carolyn Lam:               All right. Well, I've got my coffee and I'm ready to tell you about two papers. They're both on left ventricular hypertrophy. One is basic and one is clinical. I will start with the basic paper because it is a super cool one that uncovers a novel mechanism underlying myocardial hypertrophy. And this involves S-nitrosylation, a prototypic, redux-based post-translational modification, S-nitrosylation. So this is from co-corresponding authors, Drs Xie, Han, and Ji from Nanjing Medical University, who performed a series of elegant experiments using myocardial samples from patients and animal models exhibiting myocardial hypertrophy, and they demonstrated that S-nitrosylation of muscle limb protein plays a crucial role in myocardial hypertrophy. This muscle limb protein modification enhanced binding to toll-like receptor 3 and receptor interacting protein kinase 3, which stimulated NOD-like receptor pyrin domain containing 3 or NLRP3 inflammasome activation and consequent caspace-1 and interleukin 1 beta activation, ultimately promoting myocardial hypertrophy. They further showed that the deficiency of S-nitrosylated muscle limb protein governed toll-like receptor 3 really alleviates pathological myocardial hypertrophy. Okay Greg, I can see the look on your face. You're like what? That was a lot. What are the clinical implications, right? Dr Greg Hundley:            Yeah, Carolyn, you are taking me back to molecular biology course 410, that I would take as a senior in college. Wow. So tell me what are the clinical implications? Dr Carolyn Lam:               All right, here's a take-home. The data really identify that S-nitrosylated muscle limb protein is a key regulator, which together with toll-like receptor 3 made therefore serve as putative therapeutic targets in treating pathological myocardial hypertrophy in heart failure. That's the take-home. Before any further comments, let's go to the clinical study. Now, this one focuses on a malignant subphenotype of left ventricular hypertrophy in which minimal elevations of cardiac biomarkers identify individuals with left ventricular hypertrophy at high risk for developing heart failure. And this is from corresponding author Dr James de Lemos from UT Southwestern. He and his colleagues tested the hypothesis that a higher prevalence of the malignant left ventricular hypertrophy phenotype among blacks may contribute to racial disparities in heart failure risk. So they pooled data from three large multi-ethnic cohorts, that is Eric, Dallas Heart Study, and MESA, totaling more than 15,700 participants. These participants were then classified into three groups: One, those without ECG left ventricular hypertrophy; two, those with ECG left ventricular hypertrophy but normal biomarkers; and three, those with ECG left ventricular hypertrophy and at normal levels of two biomarkers, high sensitivity troponin T above six nanogram per liters, or NT-proBNP above 100 picograms per milliliter. And that last group were the malignant left ventricular hypertrophy group. They found that the prevalence of malignant left ventricular hypertrophy was threefold higher among black men and women versus white men and women. Compared to participants without left ventricular hypertrophy, the adjusted hazard ratio for heart failure was 2.8 in those with malignant ventricular hypertrophy and only 0.9 in those with left ventricular hypertrophy and normal biomarkers. And these were similar findings in each race and sex subgroups. Mediation analysis indicated that 33% of the access hazard of heart failure among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant left ventricular hypertrophy in blacks. Dr Greg Hundley:            So Carolyn, race could be a really important issue in left ventricular hypertrophy. What did the authors conclude? I mean, how should this help us perhaps manage these patients? What was the take-home? Dr Carolyn Lam:               So this really shows that a higher prevalence of the malignant hypertrophy phenotype may in part, explain the higher risk of heart failure among blacks compared to whites. And what it means too is that when left ventricle hypertrophy is detected by ECG or cardiac imaging, perhaps we should consider measuring high sensitive troponin T or NT-proBNP, which will help distinguish those in whom risk for heart failure is favorable from those at a much higher risk. Dr Greg Hundley:            Very, very interesting. Well Carolyn, I'm going to switch. I've got a basic paper and it's going to focus on dysfunctional adipocytes and how they might talk to cardiomyocytes in the situation of ischemia reperfusion injury. And the corresponding author is Xin-Liang Ma, from Thomas Jefferson University in Pennsylvania. So Carolyn, do you have any thoughts regarding how patients with diabetes might experience a greater degree of myocardial ischemia reperfusion injury in the setting of an MI? Dr Carolyn Lam:               Oh my goodness, you're really putting me on this spot here. Well, I know things that come to mind would be oxidative stress, microvascular disease. Dr Greg Hundley:            Very good. Open-ended questions for Carolyn's quiz. I'm going to give you a 90. That was very good. So Carolyn, this current study attempted to clarify whether and how small extracellular vesicles may mediate pathological communication between diabetic adipocytes and cardiomyocytes, exacerbating myocardial ischemia reperfusion injury. And to do this, adult male mice were fed a normal or high fat diet for 12 weeks. The small extracellular vesicles from diabetic serum, diabetic adipocytes, high glucose, high lipid-challenged, non-diabetic adipocytes were injected then, intramyocardially, distal of the site of a coronary ligation. Dr Carolyn Lam:               Okay. So Greg, I would not have guessed it was about extracellular vesicles, but very interesting. What did they find? Dr Greg Hundley:            Intramyocardial injection of diabetic serum small extracellular vesicles or these SEVs, in the nondiabetic heart, significantly exacerbated myocardial ischemia reperfusion injury, as evidenced by poor cardiac function recovery, larger infarct size, and greater cardiomyocyte apoptosis. And administration of small extracellular vesicles, biogenesis inhibitors, significantly mitigated the myocardial ischemia reperfusion injury in diabetic mice. And mechanistic investigations in these studies identified that MIR 130B3P is a common molecule, significantly increased in diabetic serum of small extracellular vesicles and mediated the pathological communication between the dysfunctional adipocytes and the cardiomyocytes. Therefore, if in the future, we could interfere with this molecule, that could perhaps be a novel strategy for attenuating diabetic exacerbation of myocardial ischemia reperfusion injury. Really, a clever study, I think. What else did you find in this issue of the journal? Dr Carolyn Lam:               Yeah, Greg, this week's issue is packed with other papers too. For example, there's the research priorities for HFpEF by NHLBI working group summary by Dr Shah, et al. There's a research letter by Dr Kaltman on the disparities in congenital heart disease mortality based on proximity to a specialized pediatric cardiac center. There's also another research letter by Dr Irisawa, on the impact of low-flow duration on favorable neurological outcomes of extracorporeal CPR, after out-of-hospital cardiac arrest, and this is a multicenter prospective study. Dr Greg Hundley:            It sounds like a lot's in the mailbag. In the couple of things that I wanted to talk about, Dr Giulia Rivasi from the University of Florence, and William White from University of Connecticut, exchange a series of letters back and forth regarding a previous publication on the effects of intensive versus standard ambulatory blood pressure control on cerebrovascular outcomes in older individuals. I have another research letter entitled, The Cardiac Cell Therapy Rejuvenates the Infarcted Rodent Heart via Direct Injection, but not by Vascular Infusions. And that is from Dr Jeffrey Molkentin from Cincinnati Children's Hospital Medical Center. Finally, though Carolyn, there's a very interesting piece from Dr Carl Bakker at the Ann and Robert H. Lurie Children's Hospital of Chicago, discussing are we now in a time, in the United States, where congenital heart surgery should be coalesced or regionalized? And that really comes on the back of a discussion of there have been several high-profile articles in the national media, reporting on US congenital heart surgery programs. And that's led to, the author describes, some closure of several centers and at least in five programs. So a great discussion on, should this be regionalized? But we've got a great feature article coming ahead and how about if we head to that. Dr Carolyn Lam:               Let's go, Greg. Dr Greg Hundley:            Welcome everyone, to this feature discussion where we are going to discuss the use of diagnostic ultrasound in the carotid arteries and how that pertains to selection of patients for vascular surgery. And with us today, we have Dr Jesse Columbo from the Geisel School of Medicine at Dartmouth University in Hanover, New Hampshire. We also have Dr Bob Zwolak, from the Manchester VA at the Dartmouth School of Medicine and we have our own Josh Beckman from Vanderbilt University, one of our associate editors at Circulation. And Bob, let's get started with you. Could you tell us a little bit, what was the background of this study and what hypothesis were you looking to test? Dr Robert Zwolak:           It goes without saying that stroke is still a huge health problem in the United States. If there is any good news, it's that stroke incidence is falling slightly, but there are still over 100,000 deaths from stroke each year in United States and as many as 700,000 new strokes each year, and a significant proportion of those derive from atherosclerotic plaque in the carotid bifurcations. Carotid duplex ultrasound is a fantastic way to assess the presence of plaque in the carotid bifurcations because it does not use any ionizing radiation, does not require any contrast. Ultrasound is a relatively less expensive technology than CT or MR, and the study can be repeated so we can follow people over time, who are found to have significant atherosclerotic plaque in their bifurcations. The hypothesis of our study though, was that there is variation in the diagnostic thresholds used by various carotid ultrasound testing laboratories, such that it may impact the healthcare and the treatment plans of people who undergo the studies. Jesse will tell you the details, but specifically, we hypothesized that people who undergo this carotid ultrasound test may or may not be inducted into a surveillance program and intensive therapy based on the diagnostic criteria that were used by the individuals conducting their ultrasound study. And even more substantially, we hypothesized that individuals who undergo carotid endarterectomy or potentially carotid stenting, could also have their procedure influenced, whether or not they undergo surgery or stenting based on the carotid ultrasound results. It might vary from one facility to another. So it potentially could be that an individual would be inducted into ultrasound surveillance or even undergo carotid surgery, depending on the vascular laboratory in which they were tested. Dr Greg Hundley:            Jesse, could you tell us a little bit, what was your study population and how did you design this to address the hypothesis that Bob just stated? Dr Jesse Columbo:          Sure. A review of the published literature really shows a variability in that ultrasound criteria that's used for diagnosing carotid stenosis. And so our first objective was to see if we could obtain as many in-use criteria as possible. Our first step was to partner with the Intersocietal Accreditation Commission, the commission that accredits vascular labs. We partnered with them and obtained a 25% random sample of ultrasound criteria in use across the US. And so that kind of gave us the starting point for the criteria upon which to look at. We then wanted to apply those to a couple of different groups. As Dr Zwolak mentioned, there's really two primary breakpoints here. One, you either have mild stenosis, where you get medical therapy, but no further surveillance, or moderate stenosis, at which point you then are dedicated to long-term surveillance per the AAJ recommendations, or then, the break point between moderate and severe stenosis where surgery is considered. What we wanted to do is examine the impact of moderate and severe stenosis thresholds. For the severe stenosis thresholds, we use the Vascular Quality Initiative Registry, which collects information on patients who underwent carotid endarterectomy. When we studied patients specifically that we thought the percent stenosis would be the major deciding factor in who got surgery, those are the asymptomatic stenosis and we applied the range of severe stenosis criteria from the IAC to those patients. We then wanted to study other individuals who might be committed to long-term surveillance based on the criteria used. And so for that, we used participants in the Cardiovascular Health Study, which had their induction into the study, had baseline data on carotid stenosis collected. And so that kind of formed our basis of the study, applying the criteria to those two different groups of individuals. Dr Greg Hundley:            And so how many subjects did you have in the two cohorts? And then tell us what were your study results? Dr Jesse Columbo:          Sure. Once we narrowed down that patients in the vascular quality initiative to those who underwent surgery for asymptomatic carotid stenosis, we had about 28,000 patients. And then when we examined the Cardiovascular Health Study, we had about 4,800 or 5,000 patients in that group. What we found was pretty interesting. If you look at individuals who underwent surgery, and you take the carotid threshold criteria and apply it to them, and if you say, "Well, we're going to take criteria in the fifth percentile versus criteria in the 95th percentile," what you'll find is that 10% of patients who got surgery, fall between that range. And what that means is that there are patients, approximately 10% of patients, who are undergoing surgery that may not have been offered surgery if they had gone to a different institution, which we thought a pretty important finding. The second part was studying patients who maybe committed to long-term surveillance. And if we took centers that were in the fifth percentile versus those in the 95th percentile for their carotid stenosis thresholds, we found a twofold difference in the number of patients that would be committed to long-term surveillance. And remember, this is the difference between getting aspirin and a statin and medical therapy, but no longer surveillance and getting carotid ultrasound every six months to a year for a long period of time. That twofold difference really could have a meaningful impact on patients. Dr Greg Hundley:            It sounds like we've got a variance issue here and that could really impact clinical care. So while ultrasound's very portable and advantageous, how do we use these results to more effectively select how we're going to implement ultrasound to monitor these patients? Dr Joshua Beckman:       I have to say the results of this study, when I read them the first time were eye opening. One point that doesn't come out clearly to those folks who aren't necessarily in the field, is that these are the labs that have been accredited and they are the top labs in the United States. This doesn't include at least half of the rest of the labs in the United States and suggest that if there's variation in the very best of labs, you know that there's even more variation that's being practiced routinely around the United States. So when I read this, I thought that there was a huge problem that they were uncovering. There are many, many millions of patients with atherosclerosis. And so what we have to figure out now is how to standardize the measurement and reading of these studies so that ultrasound can be deployed routinely, without a fear of your treatment varying based on which doctor you decide to see and where you decided to go. And I think the fact that these guys highlighted that in such a nice and clear way, really raises the alarm and raises the flag that attention needs to be paid here quite soon because it's quite important. Dr Greg Hundley:            So what study could we perform next? And maybe I'll ask, Bob, you just start off. What study could we perform next to help clarify and guide us to the better use of ultrasound in this situation? Dr Robert Zwolak:           Well, I think there are two issues. The first issue that this manuscript points out is the one of variation and it's real and the results speak for themselves. The second issue is the one of accuracy, and the question of what are the best thresholds? And there are several ways that this can be standardized. I'm pleased to say that the Intersocietal Accreditation Commission, the IAC, that Jesse mentioned, is actually tackling this problem. Dr Robert Zwolak:           But what's the gold standard? 40 years ago when ultrasound was developed, these thresholds that people are discussing, were related to measurements on contrast arteriograms. And the catheter-based contrast arteriogram, a relatively invasive study, was the source and we compared ultrasound velocities to the measurements on the contrast arteriograms to determine these thresholds that Jesse has investigated. That resulted in substantial variation depending on the individual authors. The question is, over time, have the machines changed? Is there really a central focus that we can look at? Most of these studies were very small and so it accounts for the variation in recommendations. Dr Robert Zwolak:           The IAC now, is going back and collecting contemporary contrast arteriograms, not so many of which are done anymore and so, it's taken a very substantial multicenter effort. But trying to look again, to see if there are more accurate results that could be published, studied in a way such that they would be universally accepted and potentially promulgated by professional societies within guidelines. And standardized such that various specialties, whether it's vascular surgeons who run the labs, or a cardiologist, or radiologist, would agree on a set of both accurate and reproducible and constant velocity thresholds to standardize this technology, which is otherwise a very, very good technology and eliminate this variation that we've seen. Dr Greg Hundley:            Well, this has been a phenomenal discussion in a very interesting piece of research. Jesse, can you give us sort of a point forward from here, how do we move forward with some of these results and what you anticipate seeing going forward? Dr Jesse Columbo:          Well, a duplex ultrasound for carotid stenosis is really important. There are lots of studies done. It's a great way to follow patients over time, in a noninvasive manner. And I might hope that this paper would open the eyes of some of the listeners as to what the carotid ultrasound really means. Instead of just looking at the percent stenosis on the report, to perhaps look at the raw velocities and interpret them in the context of the patient, because I think that has really important impact on how we might manage some of these individuals, for each person that you see. Dr Greg Hundley:            Well, listeners, we want to thank Dr Jesse Columbo, Dr Bob Zwolak, also Dr Josh Beckman, for discussing this very informative research related to the use of ultrasound for assessing carotid stenosis. Dr Greg Hundley:            On behalf of both Carolyn and myself, we wish you a great week and see you next week. This program is copyright, the American Heart Association 2020.  

Commentary by Dr. Valentin Fuster

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.  

Chronic obstructive pulmonary disease (COPD), an inflammatory disease of the small airways in the lungs, affects 16 million Americans and is the fourth leading cause of death in the United States, according to the National Heart, Lung, and Blood Institute. Physicians would like to identify the disease in its earliest stages, when it is most treatable.In a landmark study funded by the NHLBI, an international team of researchers led by Michigan Medicine discovered that a noninvasive technique called parametric response mapping, or PRM, could identify the small airway damage common in early stages of COPD.For more information about this story visit: http://michmed.org/Ylq1R See acast.com/privacy for privacy and opt-out information.

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 as well, at Circulation, and director of the Pauley Heart Center in Richmond, Virginia at VCU Health. Carolyn, this issue, we've got a super-exciting interaction to follow related to SGL2 inhibitors on 24-hour ambulatory blood pressure in African-Americans, something used to treat diabetes, and maybe a positive effect on blood pressure, but more to come on that. Now, Carolyn, you're also planning to discuss some results from another SGL2 study. Dr Carolyn Lam:                                You bet. This time, I'm taking you to Japan for the results of the SACRA study which stands for SGLT2 Inhibitor and Angiotensin Receptor Blocker Combination Therapy in Patients with Diabetes and Uncontrolled Nocturnal Hypertension and this is from Dr Kario and colleagues from Tochigi in Japan. It's a multi-centered, double-blind parallel study of 132 non-obese older adults with type 2 diabetes and uncontrolled nocturnal hypertension, receiving stable antihypertensive therapy, including angiotensin receptor blockers, who were then randomized to 12 weeks' treatment with empagliflozin 10 milligrams once daily or placebo. Clinic blood pressure was performed at baseline in weeks four, eight and 12. Twenty-four hour ambulatory blood pressure monitoring was performed at baseline and week 12 and morning home blood pressure was determined for five days before each visit. The primary efficacy endpoint was changed from baseline in nighttime blood pressure. Dr Greg Hundley:                             So, what did they find, Carolyn? Dr Carolyn Lam:                                Well, empagliflozin significantly reduced nighttime systolic blood pressure versus the baseline. The reductions in daytime 24-hour morning, home, and clinic systolic blood pressure at 12 weeks with empagliflozin was also greater than placebo. Between group differences in body weight and glycosylated hemoglobin reductions were significant, but small and the changes in antihypertensive medication during the study also did not differ significantly between the groups. Dr Greg Hundley:                             Very good. Well, I'm going to switch gears and talk also on the same theme of sugar and diabetes and evaluate the long-term consumption of sugar-sweetened and artificially-sweetened beverages and the risk of mortality in U.S. adults. This is a study by Vasanti Malik from the Harvard School of Public Health. Now, as you know, in epidemiologic studies, intake of sugar-sweetened beverages has been associated with weight gain, a higher risk of type 2 diabetes, coronary heart disease and stroke, but to date, few studies have examined the association between sugar-sweetened beverages and intake and mortality. All right, Carolyn, I'm going to give you a quiz now. Here's the first question. Dr Carolyn Lam:                                What? Dr Greg Hundley                               That's right, sugar-sweetened beverages are the single largest source of added sugar in the U.S. diet, true or false? Dr Carolyn Lam:                                I'm going to guess true. Dr Greg Hundley:                             Okay, so all those consumption of sugar-sweetened beverages in the United States has decreased in the past decade. National survey data show a slight rebound in consumption in recent years among adults in many age groups. With the average equivalent being, multiple choice, 2%, 6.5% or 10% of our total energy requirements? Dr Carolyn Lam:                                Oh, my goodness. One of the higher ones. I'm just going to go in the middle, 6.5. Dr Greg Hundley:                             Excellent, good choice, you're a good multiple-choice taker, 6.5%. So, among younger adults, sugar-sweetened beverages contributed. They're a little bit higher, 9.3% of the daily calories in men and 8.2% in women in the United States. Now, how about other parts of the world, particularly developing countries? The intake of sugar-sweetened beverages, is it dropping, is it flat or is it rising dramatically? Dr Carolyn Lam:                                Sorry, Greg, but that one's too easy. It's definitely rising. Dr Greg Hundley:                             Yup, you got that right. Dr Carolyn Lam:                                I live in those other developing countries, so I've seen so. Dr Greg Hundley:                             And it's really thought due to widespread urbanization and beverage marketing. So, now we've got an alternative, artificially-sweetened beverages. And they're often suggested as alternatives to sugar-sweetened beverages and intake levels have increased of these alternative sweeteners in the United States. So, next question. Are the artificially sweetened beverages a better alternative to sugar--sweetened beverages in regard to cardiovascular or all-cause mortality? Dr Carolyn Lam:                                Yikes. Okay, so Greg I'm afraid to guess on this one because I have to admit I sometimes, with a sweet tooth, like to take these alternative beverages. I think you're going to be telling us. Dr Greg Hundley:                             Well, we don't know. Most of the data in this area is from research and comes from associative analyses utilizing longitudinal cohorts and some studies suggest yes, some studies, no. For example, one in the elderly suggested artificially-sweetened beverages, but not sugar-sweetened beverages were associated with adverse events, but critiques indicated that finding may have related to reverse causation because the elderly patients were switching from sugar-sweetened to artificially-sweetened beverages. So, where are we now? Well this study, in our Journal, examined the associations between the consumption of sugar-sweetened beverages and artificially-sweetened beverages with the risk of total and cause-specific mortality among 37,716 men from the Health Professionals Follow-up Study between 1986 and 2014 and 80,647 women from the Nurse's Health Study from 1980 to 2014, who were free from chronic diseases. Dr Carolyn Lam:                                Wow, that's a huge combined cohort. So, come on, what were the results? Dr Greg Hundley:                             So, the researchers found after adjusting for major diet and lifestyle factors, consumption of sugar-sweetened beverages was associated with a higher risk of total mortality and cardiovascular mortality and cancer mortality and, thus, the results provide further support for the recommendations and policies to limit intake of sugar-sweetened beverages and to consume artificially-sweetened beverages in moderation did improve overall health. Now, what were the results from artificially-sweetened beverages? Well, they were associated with total and cardiovascular disease mortality in the highest intake category only. So, those consuming large amounts of those daily, but only in the cohort of women from the Nurse's Health Study, not from the men in the Health Professionals Follow-up Study. Artificially-sweetened beverages were not associated with cancer mortality in either cohort. So, moving forward, the positive association between high intake of artificially-sweetened beverages and total and cardiovascular disease mortality observed among women requires more study and further confirmation and also, we might consider that even though artificially-sweetened beverages could be used to replace sugar-sweetened beverages among habitual sugar-sweetened beverage consumers, higher consumption of the artificially-sweetened beverages would probably be discouraged. Finally, policies and recommendations should continue to call for reductions and limits on sugar-sweetened beverages intake and also address alternative beverage offerings with an emphasis on our favorite, water. Dr Carolyn Lam:                                Sweet, Greg! Or maybe not so sweet. Oh, goodness. All right, well my paper deals with related, but not related perhaps, but talking about ketone body, 3-hydroxybutyrate and the cardiovascular effects of treatment with this ketone body in chronic heart failure and this is from corresponding author, Dr Nielsen from Aarhus University Hospital in Denmark and his colleagues. Now, they performed a series of studies. In the first 16 chronic HFrEF patients were randomized in a crossover design to three hours' infusion of 3-hydroxybutyrate or placebo and monitored invasively with a Swan-Ganz catheter and studied with echocardiography and they found that infusion of 3-hydroxybutyrate increased cardiac output by two liters per minute or 40% with an absolute improvement in left ventricular ejection fraction of 8%, and the observed defects were accompanied by vasodilation with a resultant stable systemic and pulmonary blood pressure. Now, in the second part of the study, they studied eight HFrEF patients examined at increasing infusion rates of 3-hydroxybutyrate and they found a dose response relationship with a significant increase in cardiac output. And, finally, they studied 10 HFrEF patients and 10 age-matched volunteers, randomized in a crossover design to a three hour infusion of 3-hydroxybutyrate or placebo and they looked this time at myocardial external energy efficiency and oxygen consumption using 11-carbon acetate PET and what they found was 3-hydroxybutyrate increased oxygen consumption without altering myocardial external energy efficiency. The response did not differ between HFrEF and age-matched volunteers. Dr Greg Hundley:                             Wow, Carolyn, there was a lot of data in that study. So, what's your main take home? Dr Carolyn Lam:                                In summary, 3-hydroxybutyrate, this ketone body, demonstrated dose-dependent beneficial cardiac and hemodynamic effects in patients with heart failure reduced ejection fraction without deteriorating mechano-energetic coupling and without causing any safety issues. And what's significant is that this opens the door to modulating circulating 3-hydroxybutyrate as a novel treatment option in patients with heart failure. Dr Greg Hundley:                             Right, Carolyn, so I've got an interesting study from the world of basic science that's looking at the role of potassium channels as novel molecular targets and bradyarrhythmia’s and even, perhaps, in atrial fibrillation. This is from Yoshihiro Asano from Osaka University in Japan. So, the acetylcholine activated potassium channel is expressed in the sinus node, atrium, and atrioventricular node and contributes to heart rate slowing triggered by the parasympathetic nervous system. So the potassium, activated potassium channel is a heterotetramer of 2 inwardly rectifying potassium channel proteins encoded by two genes, KCNJ3 and KCNJ5, respectively. Dr Carolyn Lam:                                Okay, so what did this study show? Dr Greg Hundley:                             What it showed is a selective potassium acetylcholine channel blocker effectively inhibited a mutant potassium channel and up-regulated heart rate and bradyarrhythmias using a zebra fish model. And this is really interesting, Carolyn, because two conclusions are worth considering. First, future studies could determine the prevalence of bradyarrhythmias associated with dysfunctional mutation in this potassium channel. And, second, results raise the possibility that pharmacologic blockade of this channel might serve as a therapy for increasing heart rate and be especially beneficial for bradyarrhythmias in patients with gain of function mutations in the channel and, therefore, genetic testing for KCNJ3 and KCNJ5 in patients with bradyarrhythmias may provide a drug treatment option in lieu of an invasive surgical implantation of a pacemaker. Dr Carolyn Lam:                                Fascinating! Thanks, Greg. What a great issue and now onto an even greater feature discussion. Dr Greg Hundley:                             Welcome, everybody, to the second part of this interview. We've got a very exciting paper to discuss with you. Remember this is our backstage pass to Circulation and we've got today, Keith Ferdinand from Tulane University in Louisiana and our Associate Editor, our hypertensive expert, Dr Wanpen Vongpatanasin from the University of Texas Southwestern Medical School in Dallas. We're going to be discussing the anti-hyperglycemic and blood pressure effects of empagliflozin in African-Americans with type two diabetes and hypertension. Keith, we're going to start with you. What was your hypothesis for this study? Who's the study population? Review a little bit about your design and, importantly, what were your results? Dr Keith Ferdinand:                         Well, my hypothesis was that one of the new classes of medications, the SGLT2 inhibitors, which have a mild diuretic effect and a mild natriuretic effect, may have benefits in self-described African-Americans in not only controlling glucose, but also controlling hypertension. These medicines are approved, of course, as medications for type 2 diabetes, but we had seen in some earlier trials that did not include self-defined African-Americans, that there may be a blood pressure effect. We know that diabetes is higher in blacks, almost twice that seen in the general population and, of course, hypertension and uncontrolled hypertension is disproportionate. So, here's a medication that may be even more beneficial in that population and we wanted to study it. Dr Greg Hundley:                             And tell us a little bit about who was in the study and what was your design? Dr Keith Ferdinand:                         The design was to be a placebo-controlled randomized trial using empagliflozin starting at 10 milligrams and force-titrating to 25 milligrams versus placebo on the background of conventional anti-hypertensive agents. Everyone was on one or more anti-hypertensive agents. We used the gold standard for blood pressure control with 24-hour ambulatory blood pressure and that was the means by which patients entered the study, although the primary endpoint was changed in hemoglobin A1c, we actually designed and powered the study to see if there would be a change in blood pressure. Additionally, we looked for changes in weight, losing calories with the effects of the SGLT2 inhibitors with glycosuria has translated in some preliminary trials to weight loss. So, this was a study looking at a population. Most of them had diabetes for approximately nine to 10 years, 59 years of age, definite hypertension, obesity, a high risk population, to see if a new class of medications would be beneficial. Dr Greg Hundley:                             And what did you find? Dr Keith Ferdinand:                         Fortunately, we did find an effect. It did lower the primary endpoint of a change in hemoglobin A1c, but remember it was powered also by blood pressure effect and fortunately, we did see that both with the ambulatory and clinic blood pressure, both at 12 weeks and 24 weeks. The clinic blood pressure was a trend, but the ambulatory blood pressure was positive at 12 weeks and both had a strong difference in terms of confidence intervals for blood pressure lowering. About five millimeters of mercury at 12 weeks and up eight millimeters of mercury at 24 weeks for the change in ambulatory blood pressure which, in a large population would translate into a significant blood pressure lowering, the hemoglobin A1c reduction was also significant. But, although that was the primary endpoint, my concern is as a cardiologist and cardiovascular specialist. Dr Greg Hundley:                             And what dose did you select? Did you have to up-titrate this at all and, finally, were there any side effects? Dr Keith Ferdinand:                         You know, with the SGLT2 inhibitors, you have an effect both in terms of glycosuria, some osmotic diuresis and some natriuresis, and with the loss of body weight. But the change in body weight really wasn't that much, about 1.2 kilos and the change in blood pressure was discordant with the change in body weight. So, we think that the effects in blood pressure may be from extended diuretic effect, but it may also be from effects on endothelial function that are outside those significantly related to diuresis, per se. Because you're urinating glucose, glycosuria, you would expect the potential for superficial infections, mycotic infections and that was seen. The rates were not prohibitive and not dissimilar to what's been seen in other studies. So, overall, the drug was well-tolerated. It did not have any significant adverse effects outside of a few mycotic infections, which are basically superficial fungal infections and that's been seen in other uses of the SGLT2 inhibitors, but nothing that I think would be unusually disturbing in this population. Dr Greg Hundley:                             Outstanding. So, Wanpen, going to switch over to you and ask you to help us put this in the context of treating African-American men, women with hypertension. How do we think about using this new finding? How would we integrate it with other therapies that these individuals already might be taking? Dr Wanpen Vongpatanasin:         Sure, so I think that this study is very intriguing and interesting that empagliflozin to me actually had more prominent benefit on lowering 24-hour blood pressure than the previous study that the true analysis showed the effects of 24-hour blood pressure is much less or almost half of four to five millimeters of mercury and that could be that this was not that significant in African-Americans and maybe this drug is particularly effective and, as you know, African-Americans tend to have more salt sensitive form of hypertension and I wonder if that could explain the results, but I think it's very encouraging because this drug class approved for treatment of diabetes and medication. African-American have higher blood pressures than other ethnic groups and having diabetes makes them prone to having more resistant hypertension. In this particular trial, almost 40% of the patients enrolled is already taking three or more antihypertensive medications, so adding this on top and having that benefit is as good as adding spironolactone, for example, and I didn't see from the manuscript, how many patients are taking spironolactone already, but I would be curious to see that, as well. But I think that is something that physicians should think about and this drug is already FDA-approved for treating diabetes, so if you have a patient with difficult to control blood pressure and already needed something for diabetes, this could make a lot of sense to use it. Dr Greg Hundley:                             Keith, do you have any thoughts on Wanpen's comment regarding the use of spironolactone in the study population? Dr Keith Ferdinand:                         No, I don't have those specific data available at the time that we're speaking now, but that's certainly something that I will attempt to look at the database and get more information. But, I think Wanpen is absolutely right. If you look at some of the previous studies, for instance, EMPA-REG, the major outcomes trial that led to the indication of a decrease in cardiovascular death and heart failure, the blood pressure lowering wasn't that robust, maybe 4/2, but here we saw at week 24, 10 millimeters of mercury of blood pressure reduction and if you placebo subtract, which is what I mentioned in my first comments, you're talking about 8 to 8.5 millimeters of mercury reduction and that's a significant reduction, especially for ambulatory blood pressure measurement. Dr Greg Hundley:                             Absolutely. So, I'm going to go with each of you separately, but taking this manuscript and this work that Keith, you've performed, we'll start with you. What do you think of the next steps in the research in this area, both from the perspective of using this family of agents in individuals with both diabetes and hypertension? Dr Keith Ferdinand:                         What I would hope in the future is another outcome study is done with an SGLT2, any numbers of that class, that they particularly target enough African-Americans to see if this robust blood pressure reduction not only is found again, but also translates to decreased cardiovascular events. You know, NHLBI, for instance and ALLHAT, selectively over-represents African-Americans. They had 35% African-Americans in ALLHAT and the reason for that is you have a population that has a disproportionate degree of hypertension and a disproportionate degree of associated cardiovascular disease and renal disease, so you want to make sure that any medication that's been shown to be effective is effective in the higher risk population. So a future outcome study, regardless of whether they're renal-based or related to heart failure, I hope will target an increased population of blacks to see some of the robust reduction we have, translates in cardiovascular events. My suspicion is that self-defined African-American versus a genetic factor, describes the phenotype of patients who tend to be more obese, have more salt sensitivity, perhaps subclinical kidney disease and will respond to a medication that has some diuretic natriuretic effects and effects with endothelial dysfunction and sympathetic discharge. Dr Greg Hundley:                             Very good, well I heard sympathetic discharge. Wanpen, any comments there? That's your area. Dr Wanpen Vongpatanasin:         I think that definitely needs to be studied. To my knowledge, there was only one small study that published that tried to measure sympathetic nerve activity directly, but unfortunately that study after a very short-term treatment for like four or five days, so I’m sure that there will be more studies to come and also hope that the future study will shed light on any particular markers with surrogate that will identify patients that will respond better, for example, PATHWAY-2 trials that were done to test the effects of spironolactone on resistant hypertension they found that the lower the reading, the more likely you can have better response to Aldactone and I wonder if this might apply to empagliflozin and be something else. I think the fact that the blood pressures continued to decline from the week 12 to week 24 is very, very interesting when the body weight effect doesn't necessarily go down much further. This really tells us there's something else beyond weight and perhaps glucose that would explain this. Dr Greg Hundley:                             Very good. Well, I certainly want to thank you both for this outstanding discussion. Keith, we want to thank you for bringing this manuscript to Circulation and identifying this new application for this therapy in African-Americans. Wanpen, thank you also for your time and comments. On behalf of Carolyn and myself, we really appreciate you listening. Have a great week and we look forward to seeing you next week. Dr Carolyn Lam:                                This program is a copyright of American Heart Association 2019.  

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. 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:             I'm Greg Hundley, associated editor from the Pauley Heart Center at VCU Health Sciences in Richmond, Virginia. Dr Carolyn Lam:                A big number of acute ischemic stroke patients receiving endovascular therapy in the United States are receiving this therapy only after inter-hospital transfer. What are the temporal transient outcomes following this inter-hospital transfer? Very important discussion coming right up with our featured paper. But for now, sit back, relax with us. We're going to discuss a couple of papers that we found were interesting in this week's journal. Dr Greg Hundley:             Very good, so thanks Carolyn. I'll start off, and I'm going to talk a little bit about stress induced cardiomyopathy, and we also know it as takotsubo cardiomyopathy, looking at a paper from Dana Dawson from the University of Aberdeen in the United Kingdom. Takotsubo cardiomyopathy can result in a heart failure phenotype with a prognosis comparable to myocardial infarction.                                                 In this study, the investigators hypothesize that inflammation is central to the pathophysiology in natural history of takotsubo cardiomyopathy. They prospectively recruited 55 patients with takotsubo cardiomyopathy, and 51 age, sex, and comorbidity match control subjects.                                                 During the index event, and at five months of follow-up, the patients with takotsubo cardiomyopathy underwent a cardiac MRI study in which they looked at ultra-small, super paramagnetic particles of iron oxide, or USPIOs, enhancement for detection of inflammatory macrophages in the myocardium. What would the studies show? Patients with acute takotsubo cardiomyopathy had macrophage-mediated myocardial inflammation.                                                 They also demonstrated modulation of peripheral monocyte subsets and increased systemic pro-inflammatory cytokines. This systemic inflammation persisted for five months, and then at that five-month time point, the cardiac MRI evidence of the macrophage presence was diminished. Dr Carolyn Lam:                Wow, Greg. So this is right up your wheelhouse, isn't it? Can you explain? What are the clinical implications of these MRI findings? Dr Greg Hundley:             It was really interesting. For the first time, they've linked an ongoing inflammatory process using the USPIO contrast agent with MRI actually going on or operative in the heart, and they associate that with systemic markers in the circulation.                                                 They help us elucidate the mechanisms and the pathogenesis of takotsubo cardiomyopathy, and systemic and myocardial inflammation really may start to now serve as a therapeutic target for patients with acute takotsubo cardiomyopathy. Dr Carolyn Lam:                Very interesting. From stress-induced cardiomyopathy to early onset myocardial infarction. The first paper I chose really answers the question, "What is the relative prevalence and clinical importance of monogenic mutations, that is, a single mutation that significantly increases risk, versus a polygenic score, which really measures the cumulative impact of many common variants, in early onset myocardial infarction?"                                                 The co-corresponding authors were Doctor Amit Khera and Sekar Kathiresan and both from Massachusetts General Hospital, and they performed deep coverage, whole genome sequencing of more than 2,000 patients from four racial subgroups hospitalized in the United States with early onset myocardial infarction defined as myocardial infarction before the age of 55 years, and compared this to 3,761 population base controls.                                                 What they found was that a monogenic mutation related to familial hypercholesterolemia was identified in 1.7% of the patients, and associated with a 3.8-fold increased odd of myocardial infarction. In comparison, the high polygenic score, which was composed of 6.6 million common DNA variants and defined as the top 5% of the control population distribution, now, that was identified in 10 times as many patients, so 17% of patients, and associated with a similar 3.7-fold increased odds of myocardial infarction. Dr Greg Hundley:             Interesting. How do we apply this clinically, Carolyn? Dr Carolyn Lam:                These findings really lay the scientific foundation for the systematic identification of individuals born with a substantially increased risk of myocardial infarction. The important point is both familial hypercholesterol mutations and a high polygenic score are associated with more than three-fold increased odds of an early onset myocardial infarction.                                                 However, the high polygenic score cannot be reliably identified on the basis of elevated LDL cholesterol, and yet has a 10-fold higher prevalence among patients presenting with early onset myocardial infarction. So very intriguing that both groups matter. Dr Greg Hundley:             Very good. My next paper is from Adrian Hobbs at the London School of Medicine, and is looking at the role of endothelial C type natriuretic peptide as a critical regulator of angiogenesis and vascular remodeling. We know that a central pathway coordinating both neovascularization and ischemic extremities in PAD is driven by vascular endothelial growth factor or VEGF-A4.                                                 But preclinical studies and other large scale clinical trials have been disappointing because administering or using VEGF-A to promote angiogenesis or arteriogenesis in PAD really hasn't occurred. This group focused on endothelial-derived CMP. Why? Because it plays a fundamental role in regulating vascular homeostasis. It controls local blood flow and the resistance vasculature, and systemic blood pressure, and reduces the reactivity of leukocytes and platelets.                                                 So, what were the results? Clinical vascular ischemia was associated with reduced levels of CMP and it's cognate NPR-C. Moreover, genetic and pharmacological inhibition of CNP and NPR-C reduced the angiogenic potential of the pulmonary microvascular endothelial cells and the human umbilical vein endothelial, and it isolated vessels ex vivo.                                                 So, the study really defines a central pathophysiological role for endothelium-derived C type natriuretic peptide via activation of cognate natriuretic peptide receptor C in angiogenesis and in vascular remodeling. Moreover, the work demonstrates the therapeutic utility of pharmacologically targeting NPR-C to restore deficits in these processes following ischemia and injury. Dr Carolyn Lam:                Interesting, from new mechanisms and targets to good, old, major risk factors for coronary heart disease. Back to the basics but in a really, I think, nicely done paper from Dr Pencina and colleagues from Duke Clinical Research Institute.                                                 Now, their objective in this next paper was to compare the associations of key, modifiable coronary heart disease risk factors with incident coronary heart disease events based on their prognostic performance, the attributable risk fractions and treatment benefits overall and by age.                                                 And so really aiming at quantifying the importance of these major, modifiable risk factors for coronary heart disease. What they did is they used pool participant level data from four observational cohort studies sponsored by the NHLBI, and they created a cohort of more than 22,600 individuals ages 45 to 84 years old who are initially free of cardiovascular disease.                                                 And these individuals were followed for 10 years from baseline evaluation and followed for incident coronary heart disease. They estimated that age, sex and race captured up to 80% of the prognostic performance of cardiovascular risk models. When we add either systolic blood pressure or non-HDL cholesterol, diabetes or smoking to model with the other risk factors, the prognostic performance, as measured by the C index, increased by only 0.004 to 0.013.                                                 However, if you look at it from the attributable risk and absolute risk reduction standpoint, lowering the systolic blood pressure of all individuals to less than 130, or lowering LDL cholesterol by 30% would be expected to lower a baseline, 10-year coronary heart disease risk of 10% to 7% and 8% respectively. Dr Greg Hundley:             That's a lot of data, Carolyn. Help me synthesize all that. Dr Carolyn Lam:                This is a take-home message. Although the individual modifiable risk factors contribute only modestly to the overall model prognostic performance, when we eliminate or control these risk factors, they would actually lead to a substantial reduction in total population coronary heart disease.                                                 That's because if we look at the attributable fraction and the absolute risk reductions, we see that they actually really matter. The take-home message too from Dr Pencina was that metrics used to judge the importance of these risk factors should therefore be tailored to the question being asked. Dr Greg Hundley:             Very good. That was a very nice summary, Carolyn. Dr Carolyn Lam:                Thanks. Let's move on now to our feature discussion, shall we? Dr Greg Hundley:             Very good. Dr Carolyn Lam:                Trials have established that endovascular thrombectomy dramatically reduces disability after acute ischemic stroke due to intracranial large vessel occlusion. In fact, guidelines almost immediately adopted endovascular thrombectomy as a standard of care. However, that has created some problems.                                                 The main one being that hospitals equipped to carry out this procedure are largely limited to tertiary centers in urban areas. This is, of course, important because that means that patients may need to be transferred from another center to receive such treatment.                                                 Today's feature paper discusses this very issue, a terribly important one, and I'm so pleased to have the author with us, Dr Shreyansh Shah from Duke University Medical Center. We have our editorialist, Dr James Grotta who's director of the Mobile Stroke Unit project at Memorial Herman Hospital.                                                 And we have an associate editor, Dr Graeme Hankey from University of Western Australia. So, such an important topic. I think Shrey, could you just jump right in and tell us what your study showed. Dr Shreyansh Shah:         I'm very excited to present findings of our study, and as a Carolyn mentioned, this study is going to have a very important implication in our country here in US on the creation of systems of stroke. I think the findings are already applicable to other countries also where we are seeing endovascular care getting more and more used.                                                 As Carolyn was talking, endovascular treatment is very important and lifesaving measure. But unfortunately, it is not available at every hospital. Patients are often transferred across different hospital or institution before they can receive this endovascular care.                                                 What we did in our project was we looked at the data from the hospital that's participating in Get With The Guidelines®® Stroke, which is a quality improvement program here in US. It looked at the endovascular thrombectomy used especially in relation to inter-hospital transfer.                                                 What we found was big proportion of patients receiving endovascular care, up to about 43% to 45% of patients, were getting the care after transferring across different hospital. The outcomes in this patient were worse compared to the patient who were receiving endovascular care if they had come directly to the hospital.                                                 While there was no difference in mortality between these two groups, the endovascular care, after inter-hospital transfer, resulted in a higher rate of symptomatic ICH, patients are less likely to be discharged to home, which is the preferred outcome. And patient was also less likely to be able to ambulate independently prior to the hospital discharge.                                                 There was also delay in endovascular care initiation for patient who received this after inter-hospital transfer. I think this particular study highlights the magnitude of this problem, and that's why it's going to be important for people who are studying systems of care. The fact that about 45% of patient had to get inter-hospital transfer before endovascular care tells us that we still need to take significant steps in increasing access to this lifesaving therapy. Dr Carolyn Lam:                Thank you and indeed James, I really love the editorial you wrote that accompanied this. I mean you highlighted its importance, and you also noted that what was unusual about the paper was that even after controlling for the delay in initiating endovascular thrombectomy, there was still worse outcomes in the patients who were transferred. Could you share some thoughts? Dr James Grotta:              It is a very timely issue. Now that we have a very effective treatment, the big challenge we have is getting it to the patients as fast as possible. Right now, our system, as is pointed out, means shuffling patients from one hospital to another.                                                 I think that clearly with stroke treatment, any sort of stroke treatment, the faster we deliver it, the better. Other studies have shown that transferring patients is associated with a delay of treatment, and this study showed the same thing.                                                 There was a substantial delay in getting the patients treated if they required a transfer. And as you pointed out, however, this did not explain the entire or was not at least the entire explanation for the worst outcome. So, it is a little bit of a mystery.                                                 I do know from personal experience that transferring patients from hospital to hospital, it's not exactly a black hole, but you lose control of the patient when they're being transferred. These are patients who have large artery occlusions. That means they have their middle cerebral artery is blocked.                                                 And so, the area of brain that's affected is in a very tenuous shape. So, any drop-in oxygen concentration from breathing problems or of any drop-in blood pressure might further worsen the stroke. So, this could happen in transit. So, it's possible that in the process of transfer, these sorts of things happen.                                                 I do think that we do have to be a little bit careful in that by remembering that this was not a randomized comparison, so patients that were treated directly and those that were transferred were not randomized. And so, although they appear to be balanced in a lot of the important variables like their stroke severity, there may be other things that we can't account for that could explain some of the worst outcomes.                                                 I'd like to ask Dr Shah whether he identified any things in ... well, he and his co-authors think might have contributed to some of the worst outcomes.  Dr Shreyansh Shah:        To answer Dr Grotta's question about what other factors may have played a role in the worst outcome that we saw in patients who were getting inter-hospital transfer, I think as we correctly pointed out, transferring this very sick patient is very tricky. As we know, the hemodynamic instability or variability plays an important role in outcomes of stroke patient.                                                 And it is very likely that during the transfer process, there is not adequate control of their blood pressure variability, their oxygen saturation, and this ends up affecting their brain leading to worst outcome. The other possibilities also, as Dr Grotta was explaining, this is not a randomized control trial.                                                 And although we balance for number of important factors that can affect stroke outcome, there might be a selection bias in transferring patient who are more sicker and also patients who received thrombolysis with TPA but did not improve, while the patient who were directly arriving to the hospitals and getting endovascular care, they received the TPA.                                                 It is possible that they started to improve and still received a thrombectomy at the same time. So that group may have been more favorable in that respect, which could have also played a role in better outcomes with patient who are directly arriving. Dr Carolyn Lam:                Interesting. And, you know, with the mention of TPA, I really have to bring James back. I loved your mention about potential solution using mobile stroke units. And since you direct one of them, could you tell us what you meant there? Dr James Grotta:              Yes, of course, I have to state at the outset that I have a little bit of a bias about mobile strokes, and so I do it every day. What a mobile stroke unit is, for those who don't know, it's basically taking the emergency department to the patient.                                                 It's an ambulance with a CT scanner on board and the ability to treat with TPA in the field. But in addition, it's also the CT scanner. We can do CT angio and identify large vessel occlusions on the mobile stroke unit, not to mention the fact that you have a vascular neurologist either in-person or by telemedicine examining the patient.                                                 So clinically, you can make the determination also much more accurately than any sort of pre-hospital stroke scale, whether the patient has a large artery occlusion. That way, you don't have to take the patient to the nearest hospital. You can bypass the nearest hospital, take them right to the thrombectomy center, therefore, avoiding the transfer process.                                                 We've been implementing this in Houston, and there are now about 30 mobile stroke units around the world. The innovation actually started in Germany by Dr Fassbender about a decade ago in Hamburg, Germany. We are conducting a randomized trial, comparing mobile stroke unit care to standard management to see how much better outcomes occur as a result of this faster treatment.                                                 We obviously can treat patients with TPA faster. For example, a similar study from the Get With The Guidelines® a few years ago showed that only 1% of patients treated with TPA in emergency departments get treated within the first hour after symptom onset simply because it takes an hour in the emergency room itself to do the evaluation of the patient and get them treated.                                                 Whereas on our mobile stroke unit, at least a third and probably 40% of the patients we're treating with TPA, we can get treated within that first hour where there may be an exponential better benefit. But we don't yet know really how much that translates to better benefit, and also, of course, mobile stroke units are more intensive in terms of the amount of facilities on board and costs.                                                 So, we need to look at the cost-effectiveness. If it produces only a marginal reduction in disability but costs a fortune, then it's not worth it. But in fact, in our experience, it's pretty practical. We can cover almost the entire City of Houston, which is the fourth largest city in the country, with one mobile stroke unit. When it's well-integrated, it requires careful integration with the fire department and other hospitals in the city.  Dr Shreyansh Shah:        At those two conferences, I came across a very interesting talk from Dr Grotta's group about rendezvous with the EMS which allows extending their coverage area significantly. I think we definitely need more and more innovative solutions like this where we can identify patients by their origin, whether they have large vessel occlusion or not, and then triage them appropriately at the centers that can perform endovascular therapy. So as a result, we can provide them earlier therapy and hopefully, it will lead to better outcome. Dr Carolyn Lam:                Thank you Shrey and James for these incredible insights. Now, Graeme, I want you to have the last word and reflections from down under. Dr Graeme Hankey:        Firstly, just to congratulate Dr Shrey and colleagues on this terrific study that reports a contemporary United States experience, a very broad one across the country, really highlighting how since 2012, until a year ago, there's been a six-fold increase in the number of patients being transferred for endovascular therapy.                                                 And we're all experiencing that around the world. And moreover, since the DAWN trial and the DEFUSE trial were published just over a year ago, which is when this study stopped, there's been an expansion of the window from six hours out to 24 hours.                                                 So, in the last year, which this study doesn't cover, we've seen an exponential increase in the number of people being transferred from rural and remote areas who have had a stroke up to 24 hours ago being considered for endovascular therapy if their CT angiogram at the base hospital shows a large vessel occlusion.                                                 This is likely to be not only internally valid, but externally valid to all of us around the world. It reflects our experience of this avalanche of cases coming. And it's provided a lot of challenges for those who are trying to deliver the service at the tertiary referral center.                                                 And it highlights that nearly half of the cases who are having endovascular therapy are coming from external sites. As Jim has really highlighted in his editorial, it challenges us to reassess the current practice of inter-hospital transfer. Dr Carolyn Lam:                Thank you so much for publishing this paper with us and the editorial. And listeners, don't forget to tune in again next week. This program is copyright American Heart Association, 2019.  

From Stigma to Inclusion Bernice A. Pescosolido is distinguished professor of Sociology at Indiana University and director of the Indiana Consortium for Mental Health Services Research. Professor Pescosolido received a B.A. from the University of Rhode Island in 1974 and a Ph.D. from Yale University in 1982. She has focused her research and teaching on social issues in health, illness, and healing. Pescosolidos research agenda addresses how social networks connect individuals to their communities and to institutional structures, providing the "wires" through which peoples attitudes and actions are influenced. This agenda encompasses three basic areas: health care services, stigma, and suicide research. In the early 1990s, Pescosolido developed the Network-Episode Model which was designed to focus on how individuals come to recognize, respond to the onset of health problems, and use health care services. Specifically, it has provided new insights to understanding the patterns and pathways to care, adherence to treatment and the outcomes of health care. As a result, she has served on advisory agenda-setting efforts at the NIMH, NCI, NHLBI, NIDRR, OBSSR and presented at congressional briefings.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Welcome to Cancer Stories. I'm Dr. Daniel Hayes, a medical oncologist. And I'm a translational researcher at the University of Michigan Rogel Cancer Center. And I'm also the past president of ASCO. Over the next several podcasts, I am privileged to be your host for a series of interviews with the founders of our field. Over the last 40 years, I've been fortunate to have been trained, mentored, and frankly, inspired by many of these pioneers. It's my hope that through these conversations, we can all be equally inspired by gaining an appreciation of the courage, the vision, and the scientific understanding that led these men and women to establish the field of cancer clinical care over the last 70 years. By understanding of how we got to the present, and what we now consider normal in oncology, we can also imagine and work together towards a better future, where we offer patients better treatments, and are also able to support them and their families during and after cancer treatment. Today, I am very pleased to have as my guest on this podcast, Dr. John Minna. John is generally considered one of the pioneers of translational research in solid tumors, and he's widely recognized as a leader in lung cancer. Dr. Minna is currently the director of the Hammond Center for Therapeutic Oncology Research, and Professor of Internal Medicine and Pharmacology at the University of Texas Southwestern Medical Center in Dallas, where he also holds the Max L. Thomas Distinguished Chair in Molecular Pulmonary Oncology, and the Sarah M. and Charles E. Seay Distinguished Chair in Cancer Research. Dr. Minna received undergraduate medical degrees from Stanford in the mid-1960s, which were followed by a residency at Harvard's Massachusetts General Hospital in Boston. He then went to the NIH, and the National Heart, Lung, and Blood Institute for his fellowship in biochemical genetics at the NIH with Dr. Marshall Nirenberg. And then he stayed at the NHLBI as the head of the section on somatic cell genetics. In 1975, he became chief of the NCI-VA Medical Oncology branch within the Clinical Oncology program of the Division of Cancer Treatment. And in 1991, he then moved to University of Texas Southwestern in Dallas, where he served as the director of the Sammons Cancer Center and Chief of the Division of Medical Oncology for four years. And since, he has held his current position. Doctor Minna has authored over 700 peer-reviewed papers, and well over 100 other reviews, book chapters, and educationally related manuscripts. He's won too many awards and honors for me to go through in detail. But these include the AACR's Rosenthal award, and ASCO's Scientific Achievement Award, two of the highest in those two organizations. He's also received the ASCO Statesman Award, and he's served on both the AACR and the ASCO boards of directors. He's been PI of the combined UTSW and M.D. Anderson Cancer Center Lung Cancer Specialized Program in Research Excellence. And in 2015, he was named one of the Giants of Oncology by OncLive. Dr. Minna, that's quite a mouthful, though. Welcome to our program. Thank you so much, Dan. And thanks for all your work in ASCO and everything, too. Well, actually, it was, as you can imagine, a great privilege. I just had a fabulous time. Just as an aside, when I got elected, I interviewed about 10 former presidents. And at the end of each of my set of questions, I said, well, fill in the blanks. What do you want to talk about? Almost everyone of them said the saddest day of their career was the day they had to quit being president of ASCO. And I know that now. Anyway, now I know you went to Stanford. Were you always a California boy? Or how did you get to Stanford? Well, yes. I was born in San Francisco, actually at the Presidio, which is now a fancy movie set-- some of the priciest real estate. And then, my dad was in the Army. My mom was a nurse. And then I grew up in San Diego. And my Dad had the largest family practice in San Diego. And my mom was the nurse that ran the office. I never forget, I called them one day when I was an intern at Mass General and complained I had 25 outpatients that I saw that day. And they laughed. They'd seen 80. And I made maybe 500 house calls with my dad, carrying his bag when I was younger. And so, he obviously was in medical school just before and then right after the Depression. And so, he had had an opportunity. He was going to do a fellowship in pediatrics at Harvard, but couldn't do it. He had to support all his parents and everything. And, by the way, he had immigrated from Italy when he was a kid. So this was quite a story. And so they always encouraged me to go into academic medicine. It was interesting, because all his buddies were surgeons that kept telling me to come back and be a general surgeon in San Diego. So anyways, I grew up in San Diego. And then was lucky enough to get into Stanford undergraduate medical school. So I went back and looked at your publication list, which dates back to the mid-1960s. By the way, I was in junior high then. It looks to me from your list of publications that you weren't originally headed to a career in oncology. In fact, it looks like you were doing genetics. So you've done a lot in lung cancer. Tell us what happened at the NIH that you sort of changed gears and went into lung cancer. Well, actually, the cancer decision was actually made back in medical school. And it was those-- two of the people that you mentioned when we were talking before, Henry Kaplan and Saul Rosenberg, that really inspired me at Stanford. And they both took me under their wing. I remember the last six months of medical school I spent full-time on radiation oncology. Actually, I worked up nearly 100 new patients with Hodgkin's, if you can imagine that. It's all because of the clinical trials going on there at Stanford. So there were all these new patients coming in. So both of them absolutely got me committed to a career in cancer way back in medical school, and then helped get me internships, residencies. It was Henry's letter to get me a position with Marshall Nirenberg. But both of them were instrumental. And they took a group of young people-- another person that was a year behind me was Ron Levy, obviously, a very prominent person in oncology. And there was a group of us at Stanford that they took under wing. And so as medical students, we were going to these clinical protocol conferences in cancer, which probably didn't exist anywhere else in the United States at that time. And it was just amazing to see the two of them work together-- totally different personalities, but extremely skilled clinically and in terms of clinical trials. So that was an exciting time. And so the decision for me was made way back there when. And as part of it, at Stanford Medical School, I was fortunate enough to do my research in the Department of Genetics. And the person that took me under his wing there was Leonard Herzenberg, who was the guy that invented the fax machine. Obviously, probably should have won the Nobel Prize for that. And so it was kind of genetics on the one side, and cancer on the other. So you can see how that kind of evolved going forward. What struck me at Mass General was that there were fantastic clinicians and everything. Obviously, a lot of cancer. But nobody wanted to take care of the cancer patients in Mass General. So an intern resident, I kind of volunteered for all of that. And then when I got to the NIH with Marshall, it was more genetics and everything. And we can talk about that. But I realized after five to seven years there I was either going to be a basic researcher, or get back to my clinical love. And that would have been cancer. So those were the ties that brought genetics and cancer together for me. So can I ask you, when you were in Boston, who was the chief of medicine at Mass General? Oh, gosh. [INAUDIBLE]. The real question I'm asking is, had Dr. Farber's work filtered across town to you guys? That was just about the same time he was starting to give chemotherapy to kids over at Children's. Right. No. Obviously, they knew about it. But it really wasn't discussed at all there. And there was obviously a separation between what was going on at Farber and the Brigham and then at Mass General. Now, obviously, things are much more integrated. So what made you go into lung cancer after you got to the NIH? I think it was Vince DeVita. But it happened because I actually-- so I'd been with Marshall and they had given me my own group to work with there that we mentioned. And I'd been working on somatic cell genetics. And so I went to Vince and I said, look it, I have to do an oncology fellowship so I can learn about this stuff now and get ready. Of course, this is-- the boards came in '75, which were later. And so he said, well, John, I'm not going to do that. But I tell you what. There's this branch of the VA hospital that [INAUDIBLE] [? Anson ?] and Frank [INAUDIBLE] and [INAUDIBLE] are running. And I'm trying to decide whether or not to shut it down. So I tell you what. Why don't you go down and run that? And then you'll kind of learn on the job. And, of course, being 35, 36 years old, you think you can do everything. And I said, well, who's the staff there? And he said, well, they're all leaving. And fortunately, one guy [AUDIO OUT]. So I said, well, who are the fellows coming out of the program that are the best fellows? He said, well, that's easy. It's Dan [INAUDIBLE], Paul Bunn, and Jack McDonald. And so I said, well, if I go talk to them, will you at least back me up? And so I did. And fortunately, two of the three agreed to come. I said, you're going from being a fellow to being a senior investigator here in one fell swoop. But this is it. Jack went with Phil [? Stein ?] and did all the work on GI. Phil was leaving the NCI to go down to Georgetown. So they did that. And fortunately, Marty Cohn was down at the VA. He is fantastic clinical trials [INAUDIBLE] and done work with lung cancer. And we did all of that. And so, we went down there. And so, I said, well, OK, got to work on lung cancer. And so we've got to then start working on the genetics of lung cancer. Of course, everybody said that was totally stupid and not possible. And fortunately, I had my collaborator who had been part of the oncogenic virus program, a pathologist, Dr. Adi Gazdar [INAUDIBLE]. So I said, Adi, come on down, and we can do that. So there was people that really gambled on me. Yeah. I wanted to talk about your association with Adi. Before I get to that though, what were you doing for lung cancer in the mid '70s? It must have been pretty crude. Well, we thought it was pretty sophisticated. And, in fact, what we-- obviously, there was the whole series of the first phase of small cell lung cancer clinical trials. There were first reports that occasionally patients respond, have these dramatic responses. And so we set up these whole series of trials. And, of course, at that time, nobody out in the private world wanted to take care. So these patients would come flooding in. And we would do all the staging, get their tissues, and then try to start cell lines from them that nobody had been able to that before. But then they all went on to randomized clinical trials. And Marty Cohn played a big role in that. Obviously, Dan [INAUDIBLE] and Paul Bunn were instrumental. Des Carney came on. And so, these were various combination therapies that [INAUDIBLE] essentially leukemia-like treatment. But Vince always thought the reason we weren't in small cell lung cancer was that we weren't tough enough. And I kept saying, Vince, we're getting-- we're putting them in isolation. We're treating them with more intensive regimens than with leukemia. And so odd responses, but not. And then the other important component of that was Eli Glatstein's recruitment to the NCI as head of the NCI radiation oncology branch. And he really was-- I mean, briefly had known each other at Stanford. And because we were both tied to Henry Kaplan, that made Eli and me instant friends. And basically, we were like brothers. And so he totally threw the support of the radiation oncology branch behind that. And then there were a series of trials with that. Allen Lichter, former president, obviously, and Joel Tepper, he [? added ?] parts to that. So that was fantastic. Anyone from-- So it must have been pretty exciting for you to see some of the first complete responses with chemotherapy in a solid tumor with a small cell. Absolutely. And that's what-- you know, at that time, and particularly then when we started putting this with limited stage, we were really hoping there was going to be a big tail on the survival curve with people who got put into complete remission being able to remain there. And obviously, the therapies would combine modality with chemo and radiotherapy were complex, too. And we were very fortunate to have the various skillful skill set from the radiation oncologists to work with that. And then in '81, by the way-- so we were at the VA from '75 to '81. And then from '81 to '91, it was the NCI-Navy Medical Oncology Branch, when Vince moved us all up to the new National Naval Medical Center. So you and Dr. Gazdar obviously have had a decades-long collaboration. And how did the two of you even hook up? Was it just because you were providing specimens to him in the pathology lab? Or-- No, no. It all actually started five or six years before. We were-- as part of the somatic cell genetics effort is-- I don't know if you remember, there was also a big effort in terms of isolating tumor viruses and the study of retroviruses. And it turned out that the genetics that I was doing with somatic cell genetics could be used to map receptors for retroviruses. And so he and I collaborated on studying the genetics of RNA viruses in human cells and assigning the various linkages to different chromosomes. And so when, again, as I said, when Vince offered me this battlefield promotion, I knew were going to need a laboratory thing. So I said, Adi, come on down. I said that we were going to have to-- we can't study viruses. We're going to need to study something else. And it's going to probably be lung cancer. And so he agreed. And obviously, he has trained as a pathologist, even better part. And he's now, obviously, one of the world's leading lung cancer pathologists. The other person that was at the VA whose name you may not know is Dr. Mary Matthews, who is a pathologist. And she did a lot of the first VA studies, actually determining that small cell lung cancer was highly metastatic, even when it appeared to be localized. So she was-- I've seen her work. Yeah. Actually, so you were there when viruses were going to be the cause of every cancer. Did you get a lot of pushback if you began to say, I don't think that's the case? Well, it's kind of what goes around comes around. We didn't-- no. As it turned out, it was oncogenes that are cause of cancer, which were discovered through Bishop and [INAUDIBLE] thing too. But you do know the other interesting connection with us and viruses and cancer is that we were obviously studying lung cancers and patients and that. But then, Paul Bunn was extremely still interested in lymphomas. But the way the politics, the Onco politics at the NCI intramural program went, that was already the domain of the medicine branch, Bob Young's branch-- Bruce [? Jander ?] and Dan Longo and Bob Young. But there was one lymphoma that they absolutely wanted to have nothing to deal with. And that was Sézary syndrome mycosis fungoides. So Paul said, OK, we're going to study mycosis fungoides. So both at the VA and at the Navy, we had just huge numbers of patients with [? MF ?] come in. And that involved a variety of studies with electron beam and various therapies and staging that Paul was a major figure in. Well, as part of that-- so we started cell lines, tried to start cell lines from those as well. Well, the other thing that was happening was Bob Gallo's discovery of IL-2, T-cell growth factor. And so we got some of that from him, and were able to study, to grow several of these. And it turned out, one of these was from a young patient with highly aggressive HTLV-1 disease. It was a young black guy from the South. He had one of the first-- you know, his bone scan was a super scan with [INAUDIBLE]. Now, we know. So we didn't do that. And it turned out that Bernie Poiesz was a fellow rotating with us. And he went back to work in Gallo's lab and took those cells. And, of course, Gallo was searching everywhere for oncogenic viruses and retroviruses. And the super [? agent ?] from this cell line, H102, blew the roof off. And it turned out to produce HTLV-1. And that was [INAUDIBLE]. Actually, Henry Kaplan submitted for us to PNAS that was with Bernie and Bob Gallo. And that was the first human retrovirus that was discovered. And then it turned out there were other patients that we had, obviously with T-cell lymphomas, that didn't produce virus. But it turned out that those were ones that the virus could replicate in. And that leads off into a whole separate story that you probably need to talk to Adi Gazdar about, because he started this line. And that's the whole Bob Gallo thing. But the point is that Bob knew that if you could get a T-cell line to grow, it could make the retrovirus, and you could identify it. And so, he kept trying to grow T-cells from patients, at that time young, gay guys from New York and San Francisco. Of course, nothing would grow because they were all being killed by HIV. But there were these T-cell lymphoma lines that had that property. So, in any event, this whole thing came back to viruses, that-- it's not my [INAUDIBLE] study. But it was Adi's and Bob Gallo's. You know, you've through this talked a lot about the basic science and the observations. And the term translational medicine really hadn't been invented yet. But you, and I would argue, Marc Lippman and Bill McGuire in breast cancer, were really some of the first to span the gap between [INAUDIBLE] in the clinic in solid tumors. My impression is leukemia and lymphoma had been going on, but it was the solid tumors where you made your big step. Were you thinking about that the whole time? How can I take this and take better care of Mr. Smith or Mr. Jones? Were people trying to stop you from doing that? Who was your role model to give you the courage to move forward? No. I think if you were present back at the NCI-VA and NCI-Navy, it was pretty clear-- and this didn't require any set of smarts-- that the whole idea to start these things was to have models that you could then test to see about new therapies in order to find out what were the underlying causes. And so you remember back there was the [? Amberg ?] and Dan Von Hoff assays for tumor cell sensitivities. So a lot of our first studies were looking at drug response and radiation response phenotypes. And one of the interesting first things was that the small cells, most of them were exquisitely-- they were like lymphocytes, sensitive to radiotherapies, which was what it was like in the clinic. So I think that there was probably kind of obvious some of the things to do. I think the obstacles were-- first of all, the major obstacle was everybody blamed the lung cancer patient for having lung cancer because they smoke. And I'm sure Franco and anybody working in the lung cancer field with Franco Muggia would tell you this. And we're finally over that, I think, and also with the never smoking lung cancer cases. So that was one big obstacle. I think having these models to work with was another. And then just having the genomic techniques to study them. I look at our first publications in Nature with Southern blots and a few samples. And now, you couldn't even-- this wouldn't even qualify as supplementary supplementary data. Actually, I don't know if you were at ASCO. Bruce Johnson's presidential address was an elegant description of the progress made in lung cancer. And he showed pie charts of 10 years ago. And the entire treatment was chemotherapy. And now it's broken up into all the different precision medicine and immunoncology. I've got to think if you were in the audience, and if you weren't, that's fair. But if you were sitting here thinking, boy, shake my head. We've made a lot of progress. Oh, [INAUDIBLE]. Well, I tell you, I get-- some of those slides I know Bruce was-- I was giving those to Bruce. So, you know, clearly, those were the types of obstacles. And everybody thought that-- first of all, everybody thought that lung cancer was not a genetic disease. And in retrospect now, it's obvious. But, you know, so I think there's that-- the technologies. So one brief anecdote about-- and you probably saw this, too, at the Farber. I'll never forget at the NCI-Navy, all of the senior staff rotated. And we had several months worth of attending in there. And we were taking care of patients with all kinds of tumors-- breast, lung, everything. And we had our own ward with 40 beds. And we saw about 70 patients elsewhere in the hospital. And we had 100 patients a day in clinic. So it was a huge service. So I go up, and I'm doing my first day of attending. And I introduce myself. And I'll tell you who my fellows were on that round. So one of them was Nancy Davidson. The other was [INAUDIBLE]. The other was Neal Rosen. And one was George Morstyn, who subsequently became a-- Australian guy became a VP at Amgen. And so they're presenting these cases and everything. And I go back, and I sit down with Paul and [INAUDIBLE] and Dan [INAUDIBLE]. And I say, Jesus. I said, I can't believe it. We have some really good fellows this time. At another time offline when it's not recorded, I'll tell you some of the presentation that Neal Rosen gave that time, which was vintage Neal. And I say this mainly because to our oncology fellows now, I say, look right, look left, and there's going to be some really interesting people that you're meeting right now. Just remember them several years down the line. You know? Nancy was no different in her presentation today than when she gave her presidential address. She had all the [AUDIO OUT] and everything. And so, that was great. Nancy and I are the same age, but she's been my role model for 25 years. [AUDIO OUT] The other thing-- Well, a couple of other questions-- you've been on the board of both the AACR and ASCO. And I'm interested in what you see as both the contrasts and the mutual initiatives going forward and how they've evolved. Do you have any insights into that? Well, I think Saul Rosenberg may have said something about this [INAUDIBLE] to you. He always, from early on, lamented that, quotes, "commercialization" of ASCO, as opposed to its academic thing. I think, number one, ASCO has done a fantastic job in terms of medical education at many different levels. So I think that's a major success. I think also what clearly is needed now is that we get more of the real world experience. So if patients are treated with checkpoint inhibitors with lung cancer, we don't need to know the results of 300, or 400 patients, or 500. We need to know what happens in 10,000 or 20,000 patients. And the only way we're going to get this is to have some kind of interaction with everything that's going on in the real world. And I think ASCO is positioned to do that. And so, I see that type of interaction being very important. Back when I was on the board, there was-- well, how many people from the private sector should be on the board? And we need to have them have a voice, and all of this. And there was kind of the-- then some people in the private sector trying to take control of ASCO for their own group practices. And we won't go into any names or anything here. But I think what's eventually come out is the possibility to really be the best for everything, both educational, translation of findings. So if there's real improvement in discoveries which have happened to be made, we obviously want to get them out as quickly as possible. Patients demand it. But then also, that we can work out some way to get feedback. Actually, this is one of the reasons-- you've hit on a couple of big initiativies over the last 10 years that I've been involved with. One is the development of CancerLinQ. And we hope that CancerLinQ will provide exactly the kind of data you just asked for. The other is the establishment of the Department of Clinical Affairs, and reaching out to the state-affiliated councils. Steve Grubbs is our Vice-President for that. And it's made a big difference. So that instead of being us versus them, academic versus private practice, it's us versus cancer all together. I'm glad you noticed that, actually. One final question, and this is a bit of a trite question. But I'm asking each of my guests on the show, what do you consider your legacy, your greatest accomplishment? In the end, what are people going to remember John Minna has done to change the face of oncology? Is it your science, or your mentoring? Or what's the one thing you would put your finger on? Well, I think Bob Young and I have an agreement about this. It's the mentoring and everything. And I think training the next generation, setting the example, is very important. I would say one other thing that's really important about ASCO that I see going forward is integrating surgery, radiotherapy, other disciplines, too. And I think it's been very successful. It wasn't necessarily all that way at first. But it's been really key. And getting a chance to know some of the giants in surgery and giants in radiation oncology, like Sam Hellman and Eli Glatstein. And I think Vince, in his book, in many ways saw that, too. The DeVita textbook with Hellman and Steve Rosenberg was an important example of that. So I think that's another important legacy from ASCO too. I agree. Well, actually, I think we've run out of time. Dr. Minna, I can't tell you how much I appreciate your taking the time to speak with us today. I'm sure the memberships can be thrilled to listen to the stories you've told. It's interesting, you've referred to several people I've actually already interviewed, or have planned to interview in the near future. You dropped a lot of names. And that's because-- and you sort of alluded to this. I'm not sure any of us recognize where we are in history at the time that history is being made. And then you look back and say, wow, I was there. And that you were fortunate to be at the NIH in those days. I was fortunate to be at the Dana-Farber in a few years after that. And you shed a lot of light. It's been terrific. Any final comments or parting words? Well, no. I think the one thing I would say is I was thinking back to those early ASCO meetings where there would be 5,000, 7,000, 8,000. So you couldn't even walk from one place to another, because you were always stopping and talking. And now you go to 15,000, 17,000 more. And I remember John Niederhuber and I, when he was director of the NCI, on the third day of ASCO walks through and he grabbed me, and he said, John, you're the first person I recognize. And I [INAUDIBLE]. We had roughly 40,000 people at the meeting this year. Yeah. I think that the question-- so going forward is how we need this family, but how do we get it so it could also be on the personal level? Anyway, Dan, it's been good talking to you. And we thank you for your service, Dan. Thank you. It's been great. For more original research, editorials, and review articles, please visit us online at JCO.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening. [MUSIC PLAYING]

Despite major advances in treating and preventing heart disease, the condition is still a leading cause of death in the U.S. At the Utah Cardiac Recovery Symposium, Dr. Gary Gibbons, director of the National Heart, Lung, and Blood Institute, outlined the institute’s strategic vision for improving the health of Americans in a conversation with Dr. Stavros Drakos, a cardiologist and professor of Internal Medicine at University of Utah Health. Photo credit: National Institutes of Health

California barbershops patronized mainly by black men are dispensing advice that could save their customers lives. The businesses are participating in a study funded by the National Heart, Lung and Blood Institute at the National Institutes of Health. It uses barbershop visits to screen men for high blood pressure and, if necessary, get them into treatment. For more, Dr. Paula Einhorn, program officer for hypertension at the NHLBI, spoke to Federal Drive with Tom Temin.

It’s February — the month of love. People everywhere are rushing through Hallmark stores and florists to get their significant others heartfelt cards, flowers and heart-shaped boxes of chocolates. Although showing your loved ones that you care every day is important — not just on Valentine’s day — perhaps more important is making sure that your own heart is healthy. February is American Heart Month, and we’re proud to partner with the National Heart, Lung and Blood Institute’s (NHLBI) The Heart Truth® program, encouraging people to get more physically active and pledge to #MoveWithHeart. Heart disease is the leading cause of death in the United States, yet it is largely preventable by taking certain steps. On today’s episode, we’re joined by Dr. Jerome Fleg, a medical officer with NHLBI’s Division of Cardiovascular Sciences, discussing simple things you can do during the month of February, and throughout the year, to ensure your heart is healthy. After all, in order to live your best life and love those around you, you have to have a healthy heart. Learn more and find out what you can do to make the pledge to #MoveWithHeart.

Catalyzing innovation in clinical trial design and analysis at NHLBI by Blood Advances Talks

Commentary by Dr. Valentin Fuster

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.

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. Our podcast today highlights an important perspective piece on charting a future together and turning discovery science into cardiovascular health. You don't want to miss this, coming up right after these summaries. The first original paper tells us about the importance of changes in exercise capacity following transcatheter aortic valve replacement or TAVR.                                                 First author, Dr. Altisent, corresponding author, Dr. Rodés-Cabau, and colleagues from Quebec Heart and Lung Institute in Canada studied a total of 305 patients undergoing TAVR with baseline and six month followup exercise capacity assessments by six minute walk tests. They found that close to one-third of patients undergoing TAVR failed to improve their exercise capacity despite an optimal hemodynamic result post-procedure.                                                 Factors associated with a lesser exercise capacity improvement included patient characteristics such as older age, female sex, non-cardiac comorbidities, such as chronic obstructive lung disease, peripheral artery disease and bleeding episodes resulting in reduced hemoglobin levels. Importantly, the absence of an improvement in physical performance at six months post-TAVR was an independent predictor of mortality and adverse cardiovascular outcomes during the ensuing four years and particularly among patients with a greater impairment of exercise capacity pre-TAVR.                                                 Thus, implementing exercise capacity assessment pre and post-TAVR may help to improve patient risk stratification and augment the accuracy of the prognostic information given to patients, helping to identify those requiring more intensive followup assessment. The next study provides mechanistic insights into the adverse health outcomes associated with particulate matter exposure in the air. First author, Dr. Lee, corresponding author, Dr. Kahn, from Fudan University in Shanghai, China and colleagues conducted a randomized double-blind crossover trial in 55 healthy college students in Shanghai. Real and sham air purifiers were placed in participant's dormitories in random orders for nine days with a 12 day washout period.                                                 Serum metabolites were quantified using gas chromatography mass spec and ultra-high performance liquid chromatography mass spec. They found that higher particulate matter exposure led to a significant increase in cortisol, cortisone, epinephrine and norepinephrine. Between treatment, differences were also observed for glucose, amino acids, fatty acids and lipids. They also found that higher blood pressure, hormones, insulin resistance and biomarkers of oxidative stress and inflammation were present among individuals with higher exposure to particulate matter.                                                 Thus, this study showed that activation of the hypothalamus-pituitary-adrenal and sympathetic-adrenal medullary axis may contribute to the adverse cardiovascular and metabolic effects of particulate matter exposure in the air. In China, indoor air purification may be a practical way to reduce personal exposure to particulate matter. The next study shows that N-acetylcysteine may be new effective thrombolytic treatment. First author, Dr. Lizarrondo, corresponding author, Dr. Gauberti and colleagues from Inserm, France hypothesized that N-acetylcysteine might cleave the von Willebrand factor multimers inside occlusive thrombi, thereby leading to their disillusion and arterial recanalization.                                                 To test this hypothesis, the authors used experimental models of thrombotic stroke induced by either intra-arterial thrombin injection or ferric chloride application followed by measurement of cerebral blood flow using a combination of Laser Doppler Flowmetry and magnetic resonance imaging. They showed that intravenous and acetylcysteine administration promoted lysis of arterial thrombi that were resistant to conventional approaches such as recombinant TPA, direct thrombin inhibitors and anti-platelet treatments. Furthermore, through in vitro and in vivo experiments, they provided evidence that the molecular target underlying the thrombolytic effects of N-acetylcysteine were principally the von Willebrand factor that crosslinked platelets in arterial thrombi.                                                 Co-administration of N-acetylcysteine and a non-peptidic GP2B3A inhibitor further improved its thrombolytic efficacy essentially by accelerating thrombus disillusion and preventing rethrombosis. In a new large vessel thromboembolic stroke model in mice, this co-treatment significantly improved ischemic lesion size and neurological outcomes. Importantly, N-acetylcysteine did not worsen hemorrhagic stroke outcome suggesting that exerted thrombolytic effects without significantly impairing normal hemostasis. Thus, in summary, N-acetylcysteine was shown to be an effective and safe alternative to currently available anti-thrombotic agents to restore vessel patency after arterial occlusion.                                                 The clinical implications of the study are wide reaching considering the very wide availability, low cost and apparent safety of N-acetylcysteine. This is discussed in an accompanying editorial by Dr. Lillicrap from Queens University, Kingston, Canada. The final study identifies a novel mechanism for regulation of cardiac fibrosis that revolves around plasminogen activator inhibitor type 1 or PAI-1. First, author, Dr. Flevaris, corresponding author, Dr. Vaughan and colleagues of Northwestern University, Feinberg School of Medicine in Chicago, Illinois showed that cardiac fibrosis was detected by late gadolinium enhancement cardiac MRI in two otherwise healthy humans with complete PAI-1 deficiency due to a homozygous frameshift mutation in serpene 1.                                                 They further performed a series of mouse experiments to show that treatment of young PAI-1 deficient mice with angiotensin 2 induced extensive hypertrophy and fibrotic cardiomyopathy. Ventricular myocytes were found to be the important source of cardiac transforming growth factor beta or TGF beta and PAI-1 regulated TGF beta synthesis by cardiomyocytes in vitro as well as in vivo during cardiac injury. PAI-1 deficiency significantly enhanced multiple TGF beta signaling elements and transcriptional targets. Thus, in summary, this study show that PAI-1 is an essential repressor or cardiac fibrosis and access a molecular switch that controls the cardiac TGF beta access and its early transcriptional effects that lead to myocardial fibrosis.                                                 Modulation of the cardiomyocytes TGF beta access represents a unique therapeutic strategy that may abrogate fibrotic signaling and cardiac fibrosis. Well, that wraps it up for your summaries. Now for our featured discussion. We are incredibly privileged today to have the director of the National Heart, Lung and Blood Institute, Dr. Gary Gibbonss with us on the podcast, as he talks about his perspective piece entitled "Charting Our Future Together: Turning Discovery Science into Cardiovascular Health." Also, joining me today is our editor in chief, Dr. Joseph Hill from UT Southwestern. Joe, I know you share my incredible excitement and enthusiasm at having Dr. Gibbonss on this podcast with us.                                                 Maybe could I invite you to say a few words to frame just how important this perspective piece is for Circulation? Dr. Joseph Hill:                   We all know that cardiovascular medicine and science are evolving at an unprecedented pace. The challenges we face are evolving and yet the opportunities and the tools and the resources at our disposal are unprecedented in their scope and vision. We're very pleased that Gary has provided strong leadership at NHLBI now for several years and has laid out in this perspective piece here where he thinks the next steps are specifically around this strategic vision that focuses on precision medicine and data science. I would love to hear Gary provide additional perspective on that vision. Dr. Gary Gibbons:            Well, thank you, Joe. As the director of NHLBI, clearly we're public servants and we're accountable stewards of the nation's investment in heart, lung and blood and sleep disorders. This piece gave us an opportunity to outline some of the opportunities that lay ahead in a strategic visioning process. First, I should note that a key part of the legacy of the NHLBI is to make strategic investment with enduring principles in mind to really support investigator initiated discovery science as really the core foundational element of our research portfolio, as well as to maintain a balance portfolio to really expands to spectrum of basic translation clinical population and implementation science.                                                 In this piece, we particularly want to highlight our strategic visioning process in which we encourage the broad input of the NHLBI community that actually included over 4,000 participants in this process from every state in the country. Indeed, 42 countries around the world to provide the most compelling questions and critical challenges that the field faces around strategic goals of understanding normal human biology, reducing disease, accelerating translation and preparing a biomedical workforce and resources for the discovery science of the 21st century.                                                 Out of that strategic vision, we focus in on two elements that emerged that relate it to precision medicine and data science for this piece and really that was the central core of what we wanted to share with the Circulation readership about how these two areas we think are going to be transformative in the years ahead. Dr. Carolyn Lam:               Dr. Gibbons, you know, when the term precision medicine is used, sometimes it's a bit fuzzy I think in the minds of a lot of people. Could you maybe give a few examples or perhaps a specific idea that comes to mind? Dr. Gary Gibbons:            You're right. There's often a lot said about it than probably a bit of hype about it. In some ways you could see this as a legacy of cardiovascular medicine and science. It could be argued that the definition of cardiovascular risk factors that came out of the Framingham Heart Study many years ago was the first sort of forerunner of precision medicine. It helped us indeed define those individuals who are at the greatest risk of having a heart attack and that to this day has played a role in directing targeted preventive treatments of the highest risk individuals in order to prevent heart attacks. That has continued to evolve.                                                 I think what's new now is that we have, as Dr. Hill mentioned, new modalities of both imaging and analytics of computational science, as well as novel biomarkers and genetic markers that can help us be even more precise in that risk assessment. That's really I think the greater opportunity to further subcategorize patient populations to get the right drug to the right patient at the right time with a more strategic treatment approach. Dr. Joseph Hill:                   Gary, that's very exciting. I think your vision is absolutely compelling. I like how you categorize the NHLBI as a catalyst for the future. I'd like to think that the Biomedical Journals, the AHA Portfolio of Journals and Circulation are also catalysts that will partner with NHLBI and other entities to chart the course for the future. That again the challenges that we face now are different than they were back in the era when Framingham first got started after World War II. The tools that we have are also evolving rapidly and certainly our perspective from Circulation is that we are stewards of helping chart that course, helping identify and bring forth the best science around the world. In many ways we look to you as a partner. Dr. Gary Gibbons:            Oh, absolutely. The NHLBI really can't fulfill our mission of turning discovery science into the health of the nation and indeed around the world without a circle of partners and that certainly includes the platforms of disseminating new knowledge like Circulation, as well as partner organizations such as American Heart Association. We definitely appreciate the value that your organ brings to really enhancing our efforts to not only take discovery science, but make that knowledge available to practitioners and researchers and patients.                                                 I think a key part of the 21st century is how we not only can discover and generate new knowledge, but how we can facilitate that movement of data to knowledge and from knowledge to action that actually enhances the lives of patients in the real world context. Again I believe your journal plays an important role in helping to do that. Dr. Carolyn Lam:               You both mentioned critical challenges that we're facing and will face. The Chinese for these challenges or crisis, the word is actually wéijī. Okay? Wéi is actually meaning danger, whereas jī is for jīhuey which is opportunity. In every challenge, there's always this new opportunity and I just really would like to ask what are the greatest challenge and perhaps the greatest opportunity? Dr. Gary Gibbons:            I think the challenge that we probably face is the emerging epidemic of non-communicable diseases typically cardiovascular disease throughout the world. Not only in the most industrialized nations, but indeed mainly the developing nations. This will quickly surpass communicable infectious diseases as the major burden and causes of mortality worldwide. We're dealing with a global challenge. Increasingly, we recognize that scientific discovery and analysis is often siloed in various packets. Our vision for the future is really to promote the creation of a global reach of what we're calling a Data Commons. That is that a disease has no borders. Science should not be limited to national states.                                                 It is part of the commonwealth if you will of information and knowledge that really should transcend national borders. We say this is a global community of data and information and knowledge exchange and collaboration. As part of this global community, it's that we think this diverse and inclusive approach will be critical to the best minds and best practitioners of the world learning from each other and contributing to this commonwealth of knowledge. We're excited because the opportunity on the other side of that challenge is that it's an unprecedented capability of power to communicate now. We I think are communicating with you from Singapore and we're in a digital age in which this notion of communication and knowledge exchange should be more fast than it's ever been before.                                                 Indeed, we can create computer platforms that are similar to what exist for a Facebook or a Google that are global in scope. The vision is really to say what would happen if we could turn that toward biomedicine and make biomedicine part of this data science such that we have global contributions to our understanding, knowledge exchange and really create that sort of global sandbox if you will of knowledge exchange and discovery. That's part of this notion of creating a Data Commons and really advancing data science as an element of a strategic vision. As we move forward with precision medicine and data science, our most sacrosanct stewardship is for the next generations. A critical element is to ensure that we're providing them with the tools and training to really lead the charge of advancing these exciting areas of science and that indeed will be a global enterprise. Dr. Joseph Hill:                   That's very exciting, Gary. I take my hat off to you for the leadership that you have maintained at the NHLBI during these times that are once very challenging and at the same time exhilarating. I look forward to working with you through our journal and partnering with you to bring to fruition much of what you had laid out in your vision. Dr. Gary Gibbons:            Thank you, Joe. We look forward to our ongoing partnership. Dr. Carolyn Lam:               Thank you, listeners, for joining us today. Do join us again next week.

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.                                                 Now, the SGLT2 inhibitor, empagliflozin, has been shown to improve outcomes in the EMPA-REG OUTCOMES trial. But do these benefits also apply in the real world, and to other SGLT2 inhibitors as a class? Well, we may just have some answers this week in the CVD-REAL study. More soon right after these summaries.                                                 The first original paper this week uncovers the mechanism of beneficial action of T-cells for proper healing after myocardial infarction. Now, the pro-inflammatory danger signal, adenosine triphosphate or ATP, is released from damaged cells, and degraded by the ectonucleotidase CD73 to the anti-inflammatory mediator, adenosine.                                                 Using newly-generated CD4-CD73 null mice, first author, Dr. Borg, corresponding author, Dr. Schrader, and colleagues from Heinrich Heine University of Düsseldorf in Germany, showed that a lack of CD73 on T-cells enhanced tissue fibrosis and worsened myocardial function in the remodeling phase after myocardial infarction.                                                 T-cells migrated into the injured heart and upregulated their enzymatic machinery to enhance the extracellular degradation of ATP to adenosine. T-cells lacking CD73 showed accelerated production of pro-inflammatory and profibrotic cytokines. Finally, the adenosine 2B receptor was upregulated on cardiac immune cells in the remodeling phase.                                                 In summary, therefore, local adenosine formation by CD73 on T-cells appears to be the body's own defense mechanism to control inflammation induced by myocardial infarction. This is a mechanism that might be exploited to promote healing or remodeling by specifically targeting the adenosine 2B receptor in the infarcted heart.                                                 The next paper provides insights on genetic determinants of susceptibility to peripheral artery disease, and specifically puts the spotlight on Bcl-2-associated athanogene-3, or Bag3, which is a cell chaperone protein previously identified in a genetic screen for determinants of tissue loss with hindlimb ischemia.                                                 In the current study, Dr. McClung from East Carolina University, Brody School of Medicine in Greenville, North Carolina, and colleagues, used adeno-associated viruses to show that an isoleucine to methionine variant at position 81 in Bag3 was sufficient to confer susceptibility to ischemic tissue necrosis in BALB/c mice.                                                 In a series of elegant experiments, they demonstrated that Bag3 was a modulator of ischemic muscle necrosis and blood flow. In summary, this study provides evidence that genetic variation in Bag3 plays an important role in the prevention of ischemic tissue necrosis, and highlights a pathway that preserves tissue survival and muscle function in the setting of ischemia.                                                 The next study provides insights into inflammatory atherogenesis by studying psoriasis, a chronic inflammatory disease associated with an accelerated risk of myocardial infarction. First author, Dr. Lerman, corresponding author, Dr. Mehta from the NHLBI, National Institutes of Health in Bethesda, United States, and colleagues, hypothesized that the increased cardiovascular risk observed in psoriasis would be partially attributable to an elevated subclinical coronary artery disease burden composed of non-calcified plaques with high-risk features.                                                 To test this hypothesis, they compared total coronary plaque burden, non-calcified coronary plaque burden, and high-risk plaque prevalence between 105 psoriasis patients, 100 older hypolipidemic patients eligible for statin therapy, and 25 non-psoriasis healthy volunteers. All patients underwent CT coronary angiography, and a sample of the first 50 psoriasis patients were scanned again at one year following therapy.                                                 The authors found that patients with psoriasis had greater non-coronary burden and increased high-risk plaque prevalence compared to healthy volunteers. Furthermore, compared to older hypolipidemic patients, patients with psoriasis had elevated non-calcified burden, and equivalent high-risk plaque prevalence. Finally, improvement in skin disease severity was associated with an improvement in non-calcified coronary burden at one year.                                                 The clinical implications are that patients with psoriasis have similar coronary artery disease risk as hyperlipidemic patients one decade older, and these patients with psoriasis should be screened earlier for cardiovascular disease and educated about their elevated risks. Further investigations focus on the longitudinal impact of psoriasis treatment on high-risk plaque morphology, as well as on the extent of cardiovascular risk mitigation in randomized trials.                                                 Well, those were your summaries. Now for our feature discussion. Now, we've heard of the EMPA-REG OUTCOME trial, that prospective randomized, controlled trial, showing a substantial reduction in cardiovascular death and hospitalization for heart failure with the sodium-glucose cotransporter 2, or SGLT2 inhibitor, empagliflozin, and that's, remember, that was in patients with type 2 diabetes and established atherosclerotic cardiovascular disease.                                                 Well, our paper today really extends our knowledge and tells us a bit more about the role of SGLT2 inhibitors in real-world clinical care. And I'm so please to have with us the first and corresponding author, Dr. Mikhail Kosiborod from Saint Luke's, Mid America Heart Institute, as well as Dr. Gabriel Steg, associate editor from Paris, France, joining us today. Hello, gentlemen. Dr. Gabriel Steg:               Hello. Dr. Mikhail Kosiborod:   Hi. Good morning, Carolyn. Dr. Carolyn Lam:               Mikhail, I am going to say what I said to you at the ACC and at the ESC Heart Failure: Congratulations on CVD-REAL. Please tell us about CVD-REAL. Dr. Mikhail Kosiborod:   Right, well, we know, as you just mentioned, that the EMPA-REG OUTCOME trial showed substantial reduction in cardiovascular death, and hospitalizations for heart failure in patients with type 2 diabetes and established cardiovascular disease. We were all very excited once that data got presented in September of 2015 in Stockholm, but there were several very important questions that weren't really addressed, and truly, could not be addressed, in EMPA-REG's trial.                                                 The first, actually, and probably the most important is, we all know that clinical trials, while we regard them as the gold standard of evidence, as we should, they do have their own set of limitations, the most important of which is that they examine a relatively small sliver of patients; and many patients we see in the clinic, in the hospital, don't look like patients in clinical trials. I think the most important questions we tried to address was, "Will this translate to real-world clinical practice?"                                                 The second was, as you recall, again, all patients on EMPA-REG had established cardiovascular disease, so we wanted to know whether the benefits associated with the use of SGLT2 inhibitors could potentially extend to lower-risk patients with type 2 diabetes without established cardiovascular disease, a much broader spectrum of patients.                                                 And finally, and also very importantly, I think, the third question was, "Is it an empagliflozin-specific effect or is it a class effect?" These are all the critical questions we tried to address in the CVD-REAL study. Dr. Carolyn Lam:               Great. Could you give us the topline results, please? Dr. Mikhail Kosiborod:   Right. So, just as a reminder, we collected data from well-established registries in six countries, so the United States and some five countries in Europe, Sweden, Norway, and Denmark, and also, the United Kingdom and Germany. And really, the inclusion/exclusion criteria for the study were quite broad, you just had to have type 2 diabetes and be newly started on either an SGLT2 inhibitor or any other glucose-lowering medications, which was the comparative group.                                                 And after we did the one-to-one propensity match to make sure, comparable samples, we ended up with about 154,000 patients, and each treatment group, over 300,000 patients overall. What we actually observed was a marked and highly significant reduction in the risk of hospitalization for heart failure that was associated with use of SGLT2 inhibitors versus other glucose-lowering drugs.                                                 In fact, the magnitude of reduction in risk that was associated with SGLT2 inhibitors, so that outcome was quite similar, about 39% relative risk reduction, quite similar to what we see in the EMPA-REG OUTCOME trial. But this, of course, was for the entire class of SGLT2 inhibitors, so patients in the study were treated primarily with canagliflozin and dapagliflozin, with a small proportion being treated with empagliflozin.                                                 We also saw dramatic and highly significant associated reduction in the risk of all-cause death with SGLT2 inhibitors versus other glucose-lowering drugs, about a 51% relative risk reduction, and the composite of those two outcomes, obviously, there was significant associated reduction in risk as well.                                                 So, again, the hazard ratio estimate that we saw for these outcomes were quite similar, and in some cases, almost identical to what we've seen in EMPA-REG, but for a patient population that was much broader, in fact, about 90% of patients, close to 90% of patients in our study did not have established, documented cardiovascular disease. And, of course, as I mentioned before, important implications to these findings, in my opinion. Dr. Carolyn Lam:               Yeah, that is just remarkable. Gabriel, could you share some of the discussions that happened among the editors about this paper? Dr. Gabriel Steg:               We were really excited by this paper. I think this is truly a landmark paper for a number of reasons. It's a very large, multinational study, but even more than the size, I think what's interesting here are a couple of key aspects. First of all is data on all-cause mortality, which is a highly reliable outcome when you look at many of the observational studies.                                                 Non-fatal outcomes can easily be skewed or biased in ascertainment or assessment, but this is relatively reliable. And here, we have a very large multinational cohort that finds benefits on death, heart failure, and their composite, which are remarkably consistent internally, consistent across countries, and consistent with the randomized trial data evidence from the EMPA-REG OUTCOME trial.                                                 So that is striking, and this is consistent across six countries using a very large sample size. But again, the size of the sample is not the most important thing, because in observational studies, you often have very large sample sizes, but if you have bias in your observational study, the bias is just replicated times the size of the study.                                                 The consistency here between the treatment effects across the various countries, the consistency with the efficacy assessed in randomized clinical trials is really a crux in the quality of the data and how believable the results are. Another key aspect that got us really excited is the fact that only a minute fraction of the data is related to use of empagliflozin.                                                 Most of the data was acquired using other SGLT2, and we still only have results now with empagliflozin, we don't have outcome trial data with the other agents. They are pending, but pending the availability of these trials, the fact that this large study sees a consistent benefit, in terms of heart failure and mortality, of the other agents in the class suggests that this is a class effect.                                                 And likewise, the fact that we're seeing these benefits in a population that is much, much broader than the population of EMPA-REG OUTCOMES is also very, very intriguing, and exciting, and makes us really want to see more data not only from the randomized trials that are upcoming, but also from this study.                                                 Because now, what we would like to see is, see the detailed cardiovascular outcomes in these cohorts, and I know that Mikhail and his colleagues are working very, very actively on preparing these analyses. I think this is going to be exciting. This is the first of a series of landmark papers from a model observational study.                                                 There are many issues with observational studies. This is almost as good as it can ever get, and I want to compliment Mikhail and the consortium that's with him, because this is a tremendous effort, across several countries, on achieving this. I think it's very exciting for our readership and for clinicians around the world. Dr. Carolyn Lam:               I couldn't agree more, and I share your compliments for Mikhail. Perhaps, Mikhail, could you give us a sneak peek at the future and the ongoing work? Dr. Mikhail Kosiborod:   We frequently think of, and I think perhaps mistakenly at times, think of clinical trials and observational real-world data as competing with one another. In many cases, they're really complementary, and I think if you really, kind of, think of interventions that we consider as those gold standards enshrined in clinical guidelines, or something we absolutely should be doing for our patients.                                                 Just to pick one example, statins for secondary prevention after a cardiovascular event, for example, there is data from both sources suggesting that these drugs are highly beneficial, right? So it is very important to have data from both sides, and I think, as Gabriel mentioned, I look at CVD-REAL as a model, in many ways, of how compelling the data from non-randomized, large, real-world observational studies can be when done well.                                                 In terms of a sneak peek for the future, there are many, many things going on. We are carefully examining the outcomes that we are reporting in circulation, including heart failure and all-cause mortality in various subgroups. We are, of course, as Gabriel mentioned, intently looking at other outcomes, including myocardial infarction, stroke, cardiovascular death, and a composite of major adverse cardiac events.                                                 We're also examining some of the diabetes, one could argue, maybe, diabetes-specific outcomes, such as hypoglycemia rates. We, of course, as cardiologists tend to concentrate on cardiovascular outcomes, but it's also important to remember that there are other important outcomes that could be associated benefits.                                                 So these medications may be associated with marked reduction of cardiovascular events, such as death and heart failure, but they may also reduce hypoglycemia rates and, of course, that's important from a quality-of-life standpoint for patients with diabetes, so some of that work is ongoing.                                                 And I would say, importantly, one of the other things that we're hoping to be able to do in the future is to go beyond cardiovascular outcomes, and perhaps blood glucose-specific outcomes, such as hypoglycemia, and start looking at events such as renal disease events, which I think are very important, of course. Interact quite a bit with, I suspect, in many ways, with some of the cardiovascular benefits that we're observing with those agents, both in the clinical trials and, now, in large observational studies.                                                 And that's just the beginning. I mean, I think it's fair to say that, as Gabriel mentioned, a huge amount of work went into putting this together, right? And we're actually not only expanding things from a standpoint of outcomes. We're also expanding things from a standpoint of countries that will be participating in CVD-REAL consortium.                                                 So we're actually planning to add at least two or three more countries from Europe, Middle East, and Asia in the coming months, and more so in the future. And of course, once you have a resource like this, there are additional questions that can be addressed, actually, both with SGLT2 inhibitors as a class, but also with other classes of type 2 diabetes medication. So that's, I think, as much of a sneak peek as I can give you right now. Just definitely promise you that there is a lot more coming.                                                 In addition to ADA, we're going to have abstracts being presented at ESC in August, and also the European Association for the Study of Diabetes meeting in Lisbon, in September, and there's going to be a lot more afterwards as well. So just stay tuned, I would say. This is definitely just the beginning. There's going to be a lot more coming. Dr. Carolyn Lam:               You took the words right out of my mouth. Listeners, stay tuned, and don't forget to tune in next week as well.  

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.                                                 Today's issue features two exciting papers regarding heart failure in patients with breast cancer. We will be discussing this right after these summaries.                                                 Are we any closer to improving survival in Eisenmenger syndrome? Well, today's first original paper looks at contemporary trends and presents a multivariable mortality risk stratification model based on five simple noninvasive predictors of death in this population. Dr. Kempny and colleagues from Royal Brompton Hospital in London in the United Kingdom preform a large multicenter study in 1098 patients with Eisenmenger syndrome followed up between years 2000 and 2015.                                                 At the end of the study almost two-thirds of patients were on advance therapy for pulmonary arterial hypertension, while only six patients underwent lung or heart and lung transplantation. The study showed that despite advances in management, there was significant mortality amongst contemporary adults with Eisenmenger syndrome and 25.3% of patients died over a median follow up period of 3.1 years. Mortality was higher in older patients, those with a pre-tricuspid shunt, lower oxygen saturation, absence of sinus rhythm, or with a pericardial effusion.                                                 This important study is accompanied by an editorial by Drs. Lange, from Texas Tech University Health Sciences Center El Paso and Dr. Brickner from UT Southwest Medical Center in Dallas, Texas. The editorialists call for a prospective randomized control trials of the effect of current, or future pulmonary vasoactive disease targeting therapies on mortality in Eisenmenger syndrome patients, and say it's time to direct our efforts from improving risk-stratification towards improving survival.                                                 The next study provides experimental evidence of tolerogenic dendritic cell therapy as a novel anti-remodeling therapy in myocardial infarction. Tolerogenic dendritic cells are promising, potent, beneficial regulators of the post-infarct healing process via their control of T-regulatory cells and M1 M2 macrophages. Plus they have the advantage of the ease of administration and feasibility of a heart specific tolero-dendritic cell production.                                                 In the current paper by co-first authors, Drs. Choo and Lee, and co-corresponding authors, Drs. Chang and Lim, from Catholic University Korea and Chai University in Korea, authors generated tolerogenic dendritic cells by treating bone marrow-derived dendritic cells with TNF-alpha and cardiac lysate from mice with myocardial infarction. They then injected myocardial infarction mice twice with tolerogenic dendritic cells within 24 hours and at 7 days after LAD ligation. In treated animals, in vivo cardiac magnetic resonance imaging and ex vivo histology confirm the beneficial effects on post-infarct LV remodeling. Furthermore, subcutaneously administered tolerogenic dendritic cells near the inguinal lymph node migrated to the regional lymph nodes and induced infarct tissue specific T-regulatory T-cell populations in the inguinal and mediastinal lymph nodes, spleen, and infarcted myocardium, all of which elicited an inflammatory to reparative macrophage shift. The altered immune environment in the infarcted heart resulted in better wound remodeling, preserved left ventricular systolic function, and an improved survival following myocardial infarction. Thus, this study shows that tolerogenic dendritic cell therapy in a preclinical model of myocardial infarction may be potentially translatable into an anti-remodeling therapy for ischemic repair.                                                 The final paper reports results of cell therapy on exercise performance and limb perfusion in peripheral artery disease from the PACE trial, which is an NHLBI-sponsored randomized double-blind placebo-controlled phase two clinical trial, designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright cells in peripheral artery disease, and to explore associated claudication physiological mechanisms. In this paper from corresponding author Dr. Moye from UT School of Public Health in Houston, Texas and colleagues of the Cardiovascular Cell Therapy Research Network, a total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at nine sites to receive alcohol dehydrogenase bright cells or placebo. All patients underwent bone marrow aspiration and isolation of aldehyde dehydrogenase bright cells followed by 10 injections into the thigh and calf of the index leg. Results showed that there were no significant differences in the change over six months between study groups for the co-primary endpoint of peak walking time, collateral count, peak hyperemic popliteal flow, and capillary profusion measured by magnetic resonance imaging.                                                 Additionally, there were no significant differences for the secondary endpoints including quality of life measures. There were no adverse safety outcomes. Interestingly, a post-hoc exploratory analysis suggested that aldehyde dehydrogenase bright cell administration might be associated with an increase in the number of collateral arteries in participants with completely occluded femoral arteries.                                                 In summary, cell therapy did not improve peak walk time or magnetic resonance outcomes, and the changes in peak walk time were not associated with the anatomic or physiologic MRI endpoints. However, future peripheral artery disease cell therapy trial design may be informed by new anatomic and perfusion insights. These and other issues are discussed in an accompanying editorial by Drs. Breton-Romero and Hamburg from Boston University School of Medicine. Well, that wraps it up for our summaries, now for our feature discussion.                                                 We are really in the grove here in Washington, D.C. and I am borrowing the words of my very special, star associate editor, guest, Dr. Gregory Hundley, and he's from Wakefield University School of Medicine. We're discussing two very important papers and they deal with the risk of heart failure following breast cancer. Why they're so important? Well, first of all, it's about time we looked at this problem in detail, and secondly, they actually represent papers in a new section of the journal called "Bridging Disciplines," and in this case cardio-oncology. Very, very important topics.                                                 We're here with the corresponding authors of both papers, Bonnie Ky from University of Pennsylvania School of Medicine and Dr. Margaret Redfield from Mayo Clinic. Dr Gregory Hundley:      Thank you, Carolyn. I really appreciate that wonderful introduction and also the chance to talk with Bonnie about this exciting topic.                                                 So, Bonnie, you've got a paper here, now, where you did a study in patients with breast cancer, and it sounds like you acquired echocardiograms over a period of time. Can you tell us a little bit about that? Dr Bonnie Ky:                     Correct. So this is longitudinal prospective cohort study, it's an NIH-funded R01, whereby we are enrolling patients from the breast cancer clinic who are receiving doxorubicin or trastuzumab or a combination of the two therapies. And we're performing very careful cardiovascular phenotyping, from the time at which they initiate chemotherapy through their chemotherapy and then annually once a year we have them come back, for a total follow up time of 10 years.                                                 We took a subcohort, 277 patients, and from their echocardiograms, we analyze them very carefully for various measures of left ventricular size, function, not only systolic function but also diastolic function. We also looked at measures of contractility such as strain in multiple dimensions, and then also measures of ventricular arterial coupling, as well as arterial loads, so how the ventricle interacts with the arterial system. And what we found was that over a 3.2 period time period, on population average, these modest declines in left ventricular ejection fraction, and even across all three treatment groups, and even at three years there were persistent LVF declines. Dr Gregory Hundley:      So, I understand, Bonnie, that you also collected some information as to whether or not these patients were experiencing symptoms associated with heart failure. How did the imaging markers relate to the symptomatology associated with heart failure? Dr Bonnie Ky:                     What we found was that early changes in arterial stiffness or total arterial load, as well as early changes in EF were associated with worse heart failure symptoms at one year. A lot of our other analysis was focused on defining what echo parameters of remodeling, size, function are driving or associated most strongly with LVF decline, as well as LVF recovery. Dr Gregory Hundley:      And then at two years, what happened? Did the echo parameters, were they still associated with heart failure or was there a little discrepancy there? Dr Bonnie Ky:                     Interestingly, at two years ... no, there was no significant association with changes in arterial load and heart failure symptoms at two years. Dr Gregory Hundley:      So there might be something transient that's occurring that is associated with heart failure early, and then the patients still had heart failure late, so maybe something else is operative. What do you think we need to do next? What's the next step in your research and then other investigators around the world; what do we need to do to design studies to look at these issues further? Dr Bonnie Ky:                     Yeah. What does the field need, the field of cardio-oncology that's really growing and developing at rapid paces. Some of the major findings from the study was that changes in total arterial load were very strongly associated with both LVF decline and LVF recovery. So total arterial load is the measure of blood pressure or total arterial stiffness, it's derived from blood pressure. And to me, that begs the question, or begs the next step is that changes in blood pressure are associated with decline as well as recovery. I think, oh, as cardiologists we've also always recognized the importance of afterload reduction. And to me, this study suggests that we need a study, a randomized clinical trial, looking at blood pressure lowering in this population to help mitigate LVF declines. Dr Carolyn Lam:                I'd actually like to turn it back to you. You are world-renowned for your work in cardio-oncology. Where do you think this fits in, and where do you think we need to address most urgently? Dr Gregory Hundley:      I think where this fits in wonderfully is a lot of individuals around the world are collecting echocardiographic measures, and all different types. And what Bonnie has helped do is clarify what we would expect to see in this particular patient population. How those measures change over time and that feeds into another block of data, when the measurements head south, do we change therapy, do we add protective agents, and things of that nature. So I think Bonnie's work really contributes on that front. What she has also pointed out is that more research needs to be performed, not necessarily because the patients had heart failure symptomatology at two years, but not necessarily associated with the decline in EF; are there other systems in the cardiovascular realm that are being affected? The vascular system- Dr Carolyn Lam:                Yeah. Dr Gregory Hundley:      Skeletal muscle, many other areas. So as cardiologists start to work more with oncologists in this space, and we're all working together to make sure that not only patients survive their cancer, but they have an excellent quality of life, I think we'll see, as we have in other heart failure syndromes, a look toward other aspects of the cardiovascular system, body in general, to reduce the overall morbidity associated with the disease.                                                 I think what we need to recognize as cardiovascular medicine specialists is that now for many forms of cancer, cardiovascular events, and certainly morbidity are becoming the primary issue that folks have to deal with with survivors. It's not necessarily the cancer recurrence, it's not necessarily a new cancer, it's cardiovascular. So we've got to integrate cardiology earlier in working with oncologists to improve overall survival and create an excellent quality of life from our different perspectives. Dr Carolyn Lam:                So, Maggie, let's move on to your paper now. You looked at radiotherapy's effect, whereas Bonnie looked at chemotherapy's effect. Could you tell us what you did and what you found? Dr Margaret Redfield:    The rationale for doing this study was, of course, seeing a lot of patients with HFpEF who had had radiation therapy for breast cancer, and I always just sort of assumed that that was because 12% of women over the age of 40 get breast cancer and 20% of women over the age of 40 get heart failure, but it seemed to be somehow more common than that. The other rationale was that radiation therapy does not actually affect the cardiomyocytes; they are very radiation resistant. And what radiation does is cause microvascular endothelial cells damage and inflammation, and that is felt to be fundamental in the pathophysiology for HFpEF.                                                 So we thought we should look at this. I collaborated with a radiation oncologist and oncologists, and they were interested in looking at this because there's a lot of techniques now to reduce cardiac radiation exposure during radiation therapy, including proton beam therapy, and they're trying to prioritize who they use this new technology on. So what we did was start with a population-based study, all women who lived in Olmsted county who received radiation therapy for breast cancer in the contemporary era, where they're already using these dose reducing techniques. So we wanted to make it relevant to what's going on today. And so we started with a base cohort of all women. We matched patients' cases, it was a case-control study, so we matched cases and controls according to their age at the time of breast cancer, whether they had heart failure risk factors, like hypertension or diabetes, whether they got adjuvant chemotherapy, and tumor size, because we felt it was important that radiation could affect different parts of the heart, depending on whether it was right- or left-sided tumor.                                                 And what we found is that the risk of heart failure increased with the mean cardiac radiation dose. We measured the mean cardiac radiation dose in every case and every control from their CT scans and their radiation plants. And as the radiation dose went up, the risk of heart failure went up, even matching or controlling for chemotherapy, which wasn't used that often in this group, or heart failure risk factors. And the vast majority of these cases were indeed HFpEF.                                                 So we then looked at factors that happened in-between the radiotherapy and the onset of heart failure, making sure that this all wasn't just coronary artery disease, 'cause we know radiation can increase the risk of coronary artery disease. And indeed there were, only in about 18% of cases was there a new episode of coronary disease in the interim between the radiotherapy and the breast cancer. So, basically found that the mean cardiac radiation dose, even in today's era, does increase the risk of heart failure with preserved ejection fractions. Dr Carolyn Lam:                The things that stuck out to me ... it's population based. You did such a comprehensive study to really answer very key questions: dose of radiation, is it really just mediated by age and age-related risk factors, is it just about MI or could it be more microvascular disease? Congratulations, I really appreciated this paper. Some of the take-home messages are directly related to the treatment of breast cancer, isn't it? And about the importance of minimizing radiation dose if possible. I suppose one of the take-homes is, as well, for screening and watching out for heart failure. One thing though: how were these woman diagnosed with HEpEF? I mean, this is always the questions I get. How do you get diagnosed with HEpEF? Dr Margaret Redfield:    Right, well, first we started with looking to see if they had a ICD code for heart failure, and then we looked at each case of heart failure and determined if they either met Framingham criteria at the time of the diagnosis and the majority of them did. If they didn't actually meet the Framingham criteria, we looked to be sure there was a physician diagnosis of heart failure in the record and that they had supportive evidence of heart failure: echocardiographic findings, natriuretic peptide findings, and other clinical characteristics of heart failure.                                                 And importantly, in the large control group from where we, you know, got our controls, people, a very large group of patients who did not get heart failure, we'd use natural language processing to look at all those records to make sure we weren't missing anybody who didn't have an ICD diagnosis or code for heart failure to make sure we weren't missing any cases of heart failure. So, we really tried to use very stringent methods to make sure we had true cases and control groups. Dr Carolyn Lam:                Indeed, and it actually goes back to Bonnie's paper as well, where we have to remind everyone that the diagnosis of HEpEF really starts with the symptomatology of heart failure in particular, that you so rigorously determined. I think just one last thing, Maggie: what do you think this implies now, for HEpEF? What do we do in general so the non-radiation-associated, do we believe more the Walter Paulus-Carsten Tschope hypothesis, and if so, what do we do? Dr Margaret Redfield:    Yes, well I think it really does support that hypothesis. We know that radiation therapy, again, we know what it does to the coronary microvascular endothelial cells and that's been elegantly worked out both in patients and in animal models. I think this really supports the Paulus hypothesis because this microvascular damage was able to produce heart failure, so I think that really supports that hypothesis. And there's been some studies showing decreased coronary flow reserve in HEpEF patients; it's very common. So I think indeed it does support that hypothesis and that the coronary microvasculature is key in the pathophysiology of HEpEF.                                                 However it's a little scary to me because that sort of damage, once it's established, may be very hard to treat. You know, proangiogenic strategies in peripheral vascular disease have not yet yielded the benefits that we hoped for, so I think it's a tough therapeutic challenge that'll be very important to try to address in pre-clinical studies to try and figure out once the microvasculature is so damaged how do we treat that? How do we reverse that process? Dr Carolyn Lam:                Yeah. Words of wisdom. Maggie, thanks so much for inspiring, just all of us in this field. I just had to say that. You know, you are the reason that I am totally in love with HEpEF. (laughter) Dr Margaret Redfield:    (laughter) Dr Carolyn Lam:                So thank you so much for joining me today on the show. In fact, thank you to all my three guests.                                                 You've been listening to Circulation on the Run. You must tell everyone about this episode, it is full of gems.                                                 Thank you, and tune in next week.  

Host Dawn Davenport, Executive Director of Creating a Family, the national infertility & adoption education and support nonprofit, interviews Dr. Jason M. Franasiak, Associate Chair, Society for Reproductive Endocrinology and Infertility; and Dr. Erin Wolff, Assistant Clinical Investigator in NICHD and NHLBI.   Creating a Family has many free resources related to this topic on our website at https://creatingafamily.org/infertility/resources/. Please leave us a review on iTunes. Thanks. Click to Tweet: https://creatingafamily.org/infertility-category/the-microbiome-and-fertility/ Facebook Share: https://www.facebook.com/sharer/sharer.php?u=https%3A//creatingafamily.org/infertility-category/the-microbiome-and-fertility/ Show Highlights: https://creatingafamily.org/infertility-category/the-microbiome-and-fertility/ Support the show (https://creatingafamily.org/donation/)

Commentary by Dr. Valentin Fuster

Jovonni Spinner of the NHLBI discusses the Community Health Workers Health Disparities Initiative with ASN Manager for Policy and Government Affairs Rachel Meyer.

Jovonni Spinner of the NHLBI discusses the Community Health Workers Health Disparities Initiative with ASN Manager for Policy and Government Affairs Rachel Meyer.

Jovonni Spinner of the NHLBI discusses the Community Health Workers Health Disparities Initiative with ASN Manager for Policy and Government Affairs Rachel Meyer.

Jovonni Spinner of the NHLBI discusses the Community Health Workers Health Disparities Initiative with ASN Manager for Policy and Government Affairs Rachel Meyer.

Interview with Neil Young. Chief of the Hematology Branch of the NHLBI of the NIH, Bethesda, USA. Prof. Young discusses the topic 'Pathology of Aplastic Myeoleukemia'.The interview is led by Shaun McCann, Chair of EHATol Unit, Member of EHA Education Committee.

Interview with Neil Young. Chief of the Hematology Branch of the NHLBI of the NIH, Bethesda, USA. Prof. Young discusses the topic 'Pathology of Aplastic Myeoleukemia'.The interview is led by Shaun McCann, Chair of EHATol Unit, Member of EHA Education Committee.

In this audio interview, Dr. Nina Radford, Director of Clinical Research and a cardiologist at Cooper Clinic, discusses cholesterol in children. Earlier this year, the National Heart Lung and Blood Institute (NHLBI) and the major pediatric associations put some new guidelines out in terms of screening cholesterol in children. The panel discusses two cholesterol screening recommendations for children. 1) The Universal Screen - consider screening cholesterol in all children, regardless of risk, sometime between 9- and 11 years of age, the age range when atherosclerosis actually starts to begin. The panel believes this is a good time to identify kids who may be from families of high risk; and it's a good time to influence children to adopt healthier habits. 2) Targeted Screen - any time, from ages 2- to 21, cholesterol might be screened if the child has any other risks for heart disease - obesity; diabetes; or high blood pressure. The child should also be screened if either parent had a stroke early in life. Dr. Radford also talks about the treatment recommendations the NHLBI makes for children who have elevated cholesterol.

1) Intracranial arterial stenosis and 2) Topic of the month: Evaluation of polyneuropathy. This podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Brad Worrall with Drs. Xunming Ji and Ran Meng about their paper on intracranial arterial stenosis. Dr. Jennifer Fugate is reading our e-Pearl of the week about Kleine-Levin syndrome. In the next part of the podcast Dr. Ted Burns interviews Dr. Peter James Dyck about evaluation of demyelinating polyneuropathy. In concluding, there is a brief statement where to find other up-to date patient information and current Patient Page. The participants had nothing to disclose except Drs. Worrall, Fugate, Burns, and Dyck.Dr. Worrall has received research funding from NIH (6 grants). He serves as an outcomes adjudicator for the NHLBI for AREDS2 and as an ad hoc reviewer for the NIH and Veterans Administration study sections. Dr. Worrall received several honoraria for serving as faculty and/or director for courses at the AAN annual meetings and an honorarium for speaking for the Operation Stroke program (AHA/ASA funded) at Fairfax Inova Hospital. Dr. Worrall is on the Editorial Boards of Neurology and Seminars in Neurology. Dr. Worrall received nominal royalties for serving as a Chapter Author for Merritt's Neurology and receives an honorarium as Associate Editor of Neurology. Dr. Fugate serves on the editorial team for the Neurology® Resident and Fellow Section. Dr. Ted Burns serves as Podcast Editor for Neurology®; performs EMG studies in his neuromuscular practice (35% effort); and has received research support for consulting activities with CSL Behring and Alexion Pharmaceuticals.Dr. Dyck serves as an Associate Editor of Diabetes; is employed as a consultant in Neurology at the Mayo Clinic and receives research support from Pfizer Inc, Isis Pharmaceuticals, Inc., Anylam Pharmaceuticals and the NIH.

Guest: Samuel Gidding, MD Host: Alan S. Brown, MD, FNLA Guidelines are being changed continuously as new evidence is acquired and our environment us evolve. Most recently released are the NHLBI guidelines for pediatric care providers. Host Dr. Alan Brown welcomes Dr. Samuel Gidding. They will address the context to which the guidelines were developed, some of the key social and ethical issues faced by the panel, and a review of the results and the recommendations for the future. Dr. Samuel Gidding is the head of pediatric cardiology and interim director of heart failure and transplant at Nemours Cardiac Center, A. I. DuPont Hospital for Children, Wilmington, Delaware. Brought to you by: