Podcasts about Empagliflozin

In this episode of Cardio Buzz, we explore the intriguing concept of the 'legacy effect' of medications like those used in treating diabetes, hypertension, hypercholesterolemia, and chronic kidney disease. We'll delve into landmark studies like the UKPDS, Steno-2, and more, examining the lasting impacts of medications such as Repatha, Candesartan, and Empagliflozin. Learn how these drugs contribute to disease regression, modify genes, and prevent non-fatal events to grant long-term protective effects. 00:00 Introduction: The Challenge of Lifelong Medication 00:57 Exploring the Legacy Effect of Medications 01:33 Diabetes Medications: Long-Term Benefits 03:15 Hypertension Medications: Persistent Effects 03:58 Cholesterol Medications: Lasting Impact 04:49 Kidney Disease Medications: Prolonged Benefits 06:12 Understanding the Legacy Effect Mechanism 09:13 Implications and Final Thoughts

Diabetes Core Update is a monthly podcast that presents and discusses the latest clinically relevant articles from the American Diabetes Association's four science and medical journals – Diabetes, Diabetes Care, Clinical Diabetes, and Diabetes Spectrum. Each episode is approximately 25 minutes long and presents 5-6 recently published articles from ADA journals. Intended for practicing physicians and health care professionals, Diabetes Core Update   discusses how the latest research and information published in journals of the American Diabetes Association are relevant to clinical practice and can be applied in a treatment setting. Welcome to diabetes core update where every month we go over the most important articles to come out in the field of diabetes. Articles that are important for practicing clinicians to understand to stay up with the rapid changes in the field.  This issue will review: 1.     Dapagliflozin plus calorie restriction for remission of type 2 diabetes 2.     Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity 3.     Effectiveness of Empagliflozin vs Dapagliflozin for Kidney Outcomes in Type 2 Diabetes 4.     Tirzepatide Associated With Reduced Albuminuria in Participants With Type 2 Diabetes 5.     Use of SGLT2i Versus DPP-4i as an Add-On Therapy and the Risk of PAD-Related Surgical Events (Amputation, Stent Placement, or Vascular Surgery)   For more information about each of ADA's science and medical journals, please visit Diabetesjournals.org. Hosts: Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health John J. Russell, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Chair-Department of Family Medicine, Abington Jefferson Health

On this podcast episode of the top 200 drugs, I'm covering liraglutide, folic acid, clotrimazole, empagliflozin, and semaglutide. Liraglutide is a GLP-1 agonist that can be used for weight loss as well as diabetes. The most common adverse effect of this medication is nausea. Folic acid is a commonly used supplement in pregnancy as well as in those patients taking methotrexate. Deficiency of folic acid can lead to anemia. Clotrimazole is an antifungal agent. It is mostly used for topical purposes such as athlete's foot and vaginal yeast infections. Empagliflozin was originally developed as a diabetes medication but can be helpful in patients with heart failure and CKD. I discuss this in greater detail in the podcast. Semaglutide is another GLP-1 agonist that is used for diabetes care as well as weight loss. The formulation used for diabetes is Ozempic while the weight loss product is Wegovy.

Welcome to the 45th episode of my drug pronunciation series! As we continue through the alphabet from A-Z, we're on the letter “E” for empagliflozin. Also check out episode 228 for ezetimibe and episode 134 for eszopiclone.   In this episode, I break down empagliflozin and Jardiance into syllables, tell you which syllables to emphasize, and share my sources.     The written pronunciations are helpful. They are below

Despite advances in the management of acute myocardial infarction (MI), up to 38% of patients will experience signs of heart failure (HF) and many have a reduced left ventricular ejection fraction (LVEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors have well-documented cardiovascular benefits. However, data are limited regarding their use after an acute MI. Guest Authors: Amy Hu, PharmD and Kathleen Pincus, PharmD, BCPS, BCACP, CDCES Music by Good Talk

Diabetes Core Update is a monthly podcast that presents and discusses the latest clinically relevant articles from the American Diabetes Association's four science and medical journals – Diabetes, Diabetes Care, Clinical Diabetes, and Diabetes Spectrum. Each episode is approximately 25 minutes long and presents 5-6 recently published articles from ADA journals. Intended for practicing physicians and health care professionals, Diabetes Core Update   discusses how the latest research and information published in journals of the American Diabetes Association are relevant to clinical practice and can be applied in a treatment setting. Welcome to diabetes core update where every month we go over the most important articles to come out in the field of diabetes. Articles that are important for practicing clinicians to understand to stay up with the rapid changes in the field.  This issue will review: 1.     Insulin Efsitora versus Degludec in Type 2 Diabetes without Previous Insulin Treatment   2.     Semaglutide and Opioid Overdose Risk in Patients With Type 2 Diabetes and Opioid Use Disorder 3.     Associations of Diabetes and Prediabetes with Mortality and Life Expectancy in China: A National Study 4.     GLP-1 Medication Use for Type 2 Diabetes in the US 5.     Healthcare Utilization and Cost Associated with Empagliflozin in Older Adults with Type 2 Diabetes   For more information about each of ADA's science and medical journals, please visitwww.diabetesjournals.org. Hosts: Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health John J. Russell, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Director, Family Medicine Residency Program, Chair-Department of Family Medicine, Abington Jefferson Health

In this CCO Nephrology podcast episode, hear from nephrologists Pietro Canetta, MD, MS, and Andy Bomback, MD, PhD, experts in clinical management and research on glomerular diseases as they discuss key updates in managing IgAN. Faculty highlight the importance of a comprehensive supportive care regimen to protect patients' kidneys and prevent progression of disease. In addition, they review the merits and place in therapy of novel and emerging therapies.  Topics include:Supportive care as the foundation of IgAN managementPlace in therapy for new and emerging agentsTargeted-release formulation of budesonideEndothelin receptor antagonists (eg, sparsentan)Factor B inhibitors (eg, iptacopan)The role of clinical trial involvementLearn more about IgA nephropathy with educational activities and resources here:  CME-certified text module with animated pathophysiology video and patient voice audio clipClinicalThought commentariesResources on IgAN from the American Kidney Fund

With Guillaume Baudry, University Hospital of Brabois, Nancy - France, and Marco Metra, University of Brescia - Italy. In this episode of the HFA Cardiotalk podcast, Guillaume Baudry interviews Marco Metra, the lead author of the recent HFA clinical consensus statement on worsening heart failure. They delve into the definition of worsening heart failure, its prognosis, prevention strategies, and both acute and long-term management of this condition. Related scientific paper: Worsening of chronic heart failure: definition, epidemiology, management and prevention. A clinical consensus statement by the Heart Failure Association of the European Society of Cardiology Risk of readmission and death after hospitalization for worsening heart failure: Role of post-discharge follow-up visits in a real-world study from the Grand Est Region of France Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction   This 2024 HFA CardioTalk podcast serie is supported by Novartis in the form of an educational grant. The discussion has not been influenced in any way by its sponsor. 

Join our scientific team in the discussion of the 3 most clinically impactful papers of the month, the crème de la crème of our weekly top picks. This month we're discussing: Atorvastatin Effect on Aortic Dilatation and Valvular Calcification Progression in Bicuspid Aortic Valve (BICATOR): A Randomized Clinical Trial DOI: 10.1161/CIRCULATIONAHA.123.067537 Left Ventricular Function, Congestion, and Effect of Empagliflozin on Heart Failure Risk After Myocardial Infarction DOI: 10.1016/j.jacc.2024.03.405 Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity DOI: 10.1056/NEJMoa2404881 Scientific team: Ricardo Ladeiras Lopes, Mário Santos and João Sérgio Neves Discover Medical Portfolio App weekly top picks - the latest and most relevant papers, curated by our team of experts! ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://linktr.ee/medicalportfolioapp⁠

N Engl J Med 2024;390:1455-1466BackgroundDespite advances in the care of patients after myocardial infarction, there remains residual risk of heart failure and death. The amount of risk parallels the degree of left ventricular systolic dysfunction. Previous studies have shown that the drug class of sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular risk (especially recurrent heart failure) in multiple clinical situations.The goal of the placebo-controlled Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction (EMPACT-MI) trial was to determine whether empagliflozin reduced the risk of heart failure or death in patients with acute MI and either a new reduction in LV function or signs of congestion, or both.PatientsAdult patients who had been hospitalized with MI within 14 days before randomization. There had to be a new LVEF 65 (50%), Type 2 DM (32%) and 3-vessel CAD (31%). Slightly more than 70% of patients had more than one enrichment factor.Approximately 20% of patients had an LVEF > 45%. Slightly more than half of patients had an LVEF between 35% and 45%. Trial ProceduresRandomization was 1:1 to empagliflozin 10mg daily or matching placebo. The trial was conducted between 2020-2023 at 451 sites in 22 countries. The median time from admission to randomization was 5 days. The trial had a streamlined design, with the collection of essential data only, including information about specific safety events, and mainly remote follow-up of patients (by means of a Web-based application or a telephone call) with only a few face-to-face visits; the trial assessed investigator-reported end-point events rather than centrally adjudicated end-point events. Specifically, follow up included a remote visit at 2 weeks, a face-to-face visit at 6 months, and remote visits every 6 months thereafter until the end of the trial, when a final telephone call was performed.EndpointsThe primary end point was a composite of hospitalization for heart failure or death from any cause as assessed in a time-to-first-event analysis.The key secondary end points in the prespecified hierarchical testing strategy were the total number of hospitalizations for heart failure or death from any cause, the total number of nonelective cardiovascular hospitalizations or death from any cause, the total number of nonelective hospitalizations for any cause or death from any cause, and the total number of hospitalizations for myocardial infarction or death from any cause. Trial authors estimated that 532 patients with a primary end-point event would provide the trial with 85% power to detect a 23% lower risk of an event in the empagliflozin group than in the placebo group, with a two-sided type I error of 0.05. However, the trial originally planned to enroll about 3300 patients, with the option to enroll 5000 patients. But then the trial was further increased to 6500 patients.Key secondary endpoints were assessed using a prespecified hierarchical testing procedure. This began with the primary endpoint.ResultsAn interesting aspect of this trial, and more recent post-MI trials is that the ratio of screened to enrolled patients is almost 1:1. Whereas older trials screened many more patients than were enrolled, in EMPACT, only 88 of 6600 screened patients were excluded. In total, approximately 3200 patients were randomized in both arm.After a median follow-up of 18 months, a primary end-point event — a first hospitalization for heart failure or death from any cause — occurred in 8.2% in the empagliflozin group and in 9.1% in the placebo group, with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). A look at the two components showed that there were fewer heart failure hospitalizations in the empagliflozin group (3.6% vs 4.7%; HR 0.77 (0.60–0.98)) Overall death were similar in both groups. As for secondary endpoints, total heart failure hospitalizations was 2.4 vs 3.6 events, respectively, per 100 patient-years (rate ratio, 0.67; 95% CI, 0.51 to 0.89). The composite of total heart failure hospitalizations or death were not significantly different (HR 0.87 0.68-1.10). CV death was 4% in both groups. There were no obvious subgroup effects nor differences in safety. Conclusions The addition of empagliflozin did not significantly reduce a composite endpoint of heart failure admissions and death. Even the reduction in heart failure admissions was modest. Given the medication burden of the typical patient after myocardial infarction, coupled with the high cost of this drug class, we see no strong evidence for routine use of SGLT2i in EMPACT-MI-type patients. The null results of this trial and PARADISE-MI speak to the beneficial effects of modern post-MI care—including mostly rapid revascularization with PCI. It is difficult to improve on baseline care of the MI patient in 2024. Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

Welcome back Rounds Table Listeners!We are back today with our Classic Rapid Fire Podcast!This week, Drs. Mike and John Fralick discuss two recent papers exploring the role of ticagrelor with aspirin versus ticagrelor alone after percutaneous coronary intervention in acute MI and the efficacy of empagliflozin after acute MI. Two papers, here we go!Ticagrelor alone versus ticagrelor plus aspirin from month 1 to month 12 after percutaneous coronary intervention in patients with acute coronary syndromes (ULTIMATE-DAPT) (0:00 – 9:22). Empagliflozin after Acute Myocardial Infarction (9:22 – 16:00).And for the Good Stuff:Impact of presentation at conference with timed release of academic publication (16:00 – 17:32).Top spot in the PWHL and attendance record at stake in latest Montreal-Toronto showdown (17:32 – 19:59).Questions? Comments? Feedback? We'd love to hear from you! @roundstable

Commentary by Dr. Valentin Fuster

This week, please join author Adrian Hernandez as he discusses the article "Effect of Empagliflozin on Heart Failure Outcomes After Acute Myocardial Infarction: Insights From the EMPACT-MI Trial." For the episode transcript, visit:  https://www.ahajournals.org/do/10.1161/podcast.20240515.717282

ACC.24: EMPACT-AMI trial

Empagliflozin After Acute Myocardial Infarction: Results Of The EMPACT-MI Trial

ACC Recap #1: DanGer Shock (plus a sobering JAMA research letter on Impella use), REDUCE-AMI, PREVENT, and EMPACT-MI are the topics John Mandrola, MD, covers in this week's podcast. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I. DanGer-Shock Trial Impella CP Improves Survival in STEMI, Cardiogenic Shock https://www.medscape.com/viewarticle/impella-cp-improves-survival-stemi-cardiogenic-shock-2024a10006kz Impella Saves Lives in Cardiogenic Shock, but Patient Selection Key https://www.medscape.com/viewarticle/1000659 Published DanGer Shock Study  https://www.nejm.org/doi/full/10.1056/NEJMoa2312572 JAMA Research letter https://jamanetwork.com/journals/jama/article-abstract/2817457 II. REDUCE-AMI Trial New Data Question Beta-Blockers Post-MI With Preserved EF https://www.medscape.com/viewarticle/new-data-question-beta-blockers-post-mi-preserved-ef-2024a10006y8 Beta-Blockers Post-MI Past Their Expiration Date: REDUCE-AMI https://www.medscape.com/viewarticle/1000663 REDUCE-AMI paper https://www.nejm.org/doi/full/10.1056/NEJMoa2401479 Meta-analysis: Beta Blockers for MI https://doi.org/10.1016/j.amjmed.2014.05.032 III. PREVENT Trial Preventive PCI for Vulnerable Plaques Reduces Cardiac Events https://www.medscape.com/viewarticle/preventive-pci-vulnerable-plaques-reduces-cardiac-events-2024a10006tc Preventive Coronary Stents: Not There Yet https://www.medscape.com/viewarticle/preventive-coronary-stents-not-there-yet-2024a10006yr PREVENT https://doi.org/10.1016/S0140-6736(24)00413-6 IV. EMPACT MI trial of Empagliflozin in the Post-MI setting Empagliflozin Fails to Reduce Events After Acute MI https://www.medscape.com/viewarticle/empagliflozin-fails-reduce-events-after-acute-mi-2024a10006kn EMPACT-MI: Another SGLT2 Inhibitor Miss in Post-MI Care  https://www.medscape.com/viewarticle/1000684 EMPACT MI https://www.nejm.org/doi/10.1056/NEJMoa2314051 DAPA MI https://evidence.nejm.org/doi/full/10.1056/EVIDoa2300286 PARADISE MI https://www.nejm.org/doi/full/10.1056/NEJMoa2104508 Kaul thread https://x.com/kaulcsmc/status/1776611935842165029 Kaul paper https://www.ahajournals.org/doi/full/10.1161/circulationaha.116.022537 You may also like: The Bob Harrington Show with the Stephen and Suzanne Weiss Dean of Weill Cornell Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

Before we head off to SHM CONVERGE this weekend, here are a few articles that may be of use in your practice. A random assortment from end-of-life care to ketamine in pain control, hopefully its something for everyone. | 00.05 - Intro | | 00.48 - CONVERGE - come visit me on Saturday in Hall F! Or email boostershots@ucsd.edu if you want to discuss at other times! | | 01.42 - Empagliflozin delays CKD progression in diabetic or glomerular disease, but not necessarily hypertensive or renovascular disease [ACP Journal Club 2024 (subscription required), Lancet D&E 2024] | 03.14 - Antibiotics and end of life care - I recommend you look at the paper [CID 2024] | | 06.33 - Low dose ketamine for pain control vs. morphine → Shorter onset, but shorter duration [AJEMEN 2024] | 08.00 - Using Deep Learning models to estimate CV risk using CXR only [AIM 2024] references for the groups' other studies using Deep Learning: Long-term mortality from CXR [JAMA 2019], Identifying high risk smokers for lung cancer CT screening [AIM 2020] | 09.53 - 43s Summary (yes I lied, it wasn't 30s), disclaimers, credits, etc. | [The appearance of external hyperlinks does not constitute endorsements by UCSF of the linked websites, or the information, products, or services contained therein. UCSF does not exercise any editorial control over the information found therein, nor does UCSF make any representation of their accuracy or completeness. All information contained in this episode are the opinions of the respective speakers and not necessarily the views their respective institutions or UCSF, and is only provided for information purposes, not to diagnose or treat.]

In the sequel to last week's episode, we are back with Dr. Jonathan Davis, Director of the Heart Failure program from San Francisco General. We continue our tour of GDMT for HF, by covering SGLT2-i, MRAs, as well as some AKI and outpatient considerations. This is part 1 of 2 parts which will cover an overview of GDMT medications, and dive into Beta-blockers and ARNIs. Part 2 to come out next week! | 00.33 - Previously on Booster Shots | | 01.31 - Chapter 3: SGLT2-i | The now famous EMPA-REG OUTCOME trial [NEJM 2015] Empagliflozin in HFpEF (not discussed in this episode [NEJM 2021] | 04.24 - Chapter 4: MRAs | RALES trial demonstrating benefit in Morbidity/Mortality [NEJM 1999] | 10.04 - Organizing follow up | | 11.51 - Issues with AKI | | 15.10 - Some fun questions about Fun questions | | 16.54 - Summary of All The Things! | [The appearance of external hyperlinks does not constitute endorsements by UCSF of the linked websites, or the information, products, or services contained therein. UCSF does not exercise any editorial control over the information found therein, nor does UCSF make any representation of their accuracy or completeness. All information contained in this episode are the opinions of the respective speakers and not necessarily the views their respective institutions or UCSF, and is only provided for information purposes, not to diagnose or treat.] Music by Amit Apte. Medical Heart Vectors by Vecteezy

Commentary by Associate Editor Anita Deswal

Welcome back Rounds Table Listeners! In this throwback episode, Drs. John and Mike Fralick discuss two papers – one, exploring the use of SGLT2 inhibitors in CKD, and the second investigating the effect of RAS inhibitor discontinuation on the progression of CKD. Empagliflozin in Patients with Chronic Kidney Disease (0:00 – 9:00). Renin-Angiotensin System Inhibition in ...The post TBT – Chronic Kidney Disease appeared first on Healthy Debate.

Welcome back Rounds Table Listeners! In this throwback episode, Drs. John and Mike Fralick discuss two papers – one, exploring the use of SGLT2 inhibitors in CKD, and the second investigating the effect of RAS inhibitor discontinuation on the progression of CKD. Empagliflozin in Patients with Chronic Kidney Disease (0:00 – 9:00). Renin-Angiotensin System Inhibition in ... The post TBT – Chronic Kidney Disease first appeared on Healthy Debate. The post TBT – Chronic Kidney Disease appeared first on Healthy Debate.

Welcome back Rounds Table Listeners! As we approach the end of 2023, let's revisit five important research studies from 2022: The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial (0:00 – 2:56) Tirzepatide Once Weekly for the Treatment of Obesity (2:56 – 6:00) Empagliflozin in Patients with Chronic Kidney Disease (6:00 – ...The post TBT – The Top Papers of 2022 appeared first on Healthy Debate.

Welcome back Rounds Table Listeners! As we approach the end of 2023, let’s revisit five important research studies from 2022: The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial (0:00 – 2:56) Tirzepatide Once Weekly for the Treatment of Obesity (2:56 – 6:00) Empagliflozin in Patients with Chronic Kidney Disease (6:00 – ... The post TBT – The Top Papers of 2022 first appeared on Healthy Debate. The post TBT – The Top Papers of 2022 appeared first on Healthy Debate.

Join experts Drs Matthew Sparks and Laurence Beck as they discuss the diagnosis and management of membranous nephropathy, a rare kidney disease. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/991606). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources Chronic Kidney Disease (CKD) https://emedicine.medscape.com/article/238798-overview Membranous Glomerulonephritis https://emedicine.medscape.com/article/239799-overview M-type Phospholipase A2 Receptor as Target Antigen in Idiopathic Membranous Nephropathy https://pubmed.ncbi.nlm.nih.gov/19571279/ The Endocytic Receptor Megalin and Its Associated Proteins in Proximal Tubule Epithelial Cells https://pubmed.ncbi.nlm.nih.gov/25019425/ PLA2R Autoantibodies and PLA2R Glomerular Deposits in Membranous Nephropathy https://pubmed.ncbi.nlm.nih.gov/21323563/ Genome-Wide Association Studies (GWAS) https://www.genome.gov/genetics-glossary/Genome-Wide-Association-Studies Thrombospondin Type-1 Domain-Containing 7A in Idiopathic Membranous Nephropathy https://pubmed.ncbi.nlm.nih.gov/25394321/ New 'Antigens' in Membranous Nephropathy https://pubmed.ncbi.nlm.nih.gov/33380523/ Nephrotic Syndrome https://emedicine.medscape.com/article/244631-overview NAACCR Item #3812: B Symptoms https://staging.seer.cancer.gov/naaccr/item/eod_public/2.1/3812/ Video-Assisted Thoracoscopy https://www.ncbi.nlm.nih.gov/books/NBK532952/ Direct Oral Anticoagulants: A Quick Guide https://pubmed.ncbi.nlm.nih.gov/30416551/ Focal Segmental Glomerulosclerosis https://emedicine.medscape.com/article/245915-overview IgA Nephropathy https://emedicine.medscape.com/article/239927-overview DOAC Compared With Warfarin for VTE in Patients With Obesity: A Retrospective Cohort Study Conducted Through the VENUS Network https://pubmed.ncbi.nlm.nih.gov/36757644/ Is It Lupus Nephritis? A Path to Diagnosis and Treatment https://www.medscape.com/viewarticle/991602 Noninvasive Diagnosis of PLA2R-Associated Membranous Nephropathy: A Validation Study https://pubmed.ncbi.nlm.nih.gov/34782349/ Noninvasive Diagnosis of Primary Membranous Nephropathy Using Phospholipase A2 Receptor Antibodies https://pubmed.ncbi.nlm.nih.gov/30665573/ Proteinuria Medication https://emedicine.medscape.com/article/238158-medication Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors https://www.ncbi.nlm.nih.gov/books/NBK576405/ Dapagliflozin in Patients With Chronic Kidney Disease https://pubmed.ncbi.nlm.nih.gov/32970396/ Empagliflozin in Patients With Chronic Kidney Disease https://pubmed.ncbi.nlm.nih.gov/36331190/ Long-Term Follow-Up of Cyclical Cyclophosphamide and Steroids Versus Tacrolimus and Steroids in Primary Membranous Nephropathy https://pubmed.ncbi.nlm.nih.gov/34622104/ Strategies Towards Antigen-Specific Treatments for Membranous Nephropathy https://pubmed.ncbi.nlm.nih.gov/35185913/ Transplant Candidate https://kdigo.org/guidelines/transplant-candidate/

Welcome to the Olink® Proteomics in Proximity podcast! Below are some useful resources mentioned in this episode: Olink tools and software• Olink® Explore 3072, the platform utilized by the UK Biobank to measure ~3000 proteins in plasma: https://olink.com/products-services/explore/• Olink® Explore HT, Olink's most advanced solution for high-throughput biomarker discovery, measuring 5400+ proteins simultaneously with a streamlined workflow and industry-leading specificity: https://olink.com/products-services/exploreht/ UK Biobank Pharma Proteomics Project (UKB-PPP), one of the world's largest scientific studies of blood protein biomarkers conducted to date, https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/news/uk-biobank-launches-one-of-the-largest-scientific-studies Research articles• Dhindsa, R.S., Burren, O.S., Sun, B.B. et al. Rare variant associations with plasma protein levels in the UK Biobank. 2023 Nature, DOI: 10.1038/s41586-023-06547-xhttps://www.nature.com/articles/s41586-023-06547-x• Sun, B.B., Chiou, J., Traylor, M. et al.  Plasma proteomic associations with genetics and health in the UK Biobank. 2023 Nature, DOI: 10.1038/s41586-023-06592-6 https://www.nature.com/articles/s41586-023-06592-6• Ticau S, Sridharan G, Tsour S, et al. Neurofilament Light Chain as a Biomarker of Hereditary Transthyretin-Mediated Amyloidosis 2021 Neurology, DOI: 10.1212/WNL.0000000000011090https://n.neurology.org/content/96/3/e412.long• Zannad F, Ferreira JP, Butler J, et al.  Effect of Empagliflozin on Circulating Proteomics in Heart Failure: Mechanistic Insights from the EMPEROR Program. 2022 European Heart Journal, DOI: 10.1093/eurheartj/ehac495                https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehac495/6676779• Eldjarn GH, et al. Large-scale plasma proteomics comparisons through genetics and disease associations. Nature. 2023 Oct;622(7982):348-358. doi: 10.1038/s41586-023-06563-xhttps://www.nature.com/articles/s41586-023-06563-x#Sec44• [PREPRINT] Carrasco-Zanini et al 2023 Proteomic prediction of common and rare diseases MedRxiv https://www.medrxiv.org/content/10.1101/2023.07.18.23292811v1• Michaëlsson E, Lund LH, Hage C, et al. Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF. 2023 JACC. Heart Failure, DOI: 10.1016/j.jchf.2023.03.002https://www.sciencedirect.com/science/article/pii/S2213177923001257• Girerd N, Levy D, Duarte K, et al.  Protein Biomarkers of New-Onset Heart Failure: Insights From the Heart Omics and Ageing Cohort, the Atherosclerosis Risk in Communities Study, and the Framingham Heart Study. 2023 Circulation Heart Failure, DOI: 10.1161/CIRCHEARTFAILURE.122.009694https://www.ahajournals.org/doi/abs/10.1161/CIRCHEARTFAILURE.122.009694Subscribe to the podcast on your favorite player or app:Apple Podcasts: https://apple.co/3T0YbSm Spotify Podcasts: https://open.spotify.com/show/2sZ2wxO... Google Podcasts: https://podcasts.google.com/feed/aHR0... Amazon Music: https://music.amazon.com/podcasts/d97... Podcast Addict: https://podcastaddict.com/podcast/409... Deezer: https://www.deezer.com/show/5178787 Player FM: https://player.fm/series/series-3396598 In case you were wondering, Proteomics in Proximity refers to the principle underlying Olink technology called the Proximity Extension Assay (PEA). More information about the assay and how it works can be found here: https://bit.ly/3Rt7YiY For any questions regarding information about Olink Proteomics, please email us at info@olink.com or visit our website: https://www.olink.com/Interested in a specific podcast topic or guest? Reach out to us at PIP@olink.comWHAT IS PROTEOMICS IN PROXIMITY?Proteomics in Proximity discusses the intersection of proteomics with genomics for drug target discovery, the application of proteomics to reveal disease biomarkers, and current trends in using proteomics to unlock biological mechanisms. Co-hosted by Olink's Cindy Lawley and Sarantis Chlamydas.

On this episode, we welcome back Henry So, clinical pharmacist for Diamond's OPTICS team. As we recorded this, Henry was days away from giving an NCCHC conference presentation on evaluating high cost therapies for type 2 diabetes patients. We discuss why he was inspired to develop a presentation around this topic, look at the use of different diabetic agents in special patient populations, and dive into his clinical rationale for helping providers choose between newer often pricier agents and older more established therapies. If you missed Henry's presentation at NCCHC, you can catch up with this podcast. Links to studies mentioned in the show/futher reading: Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes | New England Journal of Medicine Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes | New England Journal of Medicine Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes | New England Journal of Medicine Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction | New England Journal of Medicine Empagliflozin in Heart Failure with a Preserved Ejection Fraction | New England Journal of Medicine Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure | New England Journal of Medicine Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes | New England Journal of Medicine Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes | New England Journal of Medicine Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial - PubMed (nih.gov) Semaglutide for cardiovascular event reduction in people with overweight or obesity: SELECT study baseline characteristics - PubMed (nih.gov)

In this week's New FDA Approval's podcast episode, Dr. Emma Hitt Nichols discusses the latest FDA approvals from September 18, 2023 – September 22, 2023.  Please check back every Monday morning so that you can stay up to date.  Check out our free downloads at nascentmc.com: Implementing AMA Style – 8 Things to Get Right in Your Next Project Needs Assessments – 7 Essentials for Getting Funded Working With Your Medical Writer – 8 Ways to Get the Most out of Them See more details summaries and links to prescribing information at nascentmc.com/podcast Here are the highlights: Jardiance (empagliflozin) for CKD  The FDA has approved Jardiance, an SGLT2 inhibitor, for patients with end-stage kidney disease, speciifically to reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression. The approval is based on the EMPA-KIDNEY phase 3 trial, demonstrating a significant reduction in kidney disease progression and cardiovascular death compared to a placebo.  Welireg (belzutifan) for Advanced Renal Cell Carcinoma The FDA granted Priority Review for Merck's Welireg for advanced renal cell carcinoma post other treatments. Welireg, a HIF-2α inhibitor, is being evaluated in the LITESPARK-005 trial, where it was compared with everolimus for advanced RCC treatment post PD-1/L1 or VEGF-TKI therapies. Tevimbra (tislelizumab) for Esophageal Squamous Cell Carcinoma The FDA is reviewing an application for Tevimbra for treating advanced or metastatic esophageal squamous cell carcinoma. Supported by the phase 3 RATIONALE 306 study, the drug improves overall survival rates when combined with chemotherapy in these patients. Neffy Epinephrine Nasal Spray The FDA rejected the approval of Neffy, a needle-free nasal spray for allergic reactions. Despite a positive Advisory Committee vote, the FDA demands further testing. ARS Pharmaceuticals plans to re-submit its application and appeal the decision in 2024.  Intro and outro music Garden Of Love by Pk jazz Collective

Experts Drs Matthew A. Sparks and Dana V. Rizk discuss the pathology, presentation, and management of IgA nephropathy. Looking for the latest on clinical trials and approved treatments? Tune in! Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/991603). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources Chronic Kidney Disease (CKD) https://emedicine.medscape.com/article/238798-overview IgA Nephropathy https://emedicine.medscape.com/article/239927-overview Polycystic Kidney Disease https://emedicine.medscape.com/article/244907-overview Biomarkers for IgA Nephropathy on the Basis of Multi-Hit Pathogenesis https://pubmed.ncbi.nlm.nih.gov/29740706/ Galactose-Deficient IgA1 as a Candidate Urinary Marker of IgA Nephropathy https://pubmed.ncbi.nlm.nih.gov/35683557/ Immunological Drivers of IgA Nephropathy: Exploring the Mucosa-Kidney Link https://pubmed.ncbi.nlm.nih.gov/34821031/ Nephrotic Syndrome https://emedicine.medscape.com/article/244631-overview Podocytopathies https://pubmed.ncbi.nlm.nih.gov/32792490/ Minimal-Change Disease https://emedicine.medscape.com/article/243348-overview IgA Vasculitis (Henoch-Schönlein Purpura) https://emedicine.medscape.com/article/984105-overview Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors https://www.ncbi.nlm.nih.gov/books/NBK576405/ Dapagliflozin in Patients With Chronic Kidney Disease https://pubmed.ncbi.nlm.nih.gov/32970396/ Empagliflozin in Patients With Chronic Kidney Disease https://pubmed.ncbi.nlm.nih.gov/36331190/ A Controlled Trial of Fish Oil in IgA Nephropathy. Mayo Nephrology Collaborative Group https://pubmed.ncbi.nlm.nih.gov/7935657/ Fish Consumption, Omega 3 Fatty Acids and Cardiovascular Disease. The Science and the Clinical Trials https://pubmed.ncbi.nlm.nih.gov/19326716/ Tonsillectomy in a European Cohort of 1,147 Patients With IgA Nephropathy https://pubmed.ncbi.nlm.nih.gov/26586175/ Sparsentan in Patients With IgA Nephropathy: A Prespecified Interim Analysis From a Randomised, Double-Blind, Active-Controlled Clinical Trial https://pubmed.ncbi.nlm.nih.gov/37015244/ Intensive Supportive Care Plus Immunosuppression in IgA Nephropathy https://pubmed.ncbi.nlm.nih.gov/26962737/ Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial https://pubmed.ncbi.nlm.nih.gov/28763548/ Targeted-Release Budesonide Versus Placebo in Patients With IgA Nephropathy (NEFIGAN): A Double-Blind, Randomised, Placebo-Controlled Phase 2b Trial https://pubmed.ncbi.nlm.nih.gov/28363480/ Results From Part A of the Multi-Center, Double-Blind, Randomized, Placebo-Controlled NefIgArd Trial, Which Evaluated Targeted-Release Formulation of Budesonide for the Treatment of Primary Immunoglobulin A Nephropathy https://pubmed.ncbi.nlm.nih.gov/36270561/ Crescents and IgA Nephropathy: A Delicate Marriage https://pubmed.ncbi.nlm.nih.gov/35806856/ Crescentic, Proliferative IgA Nephropathy: Clinical and Histological Response to Methylprednisolone and Intravenous Cyclophosphamide https://pubmed.ncbi.nlm.nih.gov/12808169/ Hydroxychloroquine Inhibits Macrophage Activation and Attenuates Renal Fibrosis After Ischemia-Reperfusion Injury https://pubmed.ncbi.nlm.nih.gov/33936063/ New Treatment Strategies for IgA Nephropathy: Targeting Plasma Cells as the Main Source of Pathogenic Antibodies https://pubmed.ncbi.nlm.nih.gov/35628935/

Join experts Drs Matt Sparks and Dawn Caster as they discuss the complexities around the management of lupus nephritis. What tools do we have now? What is on the horizon? Tune in to find out. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/991602). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources Novel Aspects in the Pathophysiology and Diagnosis of Glomerular Diseases https://pubmed.ncbi.nlm.nih.gov/36535746/ Derivation and Validation of the Systemic Lupus International Collaborating Clinics Classification Criteria for Systemic Lupus Erythematosus https://pubmed.ncbi.nlm.nih.gov/22553077 EULAR/ACR Classification Criteria for SLE https://pubmed.ncbi.nlm.nih.gov/31779843/ Sensitivity and Specificity of ANA and Anti-dsDNA in the Diagnosis of Systemic Lupus Erythematosus: A Comparison Using Control Sera Obtained From Healthy Individuals and Patients With Multiple Medical Problems https://pubmed.ncbi.nlm.nih.gov/24383972/ Podocyte Foot Process Effacement Precedes Albuminuria and Glomerular Hypertrophy in CD2-Associated Protein Deficient Mice https://pubmed.ncbi.nlm.nih.gov/34568396/  KDIGO 2023 Clinical Practice Guideline for the Management of Lupus Nephritis https://kdigo.org/wp-content/uploads/2023/03/KDIGO-2023-Lupus-Nephritis-Guideline_Public-Review_9-Mar-2023.pdf Management of Lupus Nephritis: A Systematic Literature Review Informing the 2019 Update of the Joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) Recommendations https://pubmed.ncbi.nlm.nih.gov/32699043/ Nonrenal Disease Activity Following Mycophenolate Mofetil or Intravenous Cyclophosphamide as Induction Treatment for Lupus Nephritis: Findings in a Multicenter, Prospective, Randomized, Open-Label, Parallel-Group Clinical Trial https://pubmed.ncbi.nlm.nih.gov/20039429/ Immunosuppressive Therapy in Lupus Nephritis: The Euro-Lupus Nephritis Trial, a Randomized Trial of Low-Dose Vs High-Dose Intravenous Cyclophosphamide https://pubmed.ncbi.nlm.nih.gov/12209517/ Voclosporin: A Novel Calcineurin Inhibitor for the Treatment of Lupus Nephritis https://pubmed.ncbi.nlm.nih.gov/35168373 Safety and Efficacy of Belimumab in Patients With Lupus Nephritis: Open-Label Extension of BLISS-LN Study https://pubmed.ncbi.nlm.nih.gov/36302567/ Anti-CD19 CAR T Cell Therapy for Refractory Systemic Lupus Erythematosus https://pubmed.ncbi.nlm.nih.gov/36109639/ Dapagliflozin in People With Chronic Kidney Disease https://pubmed.ncbi.nlm.nih.gov/37257897/ Empagliflozin in Patients With Chronic Kidney Disease https://pubmed.ncbi.nlm.nih.gov/36331190/

Join Drs Carol Wysham and Silvio Inzucchi as they discuss how type 2 diabetes management has evolved over the years, and the most promising developments on the horizon. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/982419). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources Continuous Glucose Monitoring in Persons With Type 2 Diabetes Not Using Insulin https://pubmed.ncbi.nlm.nih.gov/34633261/ Macrovascular Complications of Type 2 Diabetes Mellitus https://pubmed.ncbi.nlm.nih.gov/30961498/ Rate of Decline in Kidney Function and Known Age-of-Onset or Duration of Type 2 Diabetes https://pubmed.ncbi.nlm.nih.gov/34282181/ Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes https://pubmed.ncbi.nlm.nih.gov/26378978/ Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes https://pubmed.ncbi.nlm.nih.gov/27299675/ Tirzepatide Prescribing Information https://uspl.lilly.com/mounjaro/mounjaro.html#pi Glycemic Targets: Standards of Care in Diabetes-2023 https://pubmed.ncbi.nlm.nih.gov/36507646/ 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines https://pubmed.ncbi.nlm.nih.gov/30879355/ American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update https://pubmed.ncbi.nlm.nih.gov/35963508/ 2018 ESC/ESH Guidelines for the Management of Arterial Hypertension https://pubmed.ncbi.nlm.nih.gov/30165516/ The Role of BNP Testing in Heart Failure https://pubmed.ncbi.nlm.nih.gov/17168346/ Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) Rationale and Design https://pubmed.ncbi.nlm.nih.gov/32916609/ A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes (SOUL) https://clinicaltrials.gov/ct2/show/NCT03914326 GLP-1 Receptor Agonists and Kidney Protection https://pubmed.ncbi.nlm.nih.gov/31159279/ Glucagon-like Peptide 1 Receptor Agonists, Diabetic Retinopathy and Angiogenesis: The AngioSafe Type 2 Diabetes Study https://pubmed.ncbi.nlm.nih.gov/31589290/ A Study of Tirzepatide (LY3298176) Versus Insulin Lispro (U100) in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine (U100) With or Without Metformin (SURPASS-6) https://clinicaltrials.gov/ct2/show/NCT04537923 The Emerging Role of Glucagon-like Peptide-1 Receptor Agonists for the Management of NAFLD https://pubmed.ncbi.nlm.nih.gov/34406410/ Comparison of Noninvasive Markers of Fibrosis in Patients With Nonalcoholic Fatty Liver Disease https://pubmed.ncbi.nlm.nih.gov/19523535/ Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus https://pubmed.ncbi.nlm.nih.gov/30090738/

⁠DozeNews PRIME⁠⁠⁠⁠: as melhores e mais didáticas revisões de cardiologia direto na sua caixa de entrada! Assine agora e tenha acesso à todo material já produzido! - ⁠⁠⁠⁠https://dozeporoito.substack.com Continuamos com o sarrafo alto!  A parceria Doze Por Oito Cardiologia e o 81º Curso Intensivo do Dante Pazzanese continua e, dessa vez, Rapha Rossi e William Batah contam com o retorno de nossa querida convidada e especialista em disfunção ventricular, Dra. Carolina Casadei para debater as principais nuances do uso das duas novas principais medicações no tratamento da insuficiência cardíaca: os INRAs e I-SGLT2. Esse episódio tem apoio do Insituto Dante Pazzanese de Cardiologia ⏱️ Minutagem: (00:00) Apresentação (02:20) Quem são e quando usar os INRAs? (08:30) Como iniciar o INRA? (12:50) Quando nao usar os INRAs (17:15) Qual o papel dos INRAs na ICFEP (20:00) Porque usar os I-SGLT2 (27:00) Como funcionam os I-SGLT2 e quando usar? (33:00) Dapagifozina na ICFEP (37:20) Cuidados ao usar I-SGLT2 (42:00) Considerações finais Referências: McMurray JJ, et al ; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30. PMID: 25176015. Packer M,et al; EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020 Oct 8;383(15):1413-1424. doi: 10.1056/NEJMoa2022190. Epub 2020 Aug 28. PMID: 32865377. Solomon SD, et al. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial. Eur J Heart Fail. 2021 Jul;23(7):1217-1225. doi: 10.1002/ejhf.2249. Epub 2021 Jun 9. PMID: 34051124; PMCID: PMC8361994.

Commentary by Dr. Valentin Fuster

The following question refers to Section 7.6 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.  The question is asked by premedical student and CardioNerds Intern Pacey Wetstein, answered first by Baylor College of Medicine Cardiology Fellow and CardioNerds Ambassador Dr. Jamal Mahar, and then by expert faculty Dr. Nancy Sweitzer. Dr. Sweitzer is Professor of Medicine, Vice Chair of Clinical Research for the Department of Medicine, and Director of Clinical Research for the Division of Cardiology at Washington University School of Medicine. She is the editor-in-chief of Circulation: Heart Failure. Dr. Sweitzer is a faculty mentor for this Decipher the HF Guidelines series. The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Question #9 Mr. Flo Zin is a 64-year-old man who comes to discuss persistent lower extremity edema and dyspnea with mild exertion. He takes amlodipine for hypertension but has no other known comorbidities. In the clinic, his heart rate is 52 bpm and blood pressure is 120/70 mmHg. Physical exam reveals mildly elevated jugular venous pulsations and 1+ bilateral lower extremity edema. Labs show an unremarkable CBC, normal renal function and electrolytes, a Hb A1c of 6.1%, and an NT-proBNP of 750 (no prior baseline available). On echocardiogram, his LVEF is 44% and nuclear stress testing was negative for inducible ischemia. What is the best next step in management? A Add furosemide BID and daily metolazone B Start empagliflozin and furosemide as needed C Start metoprolol succinate D No change to medical therapy Answer #9 Explanation The correct answer is B – start empagliflozin and furosemide as needed. The patient described here has heart failure with mildly reduced EF (HFmrEF), given LVEF in the range of 41-49%. In patients with HF who have fluid retention, diuretics are recommended to relieve congestion, improve symptoms, and prevent worsening HF (Class 1, LOE B-NR). For patients with HF and congestive symptoms, addition of a thiazide (eg, metolazone) to treatment with a loop diuretic should be reserved for patients who do not respond to moderate or high-dose loop diuretics to minimize electrolyte abnormalities (Class 1, LOE B-NR). Therefore, option A is not correct as he is only mildly congested on examination, and likely would not require such aggressive decongestive therapy, particularly with normal renal function. Adding a thiazide diuretic without first optimizing loop diuretic dosing would be premature. The EMPEROR-Preserved trial showed a significant benefit of the SGLT2i, empagliflozin, in patients with symptomatic HF, with LVEF >40% and elevated natriuretic peptides. The 21% reduction in the primary composite endpoint of time to HF hospitalization or cardiovascular death was driven mostly by a significant 29% reduction in time to HF hospitalization, with no benefit on all-cause mortality. Empagliflozin also resulted in a significant reduction in total HF hospitalizations, decrease in the slope of the eGFR decline, and a modest improvement in QOL at 52 weeks. Of note, the benefit was similar irrespective of the presence or absence of diabetes at baseline. In a subgroup of 1983 patients with LVEF 41% to 49% in EMPEROR-Preserved, empagliflozin, an SGLT2i, reduced the risk of the primary composite endpoint of cardiovascular death or hospitalization f...

Efficacy and Safety of Intensive Versus Nonintensive Supplemental Insulin With a Basal-Bolus Insulin Regimen in Hospitalized Patients With Type 2 Diabetes: A Randomized Clinical Study | Diabetes Care | American Diabetes Association (diabetesjournals.org)   randomized noninferiority study from Emory University, 224 hospitalized patients with longstanding type 2 diabetes  Both groups received basal/bolus insulin; both the starting dose and subsequent changes were specified by the study protocol. Additional premeal SSI was added to scheduled premeal bolus doses.randomized to either intensive SSI (at BG >140 mg/dL) or nonintensive SSI (at BG >260 mg/dL) before meals and at bedtime.  Mean baseline glycosylated hemoglobin (HbA1c) was 9%, and 60% of patients were using insulin at home. Patients with a presenting glucose level of >400 mg/dL or diabetic ketoacidosis were excluded.  Outcome---Mean daily BG level, hypoglycemia, severe hyperglycemia, percent of BGs in the target range (70–180 mg/dL), and the amount of total, basal, or prandial insulin used did not differ between groups. However, significantly fewer patients in the nonintensive group than in the intensive group received SSI (34% vs. 91%).   COMMENTAlthough this is a single-center study, its results are persuasive and suggest that a less-intense SSI regimen can achieve similar glucose outcomes in hospitalized patients with type 2 diabetes who are receiving basal/bolus insulin. It also could decrease nursing treatment burden. As we move slowly toward more continuous glucose monitoring in hospitals, reducing use of SSI is another opportunity to achieve similar results with less staff burden and more patient comfort.  Comparative Effectiveness and Safety Between Apixaban, Dabigatran, Edoxaban, and Rivaroxaban Among Patients With Atrial Fibrillation: A Multinational Population-Based Cohort Study: Annals of Internal Medicine: Vol 175, No 11 (acpjournals.org) In a retrospective study, investigators accessed five electronic health databases from Europe and the U.S. to compare >500,000 new DOAC users with newly diagnosed atrial fibrillation. Follow up varied from 1.5 to 4.5 years.   In propensity score–adjusted analyses, patients who received apixaban had significantly less gastrointestinal (GI) bleeding did those who received any of the other three drugs (hazard ratios, 0.7–0.8). This result was consistent among older patients and those with chronic kidney disease (CKD). Risk for stroke or other systemic embolism, intracranial hemorrhage, and all-cause mortality did not differ significantly among DOACs.    COMMENTThis is the largest comparison of individual DOACs, and it demonstrates similar efficacy among all agents. Although apixaban was associated with less GI bleeding, absolute percentages of GI bleeds ranged from ≈2% to ≈3.5% for all DOACs; therefore, apixaban's statistically significant safety benefit might amount to marginal clinical benefit for any individual patient. I might turn to apixaban for patients at high risk for GI bleeding (and those with CKD), but all DOACs remain reasonable options for preventing thromboembolism in most patients with atrial fibrillation. Ellenbogen MI et al. Safety and effectiveness of apixaban versus warfarin for acute venous thromboembolism in patients with end-stage kidney disease: A national cohort study. J Hosp Med 2022 Oct; 17:809. (https://doi.org/10.1002/jhm.12926. opens in new tab)  . In an industry-funded retrospective study, investigators used a national database (years, 2014–2018) and propensity score–adjusted analysis to compare outcomes among >11,500 patients with ESRD and newly diagnosed VTE who received either apixaban or warfarin.Only 2% of patients received apixaban in 2014, but 47% received apixaban in 2018.during the 6 months following initiation of therapy, apixaban — compared with warfarin  associated with significantly lower incidence of major bleeding (10% vs. 14%), including intracranial bleeding (1.8% vs. 2.5%) and gastrointestinal bleeding (8.6% vs. 10.4%). Recurrent VTE and all-cause mortality were similar in the two groups.   VTE and creatine clearence less than 30 then I think apixaban is the drug of choice—I would like to see this study don't with afib and done with exclusively

The NACE Journal Club with Dr. Neil Skolnik, is a new series of episodes that provide review and analysis of recently published journal articles important to the practice of primary care medicine. In this episode Dr. Skolnik and guests review the following publications:1. The protective effect of exercise against Covid infection and hospitalization in individuals vaccinated against covid, Association between regular physical activity and the protective effect of vaccination against SARS-CoV-2 in a South African case–control study. Collie S, et al. Br J Sports Med2022;0:1–7. doi:10.1136/bjsports-2022-105734Guest: Connie Jiang, MD is chief resident in the family medicine residency at Jefferson-Abington Health, Abington Hospital, Abington, PA2. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. Solomon, et.al. N Engl J Med 2022; 387:1089-1098DOI: 10.1056/NEJMoa2206286Guest: Orly Vardeny, Pharm.D is a BPS Board Certified clinical pharmacist with current research that focuses on novel therapies in the treatment of heart failure and the impact of influenza vaccination on heart disease. She has over 10 years of experience researching the effects of medications on cardiovascular conditions. Dr. Varney is a Core Investigator at the Center for Care Delivery and Outcomes Research, United States Department of Veterans Affairs, Associate Professor of Medicine, University of Minnesota Medical School, and Adjunct Faculty, University of Minnesota College of Pharmacy.3. Mindfulness-Based Stress Reduction vs Escitalopram for the Treatment of Adults With Anxiety Disorders: A Randomized Clinical Trial. Hoge EA, et al, JAMA Psychiatry. 2023 Jan 1;80(1):13-21. doi: 10.1001/jamapsychiatry.2022.3679.Guest: Bridget Smith, MD is a second-year resident in the family medicine residency at Jefferson Health – Abington, Abington Hospital, Abington, PA 4. Empagliflozin in Patients with Chronic Kidney Disease. The EMPA-KIDNEY Collaborative Group, N Engl J Med 2023; 388:117-127DOI: 10.1056/NEJMoa2204233Guest: Katie McKormick, MD  is a second year resident in the family medicine residency at Jefferson Health – Abington, Abington Hospital, Abington, PAMedical Director and Host: Neil Skolnik, MD, is an academic family physician who sees patients and teaches residents and medical students as professor of Family and Community Medicine at the Sidney Kimmel Medical College, Thomas Jefferson University and Associate Director, Family Medicine Residency Program at Abington Jefferson Health in Pennsylvania. Dr. Skolnik graduated from Emory University School of Medicine in Atlanta, Georgia, and did his residency training at Thomas Jefferson University Hospital in Philadelphia.Please visit http://naceonline.com to engage in more live and on demand CME/CE content.

Please join author Subodh Verma and Guest Editor Christopher Granger as they discuss the article "Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial." 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-host. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Peder Myhre: And I'm Dr. Peder Myhre, social media editor and doctor at Akershus University Hospital at University of Oslo in Norway. Dr. Carolyn Lam: Peder, I am so excited to be discussing this issue. So many great articles and a feature discussion coming up on the SGLT2 inhibitor, empagliflozin. And do you think it's got effects on left ventricular remodeling in people without diabetes? Very interesting question. Dr. Peder Myhre: That is so interesting, Carolyn. I can't wait to hear this discussion. Dr. Carolyn Lam: Yep, I agree, but we got to wait till we discuss the other papers in today's issue. I want to go first. So we know that non-vitamin K oral anticoagulants, or NOACs, they've become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation. But, what is the effectiveness and safety of NOACs in patients on dialysis? That is hemodialysis. The AXADIA-AFNET 8 study sought to test the hypothesis that apixaban would be non-inferior to vitamin K antagonists in these very patients undergoing hemodialysis. Dr. Peder Myhre: Oh wow. This is really a gap of knowledge that we've been waiting to hear more about. NOACs in patients with hemodialysis. Tell us about this trial, Carolyn. Dr. Carolyn Lam: Sure. So this is from corresponding author, Dr. Reinecke, and colleagues, from University of Munster in Germany. And it's an investigator initiated prospective randomized open-blinded outcome assessment of 97 patients with atrial fibrillation on chronic hemodialysis randomized to either apixaban 2.5 mg BID, or a vitamin K antagonist, aiming for an INR between 2 and 3. Over a median follow-up time of 429 days for apixaban, and 506 days for the vitamin K antagonist, the composite primary safety outcome of first, major bleeding, clinically relevant, non-major bleeding, or all cause death, occurred in 46% of patients on apixaban, and 51% of patients on the vitamin K antagonist. That would be a hazard ratio of 0.91, with a p for non-inferiority being 0.157. How about the primary efficacy outcome? While this was a composite of ischemic stroke, all cause death, myocardial infarction, or deep vein thrombosis, and/or pulmonary embolism, and that occurred in 21% of patients on apixaban and 31% of patients on the vitamin K antagonists. Again, no difference when there was testing. So, in summary, Peder, there were no differences in the safety or efficacy observed between apixaban and vitamin K antagonists in patients with atrial fibrillation on chronic hemodialysis. Of note, however, even receiving oral anticoagulations, these patients remain at very high risk of cardiovascular events. So these data really support the consideration of apixaban for prevention of cardiovascular complications in patients with atrial fibrillation on chronic hemodialysis, but larger studies are definitely needed. Dr. Peder Myhre: Oh wow, Carolyn, that is so clinically relevant. And the next paper is also a clinically relevant paper. And it comes to us from the SPRINT authors. And to remind you, the SPRINT study was a study of intensive systolic blood pressure lowering compared to standard blood pressure lowering. And the results demonstrated that there was a robust reduction in both heart failure endpoints and all cause mortality. And in this sub-study that comes to us from corresponding author Jarett Berry from University of Texas Tyler School of Medicine, these authors look at the mechanisms through which intensive blood pressure lowering reduces the risk of these endpoints. And given the important role of cardiac injury and neurohormonal activation in the pathways leading from hypertension to heart failure, and strong association that has been observed between hypertension and levels of cardiac troponin and NT-proBNP, the authors hypothesized that intensive systolic blood pressure lowering would decrease levels of high sensitivity cardiac troponin T and NT-proBNP. Dr. Carolyn Lam: Cool. That's interesting. So how did they do this, and what did they find? Dr. Peder Myhre: So, as expected, Carolyn, the authors found that increases in troponin and NT-proBNP from baseline to 1 year were associated with a higher risk of heart failure and death. And there were really no significant interaction by treatment assignment. But let's look at the changes in troponin. And these results showed that randomization to intensive blood pressure lowering versus standard blood pressure lowering resulted in a significant 3% increase in cardiac troponin T level over 1 year follow up, and a higher proportion of participants with more than 50% increase, and that's with an odds ratio of 1.47. And Carolyn, in contrast, NT-proBNP decreased by 10% in intensive blood pressure arm. And these patients had substantially lower probability of increasing more than 50% in NT-proBNP, with an odds ratio of 0.57 compared to the standard arm. And now, to the most interesting part of this analysis, Carolyn, the association of randomized treatment assignment on changes in troponin was completely attenuated after accounting for changes in eGFR during the follow up, whereas the association of treatment with NT-proBNP changes were completely attenuated after adjusting for changes in systolic blood pressure. So Carolyn, the authors highlight in their discussion the importance of non-cardiac factors influencing variation in cardiac biomarkers, and raise questions about the potential role of cardiac troponin T as a surrogate marker for heart failure or death in blood pressure lowering studies. Dr. Carolyn Lam: Wow, very interesting. Thanks, Peder. Can I tell you now about a preclinical study? Very interesting, because it shows that cardiac inflammation and hypertrophy are regulated by a heart-brain interaction. Dr. Peder Myhre: Wow, Carolyn, a heart-brain interaction. I'm excited to hear more about this. Please explain. Dr. Carolyn Lam: I'd love to, but first some background. Interleukin-1 beta, now that is a pro-inflammatory cytokine that causes cardiac hypertrophy and heart failure. I need to familiarize you with this, the nucleotide-binding domain leucine-rich containing family, pyrin domain-containing-3, NLRP3 for short, which is an inflammasome, which is a cytosolic multiprotein complex that mediates active interleukin-1 beta production. Okay? So you know these terms, and now I want to tell you about the study. This is an elegant series of experiments performed by co-corresponding authors, Dr. Higashikuni, from University of Tokyo, and Dr. Sata, from Tokushima University Graduate School of Medicine, and their colleagues. They first showed that genetic disruption of the NLRP3 inflammasome resulted in significant loss of interleukin-1 beta production, cardiac hypertrophy, and contractile function during pressure overload. Next, a bone marrow transplantation experiment revealed an essential role of NLRP3 inflammasome in cardiac non-immune cells in myocardial interleukin-1 beta production and the cardiac phenotype. It was extracellular ATP released from sympathetic nerve terminals that induced the hypertrophic changes of cardiac cells in an NLRP3 and interleukin-1 beta dependent manner in vitro. And finally, depletion of ATP release from sympathetic efferent nerves, or ablation of cardiac afferent nerves, or a lipophilic beta-blocker, all reduced cardiac extracellular ATP, and inhibited the NLRP3 inflammasome activation, the interleukin-1 beta production, and the adaptive cardiac hypertrophy during pressure overload. So all of this suggests that controlling the neuronal brain signals might have therapeutic potential for the treatment of hypertensive heart disease. Neat, huh? Dr. Peder Myhre: Oh, that is so interesting. The heart and brain interaction. And, Carolyn, we're going to stay in the field of preclinical science. And now we're going to talk about another field that is really interesting, and that is regeneration of cardiomyocytes. Because, Carolyn, developmental cardiac tissue holds remarkable capacity to regenerate after injury, and consists of regenerative mononuclear and deployed cardiomyocytes. Whether reprogramming metabolism promotes persistence of these regenerative mononuclear and deployed cardiomyocytes that enhance cardiac function in repair after injury is unknown. Therefore, these researcher, led by corresponding author, Mohsin Khan, from Temple University School of Medicine, investigated whether the RNA binding protein, LIN28a, which is a master regulator of cellular metabolism, plays a role in cardiac repair following injury. Dr. Carolyn Lam: Wow. That is always, always interesting, regeneration and repair following injury. So what did the authors find? Dr. Peder Myhre: Well, Carolyn, through a number of elegant experiments, the authors made the following key findings. For the first time, they documented a role for RNA binding protein LIN28A in regulating cardiomyocyte turnover in the postnatal and adult heart. And LIN28a overexpression promotes cardiomyocyte cell cycle activity during postnatal development and extends cardiac regenerative ability of the mammalian heart to postnatal day 7. And in the adult heart, the authors could demonstrate that LIN28a drives new myocyte formation, augmenting cardiac structure and function after myocardial injury. And Carolyn, I'm sure you're going to ask the clinical implications of this study. Dr. Carolyn Lam: Indeed. Dr. Peder Myhre: And that is that these results may suggest a novel translational role for LIN28a based strategy to replenish cardiomyocytes in the adult heart after injury. Dr. Carolyn Lam: Very nice, Peder. Thank you. Also in the issue is a Research Letter by Dr. Bick on interleukin-6 receptor polymorphism attenuates clonal hematopoiesis mediated coronary artery disease risk among many individuals in the UK Biobank. There's also Cardiology News by Tracy Hampton, where she highlights few really interesting things, like aging cardiomyocytes accumulate new genetic mutations that was published in Nature Aging, cytokines promote tissue repair after a heart attack in mice, and that was published in Science, and scientists identifying molecular alterations in a failing heart at a single cell resolution, which was published in Nature. Dr. Peder Myhre: And there are a couple of other papers also in this issue, Carolyn. And there's first, an exchange of letters by Drs. Halushka, Lu, and Mayr, regarding the article "Circulating MicroRNA-122-5p is Associated with a Lack of Improvement in Left Ventricular Function after TAVR and Regulates Viability of Cardiomyocytes Through Extracellular Vesicles." And finally, we have an "On My Mind" piece by doctors Monda and Limongelli entitled "An Integrated Sudden Cardiac Risk Prediction Model for Patients with Hypertrophic Cardiomyopathy." Dr. Carolyn Lam: Oh, nice. Nice full issue. Thank you, Peder. Let's go to our feature discussion now. Shall we? Dr. Peder Myhre: Let's go. Dr. Greg Hundley: Welcome listeners to this feature discussion on January 24th. And we have with us Dr. Subodh Verma, from St. Michael's University in Toronto, Canada. And a guest editor, Dr. Christopher Granger, from Duke University in Durham, North Carolina. Welcome gentlemen. Well, Subodh, we will start with you. Can you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address? Dr. Subodh Verma: First, my great pleasure to be here, and thank you very much for the opportunity to discuss this paper with your viewers. As you know, SGLT2 inhibitors have been truly transformative therapies. From a heart failure perspective, we know that they prevent incident heart failure in people with diabetes who have vascular disease or risk factors. They also have been shown to treat prevalent heart failure in people with heart failure and either a reduced, mildly reduced, or preserved ejection fraction independent of glycemic status. And really, these have been the basis of very strong recommendations to use these agents in the prevention of heart failure in people with diabetes, and also in the treatment of prevalent heart failure in people with and without diabetes. Now, the fact that these drugs have such broad effects in people with heart failure has led to a theory that maybe these drugs could be introduced earlier on in the natural history of heart failure in people who neither have diabetes nor have significant heart failure, the so-called sort of stage A or stage B patient. But there really have been no clinical trials evaluating this question. There've been a lot of translational randomized trials that have provided some mechanistic insights about LV remodeling in people with diabetes or in people with prevalent heart failure. And we hypothesized that maybe the first step to evaluate whether SGLT2 inhibitors may have favorable effects on cardiac remodeling in people without diabetes or without heart failure would be to conduct a randomized double-blind control trial looking at indices of left ventricular remodeling in a population that I've just described. Dr. Greg Hundley: Very nice, Subodh. So you've started us into your study design. Maybe describe that a little more fully, and then who was included in your study population? Dr. Subodh Verma: So EMPA-HEART 2 CardioLink was a multi-center double-blind placebo control randomized trial in which we studied the effects of empagliflozin, an SGLT2 inhibitor, at a dose of 10 mg per day versus placebo in people who did not have type 2 diabetes or significant heart failure. We included people who were adults between the age of 40 and 80 who met 1 of 2 entry criteria. Either they had to have one major criteria, which was an increase in left ventricular mass index by specific echo criteria or MRI criteria, or they could have increased LVH as identified by ECG or by intraventricular septal or posterior wall thickness. They could also get in if they had resistant hypertension, hypertension despite being on 3 antihypertensive agents, or the second strata was entry through 2 minor criteria, which included a history of myocardial infarction, a GFR between 30 or 60, or evidence of overweight or obesity. Dr. Greg Hundley: And how many subjects did you randomize? Dr. Subodh Verma: So we randomized, of the 318 that we screened, 169 were randomized to receive empagliflozin 10 mg or a placebo. Patients had a baseline cardiac MRI done, and then the exposure was 6 months. They had a follow-up MRI at the end of 6 months. And the primary outcome measure was a 6-month change in left ventricular mass index from baseline to 6 months between the two groups. Dr. Greg Hundley: Very nice. And so , Subodh, can you describe for us now, what did you find? What were your study results? Dr. Subodh Verma: So, first and foremost, what we found in terms of baseline characteristics was that we enrolled a population of people with a mean age of around 60 with a BMI of around 30 kg/m2, predominantly men, about 80% or so were men. These were patients who did not have significant heart failure. The NT-proBNP at baseline was around 50 pg/mL. The eGFR was around 80 mL/minute, and the vast majority of these patients actually had a history of hypertension. Of course, none of them had diabetes by definition. The hemoglobin A1C was around 5.8%. Now what we found was, despite the fact that we went after patients who we thought would be enriched for a baseline increase in LV mass indices, the baseline LV mass index was mildly elevated, was around 63 g/m2. And over the course of 6 months, we did not find any significant difference in terms of LV mass regression between the placebo and empagliflozin groups. In fact, the adjusted treatment effect was minus 0.30 g/m2, which was not statistically significant. No other differences were found in terms of other indices of a remodeling, including left ventricular and diastolic or end systolic volume indices or in terms of left ventricular ejection fraction. There was a 2% increase in ejection fraction, and the p-value for that was 0.07, but really was not statistically significant. Dr. Greg Hundley: And very nice. And realizing that women may have smaller LV masses, any stratified analysis that evaluated effects on men versus women? And then what about, perhaps in the higher quartile versus lower quartile, of age? Dr. Subodh Verma: Right. So, Greg, we actually did look at various subgroups and covariates, including gender, including age. And age or gender did not really influence the overall result that we obtained. There was really a neutral result in empagliflozin, irrespective of these 2 covariates. We also looked at baseline blood pressure, baseline NT-proBNP, LV mass indices, the presence or absence of heart failure, chronic kidney disease. So for the covariates that we have evaluated over a short term of 6 months in this relatively low risk population, we did not find any heterogeneity the result, per se. Dr. Greg Hundley: Very good. Well, Subodh, thank you so much for that beautiful presentation. And listeners, now we're going to turn to our guest editor, Dr. Chris Granger. And Chris is an expert in the field of heart failure. Also, a lot of familiarity with HFpEF, which sounds a little bit, we're looking at precursors. We don't have HFpEF yet, but maybe trying to inhibit this from happening using empagliflozin. How do you put these results in the context with other studies that have emphasized utilizing SGLT2 inhibitors in patients with sort of a preserved ejection fraction and absence of diabetes? Dr. Christopher Granger: Yeah. Well thanks, Greg. And again, congratulations, Subodh, to your study. And I think you framed some of the context here as these drugs, the SGLT2 inhibitors, as being transformative, which I think is exactly right. And it's such a fascinating story. Right? These drugs, which we thought originally, with their cause of glucose spilling in the urine, and a modest decrease in blood glucose, might have a role for modestly improving glucose control in diabetes. And low and behold, they've turned out to be one of the great stories I think in recent, across all of medicine, in terms of their consistent and substantial improving clinical outcomes for patients with heart failure, with diabetes and cardiovascular disease, and now even kidney protection, and much broader implications. And their well tolerated, and they don't have dose titration. So there's some practical appeal to this class of drugs in terms of their benefits, in terms of clinical outcomes. But we're left with having this amazing evidence-based generated without really understanding why are these drugs so effective? And what are they doing? And you've provided, I think, an important piece to the puzzle. We did have the data from patients with diabetes and heart failure, with diabetes and left ventricular hypertrophy, that there is a modest reduce in LV mass with SGLT2 inhibitors. And what you've shown is that for patients that with mild LVH, with risk for LVH, that we simply don't see a substantial reduction in LV mass with the use of these drugs. So I think that provides this evidence that that's not a major cause of benefit, at least in this earlier phase of development of heart failure. And I think it really underscores the fact that there's a lot of work to do still to understand. We know that the renal effects are obvious place that these drugs have such an important benefit. And then the linkage of renal disease and cardiac performance is one of the areas, I think, that's a very exciting aspect of a probable contribution of the mechanism of these drugs. But I think in the end, we're left with still not really understanding why these drugs are so beneficial. But understanding that, I think, will be important, both for opening new avenues of targeting pathways, as well as being able to tell the clinical community, okay, you have these important benefits, but people do want to also know why are we seeing these benefits. Dr. Greg Hundley: Very nice. Well, listeners, we're going to turn back to Dr. Verma here. Subodh, what do you see is the next study to be performed in this sphere of research? Dr. Subodh Verma: Well, first, my thanks to Professor Granger, Chris, for handling this paper and for his very thoughtful comments. And he's absolutely right. We have such wonderful clinical data, and these results, of course, should not in any way take away from the importance of using empagliflozin or other SGLT2 inhibitors in the prevention of heart failure in people with diabetes, or in the treatment of HFpEF or HFrEF. But we're struggling with trying to understand what is the dominant mechanism of action here. And, in the previous precursor to EMPA-HEART 2, we did EMPA-HEART 1 in people with diabetes, and we saw a modest effect that was statistically significant of reduction in LV mass index. And we did not see this, of course, in a lower risk population without diabetes. And that tells me that remodeling may be occurring to a modest effect, it may require a longer time to actually show its benefits, but that this is unlikely a dominant sort of mechanism through which these drugs are working. And I do share Chris's thoughts that one of the key mechanisms of benefit that needs to be further explored is looking at the renal cardiac axes. We know that these drugs are profoundly renal protective, and that the benefits may actually be secondary to improvements in renal hemodynamics, improvements in renal function. And I think that is a population that needs to be, that's a mechanism that needs to be studied further. So I think the next generation of translational mechanistic studies need to really tease out the renal cardiac axes, maybe tease out populations that are at risk but have more significant left ventricular hypertrophy, maybe evaluate patients for a longer duration of treatment, or select people who truly have significant hypertension at baseline. I think those are groups and questions that need further exploration. And, of course, the translational science needs to be also studied in the context of larger completed clinical trials, where biomarkers are currently available and they can be linked, of course, to the outcomes in those trials. So those are some of my thoughts as to where the field could move towards. Dr. Greg Hundley: Very nice. And Chris, do you have anything to add? Dr. Christopher Granger: Subodh, I think that was a great summary. And I might just make a comment on the other end of the spectrum. That is, we have these drugs and the evidence of their benefit, and yet they're grossly underused in the populations that have proven to have benefit. Now it takes some time to educate, to get people familiar with, and get them to integrate these treatments into practice, but there's an enormous opportunity, and I think there is a linkage here. I think when people understand the mechanism, and when they're thoughtful about how these drugs may be working, that that really helps to make the case that the drug should be used, and that people are on board with using them. So I think there's this linkage here, there's the need to both better understand mechanism, and there's the need to have systems of care where these treatments are integrated to provide the benefit that's been so clearly shown in the randomized trials. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Subodh Verma, from St. Michael's University in Toronto, and our guest editor, Dr. Chris Granger, from Duke University in Durham, North Carolina, for bringing this paper highlighting that among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, that SGLT2 inhibition with empagliflozin did not, did not, result in a meaningful reduction in LV mass index after 6 months. Well, on behalf of Carolyn, Peder, 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.

Please join author Pieter Martens and Associate Editor Justin Grodin as they discuss the article "Decongestion With Acetazolamide in Acute Decompensated Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Prespecified Analysis From the ADVOR Trial." Dr. Greg Hundley: Welcome listeners to this January 17th issue of Circulation on the Run. And I am Dr. Greg Hundley, Director at the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Peder Myhre: And I'm Dr. Peder Myhre from Akershus University Hospital and University of Oslo, in Norway. And today, Greg, we have such an exciting feature paper. It comes to us from the ADVOR trialists. And the ADVOR trial examined the effect of acetazolamide in acute decompensated heart failure. And in this paper we're going to discuss how that treatment effect was across the left ventricular ejection fraction, across the spectrum. Greg, what do you think? Dr. Greg Hundley: Oh, wow. Sounds very interesting. But we might have some other articles in the issue. How about we grab a cup of coffee and Peder maybe this week, I'll go first and we'll start with preclinical science. How about that? Dr. Peder Myhre: Let's do preclinical science, Greg. Dr. Greg Hundley: Well, Peder, this particular paper focuses on the relationship between cardiac fibroblasts and cardiomyocytes. Remember that myocytes sit on a lattice of network of fibroblasts. And when the myocytes die, the fibroblasts then proliferates, secrete collagen and form this thick scar. Now, if we're going to try to regenerate, how are we going to get myocytes to get back into that thick scar when there's really a complete absence? And so as adult cardiomyocytes have little regenerative capacity, resident cardiac fibroblasts synthesize extracellular matrix, post myocardial infarction to form fibrosis, leading to cardiac dysfunction and heart failure. And therapies that can regenerate the myocardium and reverse fibrosis in the setting of a chronic myocardial infarction are lacking. Now, these investigators led by Professor Masaki Ieda from University of Tsukuba, were going to evaluate this process. The overexpression of cardiac transcription factors, including Mef2c, Gata4, Tbx5, Han2, all combined as MGTH. They can directly reprogram cardiac fibroblasts into induced cardiomyocytes and improve cardiac function in and under the setting of an acute myocardial infarction. However, the ability of an in vivo cardiac reprogramming to repair chronic myocardial infarction with established scars, well, that is really undetermined. Dr. Peder Myhre: Oh, what a wonderful introduction, Greg. And the way you described to us how cardiomyocytes and fibroblasts interact was really fascinating. Thank you. And now let's hear what the authors found and don't forget the clinical implications. Dr. Greg Hundley: Thanks, Peder. So these authors developed a novel transgenic mouse system where cardiac reprogramming and fibroblasts lineage tracing could be regulated spatiotemporally with tamoxifen treatment to analyze in vivo cardiac reprogramming in the setting of chronic MI. Then with this new model, the authors found in vivo cardiac reprogramming generates new induced cardiomyocytes from resident cardiac fibroblasts that improves cardiac function and reduces fibrosis in chronic myocardial infarction in mice. Wow. And additionally, they found that overexpression of cardiac reprogramming factors converts profibrotic cardio fibroblasts to a quiescent state, and that reverses fibrosis in chronic myocardial infarction. And therefore, Peder, direct cardiac reprogramming may be a promising therapy for chronic ischemic cardiomyopathies and heart failure. Really exciting work, converting scar tissue to actual functional cardiomyocytes. Dr. Peder Myhre: That was such a fantastic summary, Greg, and a very interesting paper. And I'm now going to take us back to clinical science and epidemiology. Because Greg, we all know that social and psychosocial factors are associated with cardiovascular disease risk. But the relative contributions of these factors to racial and ethnic differences in cardiovascular health has not been quantified. So these authors, led by the corresponding author, Nilay Shah from Northwestern University Feinberg School of Medicine in Chicago, used data from NHANES to examine the contributions of individual level social and psychosocial factors to racial and ethnic differences in population cardiovascular health. And that was measured by something called the cardiovascular health score, CVH score, which ranges from zero to 14, and it counts for diet, smoking, physical activity, body mass index, blood pressure, cholesterol, and blood glucose. Dr. Greg Hundley: Wow, really interesting, Peder. So what did they find here? Dr. Peder Myhre: So Greg, among males, the mean cardiovascular health score was 7.5 in Hispanic, 8.7 in non-Hispanic Asian, 7.5 in non-Hispanic black, and 7.6 in non-Hispanic white adults. And the authors found that the education explained the largest component of cardiovascular health differences among males. And now what about females? In females, the mean score was 8.0 in Hispanic, 9.3 in non-Hispanic Asian, 7.4 in non-Hispanic black, and 8.0 in non-Hispanic white adults. And for women, education explained the largest competence of cardiovascular health difference in non-Hispanic black. And place of birth, and that is US born versus born outside the US, explained the largest component of cardiovascular health difference in Hispanic and non-Hispanic Asian females. So Greg, the authors conclude that education and place of birth conferred the largest statistical contributions to the racial and ethnic differences in cardiovascular health among US adults. Dr. Greg Hundley: Very nice, Peder. What a beautiful description and outline that so well highlighting the differences in men versus women. Well, now we're going to turn back to the world of preclinical science, listeners. And we will continue with the paper by Dr. Amit Khera from Verve Therapeutics. Now, Peder, VERVE-101, this is an investigational in vivo CRISPR base editing medicine designed to alter a single DNA base in the PCSK9 gene. And that permanently turns off hepatic protein production and thereby, durably lowers LDL cholesterol. In this study, the investigators tested the efficacy, durability, tolerability, and potential for germline editing of VERVE-101 in studies of non-human primates and also in a murine F1 progeny study. Dr. Peder Myhre: So more on PCSK9s, and this time CRISPR technology. Very exciting. Greg, what did they find? Dr. Greg Hundley: Right, Peder. So VERVE-101 was well tolerated in non-human primates and led to, listen to this, an 83% lower blood PCSK9 protein and 69% lowering of LDL-C with durable effects up to 476 days following the dosing. These results have supported initiation of a first inhuman clinical trial. That's what needs to come next in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease. Wow. Dr. Peder Myhre: Even greater reductions from this therapy on PCSK9 than the previous PCSK9 inhibitor therapies. Wow. Okay, Greg, and now we go from one fascinating study to another. And this time we actually have the primary results from a large randomized clinical trial, Greg. Isn't that exciting? Dr. Greg Hundley: Yes. Dr. Peder Myhre: And this paper describes the primary results of a trial testing in Indobufen versus aspirin on top of clopidogrel in patients undergoing PCI with drug-eluting stent DES who did not have elevated troponin. So that is patients without mycardial infarction. And in fact, fact, this is the first large randomized control trial to explore the efficacy and safety of aspirin replacement on top of P2Y12 inhibitor in patients receiving PCI with death. And Greg, I suppose you like I wonder what Indobufen is, and I just learned that that is a reversible inhibitor of platelet Cox-1 activity and it has comparable biochemical and functional effects to dose of aspirin. And previous data indicate that Indobufen could lessen the unwanted side effects of aspirin and that includes allergy intolerance and most importantly, aspirin resistance, while it retains the antithrombotic efficacy. Dr. Greg Hundley: Wow, Peder. Really interesting and great explanation. Indobufen. So how did they design this trial and what were the primary results? Dr. Peder Myhre: So Greg, the investigators of this trial, called OPTION, led by corresponding authors, Drs. Ge, Quian, and Wu from Fudan University in Shanghai, randomized 4,551 patients from 103 center to either indobufen based DAPT or conventional, and that is aspirin based DAPT for 12 months after DES implementation. And the trial was open label and with a non-inferiority design, which is important to keep in mind. And the primary endpoint was a one year composite of cardiovascular death, non-fatal MI, ischemic stroke, definite or probable stent thrombosis or bleeding, defined as BARC criteria type 2, 3, or 5. And now Greg, the primary endpoint occurred in 101, that is 4.5% of patients in the indobufen based DAPT group compared to 140, that is 6.1% patients, in the conventional DAPT group. And that yields an absolute difference of 1.6%. And the P for non-inferiority was less than 0.01. And the hazard ratio was 0.73 with confidence intervals ranging from 0.56 to 0.94. And Greg, the occurrence of bleeding was particularly interesting and that was also lower in the indobufen based DAPT group compared to the conventional DAPT group. And that was 3.0% versus 4.0% with the hazard ratio of 0.63. And that was primarily driven by a decrease in BARC type two bleeding. So Greg, the authors conclude that in Chinese patients with negative cardiac troponin undergoing DES implementation, indobufen plus clopidogrel DAPT compared with aspirin plus clopidogrel DAPT significantly reduced the risk of one year net clinical outcomes, which was mainly driven by reduction in bleeding events without an increase in ischemic events. Dr. Greg Hundley: Very nice, Peder. So another reversible inhibitor of platelet COX-1 activity, indobufen. And seems to be very, have high utility in individuals of Chinese ethnicity and Asian race. Well, perhaps more to come on that particular drug. Peder, how about we dive into some of the other articles in the issue? And I'll go first. So first, there's a Frontiers article by Professor Beatty entitled “A New Era and Cardiac Rehabilitation Delivery: Research Gaps, Questions, Strategies and Priorities.” And then there's a Research Letter by Professor Zuurbier entitled, “SGLT-2 inhibitor, Empagliflozin, reduces Infarct Size Independent of SGLT-2.” Dr. Peder Myhre: And then Greg, we have a new ECG challenge by Drs. Haghighat, Goldschlager and Oesterle entitled, “AV Block or Something Else?” And then there is a Perspective piece by Dr. Patrick Lawler entitled, “Models for Evidence Generation During the COVID-19 Pandemic: New Opportunities for Clinical Trials in Cardiovascular Medicine.” And Greg, there's definitely so much to learn from all the research that has been done through the pandemic. And finally, we have our own Molly Robbins giving us Highlights from the Circulation Family of Journals. And first, there is a paper describing the characteristics of postoperative heart block in patients undergoing congenital heart surgery described in Circulation: Arrhythmia Electrophysiology. Next, the impact of socioeconomic disadvantages on heart failure outcomes reported in Circulation: Heart Failure. Then there is social and physical barriers to healthy food explored in circulation, cardiovascular quality and outcomes. And then there is the association of culprit-plaque morphology with varying degrees of infarct, myocardial injury size reported in Circulation: Cardiovascular Imaging. And finally, the impact of optical coherence tomography on PCI decisions reported in circulation cardiovascular interventions. Dr. Greg Hundley: Fantastic, Peder. Well, how about we get off to that feature discussion? Dr. Peder Myhre: Let's go. Dr. Mercedes Carnethon: Well, thank you and welcome to this episode of the Circulation on the Run Podcast. I'm really excited today to host this show. My name is Mercedes Carnethon. I'm an associate editor at Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine. I'm really excited to learn from the lead author of a new study on decongestion with Acetazolamide and acute decompensated heart failure across the spectrum of LV ejection fraction. And I've got the lead author with me today, Pieter Martens, as well as my colleague and associate editor Justin Grodin, who handled the paper. So I'd love to start off with just welcoming you, Dr. Martens. Dr. Pieter Martens: Thank you for having me. It's a pleasure to be here today. Dr. Mercedes Carnethon: Yes. And thank you so much for submitting your important work to the journal, Circulation. I'd love to start to hear a little bit about what was your rationale for carrying out this trial and tell us a little bit about what you found. Dr. Pieter Martens: So the ADVOR trial was a double blind placebo controlled randomized trial, which was performed in Belgium. And it set out to assess the effect of acetazolamide in acute decompensated heart failure and this on top of standardized loop diuretic therapy and patients with heart failure. And the goal of the current analysis was to assess whether the treatment effect of acetazolamide in acute heart failure differs amongst patients with a different ejection fraction at baseline at randomization. So we looked specifically at patients with heart failure, reduced, mildly reduced and preserved ejection fraction to determine whether acetazolamide works equally well in those patients. Dr. Mercedes Carnethon: Well, thank you so much. Tell me a little more. What did you find? Did your findings surprise you? Dr. Pieter Martens: All patients that were randomized in the ADVOR trial, we registered a baseline left ventricular ejection fraction at baseline. And what we saw was at the multiple endpoints that we collected in the ADVOR trial, that randomization towards acetazolamide was associated with a pronounced and preserved treatment effect. And different endpoints that we looked at was a primary endpoint which was successful, which is an important endpoint, which we all strive towards in acute decompensated heart failure. And we saw that irrespective of what your baseline ejection fraction was, that randomization towards acetazolamide was associated with a higher odds ratio for having successful decongestion. And also looking at other endpoints which we find important in the treatment of patients with acute compensated heart failure, such as renal endpoints such as the diuresis, the amount of urine that they make, or the natruresis, the amount of sodium that they excrete, we again saw that randomization towards acetazolamide was associated with a higher treatment effect, so more diuresis, more natruresis, which was not effective, whether you had heart failure, reduced, mildly reduced or preserved eject fraction. We did see a slight increase in the creatinine, which was a little bit more pronounced in patients with heart failure with reduced ejection fraction. Dr. Mercedes Carnethon: Thank you so much for that excellent summary. I'm an epidemiologist, so I'm certainly aware that of the cardiovascular diseases and their changes over time, heart failure is one that is going up over time and affecting more of the population. So I know I really enjoyed hearing about an additional therapy that helps to improve quality of life and improve clinical outcomes in individuals who are experiencing heart failure. And I'm really curious as I turn to you, Justin, what attracted you to this particular article and why did you find it to be such a good fit for our audience here at Circulation? Dr. Justin Grodin: Well, Mercedes, I mean, I think you hit the nail on the head with your comment. And clearly when we look at Medicare beneficiaries in the United States, hospitalization for decompensated heart failure is the number one or most common cause for hospitalization. And up to this time, we really haven't had any multi-center randomized control clinical trials that have really informed clinical care with a positive result or a novel strategy that says, "Hey, this might be a better way to treat someone in comparison with something else." And so when we have a clinical trial like ADVOR, one of the crucial things that we want to understand is how does this work and does it work for everybody? And now when we look at the population hospitalized with heart failure, we know that approximately half of them have a weak heart or low ejection fraction, and the other half have a stiff heart, a normal ejection fraction. And so since we've got this 50/50 makeup, it is a crucially important question to understand if we have an important study like ADVOR, does this apply? Are these benefits enjoyed by all these individuals across the spectrum? Dr. Mercedes Carnethon: Thank you so much for really putting that in context. And I believe you had some additional questions for Dr. Martens. Dr. Justin Grodin: Yes. Yeah, thank you. So Pieter, I mean obviously this was a terrific study. One question I had for you guys is, you and your colleagues and the ADVOR research team is whether you had expected these results. Because we know at least historically, that there might be different cardiorenal implications for individuals that have a weak heart or heart failure with reduced ejection fraction in comparison with a stiff heart or heart failure with preserved ejection fraction. Dr. Pieter Martens: Thank you for that comment. And thank you also for the nice feedback on the paper. I think we were not really completely surprised by the results. I think from a pathophysiologic perspective, we do wonder whether heart failure with reduced ejection fraction from a kind of renal perspective is different from heart failure with preserved ejection fraction. Clearly, there are a lot of pathophysiological differences between heart failure with reduced, mildly reduced and preserved ejection fraction. But when it comes to congestion and acute heart failure, they seem to behave, or at least similarly in terms of response to acetazolamide, which was very interesting. We do think there are neurohormonal differences between heart failure reduced ejection fraction, preserved ejection fraction. But at least how acetazolamide works seems relatively unaffected by the ejection fraction. Dr. Justin Grodin: And Pieter, another question that comes to mind, and this is getting a little bit technical, but there have been studies that have shown that people that present to the hospital with decompensated heart failure, that have HFpEF, have a very different perhaps congestion phenotype where they might not have as much blood volume expansion. And so I, for one, was pretty curious as to how these results were going to play out. And I wonder what your thoughts are on that, or maybe that's perhaps more niche and less widely applicable than what you observed. Dr. Pieter Martens: Now, I can completely agree that when we are thinking about congestion, the congestion itself is a sort of pressure based phenomenon. And the pressure based phenomenon is based on what your volume is and the compliance within your cardiovascular system. But I think one of the important things to remember is that how we enrolled patients in the ADVOR trial was that we enrolled patients who had clear signs of volume overload. Remember, we used a volume score to assess clinical decongestion or actually getting rid of the volume. Volume assessment isn't really necessarily a pressure based assessment. And pressures might be the genesis of elevated pressures might be different amongst heart failure with reduced versus preserved ejection fraction. But what was really clear was that all these patients were volume overloaded. And when you think about the volume axis, then it's really about getting rid of that additional sodium, water, and that's where really acetazolamide works. So I do think we differ a little bit from historical acute decompensated heart failure trials in which they sometimes use signs and symptoms of more congestion, a pressure based phenomenon, where our endpoint was truly at volume endpoint. And we do believe that diuretics work really on a volume component of heart failure. Dr. Mercedes Carnethon: Thank you so much, especially for explaining that in a way that even non-clinicians such as myself can understand the potential implications. A big picture question that I have, and I really enjoy these discussions because they give us an opportunity to speculate beyond what we read in the paper. And that question is we do clinical trials and we identify effective therapies. And one of the bigger challenges we often face is getting those therapies out to the people who need them. Do you perceive any barriers in uptake of the use of acetazolamide in clinical practice? Dr. Pieter Martens: That's an excellent question. So one of the, I think beauties about acetazolamide is that this drug has been on the market for about 70 years. So I think everybody has access to it. This is not a novel compound which needs to go through different steps of getting marketing approval and getting a sort of reimbursement before it becomes available in clinical practice. And in theory, everybody should have access to this relatively cheap agent and can use it in its clinical practice. And I think it was very interested when we came out with the initial paper. I think already the day afterwards, we were getting messages from across the world that people have been using acetazolamide. So I think it is an agent which is available in current clinical practice and should not be too many barriers to its current implementation and clinical practice. Dr. Mercedes Carnethon: Well, that's fantastic to hear. So I hope Justin, that you will certainly help to ring the bell to get the information out about this wonderful study. I do want to turn to you, Pieter, to find out whether or not there are any final points that you didn't have an opportunity to discuss with us today. Dr. Pieter Martens: Think some of the other end points we didn't discuss were the effect, for instance, on length of stay. I think length of stay is a very important endpoint because hospital admissions, like Justin said, heart failure is the number one reason why elderly patients are being admitted. And just shortening the length of stay from a financial perspective might be important. So it was also very interesting to see that the use of acetazolamide in the study also translated into a shorter length of stay, which was also was unaffected, whether you had heart failure, reduced, mildly reduced or preserved ejection fraction, Dr. Mercedes Carnethon: Well, I certainly know people appreciate being in their own homes and being able to discharge is certainly a major benefit. So thank you so much for sharing that final point. I really want to thank you so much for a stimulating discussion today. I know that I learned a lot from you, Pieter, and the hard work of your research team as well as from you, Justin, for putting these findings in context and really helping our listeners and the readers of our journal understand why this paper is so important and how it's really moving the field forward for a clinically important problem. So thank you both so much for joining us here today on Circulation on the Run. Dr. Justin Grodin: Thank you. Dr. Pieter Martens: Thank you for having me. Dr. Mercedes Carnethon: I really want to thank our listeners for joining us today for this episode of Circulation on the Run. I hope you will join us again next week for more exciting discussions with our authors. Dr. Greg Hundley: 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.

This week, please join author Judith Hochman, Editorialist Steven Bradley, and Guest Host Mercedes Carnethon as they discuss the article " Survival After Invasive or Conservative Management of Stable Coronary Disease" and editorial “If the Fates Allow: The Zero-Sum Game of ISCHEMIA-EXTEND.” Dr. Greg Hundley: Welcome everyone to our new year 2023, and we are here on this January 3rd edition of Circulation on the Run. I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Peder Myhre: I am Dr. Peder Myhre, Social Media Editor and doctor at the Akershus University Hospital and University of Oslo. Dr. Greg Hundley: Very nice. Well, welcome listeners and this week's feature, ah, very interesting. You know many times patients with stable coronary artery disease, we're seeing a lot in the literature about an invasive strategy versus a conservative strategy. But what happens long term for these patients? What's their prognosis? Well, more to come in the feature discussion. But first, how about we grab a cup of coffee and we discuss some of the other issues in this session. Peder, would you like to go first? Dr. Peder Myhre: Yes, Greg I would love to and the first paper today is very interesting and relates to one of the most important challenges globally, namely climate changes and extreme temperatures. And in this paper, which comes to us from corresponding author, Barrak Alahmad from Harvard Chan School of Public Health in the United States, together with a large international group of authors, investigated the associations between extreme temperatures and cardiovascular cause-specific mortality in 567 cities in 27 countries from 1979 to 2019. Dr. Greg Hundley: Wow Peder, that is a really large comprehensive study. So, how did they perform this analysis? What did they find? Dr. Peder Myhre: So Greg, the investigators collected city-specific daily ambient temperatures from weather stations and analyzed cause-specific cardiovascular mortality and excess deaths in association with extreme hot and extreme cold temperatures. And in total, the analysis included more than 32 million deaths from any cardiovascular cause, which were subdivided into deaths from ischemic heart disease, stroke, heart failure and arrhythmia and at extreme temperature percentiles. And that is defined as heat above the 99th percentile and as cold below the first percentile were associated with a high risk of dying from any cardiovascular cause, ischemic heart disease, stroke and heart failure as compared to the minimum mortality temperature, which is the temperature associated with least mortality. And Greg, across a range of extreme temperatures, hot days above the 97.5 percentile and cold days below the 2.5 percentile accounted for more than two and more than nine excess deaths for every thousand cardiovascular death respectively. And heart failure was associated with the highest excess death proportions from extreme hot and cold days. So Greg, it seems like extreme temperatures really impact the cardiovascular mortality across the globe. Dr. Greg Hundley: Yeah, beautiful description Peder. And I think what was really exciting about that particular article is you had results from 27 countries. Wow, so really quite a global study and very informative. Dr. Peder Myhre: Yes, indeed very impressive. Dr. Greg Hundley: Well, Peder my next study comes to us from the world of preclinical science. And Peder, these investigators led by Professor Jose Luis de la Pompa from CNIC, evaluated two structural cardiac diseases, left ventricular non-compaction and bicuspid aortic valve. And they wanted to determine if those two conditions were caused by a set of inherited heterozygous gene mutations affecting the notch ligand regulator, Mind bomb-1 and co-segregating genes. Dr. Peder Myhre: Okay Greg, so we are looking at mechanisms for non-compaction and bicuspid aortic valve. What did they find? Dr. Greg Hundley: Right Peder, so whole exome sequencing of the left ventricular non-compaction families identified heterozygous missense mutations in five genes co-segregating with E3 ubiquitin protein ligase-1 Mib-1 as well as left ventricular non-compaction. And corresponding mouse models showed that left ventricular non-compaction or bicuspid aortic valve in a notch-sensitized genetic background. Now, also gene profiling showed that increased cardiomyocyte proliferation and defective morphological and metabolic maturation in mouse hearts and human pluripotent stem cell cardiomyopathy. Biochemistry suggested a direct interaction between notch and some of the identified gene products. And so, these data Peder support a shared genetic basis for left ventricular non-compaction and bicuspid aortic valve with Mib-1 notch playing a crucial role. And thus, identification of heterozygous mutations leading to left ventricular non-compaction or bicuspid aortic valve may allow us to expand the genetic testing panel repertoire for better diagnosis and or risk stratification of both of these conditions, left ventricular non-compaction and bicuspid aortic valve. Dr. Peder Myhre: All right, that is really great and novel linking left ventricular non-compaction to bicuspid aortic valve, really great. And now Greg, we're going to go back to clinical science and we're going to talk about lipoprotein(a) or Lp(a). And as you know, elevated Lp(a) is a common risk factor for cardiovascular disease outcomes with unknown mechanisms. And the authors of this next paper coming to us from corresponding author Olli Raitakari from University of Turku in Finland, examined Lp(a)'s potential role in identifying youths who are at increased risk of developing adult atherosclerotic cardiovascular disease, ASCVD. And they did this by measuring Lp(a) in youths nine to 24 years old and linking that to a diagnosis of ASCVD as adults and also linking it to carotid intermediate thickness in the Young Finns Study. And in addition, these results were validated in the Bogalusa Heart Study. Dr. Greg Hundley: Oh, very nice Peder. So, what did they find? Dr. Peder Myhre: So Greg, those who have been exposed to high Lp(a) levels in youth and that was defined as greater than or equal to 30 milligrams per deciliter, had about two times greater risk of developing adult ASCVD compared to non-exposed individuals. In fact, all the following youth risk factors were independently associated with a higher risk. Lp(a), LD, cholesterol, body mass index and smoking all independently associated with ASCVD. And similar findings were made in the validation cohort who were participants with a high Lp(a) had 2.5 times greater risk of developing adult ASCVD compared to non-exposed individuals. And this also persisted in adjusted models. Now, what about the carotid intermediate thickness? In that analysis, there were no associations detected to youth Lp(a) levels in either of the cohorts. Dr. Greg Hundley: Very nice, Peder. So, great description of the utility of lipoprotein(a) measurements in the youth and for predicting future major cardiovascular events. Well, the next paper goes back to the world of preclinical science. And Peder, cardiac hypertrophy increases demands on protein folding, which causes an accumulation of misfolded proteins in the endoplasmic reticulum. Now, these misfolded proteins can be removed via the adaptive retro-translocation, poly-ubiquitylation and a proteasome mediated degradation process. The endoplasmic reticulum-associated degradation, ERAD, which altogether as a biological process and rate has not been studied in vivo. So, these investigators led by Dr. Christopher Glembotski from University of Arizona College of Medicine, investigated the role of ERAD in a pathophysiological model and they examined the function of the functional initiator of ERAD, VCP-interacting membrane protein and positing that the VCP-interacting membrane protein would be adaptive in pathological cardiac hypertrophy in mice. Dr. Peder Myhre: Thanks Greg. So, we're talking about degradation of the endoplasmatic reticulum and the association to hypertrophy. So, what did these investigators find, Greg? Dr. Greg Hundley: Right, Peder. So, this was really the first study to demonstrate that endoplasmic reticulum-associated protein degradation or ERAD is responsible for degrading and thus, regulating the levels of a cytosolic non-endoplasmic reticular protein. The results reported here describe a new mechanism mediating the pathological growth of the heart, such that in the healthy heart SGK-1 levels are low due to ERAD-mediated degradation. While in the setting of pathology, ERAD-mediated degradation of SGK-1 is disrupted, allowing the pro-growth kinase to accumulate and contribute to pathological cardiac hypertrophy. And so Peder, the clinical relevance of these findings is that the investigators found that a variety of proteins that constitute the ERAD machinery were decreased in both mouse and human heart failure samples while SGK-1 was increased, supporting the possibility that SGK-1 is a contributor to the disease phenotype. And this is notable and that these studies could lead to the development of new therapeutic approaches for managing pathological cardiac hypertrophy and heart failure that target the ERAD to restore efficient SGK-1 degradation. Dr. Peder Myhre: That was an excellent explanation of a very difficult topic. Thank you, Greg. Dr. Greg Hundley: Well, Peder how about we take a look and see what else is in the issue? And now I'll go first. Well, first there's an In Depth by Professor Ntsekhe entitled, "Cardiovascular Disease Among Persons Living with HIV: New Insights into Pathogenesis and Clinical Manifestations within the Global Context." And then, there's a Research Letter by Professor Verma entitled, "Empagliflozin in Black Patients Versus White Patients With Heart Failure: Analysis of EMPEROR results-Pooled." Dr. Peder Myhre: Great Greg and there is an On My Mind by Gabriel Steg entitled, "Do We Need Ischemia Testing to Monitor Asymptomatic Patients With Chronic Coronary Syndromes?" Very timely and interesting. And finally, there is an AHA Update from Michelle Albert, the President of the AHA entitled, "Tackling Adversity and Cardiovascular Health: It is About Time." Dr. Greg Hundley: All right. Well Peder, how about we get onto that feature discussion looking at survival after invasive or conservative management in stable coronary heart disease? Dr. Mercedes Carnethon: Thank you so much for joining us for this episode of Circulation on the Run. I'm Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University, Feinberg School of Medicine. And I'm very excited today to have as a guest, Dr. Judith Hochman, who is going to be discussing the long-awaited findings from the ISCHEMIA-EXTEND trial that are looking at survival after invasive or conservative management of stable coronary disease. Really pleased to have you with us today, Judy to hear about these findings. Dr. Judith Hochman: It's a pleasure to be here. Dr. Mercedes Carnethon: Thank you. So, just to start off, can you tell us about this study? What motivated this long-term follow-up of this particular trial? Dr. Judith Hochman: Yeah, so as I think the viewers or the listeners will recall, we built on a wealth of data from COURAGE and BARI 2D, some of the landmark trials that looked at revascularization versus optimal medical therapy or guideline-directed medical therapy alone. We tested an invasive strategy versus a conservative strategy dating back already to 2012 is when we started. And we had a five component primary outcome, which included cardiovascular death, myocardial infarction or hospitalization for unstable angina, heart failure or resuscitated cardiac arrest. And at the end of 3.2 median years of follow-up, we saw no difference in the primary outcome in that the curves crossed with some excess risk upfront due to periprocedural MI and decreased risk of spontaneous MI long-term. But the net overall timeframe spent free of event was similar between the groups. So, we did observe improved quality of life for the invasive strategy, but in terms of clinical outcomes there was no difference. So, cardiovascular death at the end of that time period was no different between the groups, all-cause mortality was no different, non-cardiovascular death, there was actually an increase in the invasive group, which was somewhat of a mystery. We can get into that a little bit later because I think that becomes important. But 3.2 years meeting and follow-up is relatively short. So, everyone was very interested in what would the long-term outcomes be. So, we had another grant from the National Heart, Lung and Blood Institute to follow these patients long-term. And this is an interim report with seven years of follow-up, a median of 5.7 years. And the bottom line is that all-cause mortality was the same at seven years but for the first time, an invasive strategy resulted in lower cardiovascular mortality, which was very interesting and very exciting except that it was offset, exactly offset by the continued excess that we had previously observed in non-cardiovascular mortality. And that's basically the upshot of what we just reported and why we continue to follow patients and why we're going to continue to follow patients and have a final report in 2026. Dr. Mercedes Carnethon: This is really fantastic work. As you point out, the initial follow-up was fairly short and the findings were so critically important demonstrating that there were subtle differences between the two approaches but that overall, things appeared relatively similar. Did it surprise you? Oh, please correct me. Dr. Judith Hochman: I should point out that because there were less spontaneous MIs during follow-up and spontaneous MIs are associated with a heightened risk of subsequent death more so than the periprocedural MIs, we did hypothesize and we're very interested in longer term cardiovascular and all-cause mortality thinking that those reduced spontaneous MIs in the invasive group would be associated with reduced cardiovascular death and perhaps reduced mortality. As I did indicate, cardiovascular death mortality was reduced but all-cause mortality was the same with a hazard ratio of 1.0. Dr. Mercedes Carnethon: Well, nothing seems more clear than a hazard ratio of 1.0 with those very tight confidence limits so thank you so much. I'm really pleased that our editorialist, Dr. Steve Bradley was also able to join us today because to hear his thoughts about where this fits in the context of what we know can be really insightful. So, I'd really love to turn to you, Dr. Bradley. In your opinion, why was this study question so important and tell us a little bit about how you think the clinical field should use these findings. Dr. Steven Bradley: Absolutely and thanks for having me. I think there were some indication that perhaps the farther we follow the patients out from the original ISCHEMIA trial that we might start to see some evidence of benefit for revascularization. I think Dr. Hochman spoke about the evidence of more of these spontaneous myocardial infarctions that were happening in the non-revascularization arm of the study and an association with worse cardiovascular outcomes in patients that experience spontaneous events. And so, the thoughts might be that over time we would see the benefit of that. And certainly if you parse out cardiovascular versus non- cardiovascular outcomes, we do, we see lower rates of cardiovascular death in the patients who undergo revascularization but it's balanced out by non-cardiovascular death. And so, it becomes a zero sum game for a patient. They want to be alive, it doesn't matter by what mechanism. So, if we have a therapy that doesn't actually prolong their life but it leads to different mechanisms by which they have an outcome, that's important for us to understand. This adds to an already robust evidence-based that ISCHEMIA really did inform and it gives us that long-term trajectory to help us understand for patients what the implications are. I will note that and we've commented in the editorial and this is something that was shown in the original ISCHEMIA trial, that it's not just about mortality for patients, it's important that we help them live better as well. And certainly we know that revascularization is associated with quality of life improvement so that's an important part of the conversation with patients. But again, continuing to refine our understanding of what the implications of revascularization are for mortality is where this study leads us now. Dr. Mercedes Carnethon: Thank you so much. One of the things that I find so impressive about clinical trials of this scale are that you incorporate such a broad audience. I note that 36 countries contributed data to this particular trial. I wonder whether, did you have an opportunity to investigate whether these findings were similar in low and middle income countries as compared with higher income countries? And how would you expect clinicians in low and middle income countries to use this information? Dr. Judith Hochman: That's a great question and yes, the treatment effect was similar across regions, didn't really have any very low income regions but we did have India was in the study and a number of South American countries. And I think it's incredibly important for those countries where there are very limited resources to reassure them, the practitioners and their patients that just because they can't afford an expensive invasive procedure, stenting or bypass, does not mean it's going to cut their life shorter, it's not going to make them survive for a shorter amount of time. Therefore, they can limit the use of scarce resources to the most severely impaired in terms of quality of life, the patients with the most frequent angina. It also became extremely relevant during COVID. Dr. Mercedes Carnethon: Tell me more. Dr. Judith Hochman: Well, elective procedures were shut down during COVID and more publications that cited the ISCHEMIA trial to say that they felt comfortable not being able to do elective stenting in patients with stable ischemic heart disease that would've met the ISCHEMIA trial criteria, which by the way we should add was preserved ejection fraction, we excluded ejection fraction less than 35, patients had to be stable. They could not have had two coronary syndrome within the last few months. They could not have had angina refractory to medical therapy and they could not have had left main disease. So, those are key. There are other exclusion criteria but those are the key exclusion criteria. Dr. Mercedes Carnethon: Thank you for that. And I can really see a corollary and I appreciate the messaging around similar outcomes and preserving resources. And I think certainly even within our own country where we see vast differences in access to intensive medical therapies or tertiary care medical centers who do these procedures on a higher volume, at least we can feel reassured that outcomes may be quite similar as far as mortality. What do you- Dr. Judith Hochman: If they take their guideline-directed medical therapy. Dr. Mercedes Carnethon: Thank you for pointing that out. Dr. Judith Hochman: It's incredibly important. John Curtis' group looked at adherent patients by the modified Morisky score versus non-adherent patients. Non-adherent patients don't have as good a health status as adherent patients. So, just that also adds to a wealth of literature that you have much better outcomes if you actually take your medications. Dr. Mercedes Carnethon: No, I think that's a very good point. What are your thoughts, Steve on what the next steps might be? Dr. Steven Bradley: Well, I know that as was pointed out earlier, there's going to be the opportunity to see additional longer term follow-up beyond this interim analysis. So, it'll be interesting to see what that continues to show us in terms of understanding applications on mortality. I'll pose a question that we posed within our editorial around trying to identify non-fatal outcomes to see if there are any opportunity to capture those non-fatal outcomes to give us an understanding of potential mechanisms for why there is this cardiovascular versus non- cardiovascular mortality difference by treatment arm? Certainly, that may be helpful. Dr. Judith Hochman: Sorry. We're very, very interested in the excess in non-cardiovascular death. So, we are as a result of this interim analysis, revising our case report form, which was very lean, pragmatic because the funding is relatively limited to include especially collection of data around malignancy. Because as we reported before, the non-cardiovascular deaths were largely malignancy and to some extent infection. And what was driving the difference, the excess in non-cardiovascular death as we published in American Heart Journal in the invasive group was excess malignancy. Dr. Mercedes Carnethon: That's really interesting. Dr. Judith Hochman: To our deep surprise and shock, it appeared that the only variable associated with that excess risk was the number of tests or procedures you had that involve radiation. And of course, we're talking about medical doses of radiation. And this short timeframe, three and a half to seven years, which is when the curve started to diverge to three and a half, we filed to seven years is not thought to ... it's thought to be too short a timeframe for exposure to radiation to lead to excess malignancy. So, we have partnered with some radiation experts, we are adding much more details to our case report form, not only in terms of death from malignancy but just the occurrence of malignancy. Did you get malignancy during the course of follow-up? And that's really critically important. We are not adding information about additional myocardial infarctions. We think that the key, if we're going to focus on site burden and how much they can actually collect, is to look at the mechanisms of death and the occurrence of malignancy, whether that leads to death or not, those are our top priorities at this point. Dr. Mercedes Carnethon: I could go on and on, I'm learning so much speaking with the two of you. And again, that really is the primary goal of our podcast to really have an opportunity to extend beyond what's written in the paper and really hear directly from the authors who led the study to hear your thoughts as well as those of the editorialists on where this is going. I really want to thank you both for the time you've spent today to share with our audience of the Circulation on the Run podcast. Dr. Judith Hochman: You're very welcome. Dr. Steven Bradley: My pleasure. Dr. Mercedes Carnethon: I just want to thank all of our listeners for joining us on this really stimulating discussion today on this episode of Circulation on the Run. Please tune in next week where we will have more exciting discussions like this one. Thank you. Dr. Greg Hundley: 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.

It's another session of CardioNerds Rounds! In these rounds, Dr. Loie Farina (Advanced Heart Failure and Transplant Fellow at Northwestern University) joins Dr. Jane Wilcox (Chief of the Section of Heart Failure Treatment and Recovery at Northwestern University) to discuss the nuances of HFpEF diagnosis and management. Dr. Wilcox is also the Associate Director of the T1 Center for Cardiovascular Therapeutics in the Bluhm Cardiovascular Institute and Director of the Myocardial Recovery Clinic at Northwestern University. Dr. Wilcox is a prolific researcher, clinician, and thought leader in Heart Failure and we are honored to have her on CardioNerds Rounds! Notes were drafted by Dr. Karan Desai. Audio editing by CardioNerds Academy Intern, student doctor Akiva Rosenzveig. This episode is supported with unrestricted funding from Zoll LifeVest. A special thank you to Mitzy Applegate and Ivan Chevere for their production skills that help make CardioNerds Rounds such an amazing success. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds. Case details are altered to protect patient health information. CardioNerds Rounds is co-chaired by Dr. Karan Desai and Dr. Natalie Stokes.  Speaker disclosures: None Challenging Cases - Atrial Fibrillation with Dr. Hugh Calkins CardioNerds Rounds PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Show notes - Antithrombotic Management with Dr. Deepak Bhatt Case #1 Synopsis: A woman in her 80s with a history of HFpEF presented with worsening dyspnea on exertion over the course of a year but significantly worsening over the past two months. Her other history includes prior breast cancer with chemotherapy and radiation therapy, permanent atrial fibrillation with AV node ablation and CRT-P, and CKD Stage III. She presented for an outpatient RHC with exercise to further characterize her HFpEF. Her echo showed normal LV size, no LVH, LVEF of 50%, decreased RV systolic function, severe left atrial enlargement, significantly elevated E/e' and mild MR. Right heart catheterization showed moderately elevated bi-ventricular filling pressures at rest but with passive leg raise and Stage 1 exercise the wedge pressure rose significantly. We were asked to comment on management. Case #1 Takeaways Amongst the things that were discussed were the role of specific therapies in symptomatic patients with HFpEF. In patients with HFpEF and documented congestion, they will require diuretic therapy for symptomatic relief. But in addition to diuretic therapy, we discussed starting HFpEF-specific therapies. Amongst, those specific therapies mineralocorticoid receptor antagonist (MRA) and sodium-glucose co-transporter 2 (SGLT2) inhibitor. In multiple trials that have included patients with HFPEF, SGLT2i have reduced the risk of hospitalization. This includes the EMPEROR-PRESERVED Trial (see the CardioNerds Journal Club discussion on the trial) in which nearly 6000 patients with NYHA Class II-IV symptoms, EF > 40% and elevated NT-proBNP with a prior HF hospitalization within the past 12 months were randomized to Empagliflozin or placebo. The primary outcome – death from CV causes or hospitalization for Heart Failure – was significantly lower in the SGLT2i arm (13.8% vs 17.1%, 95% CI 0.69-0.90, P 45% to receive either spironolactone or placebo. The primary endpoint (death from CV cause, aborted cardiac arrest, or hospitalization for HF) was not statistically different between treatment arms. Of note, however, there were concerns for regional differences which is outlined well in this NEJM Evidence piece. Case #2 Synopsis: A woman in her 70s with history of hypertension, obesity,

New authorization for COVID-19 vaccines in certain children; Narcan nasal spray to be reviewed for OTC status; Empagliflozin assessed in children with diabetes; a major depressive disorder therapy gains fast track status; and Tecentriq has an indication withdrawn. 

SGLT2 inhibitors, publishing choices, second and third order effects of interventions, decision support, and patient selection for preventive procedures are the topics John Mandrola, MD, discusses in this week's podcast. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I. EMPA Kidney - EMPA-Kidney Seals SGLT2 Inhibitors as 'Foundational' for CKD https://www.medscape.com/viewarticle/984439 - EMPA-Kidney Moves the Needle for SGLT2 Inhibitors in Kidney Disease https://www.medscape.com/viewarticle/983521 - Empagliflozin in Patients with Chronic Kidney Disease https://www.nejm.org/doi/pdf/10.1056/NEJMoa2204233 - Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy https://www.nejm.org/doi/10.1056/NEJMoa1811744 - Dapagliflozin in Patients with Chronic Kidney Disease https://www.nejm.org/doi/full/10.1056/NEJMoa2024816 - Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials https://doi.org/10.1016/S0140-6736(22)02074-8 II. Publishing Choices - Motorcycle Rallies Linked to Spike in Organ Transplants https://www.medscape.com/viewarticle/984623 - Organ Donation and Transplants During Major US Motorcycle Rallies https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2798550 III. Second and Third Order Effects - Heart Disease Deaths Spiked During COVID After 10-Year Decline https://www.medscape.com/viewarticle/984605 IV. Decision Support - Patient App Aids Decisions on Anticoagulants: ENHANCE-AF https://www.medscape.com/viewarticle/984253 - A Randomized Clinical Trial to Evaluate an Atrial Fibrillation Stroke Prevention Shared Decision‐Making Pathway https://www.ahajournals.org/doi/10.1161/JAHA.122.028562 V. Percutaneous Left Atrial Appendage Closure - Consider Life Expectancy When Referring for LAA Closure? https://www.medscape.com/viewarticle/981117 - Transcatheter Left Atrial Appendage Occlusion: A Multi-Center Real Life Experience https://www.mdpi.com/2077-0383/11/23/6944 - Incidence and Predictors of Early Death in Patients Undergoing Percutaneous Left Atrial Appendage Closure https://www.jacc.org/doi/full/10.1016/j.jacep.2022.06.012 - Indications for Left Atrial Appendage Occlusion in the United States and Associated In-Hospital Outcomes: Results From the NCDR LAAO Registry https://www.ahajournals.org/doi/full/10.1161/CIRCOUTCOMES.121.008418 You may also like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

Diabetes Core Update is a monthly podcast that presents and discusses the latest clinically relevant articles from the American Diabetes Association's four science and medical journals – Diabetes, Diabetes Care, Clinical Diabetes, and Diabetes Spectrum. Each episode is approximately 20 minutes long and presents 5-6 recently published articles from ADA journals. Intended for practicing physicians and health care professionals, Diabetes Core Update discusses how the latest research and information published in journals of the American Diabetes Association are relevant to clinical practice and can be applied in a treatment setting. This issue will review: Empagliflozin in Patients with Chronic Kidney Disease NEJM Prescription Patterns of Cardiovascular- and Kidney-Protective Therapies Among Patients With Type 2 Diabetes and Chronic Kidney Disease Relationship Between Carbohydrate Intake (Quantity, Quality, and Time Eaten) and Mortality (Total, Cardiovascular, and Diabetes) Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) Finerenone in Patients With Chronic Kidney Disease and Type 2 Diabetes by Sodium–Glucose Cotransporter 2 Inhibitor Treatment: The FIDELITY Analysis Effects of a Low-Carbohydrate Dietary Intervention on Hemoglobin A1c A Randomized Clinical Trial   For more information about each of ADA's science and medical journals, please visitwww.diabetesjournals.org. Presented by: Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health John J. Russell, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Director, Family Medicine Residency Program, Chair-Department of Family Medicine, Abington Jefferson Health

Maria Veiga-da-Cunha, Claudia Soler-Alfonso and Sarah Grünert join the podcast to talk about Empagliflozin, a repurposed drug with impressive efficacy in GSD 1b and G6PC3 deficiency. Successful use of empagliflozin to treat neutropenia in two G6PC3-deficient children: Impact of a mutation in SGLT5 Cécile Boulanger, et al https://doi.org/10.1002/jimd.12509 Untargeted metabolomic profiling in a patient with glycogen storage disease Ib receiving empagliflozin treatment Eran Tallis, et al https://doi.org/10.1002/jmd2.12304 Two successful pregnancies and first use of empagliflozin during pregnancy in glycogen storage disease type Ib Sarah Catharina Grünert, et al https://doi.org/10.1002/jmd2.12295

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.

The safety of very low LDL-C, the win-ratio analytic method, sacubitril/valsartan, SGLT2 inhibitors, and percutaneous left atrial appendage closure are discussed in this week's podcast. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I PCSK9I Evolocumab Benefits Accrue With Longer Follow-up: FOURIER OLE https://www.medscape.com/viewarticle/979950 - Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease https://www.nejm.org/doi/full/10.1056/nejmoa1615664 - Long-Term Evolocumab in Patients with Established Atherosclerotic Cardiovascular Disease https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.061620 II Analytic Methods and Re-Analysis of Old Trials - PARADISE-MI Results Obscured As Post Hoc Analysis Finds Flaws https://www.medscape.com/viewarticle/980776 - Angiotensin Receptor–Neprilysin Inhibition in Acute Myocardial Infarction https://www.nejm.org/doi/10.1056/NEJMoa2104508 - Impact of Sacubitril/Valsartan Versus Ramipril on Total Heart Failure Events in the PARADISE-MI Trial https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.057429 - The Year's Most Important Study Adds to Uncertainty in Science https://www.medscape.com/viewarticle/904286 III SGLT2i Post MI - Early Signal of Benefit for Empagliflozin in Acute MI: EMMY https://www.medscape.com/viewarticle/980180 - Empagliflozin in acute myocardial infarction: the EMMY trial https://doi.org/10.1093/eurheartj/ehac494 IV Percutaneous Left Atrial Appendage Closure - Incidence and Predictors of Early Death in Patients Undergoing Percutaneous Left Atrial Appendage Closure https://www.jacc.org/doi/10.1016/j.jacep.2022.06.012 - Cost‐Effectiveness of Left Atrial Appendage Closure for Stroke Reduction in Atrial Fibrillation: Analysis of Pooled, 5‐Year, Long‐Term Data https://www.ahajournals.org/doi/10.1161/JAHA.118.011577 - Baseline Comorbidities And Bleeding Events Of Patients Undergoing Percutaneous Left Atrial Appendage Occlusion Among Medicare Beneficiaries https://www.jacc.org/doi/10.1016/S0735-1097%2822%2901158-5 You may also like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.122.059410?af=RThe Biomarkers say REDUCE-IT was a scamhttps://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2791663NO! Just NO-- stick with the calculator for nowhttps://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.059038start the SLGT-2 inhibitors early! maybe an early dischargehttps://pubmed.ncbi.nlm.nih.gov/35849407/If we could get the EMR to do it automatically else you cant expect providers tohttps://pubmed.ncbi.nlm.nih.gov/35727595/the head CT for psych stuff can probably be put on holdhttps://eprints.whiterose.ac.uk/180135/continue the disease modifying agents

This week, please join author Rod Stables and Associate Editor Nick Mills as they discuss the article "Routine Pressure Wire Assessment Versus Conventional Angiography in the Management of Patients With Coronary Artery Disease: The RIPCORD 2 Trial." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass through 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... Very interesting. There is a lot of information about using fractional flow reserve during contrast coronary angiography. But how does that compare to just reviewing the angiograms when managing patients with coronary artery disease? Well, we are going to hear some results from the RIPCORD 2 trial, and they may surprise you a little bit. But, before we get to that interesting feature discussion with authors and editors, how about we grab a cup of coffee and dive into some of the other articles in the issue? Dr. Carolyn Lam: Yeah, let's do that, Greg. Do you have a paper to share first? Dr. Greg Hundley: Oh, thanks Carolyn. Sure. So Carolyn, as we know, Apolipoprotein B or apoB, provides an integrated measure of atherogenic risk. But whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndromes, beyond that provided by low density, lipoprotein cholesterol, or LDLC, that's uncertain. So Carolyn this study emanates from the Odyssey Outcomes trial, which compared the Proprotein Convertase Subtilisin/Kexin Type 9 inhibitor, Evolocumab with placebo in 18,924 patients with recent ACS and elevated atherogenic lipoproteins despite optimized statin therapy. Now the primary outcome was major adverse cardiovascular events. So MACE was coronary heart disease, death, nonfatal myocardial infarction, fatal non-fatal ischemic stroke, and hospitalization for unstable angina. And associations between baseline ApoB or ApoB at four months and MACE were assessed in adjusted Cox proportional hazards and propensity score matched models over median of 2.8 years. Dr. Carolyn Lam: Oh, right. So what were the results, Greg? Dr. Greg Hundley: Right, Carolyn so impatience with recent ACS and elevated atherogenic lipoproteins, MACE increased across baseline ApoB strata, and now evolocumab reduced MACE across all strata of baseline ApoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved ApoB was associated with lower risk of MACE, even after accounting for achieved LDLC or Non-HDLC indicating that ApoB provides incremental information. And therefore, Carolyn, if it is modified achievement of an ApoB level less than or equal to 35 milligrams per deciliter may reduce lipoprotein attributable residual risk after ACS. Isn't that interesting? Dr. Carolyn Lam: Yes. Very nice, Greg. Thank you. This next paper is a pre-specified analysis of the EMPEROR-Preserved trial, looking at patients with and without diabetes. Dr. Greg Hundley: So remind us, Carolyn, what was the EMPEROR-Preserved trial and what did it show? Dr. Carolyn Lam: Well, in EMPEROR-Preserved Empagliflozin, the SGLT2 inhibitor reduced risk of the composite of cardiovascular death or heart failure hospitalization, as well as first and recurrent heart failure hospitalizations and slowed renal function decline in patients with heart failure and an ejection fraction greater than 40%. So the current paper sought to determine if effects were consistent in patients with, and without diabetes, of the almost 6,000 patients enrolled, 49% had diabetes. The risk of adverse outcomes, first of all, was higher in patients with diabetes. Now the treatment effect of Empagliflozin was however, similar in that Empagliflozin reduced the rate of the primary outcome and total heart failure hospitalization, irrespective of diabetes status. The effect of Empagliflozen falls into attenuate GFR decline, however, was also present in patients with, and without diabetes, although more pronounced in patients with diabetes. Now across all these three endpoints, the effect of Empagliflozen did not differ in patients with prediabetes or normal glycemia. And importantly, there was no increased risk of hypoglycemic events in either subgroup compared with placebo. So a very nice paper there. And that was from Dr. Gerasimos Filippatos from Athens University Hospital Attikon and colleagues. Dr. Greg Hundley: Wow, Carolyn, just really interesting information coming out of the world of SGLT2 innovation. Well, Carolyn, my next paper comes to us from the world of preclinical science and it's from Dr. Kunhua Song from the University of Colorado Anschutz Medical campus. So Carolyn, abnormalities of calcium homeostasis are closely associated with cardiac arrhythmias and heart failure and conditions that cause death of millions of people every year. Now, Carolyn Triadin physically interacts with the Ryanodine receptor 2 and plays an important role in releasing calcium from the sarcoplasmic reticulum to increase the free intracellular calcium concentration in cardiomyocytes. Now alternative splicing of a single Triadin gene produces multiple Triadin isoforms, the predominant cardiac Triadin isoform mouse Mt1 or human Trisk 32 is encoded by Triadin exons from one to eight. In humans, mutations in the Triadin gene that lead to a reduction in Trisk 32 levels in the heart cause cardiac dysfunction, cardiac arrhythmias and sudden death. Decreased levels of Trisk 32, in the heart, are also common in patients with heart failure. However, mechanisms that regulate alternative splicing of the Triadin gene to maintain levels of cardiac Triadin protein in the heart, remains somewhat elusive. Dr. Carolyn Lam: Wow. I am always learning from these cool papers. Thanks Greg. So what were the results? Dr. Greg Hundley: So Carolyn, the investigators found several things. First, the cardio MyoSite specific long non-encoding RNA or link RNA Triadin AS is essential for maintenance of cardiac function, exercise capacity and normal lifespan and Triadin AS knockout mice were found predisposed to cardiac arrhythmias in response to catecholamine challenge. And finally Carolyn, Triadin AS controls, levels, of cardiac Triadin isoforms, by regulating the splicing of the Triadin gene. Dr. Carolyn Lam: Oh, wow. All right. So could you bring it home for us, Greg? What are the clinical take home messages? Dr. Greg Hundley: Right, Carolyn. So cardiac explants from human heart failure patients as well as patients with cardiac arrhythmias, demonstrate reduced expression of Triadin AS and Triadin. And then next the mechanism of the Triadin AS and Triandin AS mediated alternative splicing of the Triadin gene to specifically control levels of cardiac isoforms of Triadin in the heart, provides a potential strategy for the treatment of cardiac arrhythmias and heart failure. Dr. Carolyn Lam: Wow. Thank you, Greg. Well, let's talk about what else is in today's issue. There's a Research Letter by Dr. Agarwal on Chlorthalidone for resistant hypertension and advanced chronic kidney disease. Dr. Greg Hundley: And Carolyn, I've got a perspective piece by Professor Cowie pertaining to atrial fibrillation entitled, “I'm Sorry, Mrs. Jones, but We Cannot Make You Feel Better Today.” Well, Carolyn, how about we get onto that feature discussion and review the utility of fractional flow reserve measurements, in patients undergoing contrast coronary angiography. Dr. Carolyn Lam: Great, let's go. Dr. Greg Hundley: Welcome listeners to this August 30th feature discussion. And we have with us this afternoon, Dr. Rod Staples from Liverpool and our own associate editor, Dr. Nick Mills from Edinburgh, Scotland. And gentlemen, welcome, Rod we'll start with you. Can you describe for us the background information that went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Rod Staples: Okay, well thanks very much for hosting today. I'm very grateful to be working circulation on this. I'm working with my co-lead investigator Professor Nick Harrison from Southampton, who's been doing an enormous amount of work on coronary physiology. He actually did the original RIPCORD study, what I suppose we'd now call RIPCORD 1, but it was called RIPCORD in the early days, an observational study that showed that systematic use of fractional flow reserve at the time of diagnostic angiography. Assessing the functional significance measured in each of the major coronary vessels, appeared in an observational study to have a dramatic effect on the subsequent management plans allocated to patients. And we decided to test this in a prospective randomized trial. Dr. Greg Hundley: Very nice. And so the exact hypothesis that you were going to test was what? Dr. Rod Staples: At the time of coronary angiography, a strategy of systematic measurement of fractional flow reserve in each and every coronary vessel, large enough to be considered for revascularization, would improve outcomes compared to a strategy based on angiographic assessments alone. Dr. Greg Hundley: Very nice. And so you mentioned a randomized trial. Can you describe further your study design and then which study population did you include? Dr. Rod Staples: Well, this is a classic multicenter randomized trial performed in the UK. We actually recruited in 17 different UK centers. We asked them to assess patients who were scheduled for invasive, currently angiography for participation against some very minimal inclusion and exclusion criteria, trying to keep the trial generalizable with good external validity. I think one important point to note is that we did allow the inclusion of both patients being assessed with elective angiography for stable symptoms, but in the end half of the population were recruited in the context of a stabilized acute coronary syndrome, a Non-ST-elevation event a day or so down the line. Dr. Greg Hundley: And just a quick breakdown, how many men, how many women? Dr. Rod Staples: Well, it's in that respect, the population is very, very typical for this type of cardiovascular trial. A 70, 30 split an age in the midsixties, a diabetic population in the high teens. So a very typical population we've seen in all this kind of trial environment. Dr. Greg Hundley: Very nice. And so about 1100 patients. And then what were your study results? Dr. Rod Staples: Well, I think there was a very good adherence to the study protocol, very, very few crossovers. And also we were pleased to see that our investigators stayed true to the protocol in that the median number of epicardial vessels assessed by FFR in that randomized arm was four. So there was a good assessment by FFR. The trial was interesting in another respect, in that we assessed an economic outcome based on all NHS hospital costs over the following year and a patient reported outcome based on quality of life using the WHOQOL, and interestingly we found no significant differences either in total subsequent hospital costs from randomization for a year, or indeed in patient reported quality of life by WHOQOL or Angina symptoms by the Canadian Cardiovascular Society classification. Dr. Greg Hundley: Very nice. And then, what about clinical events? Did you examine those as well? Dr. Rod Staples: We did. And again, just a little caveat here, the trial is again interesting in that, what is often in the UK these days called a lean efficient methodology. Whereby, rather than individually contacting individual trial participants or scouring medical records, we interrogated the central national NHS digital repository of all hospital admissions. And we examined electronically a download of every hospitalization event for every patient using algorithms based on diagnostic and procedural codes to define events. And again, we found a very credible representative rate exactly at incidents and events we would've predicted, but again, no difference between the randomized groups. Dr. Greg Hundley: Very nice, well listeners, now we're going to turn to our own Associate Editor, Dr. Nick Mills. And Nick, again, you see many papers come across your desk. What attracted you to this particular manuscript? And it's very interesting study results. Dr. Nick Mills: Thanks, Greg. Firstly, it addresses an important clinical question. Going beyond that, what appealed to me was it was investigator initiated. It was managed by independent trials unit. It recruited a target, it reported the registered outcomes and it was thoughtfully interpreted. And the fact that it didn't prove the hypothesis was irrelevant because it addresses a really important clinical question. And I think it requires some context, and that is that from the previous randomized trials The FAME series, we have been chastised as interventional cardiologists for not using FFR for relatively low use of FFR clinical practice. It's always around one in 20 patients in most series, given the evidence that FFR guided intervention improves outcomes. But actually what FFR is good at is discouraging you from stenting patients with stable Coronary Disease. And so, I think a pragmatic trial that addresses that, the fundamental question, should we be doing more FFR more broadly in both acute and stable disease to guide revascularization with a definitive message that we shouldn't, it doesn't improve quality of life. It doesn't alter costs. Clinical outcomes are similar, but there are more complications associated with routine pressure wire use, gives us a very clear steer for the future. So this is a really important trial addressing a fairly fundamental clinical question. Dr. Greg Hundley: Very interesting. Well, Rod, we're going to turn back to you with Nick's comments and how we're really seeing an evolution in thought processes regarding both diagnostic angiography, and then also the use of functional testing. What do you see is the next study, really in this sphere of research that would be performed? Dr. Rod Staples: Well, I agree with Nick in a way that this raises important philosophical points about the use of intelligence, selective employment of tests or interventions, and that perhaps we need to reflect this in the way we conduct our future studies. I think we're all aware that fractional flow reserve and other measures of functional significance are tremendously valuable in certain clinical settings. And that value's been proven in randomized trials, but in PRECORD 2, for example, if a patient randomized to angiography only was an acute coronary syndrome patient, who had inverted their T waves in their anterior leads, had an associated troponin rise, an echocardiogram had shown some Hypokinesia in the anterior territory. Then I think the potential value of PCI in the LAD does not necessarily require FFR confirmation, and hence that patient will have an equivalent outcome in the angiography group. Similarly, high quality pre-angiography preparation in the elective population with functional testing, stress testing, other forms of imaging mean that we can reserve the use of invasive fractional flow reserve, tight indices to more selective use. Dr. Greg Hundley: And Nick, turning to you, what do you think is the next research study that could be informative in this space? Dr. Nick Mills: I think our whole philosophy by how to manage stable coronary disease is changing. In part because of some other landmark trials that the Ischemia trial and some of the key secondary analyses of the Ischemia trial that tells the Pathoma burden, low attenuation plaque, other aspects of chronic disease are vitally important in predicting major events in the future. And that leaves us with the role for FFR or CT FFR, primarily to manage symptoms. And I think we're getting increasingly good evaluating patients before they get to the Cathflow, optimizing their medical treatment. And so for me, the trial that we really need to help us, is a CT FFR trial to understand the role of Ischemia testing plus anatomical testing and how they dovetail in guiding treatment decisions before they get to the cath lab. I think we need to move this before the lab, always going to be a role for intelligent FFR testing in selected patients once we get to it. But I think that the question probably needs to be addressed before they get to the cath lab. Dr. Greg Hundley: Very nice. Well listeners, we want to thank, Dr. Rod Staples from Liverpool and Dr. Nick Mills from Edinburgh, Scotland for bringing us this very interesting study, highlighting that a strategy of systematic FFR assessment, when compared to angiography alone, did not result in a significant reduction in cost or improvement in quality of life. 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, 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.

Commentary by Dr. Valentin Fuster

Diabetes Core Update is a monthly podcast that presents and discusses the latest clinically relevant articles from the American Diabetes Association's four science and medical journals – Diabetes, Diabetes Care, Clinical Diabetes, and Diabetes Spectrum. Each episode is approximately 20 minutes long and presents 5-6 recently published articles from ADA journals. Intended for practicing physicians and health care professionals, Diabetes Core Update discusses how the latest research and information published in journals of the American Diabetes Association are relevant to clinical practice and can be applied in a treatment setting. This issue will review: Risks and burdens of incident diabetes after Covid-19 Trends in Timing of and Glycemia at Initiation of Second-line treatment for T2DM Safety of Empagliflozin in Patients with Type 2 Diabetes and CKD Weight Change During Postintervention Follow-up of the Look AHEAD Study Progression to Diabetes Among Older Adults With Prediabetes Association between DM and gray matter atrophy patterns in Older Adults For more information about each of ADA's science and medical journals, please visitwww.diabetesjournals.org. Presented by: Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health John J. Russell, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Director, Family Medicine Residency Program, Chair-Department of Family Medicine, Abington Jefferson Health

Obstructive hypertrophic cardiomyopathy and mavacamten, SGLT2 inhibitors, the triple whammy, espresso, and clinician burnout are the topics John Mandrola, MD, covers in today's podcast. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I – Mavacamten - FDA Clears Mavacamten (Camzyos) for Obstructive Hypertrophic Cardiomyopathy https://www.medscape.com/viewarticle/972945 - Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial https://doi.org/10.1016/S0140-6736(20)31792-X - FDA approves new drug to improve heart function in adults with rare heart condition https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-new-drug-improve-heart-function-adults-rare-heart-condition II – Dapagliflozin in HFpEF - Positive Topline Results for Dapagliflozin in HFpEF: DELIVER https://www.medscape.com/viewarticle/973490 - Empagliflozin in Heart Failure with a Preserved Ejection Fraction https://www.nejm.org/doi/full/10.1056/NEJMoa2107038 III – Triple Whammy for AKI - Mixing BP Meds With NSAID May Be 'Triple Whammy' for Kidneys https://www.medscape.com/viewarticle/973885 IV – Espresso - Espresso Coffee Associated With Increased Total Cholesterol https://www.medscape.com/viewarticle/973819 - Association between espresso coffee and serum total cholesterol: the Tromsø Study 2015–2016 https://openheart.bmj.com/content/9/1/e001946 - Is everything we eat associated with cancer? A systematic cookbook review https://pubmed.ncbi.nlm.nih.gov/23193004/ - Enough With the Coffee Research and Other Distractions https://www.medscape.com/viewarticle/883709 V – Clinician Burnout - Administrative Hassle Hacks: Strategies to Curb Physician Stress https://www.medscape.com/viewarticle/973597 You may also like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net