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Despite extensive research on drugs targeting sarcolemmal ion channels, none have proven sufficiently effective for preventing SCD. Sarcoplasmic ryanodine receptor 2 (RyR2) Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release channels, the downstream effectors of sarcolemmal ion channels, are underexplored in this context. Recent evidence implicates reactive oxygen species (ROS)-mediated oxidation and hyperactivity of RyR2s in the pathophysiology of SCD. We tested the hypothesis that RyR2 inhibition of failing arrhythmogenic hearts reduces sarcoplasmic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    leak and repolarization lability, mitigates VT\/VF\/SCD and improves contractile function. We used a guinea pig model that replicates key clinical aspects of human nonischemic HF, such as a prolonged QT interval, a high prevalence of spontaneous arrhythmic SCD, and profound Ca\n                    <jats:sup>2+<\/jats:sup>\n                    leak via a hyperactive RyR2. HF animals were randomized to receive dantrolene (DS) or placebo in early or chronic HF. We assessed the incidence of VT\/VF and SCD (primary outcome), ECG heart rate and QT variability, echocardiographic left ventricular (LV) structure and function, immunohistochemical LV fibrosis, and sarcoplasmic RyR2 oxidation. DS treatment prevented VT\/VF and SCD by decreasing dispersion of repolarization and ventricular arrhythmias. Compared to placebo, DS lowered resting heart rate, preserved chronotropic competency during transient \u03b2-adrenergic challenge, and improved heart rate variability and cardiac function. Inhibition of RyR2 hyperactivity with dantrolene mitigates the vicious cycle of sarcoplasmic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    leak-induced increases in diastolic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    and ROS-mediated RyR2 oxidation, thereby reducing repolarization lability and protecting against VT\/VF\/SCD. Moreover, the consequent increase in sarcoplasmic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    load improves contractile function. These potentially life-saving effects of RyR2 inhibition warrant further investigation, such as clinical studies of repurposing dantrolene as a potential new therapy for heart failure and\/or SCD.\n                  <\/jats:p>","DOI":"10.7554\/elife.88638","type":"journal-article","created":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T11:31:57Z","timestamp":1689161517000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.88638","source":"Crossref","is-referenced-by-count":11,"title":["Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function, and prevents sudden arrhythmic death in failing hearts"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1415-1251","authenticated-orcid":true,"given":"Pooja","family":"Joshi","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dq2gs74","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center","place":["Nashville, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanea","family":"Estes","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dq2gs74","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center","place":["Nashville, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deeptankar","family":"DeMazumder","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02qm18h86","id-type":"ROR","asserted-by":"publisher"}],"name":"Section of Cardiac Electrophysiology, Division of Cardiology, Department of Internal Medicine, Veterans Affairs Pittsburgh Health System","place":["Pittsburgh, United States"]},{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Section of Cardiac Electrophysiology, Division of Cardiology, Department of Internal Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center","place":["Pittsburgh, United States"]},{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Surgery, University of Pittsburgh School of Medicine","place":["Pittsburgh, United States"]},{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine","place":["Pittsburgh, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bjorn C","family":"Knollmann","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dq2gs74","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center","place":["Nashville, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4692-6848","authenticated-orcid":true,"given":"Swati","family":"Dey","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dq2gs74","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center","place":["Nashville, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2023,12,11]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"e272","DOI":"10.1161\/CIR.0000000000000549","article-title":"2017 AHA\/ACC\/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society","volume":"138","author":"Al-Khatib","year":"2018","journal-title":"Circulation"},{"key":"bib2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-020-00443-x","article-title":"Mechanisms of ryanodine receptor 2 dysfunction in heart failure","volume":"17","author":"Alvarado","year":"2020","journal-title":"Nature Reviews. 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