{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T01:38:53Z","timestamp":1772156333050,"version":"3.50.1"},"posted":{"date-parts":[[2023,1,31]]},"group-title":"Physiology","reference-count":68,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,8,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec id=\"s1\">\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>\n                    Sudden cardiac death (SCD) from ventricular tachycardia\/fibrillation (VT\/VF) are a leading cause of death, but current therapies are limited. 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.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec id=\"s2\">\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>\n                    To test 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.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec id=\"s3\">\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    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.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec id=\"s4\">\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec id=\"s5\">\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                    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 increasing 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>\n                <\/jats:sec>","DOI":"10.1101\/2023.01.29.526151","type":"posted-content","created":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T22:40:12Z","timestamp":1675204812000},"source":"Crossref","is-referenced-by-count":0,"title":["Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function and prevents sudden arrhythmic death in failing hearts"],"prefix":"10.64898","author":[{"given":"Pooja","family":"Joshi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shanea","family":"Estes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deeptankar","family":"DeMazumder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bjorn C.","family":"Knollmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swati","family":"Dey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023082514550737000_2023.01.29.526151v3.1","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.jaccas.2020.12.029","article-title":"Bilateral Cardiac Sympathectomy and Extrapericardial Coil Implantation for the Management of Electrical Storm","volume":"3","year":"2021","journal-title":"JACC. 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