{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:51:06Z","timestamp":1791931866513,"version":"4.3.4"},"reference-count":38,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,3]]},"abstract":"\n Abstract<\/jats:title>\n \n Ryanodine receptor 2 (RyR2)\u00a0hyperactivity is frequently observed in structural heart disease (SHD), commonly caused by ischemic heart disease. This aberrant Ca\n 2+<\/jats:sup>\n release promotes irregular electrical activity and life\u2010threatening arrhythmias. Our previous work demonstrated that the pan\u2010ryanodine receptor (RyR) inhibitor dantrolene can reverse arrhythmogenic substrates, but its lack of RyR2\u00a0selectivity limits its therapeutic potential. The unnatural verticilide enantiomer (\n ent<\/jats:italic>\n \u2010verticilide) was identified as a selective RyR2 inhibitor, showing promising specificity without activating skeletal muscle RyR1. This study evaluated the antiarrhythmic potential of a selective RyR2 antagonist,\n ent<\/jats:italic>\n \u2010(+)\u2010verticilide (\n ent<\/jats:italic>\n \u2010Vert), in human ventricular slices. Right and left ventricular slices were prepared from human hearts not designated for transplantation. Pseudo\u2010electrocardiograms (ECG) tracked premature ventricular contraction (PVC) incidence, and optical mapping identified arrhythmogenic substrates. Baseline optical recordings were obtained before treatment with isoproterenol (Iso) (250\u00a0nM) and caffeine (200\u00a0\u00b5M) to induce Ca\n 2<\/jats:sup>\n +<\/jats:sup>\n leak and arrhythmogenic activity, followed by sequential\n ent<\/jats:italic>\n \u2010Vert application (1 and 3\u00a0\u00b5M). The effects of\n ent<\/jats:italic>\n \u2010Vert alone were tested with baseline recordings followed by a single 3\u00a0\u00b5M dose. Iso and caffeine increased PVC incidence in both right (RV) and left ventricular (LV) slices, but\n ent<\/jats:italic>\n \u2010Vert (1 and 3\u00a0\u00b5M) significantly reduced it. Iso and caffeine also shortened action potential duration (APD) in both slice types, but\n ent<\/jats:italic>\n \u2010Vert, after Iso and caffeine or alone (under control conditions), did not significantly change APD. In conclusion,\n ent<\/jats:italic>\n \u2010Vert suppressed arrhythmic triggers and reduced arrhythmogenic substrates in human ventricular slices, highlighting its potential as a targeted antiarrhythmic therapy for SHD.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n RyR2 hyperactivity is a major driver of arrhythmias in structural heart disease, producing abnormal Ca\n 2<\/jats:sup>\n +<\/jats:sup>\n release and premature ventricular contractions.\n <\/jats:p>\n <\/jats:list-item>\n \n \n The RyR2\u2010selective inhibitor\n ent<\/jats:italic>\n \u2010Vert was evaluated in human RV and LV slices to determine its antiarrhythmic potential.\n <\/jats:p>\n <\/jats:list-item>\n \n \n \u03b2\u2010Adrenergic and RyR2 activation with Iso + caffeine induced Ca\n 2<\/jats:sup>\n +<\/jats:sup>\n leak, ectopic beats and shortened APD. Sequential\n ent<\/jats:italic>\n \u2010Vert application (1 and 3\u00a0\u00b5M) significantly suppressed ectopy incidence in a dose\u2010dependent manner.\n <\/jats:p>\n <\/jats:list-item>\n \n \n ent<\/jats:italic>\n \u2010Vert did not alter APD or conduction velocity under control or stimulated conditions, demonstrating that it suppresses arrhythmic triggers without disrupting normal cardiac electrophysiology.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp290283","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T15:00:46Z","timestamp":1769698846000},"page":"1809-1819","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Selective RyR2 inhibition reduces arrhythmia susceptibility in human cardiac slices"],"prefix":"10.1113","volume":"604","author":[{"given":"Micah 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