{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:08:42Z","timestamp":1791914922244,"version":"4.3.4"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T00:00:00Z","timestamp":1712707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Hypertrophic cardiomyopathy (HCM) is a leading cause of lethal arrhythmias in the young. Although the arrhythmic substrate has been hypothesised to be amenable to late Na<jats:sup>+<\/jats:sup> block with ranolazine, the specific mechanisms are not fully understood. Therefore, this study aimed to investigate the substrate mechanisms of safety and antiarrhythmic efficacy of ranolazine in HCM.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Computational models of human tissue and ventricles were used to simulate the electrophysiological behaviour of diseased HCM myocardium for variable degrees of repolarisation impairment, validated against <jats:italic>in vitro<\/jats:italic> and clinical recordings. S1-S2 pacing protocols were used to quantify arrhythmic risk in scenarios of (i) untreated HCM-remodelled myocardium and (ii) myocardium treated with 3\u00b5M, 6\u00b5M and 10\u00b5M ranolazine, for variable repolarisation heterogeneity sizes and pacing rates. ECGs were derived from biventricular simulations to identify ECG biomarkers linked to antiarrhythmic effects.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> 10\u00b5M ranolazine given to models manifesting ventricular tachycardia (VT) at baseline led to a 40% reduction in number of VT episodes on pooled analysis of &amp;gt;40,000 re-entry inducibility simulations. Antiarrhythmic efficacy and safety were dependent on the degree of repolarisation impairment, with optimal benefit in models with maximum JT<jats:sub>c<\/jats:sub> interval &amp;lt;370\u00a0ms. Ranolazine increased risk of VT only in models with severe-extreme repolarisation impairment.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Ranolazine efficacy and safety may be critically dependent upon the degree of repolarisation impairment in HCM. For moderate repolarisation impairment, reductions in refractoriness heterogeneity by ranolazine may prevent conduction blocks and re-entry. With severe-extreme disease substrates, reductions of the refractory period can increase re-entry sustainability.<\/jats:p>","DOI":"10.3389\/fphar.2024.1379236","type":"journal-article","created":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T04:19:50Z","timestamp":1712722790000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Effects of ranolazine on the arrhythmic substrate in hypertrophic cardiomyopathy"],"prefix":"10.3389","volume":"15","author":[{"given":"James A.","family":"Coleman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben","family":"Doste","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Beltrami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Argir\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Coppini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iacopo","family":"Olivotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betty","family":"Raman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso","family":"Bueno-Orovio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,4,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1161\/01.CIR.0000139333.83620.5D","article-title":"Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties","volume":"110","author":"Antzelevitch","year":"2004","journal-title":"Circulation"},{"key":"B2","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.ijcard.2022.10.014","article-title":"Safety and efficacy of ranolazine in hypertrophic cardiomyopathy: real-world experience in a National Referral Center","volume":"370","author":"Argir\u00f2","year":"2023","journal-title":"Int. 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