{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T02:34:58Z","timestamp":1783650898371,"version":"3.55.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T00:00:00Z","timestamp":1742169600000},"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>Drug-induced changes in cardiac contractility (inotropy) can lead to cardiotoxicity, a major cause of discontinuation in drug development. Preclinical approaches to assess cardiac inotropy are imperfect, with <jats:italic>in vitro<\/jats:italic> assays limited to stem cell-derived or adult human primary cardiomyocytes. Human mechanistic <jats:italic>in silico<\/jats:italic> modelling and simulations are already successfully applied for proarrhythmia prediction, contributing to cardiac safety assessment strategies in early drug development. In this study, we investigated their ability to predict drug-induced effects on cardiac inotropy. We considered a validation set of 28 neutral\/negative inotropic and 13 positive inotropic reference compounds and simulated their effects on cell contractility via ion channel inhibition and perturbation of nine biomechanical modelling parameters, respectively. For each compound, a wide range of drug concentrations was simulated in an experimentally calibrated control population of 323 human ventricular <jats:italic>in silico<\/jats:italic> cells. Simulated biomarkers indicating drug-induced inotropic effects were compared with <jats:italic>in vitro<\/jats:italic> preclinical data from the literature. Computer simulations predicted drug-induced inotropic changes observed <jats:italic>in vitro<\/jats:italic> for 25 neutral\/negative inotropes and 10 positive inotropes. Predictions of negative inotropic changes were quantitatively in agreement for 86% of tested drugs. Active tension peak was identified as the biomarker with highest predictive potential. This study describes the validation and application of an <jats:italic>in silico<\/jats:italic> cardiac electromechanical model for drug safety evaluation, combining ion channel inhibition data and information on potential inotropic mechanisms to predict inotropic changes. Furthermore, a route for its integration as part of a preclinical drug safety assessment strategy is outlined.<\/jats:p>","DOI":"10.3389\/fphar.2025.1500668","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T07:20:36Z","timestamp":1742196036000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["In silico predictions of drug-induced changes in human cardiac contractility align with experimental recordings"],"prefix":"10.3389","volume":"16","author":[{"given":"Cristian","family":"Trovato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Longobardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Passini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kylie A.","family":"Beattie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxx","family":"Holmes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khuram W.","family":"Chaudhary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric I.","family":"Rossman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7692","DOI":"10.1038\/s41598-020-64657-2","article-title":"Multiparametric mechanistic profiling of inotropic drugs in adult human primary cardiomyocytes","volume":"10","author":"Abi-Gerges","year":"2020","journal-title":"Sci. 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