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Post-extrasystolic potentiation (PESP), which is the transient increase in contractility following a PVC, may serve as a predictive marker for heart failure risk; yet, the underlying calcium-mediated mechanisms and their relative contribution compared to loading conditions remain poorly understood. We integrated a mechanochemical model coupling intracellular calcium dynamics to sarcomere mechanics within the CircAdapt closed-loop cardiovascular framework. A novel calcium source model incorporating the force\u2013interval relationship was calibrated using experimental canine data. We simulated single PVCs across varying coupling intervals and systematically investigated the contributions of calcium dynamics versus loading conditions to PESP, quantified as changes in systolic blood pressure (\u2206SBP), maximum rate of left ventricular pressure rise (\u2206max(d\n                    <jats:italic>P<\/jats:italic>\n                    <jats:sub>Lv<\/jats:sub>\n                    \/d\n                    <jats:italic>t<\/jats:italic>\n                    )), and left ventricular ejection fraction (\u2206LVEF). The calcium-based force\u2013interval relationship reproduced experimental mechanical restitution curves with high accuracy (RMSE 9.59\u2009\u00b1\u20090.08%). Shorter coupling intervals reduced premature beat contractility while enhancing PESP in subsequent beats. Systematic variation of preload, afterload, and intrinsic contractility revealed that calcium dynamics reproduce the observed PESP patterns, with loading conditions as modulators. Notably, \u2206max(d\n                    <jats:italic>P<\/jats:italic>\n                    <jats:sub>Lv<\/jats:sub>\n                    \/d\n                    <jats:italic>t<\/jats:italic>\n                    ) and \u2206SBP responded differently, with \u2206SBP exhibiting complex non-monotonic behavior. The model qualitatively reproduced pressure\u2013volume patterns from a single clinical quadrigeminy case. This study demonstrates that a calcium-based force\u2013interval formulation reproduces the qualitative features of PESP within this framework, with preload and afterload modulating the pattern of beat-to-beat pressure response. The divergent behavior among contractility metrics emphasizes the need for multimetric assessment. This framework enables distinguishing intrinsic myocardial dysfunction from extrinsic loading effects, facilitating patient-specific risk stratification in PVC-induced cardiomyopathy.\n                  <\/jats:p>","DOI":"10.1007\/s10237-026-02119-w","type":"journal-article","created":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T05:40:06Z","timestamp":1788068406000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Calcium-mediated force\u2013interval relationship drives post-extrasystolic potentiation in premature ventricular complexes: a computational study"],"prefix":"10.1007","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2011-5995","authenticated-orcid":false,"given":"Sjoerd","family":"Vossen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8927-9110","authenticated-orcid":false,"given":"Nick","family":"van Osta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5413-7502","authenticated-orcid":false,"given":"Guilherme Pedro Carvalho","family":"Louren\u00e7o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2169-4024","authenticated-orcid":false,"given":"S\u00e9rgio Matoso","family":"Laranjo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8129-7384","authenticated-orcid":false,"given":"Joost","family":"Lumens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,30]]},"reference":[{"key":"2119_CR1","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/S0006-3495(91)82201-9","volume":"59","author":"T Arts","year":"1991","unstructured":"Arts T, Bovendeerd PH, Prinzen FW, Reneman RS (1991) Relation between left ventricular cavity pressure and volume and systolic fiber stress and strain in the wall. 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