{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T15:42:14Z","timestamp":1792683734056,"version":"4.5.0"},"reference-count":59,"publisher":"American Physiological Society","issue":"5","funder":[{"name":"the innocore program of the ministry of science and ict","award":["Y1112692025"],"award-info":[{"award-number":["Y1112692025"]}]},{"name":"the innocore program of the ministry of science and ict","award":["N10260100"],"award-info":[{"award-number":["N10260100"]}]},{"DOI":"10.13039\/501100010446","name":"Institute for Basic Science","doi-asserted-by":"publisher","award":["IBS-R029-C3"],"award-info":[{"award-number":["IBS-R029-C3"]}],"id":[{"id":"10.13039\/501100010446","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2025-25397599"],"award-info":[{"award-number":["RS-2025-25397599"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.physiology.org"],"crossmark-restriction":true},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2026,11,1]]},"abstract":"<jats:p>Cardiac electrophysiology models resolve processes ranging from millisecond-scale ion-channel gating to hour-scale protein trafficking; yet, most do not explicitly represent circadian time. Consequently, ion-channel conductance, autonomic input, body temperature, and clock-regulated gene expression are often treated as fixed parameters or time-invariant inputs, causing simulated cardiac cells to correspond to an implicit and potentially arbitrary biological phase. In vivo, however, these factors vary across the \u223c24-h cycle and jointly shape sinoatrial nodal pacemaking, ventricular repolarization, arrhythmia susceptibility, and drug response. In this mini-review, we examine recent efforts to incorporate circadian regulation into computational models of cardiac electrophysiology, including sinoatrial nodal and ventricular myocyte models of pacemaking, arrhythmogenesis, seizure-induced sinus arrhythmias, and drug-induced proarrhythmic risk. We synthesize these studies using a layered \u201csource-transfer-target\u201d organization in which intrinsic and systemic circadian sources act through source-specific transfer processes\u2014including transcription, translation, channel trafficking, receptor-mediated signaling, and direct thermal modulation\u2014to regulate shared electrophysiological targets. Building on this synthesis, we propose a general current-level formulation for incorporating circadian regulation of maximal conductance, channel gating, and ionic driving force into Hodgkin\u2013Huxley-type models. Finally, we identify the experimental, computational, and clinical advances needed to translate these formulations into human-specific, personalized models of cardiac rhythm and arrhythmogenesis, with the long-term goal of enabling circadian-aware cardiac digital twins for time-resolved risk prediction and chronotherapeutic optimization.<\/jats:p>","DOI":"10.1152\/ajpcell.90162.2026","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:22:18Z","timestamp":1792671738000},"page":"C1389-C1399","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["It's about time: modeling circadian regulation of cardiac electrophysiology and arrhythmogenesis"],"prefix":"10.1152","volume":"331","author":[{"given":"Pan","family":"Li","sequence":"first","affiliation":[{"name":"Zhejiang University","place":["People\u2019s Republic of China"]},{"name":"State Key Laboratory of Transvascular Implantation 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