["The Journal of Physiology, Volume 604, Issue 13, Page 5421-5439, 1 July 2026. ", "\nAbstract figure legend Schematic depicting the multiscale nature of cardiac electromechanical pacing with inserts showing: 1) A schematic representation of the proposed Piezo1 Markov chain model with four states and the proposed transition structure between these states (bottom right); and 2) The performance of the proposed model in one of the validation experiments (top right).\n\n\n\n\n\n\n\n\n\nAbstract\nPiezo1 ion channels are voltage‐modulated, stretch‐activated ion channels involved in a variety of important physiological and pathophysiological processes, as, for example, cardiovascular development and homeostasis. Since their discovery, it has been known that this type of ion channel desensitizes when exposed to stretch. However recent experiments on Piezo1 ion channels have uncovered that their stretch response is qualitatively different when exposed to positive electrochemical driving forces, where the desensitization is reset. In this work we propose a novel voltage‐modulated mathematical model of Piezo1 based on a continuous‐time Markov chain. We show that our Piezo1 model is able to quantitatively reproduce a wide range of experimental observations. Furthermore we integrate our new ion channel model into the Mahajan–Shiferaw ventricular cardiomyocyte model to study the effect of electromechanical pacing at the cellular scale. This integrated cell model is able to qualitatively reproduce some aspects of the experimental observations regarding the rate‐dependence of electromechanical pacing protocols. Our studies suggest that the Piezo1 ion channel is an important component that significantly contributes to the electromechanical coupled response of cardiomyocytes.\n\n\n\n\n\n\n\n\n\nKey points\n\nPIEZO ion channels are voltage‐modulated, mechanically gated ion channels involved in a large variety of mechanically regulated physiological processes and diseases.\nRecent experiments on Langendorff‐perfused rabbit hearts by A. Quinn and P. Kohl [2016] suggest a non‐trivial relation between the number of captured mechanical stimuli and the electromechanical pacing protocol.\nWe present a novel thermodynamically consistent in silico model of the Piezo1 ion channel with electromechanical gating that can reproduce a large variety of experimental observations during combined exposure to electrical and mechanical stimuli.\nThe new ion channel model is integrated into the well‐established Mahajan–Shiferaw rabbit ventricular cardiomyocyte model to study its role during normal heart beat and during electromechanical pacing protocols.\nOur in silico studies suggest that the Piezo1 ion channel alone may not be sufficient to explain the experimental observations made by A. Quinn and P. Kohl.\n\n"]