BPS2026 – Sex- and age-dependent mechanisms of the mechano-chronotropic response in the sinoatrial node

The sinoatrial node (SAN) mediates the mechano-chronotropic response, providing structural basis for hemodynamic heart rate (HR) regulation (Bainbridge response); however, whether this response is sex-dependent and/or altered during aging remains unknown. Ex-vivo electrocardiography was utilized to determine HR changes upon atrial distention in Langendorff-perfused hearts from young (10–12-weeks, n=7/5 male/female) and middle-age (12–14-months, n=8/6 male/female) mice and rats (n=7/6 and n=3/5 male/female young and aged, respectively). Atrial stretch was confirmed by increase in cardiomyocyte length/width and extracellular matrix (ECM) volume via immunohistological analysis. Mice had a larger HR increase upon stretching (22–27%) compared with rats (9–17%), and the response displayed reverse rate-dependence. Female rats were more sensitive to stretch, whereas no sex-specific differences were observed in mice. Computational modelling reproduced the mechano-chronotropic response (15.2%) through activation of mechanosensitive chloride current (73% of HR increase) and augmentation of sarcoplasmic reticulum calcium release (27% of HR increase). A population-based modelling approach revealed that mechano-chronotropic responses positively correlated with the levels of I CaT , I CaL and NCX1 and negatively correlated with levels of I Na , I f , and I Kr . These results align with recently reported sex-specific SAN differences in I CaL and NCX1, but not I f , in human SAN, which may underlie faster HR and a lower threshold for inappropriate sinus tachycardia in women (Li et al. (2025). CircA&E 18(5), e013534). The observed species- and sex-dependent differences were preserved with aging. While aged animals showed consistent chronotropic response, they exhibited smaller cardiomyocyte deformation suggesting ECM remodeling. Interestingly, atrial distention resulted in heterogenous, region-specific cardiomyocyte stretch, with SAN region affected significantly more than right atrial appendage. Our findings suggest that both membrane and calcium components of the SAN coupled-clock pacemaker system are engaged during the mechano-chronotropic response and that ECM composition and sex-specific molecular determinants modulate this regulation.