Elucidating the cellular determinants of the end-systolic pressure-volume relationship of the heart via computational modelling.

The left ventricular end-systolic pressure-volume relationship (ESPVr) is a key indicator of cardiac contractility. Despite its established importance, several studies suggested that the mechanical mode of contraction, such as isovolumetric or ejecting contractions, may affect the ESPVr, challenging the traditional notion of a single, consistent relationship. Furthermore, it remains unclear whether the observed effects of ejection on force generation are inherent to the ventricular chamber itself or are a fundamental property of the myocardial tissue, with the underlying mechanisms remaining poorly understood. We investigated these aspects using a multiscale in silico model that allowed us to elucidate the links between subcellular mechanisms and organ-level function. Simulations of ejecting and isovolumetric beats with different preload and afterload resistance were performed by modulating calcium and cross-bridge kinetics. The results suggest that the ESPVr is not a fixed curve but depends on the mechanical history of the contraction, with potentially both positive and negative effects of ejection. Cell scale simulations suggest that these phenomena are intrinsic to the myocardial tissue, rather than properties of the ventricular chamber. Our results suggest that the ESPVr results from the balance between positive and negative effects of ejection, related to a memory effect of the increased apparent calcium sensitivity at high sarcomere length, and to the inverse relationship between force and velocity. Numerical simulations allowed us to reconcile conflicting results in the literature and suggest translational implications for clinical conditions such as hypertrophic cardiomyopathy, where altered calcium dynamics and cross-bridge kinetics may impact the ESPVr. KEY POINTS: The left ventricular end-systolic pressure-volume relationship (ESPVr) is a fundamental indicator of cardiac contractility, but the traditional notion of a single, consistent curve across different mechanical modes of contraction (isovolumetric vs. ejecting) has been challenged. Using multiscale computational simulations, our findings suggest that the ESPVr is not a fixed curve but depends on the mechanical history of the contraction, with both positive and negative inotropic effects during muscle shortening (ejection). Our results suggest that these phenomena are intrinsic to myocardial tissue properties, specifically involving calcium kinetics and cross-bridge cycling, rather than being due to ventricular chamber mechanics. Our study reconciles conflicting findings in the literature by providing a mechanistic explanation of how length-dependent activation and the force-velocity relationship influence ESPVr. This work has potential translational implications for clinical conditions such as hypertrophic cardiomyopathy, where altered calcium dynamics and enhanced cross-bridge kinetics may significantly affect cardiac contractility and the ESPVr.