A multiscale mechanobiological model of physiological and pathological cardiac hypertrophy

Abstract

Cardiac hypertrophy involves dynamic heart remodeling associated with mechanical and biochemical stimuli, while physiological and pathological cardiac hypertrophy can lead to distinct clinical outcomes. However, most previous models fail to distinguish these types, or properly account for cytoskeletal-extracellular matrix (ECM) remodeling effects. In this study, we develop a multiscale mechanobiological model by coupling cardiac mechanical behaviors with cardiomyocyte growth through mechanosensitive signaling pathways. This model considers tissue microstructures to characterize how cytoskeletal-ECM remodeling alters the mechanical forces sensed by cardiomyocytes. Our model can well predict experimental measurements of ventricular wall thickness and signaling activation in both physiological and pathological hypertrophy, enabling their clear differentiation. We demonstrate that exercise-induced hypertrophy attenuates pathological remodeling by alleviating myocardial mechanical stress to suppress mechanotransduction. We also elucidate the synergistic or antagonistic interaction mechanisms among factors such as hypertension, exercise, cardiomyocyte death and fibrosis in cardiomyocyte growth and pathological signaling. These results highlight the importance of myocardial microenvironment in cardiac remodeling. Furthermore, computational evaluation demonstrates that muscle LIM protein-targeted therapies have potential for treating pathological hypertrophy through mechanotransduction modulation, but excessive dosing may elevate arrhythmia risks. This study not only advances mechanistic understanding of physiological and pathological cardiac hypertrophy, but also provides a theoretical basis for developing mechanobiology-informed therapeutic techniques.