Mechanical factors in cardiac function: Stiffness and dynamic mechanotransduction pathways regulating contractility

The function of the heart is intrinsically linked to its mechanical properties and the contractile force generated by cardiac muscle cells (cardiomyocytes). Contractility is the composite ability to functionally contract, especially in a coordinated fashion on a tissue and organ scale, and to modulate the force and velocity of this contraction in accordance with the paced rate, as well as the applied preload and afterload. Reduced contractility is a major concern in clinical contexts, such as heart failure and cardiomyopathy. Despite significant advances in research and therapeutic interventions, controlling cardiomyocyte contractility remains a substantial challenge. A growing body of research highlights that biophysical cues, particularly microenvironment stiffness, play a crucial role in regulating myocardial contractility at both cellular and tissue levels. Here, we explore the tissue forming cardiac contractile, and specifically that of the ventricles, detailing the roles of excitation–contraction coupling and the role of mechano-electric feedback, as well as mechanisms of loss of function in relevant examples of hereditary or acquired disease. We further integrate how sarcomeric structure and its dynamic remodeling contribute to these regulatory processes, emphasizing their importance in both physiological load adaptation and disease-associated dysfunction. We then review methods of measurement of myocardial stiffness and modeling across different species and experimental setups. Finally, we examine the cellular and molecular mechanisms that integrate these processes and their potential applications in regulating cardiac contraction. This review aims to foster interdisciplinary approaches to advancing cardiac physiology and disease research.