The Role of Mechanical Load in Cardiovascular Development, Health, and Disease: Current Knowledge and Future Perspectives

Abstract

Mechanical load is a critical regulator of cardiac structure and function under both physiological and pathological conditions. Mechanotransduction pathways play a critical role to mediate mechanical load-induced myocardial remodeling, whereby the morphology and function of cardiomyocytes and the extracellular matrix are altered, resulting in changes in cardiac function. Mechanical loading not only governs the function of the adult heart but is also responsible for normal morphogenesis of the cardiovascular system during prenatal development. In this review, the role of mechanical load in development, health, and disease are highlighted. First, how mechanical load governs the development of the heart from a primitive heart tube to a functional organ, its role in the maturation of the vasculature, as well as the mechanisms which control load-induced cardiac alterations in the adult heart during exercise and pregnancy are discussed. Subsequently, the mechanisms that contribute to mechanical load-induced pathologic cardiac remodeling are underlined. Mechanical overloading of the heart due to pressure or volume cause different alterations in cardiac structure and function which lead to heart failure. These differences translate to differences in disease phenotype that are reflected on pressure-volume loops. Next, the therapeutic interventions for mechanical load-induced heart failure are explored with a focus on mechanical unloading by left ventricular assist devices. Insights into the various types and function of these devices, as well as the mechanical unloading-induced mechanisms that contribute to reverse remodeling are provided. Finally, the current in vivo and in vitro models of mechanical loading and unloading are presented. These models have allowed for various discoveries in the field of cardiac mechanobiology. However, although significant advances have been made in our knowledge of the function of cardiac mechanical load, several mechanisms underlying cardiac mechanical properties, load-induced pathologic remodeling, and unloading-induced reverse remodeling remain unexplored. Thus, future advancements of in vivo and in vitro models are necessary to fill the gaps in our current understanding of myocardial mechanical properties, mechanotransduction, and reverse remodeling.