Integrative Mathematical Model of Electrical, Metabolic and Mechanical Processes in Human Cardiomyocytes

A complex sequence of electrical and mechanical processes at different levels of the heart organization provides its pumping function. The force generation by the contractile proteins of cardiomyocytes requires energy expenditure. In addition, some ion transport mechanisms in the cell consume ATP to redistribute ions between various cell structures and transfer them to the extracellular space during the excitation-contraction of the cardiomyocyte. Intracellular mitochondria are involved in ATP synthesis. We have developed an integrative mathematical model of a human left ventricular cardiomyocyte, which describes the processes of electromechanical coupling in the cell, the process of ATP synthesis in mitochondria in the tricarboxylic acid cycle, and the utilization of ATP by the activities of various pathways. The integrative model shows that a change in the mechanical conditions of cardiomyocyte contraction in the normal state (for example, a change in its initial length or applied load) not only affects the time course of the action potential in the cell but also modulates the processes associated with the ATP production and utilization. The mechano-dependence of mitochondrial energetics is provided by a complex system of mechano-electric, mechano-calcium and mechano-metabolic direct links and feedbacks. Our simulations reveal that despite the mechano-dependent changes, the ATP level remains within the range of values characteristic of healthy myocardium.