Role of the Cardiomyocyte Microenvironment in Regulating Cardiac Muscle Function in Health and Disease: Experiment and Mathematical Modeling

The efficiency and stability of cardiac muscle contraction and electrical activity in both health and disease largely depend on the complex interactions of cardiomyocytes with cells of their microenvironment. This review systematizes current experimental and theoretical data on the influence of the main types of non-muscle cells (fibroblasts, macrophages, adipocytes, and mast cells) on the electrophysiological properties of cardiomyocytes and their mechanical activity. A special focus is on different modes of influence microenvironmental cells can exert on cardiomyocytes. Experimental data show that fibroblasts and macrophages exert both direct electrotonic and mechanical effects on cardiomyocytes, as well as indirect effects through the secretion of a wide range of biologically active substances, specifically, various immune factors. In turn, intracardiac adipocytes and mast cells influence cardiomyocytes through paracrine secretion, leading to changes in their functional state. The effects of such intercellular communication can be both positive and negative (e.g., proarrhythmic, causing contractile dysfunction). Modern detailed mathematical models describing cell functions serve as a unique tool for analyzing the multifactorial cross-talk between cardiomyocytes and their microenvironmental cells, as well as its impact on cardiac electromechanics in health and disease. Here, we systematize mathematical models describing the effects of these interactions.