Impact of Non-Muscle Cells on Excitation-Contraction Coupling in the Heart and the Importance of In Vitro Models.

Excitation-coupling (ECC) is paramount for coordinated contraction to maintain sufficient cardiac output. The study of ECC regulation has primarily been limited to cardiomyocytes (CMs), which conduct voltage waves via calcium fluxes from one cell to another, eliciting contraction of the atria followed by the ventricles. CMs rapidly transmit ionic flux via gap junction proteins, predominantly connexin 43. While the expression of connexin isoforms has been identified in each of the individual cell populations comprising the heart, the formation of gap junctions with nonmuscle cells (i.e., macrophages and Schwann cells) has gained new attention. Evaluating nonmuscle contributions to ECC in vivo or in situ remains difficult and necessitates the development of simple, yet biomimetic in vitro models to better understand and prevent physiological dysfunction. Standard 2D cell culture often consists of homogenous cell populations and lacks the dynamic mechanical environment of native tissue, confounding the phenotypic and proteomic makeup of these highly mechanosensitive cell populations in prolonged culture conditions. This review will highlight the recent developments and the importance of new microphysiological systems to better understand the complex regulation of ECC in cardiac tissue.