Title: Myofilament Cooperative Activation in Human and Porcine Myocardium

Project Team: Daniel Fitzsimons, Tuan Phan

Start Date: September 2021

Contraction and relaxation of the mammalian heart is a cooperative process involving the binding of Ca2+ and myosin cross-bridges to the thin filament. While the cooperative effects of Ca2+ and myosin cross-bridge binding to the thin filament have been well-characterized in the rodent myocardium, the relative contributions of these molecular processes remained unexamined in human and porcine myocardium. Given the nearly ten-fold difference in resting heart rates (i.e., mouse: 600 beats/min vs. human: 60-80 beats/min) and myocardial twitch kinetics between small and large mammals, it is unlikely that the relative contributions of Ca2+ and myosin cross-bridges in the cooperative activation are the same. Therefore, using contractile data collected in murine, human, and porcine hearts as a starting point, we propose a mathematical model to describe molecular mechanisms of force generation in human/porcine cardiac muscle. The purpose of this project is two-fold: (i) to ascertain the effects of nearest-neighbor molecular interactions along the thin filament on force development and relaxation in human myocardium; (ii) to determine whether thick filament proteins have a greater contribution to the cooperative response in human myocardium compared to rodents.