Integrative Systems Models of Cardiac Excitation–Contraction Coupling Alternans and Arrhythmias: From Cells to the Heart Computational Models Reduce Complexity and Accelerate Insight Into Cardiac Signaling Networks Whole Heart Modeling: Applications to Cardiac Electrophysiology and Electromechanics

Excitation–contraction coupling in the cardiac myocyte is mediated by a number of highly integrated mechanisms of intracellular Ca transport. The complexity and integrative nature of heart cell electrophysiology and Ca cycling has led to an evolution of computational models that have played a crucial role in shaping our understanding of heart function. An important emerging theme in systems biology is that the detailed nature of local signaling events, such as those that occur in the cardiac dyad, have important consequences at higher biological scales. Multiscale modeling techniques have revealed many mechanistic links between microscale events, such as Ca binding to a channel protein, and macroscale phenomena, such as excitation–contraction coupling gain. Here, we review experimentally based multiscale computational models of excitation–contraction coupling and the insights that have been gained through their application. (Circ Res. 2011;108:70-84.)