Constantino J, Hu Y, Lardo AC, Trayanova NA. Mechanistic insight into prolonged electromechanical delay in dyssynchronous heart failure: a computational study. Am J Physiol Heart Circ Physiol 305: H1265-H1273, 2013. First published August 9, 2013 doi:10.1152/ajpheart.00426.2013.-In addition to the left bundle branch block type of electrical activation, there are further remodeling aspects associated with dyssynchronous heart failure (HF) that affect the electromechanical behavior of the heart. Among the most important are altered ventricular structure (both geometry and fiber/sheet orientation), abnormal Ca 2ϩ handling, slowed conduction, and reduced wall stiffness. In dyssynchronous HF, the electromechanical delay (EMD), the time interval between local myocyte depolarization and myofiber shortening onset, is prolonged. However, the contributions of the four major HF remodeling aspects in extending EMD in the dyssynchronous failing heart remain unknown. The goal of this study was to determine the individual and combined contributions of HF-induced remodeling aspects to EMD prolongation. We used MRI-based models of dyssynchronous nonfailing and HF canine electromechanics and constructed additional models in which varying combinations of the four remodeling aspects were represented. A left bundle branch block electrical activation sequence was simulated in all models. The simulation results revealed that deranged Ca 2ϩ handling is the primary culprit in extending EMD in dyssynchronous HF, with the other aspects of remodeling contributing insignificantly. Mechanistically, we found that abnormal Ca 2ϩ handling in dyssynchronous HF slows myofiber shortening velocity at the early-activated septum and depresses both myofiber shortening and stretch rate at the late-activated lateral wall. These changes in myofiber dynamics delay the onset of myofiber shortening, thus giving rise to prolonged EMD in dyssynchronous HF. cardiac electromechanics; electromechanical modeling; dyssynchronous heart failure HEART FAILURE (HF) is a major cause of morbidity and mortality, contributing significantly to healthcare expenditures. A subset of HF patients exhibit contractile dyssynchrony due to electrical intraventricular delay of the left bundle branch block (LBBB) type. In addition to this altered electrical activation pattern, other detrimental remodeling aspects of HF also contribute to electromechanical dysfunction of the heart and to the dyssynchrony between its electrical and mechanical behavior. Among these are remodeled ventricular structure and fiber/ sheet architecture (14), slowed electrical conduction (2), deranged Ca 2ϩ handling (40), and reduced stiffness of the failing myocardium (18).The electromechanical delay (EMD), the time interval between the local myocyte depolarization and the onset of myofiber shortening, and its three-dimensional (3-D) distribution are manifestations of the intricate relationship between the electrical and mechanical activity of the heart. Computational (12) and experimental (3, 27, 35) studie...