matical models of cardiac mechanics can potentially be used to relate abnormal cardiac deformation, as measured noninvasively by ultrasound strain rate imaging or magnetic resonance tagging (MRT), to the underlying pathology. However, with current models, the correct prediction of wall shear strain has proven to be difficult, even for the normal healthy heart. Discrepancies between simulated and measured strains have been attributed to 1) inadequate modeling of passive tissue behavior, 2) neglecting active stress development perpendicular to the myofiber direction, or 3) neglecting crossover of myofibers in between subendocardial and subepicardial layers. In this study, we used a finite-element model of left ventricular (LV) mechanics to investigate the sensitivity of midwall circumferential-radial shear strain (Ecr) to settings of parameters determining passive shear stiffness, cross-fiber active stress development, and transmural crossover of myofibers. Simulated time courses of midwall LV Ecr were compared with time courses obtained in three healthy volunteers using MRT. Ecr as measured in the volunteers during the cardiac cycle was characterized by an amplitude of ϳ0.1. In the simulations, a realistic amplitude of the Ecr signal could be obtained by tuning either of the three model components mentioned above. However, a realistic time course of Ecr, with virtually no change of Ecr during isovolumic contraction and a correct base-to-apex gradient of Ecr during ejection, could only be obtained by including transmural crossover of myofibers. Thus, accounting for this crossover seems to be essential for a realistic model of LV wall mechanics. magnetic resonance tagging; finite-element model; cardiac mechanics; myofiber angle DEFORMATION OF THE CARDIAC WALL can be assessed noninvasively using ultrasound strain rate imaging (11) or magnetic resonance tagging (MRT) (4). The deformation patterns acquired may deviate from normal in the case of cardiac pathology, e.g., aortic stenosis, ischemia, or conduction disorders (39,40,43). The analysis of abnormal deformation patterns toward the underlying pathology is not straightforward: the relation between the change in the deformation pattern and the pathology is complex, and the criteria for normal and abnormal strain patterns have not yet been defined. A mathematical model capable of predicting the forward relation between pathology and deformation could, if used in an inverse analysis, be a useful clinical tool, not only in diagnosis but also in intervention selection and planning, by simulating candidate interventions beforehand.Several models describing the deformation of cardiac walls have been proposed (5,6,14,19,20,28,35,41,42,45), but none of these models have already been used as a diagnostic tool. As a first step toward this application, one would require the models to be able to correctly predict deformation in the wall of the healthy heart. Most models are able to correctly predict circumferential, longitudinal, and radial strain (5,14,28,41,42,45). However, ...