We developed a three-dimensional computational model for describing electro-mechanical behavior of wedge-shaped region of the LV wall that incorporates biophysically detailed, spatially heterogeneous excitation, and high-resolution geometry and fiber orientation. The cardiac tissue is simulated by an incompressible hyperplastic material. We used non-linear partial differential equations describing the deformation of the cardiac tissue, and a detailed “Ekaterinburg-Oxford” (EO) cellular model of the electrical and mechanical activity of cardiomyocytes (Sulman et al., 2008). Active mechanical contraction is initiated by transients in intracellular calcium concentration, following action potential generation in the cells and excitation wave spreading in the tissue. Electro-mechanical coupling accounts for the mechano-electric feedback in the cells and tissue. All the phases of the cardiac cycle with different conditions of the mechanical loading were simulated and studied in the electromechanical model of a myocardial wedge of the human left ventricle. Electrical and mechanical interactions between the cells in the wedge model, as well as intracellular mechano-electric feedback caused pronounced nonuniformity in the activity of normal tissue formed of inherently identical cells. In a wedge with local Ca2+ overload, the cellular mechanical interactions triggered arrhythmia. Model analysis suggested that cooperative mechanisms of myofilament calcium activation play a key role in the dynamic adjustment of electrical and mechanical activity of the interacting cardiomyocytes in the tissue.