This proposal will examine how active sarcomeres are coupled with the cytoskeletal-extracellular matrix to determine 3D myocardial mechanics during systole. In the beating heart, sarcomeres are exposed to forces not only parallel but also perpendicular to their direction. Sarcomeres are also sheared relative to one another as the ventricle twists or experiences nonuniform contraction. These 3D mechanical effects imply that substantial systolic stresses and strains are applied to the cytoskeleton and extracellular matrix during systole. The project will test 3 hypotheses: (1) Mechanical coupling between active myofibrils and the cytoskeletal-extracellular matrix causes significant stiffening of systolic myocardium against shear and transverse stretch. (2) A microstructural composite model can explain systolic-diastolic differences in myocardial 3D mechanics in terms of 2 interwoven networks (myofibrils vs the cytoskeletal-extracellular matrix), when each network is independently stiffened or made more compliant. (3) When a regional difference exists in myocardial contractility, predictions of the regional pattern of wall deformation are significantly more accurate when they incorporate the systolic increase in shearing stiffness. Studies will utilize myocardium in a state of sustained systole (barium contracture). Myocardial mechanical behavior will be evaluated multiaxially by simultaneous twist and stretch of a papillary muscle, while measuring axial torque and force, and observing twist and stretch from surface makers. Sarcomere stiffness will be varied via barium concentration. Extracellular matrix stiffness will be varied acutely by agents that remodel the microtubular network, and chronically by comparing pressure overloaded myocardium (having excess collagen) to normal and volume loaded. Regional deformation within the LV will be obtained from tagged magnetic resonance images in 3 dimensions. Predictions of deformation will be achieved via a fully 3D finite element model incorporating fiber angle distributions and asymmetric geometry.
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