Mechanisms of Diastolic Relaxation in Normal and Diseased Hearts

his study is based on an innovative fundamental finding: that myocardial strain rate of muscle relengthening at the end of systole controls diastolic pressure relaxation rate. That finding may explain why current treatments for diastolic dysfunction, which focus on systemic factors, such as hypertension and aldosterone, have failed. This study will use techniques that measure the molecular content of muscle, along with strain rate and force from the level of a single cardiomyocyte to the in vivo heart. Ex vivo intact muscle preparations (trabeculae and cardiomyocytes) will be attached to length motors and force transducers. As they relengthen at the end of systole, the muscle’s strain rate will be monitored. The relationship between the muscle strain rate and relaxation will be determined. In vivo, the pressure in the ventricle will be monitored while the muscle strain rate will be measured using the state of the art Displacement ENcoded Stimulated Echo (DENSE) MRI method. These experimental methods will be used to examine potential molecular mechanisms that can alter strain rate and the subsequent diastolic relaxation. This research proposal integrates molecular mechanism to functional measurements of muscle and the in vivo ventricle. The aims will provide insight into the regulation of diastolic relaxation. Thus the specific aims of this study are to: 1) determine the role of intracellular passive stiffness by examining hearts with different titin isoform sizes, 2) determine the role of extracellular passive stiffness by examining hearts with increased collagen expression, and 3) determine the role of crossbridge regulation by examining hearts with altered troponin-T function. All three aims will test the hypothesis that changes in these proteins lead to a slowing in diastolic relaxation. This project provides a unique and clear path for the Principal Investigator to attain an independent research career that will both determine molecular mechanisms underlying diastolic relaxation and provide novel targets to treat and improve the health of patients.