Extracellular drivers of myocyte stiffening in diastolic heart disease

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Diastolic heart disease, DHD, is a leading cause of death and disability worldwide. With no FDA approved therapies to improve diastolic dysfunction, the NIH has placed special emphasis on collaborative initiatives between basic scientists and clinicians focusing on understanding the molecular mechanism of diastolic heart failure. Cardiac stiffening is a hallmark of diastolic dysfunction and occurs through mechanisms intrinsic to both cardiomyocytes and extracellular matrix, ECM. With the majority of heart failure therapies designed to target cardiomyocytes and not, the influence of pathologically remodeled ECM on cardiomyocyte and cardiac function is of particular clinical importance. In this proposal we leverage a recently developed cardiac preparation to probe the mechanical properties of the DHD ECM and determine its influence of cardiomyocyte diastolic function. Using an established model of DHD, the obese ZSF1 rat, we determine the degree to which myocardial stiffening depends on cardiomyocyte and ECM stiffening respectively and quantify the structural and compositional changes of ECM in hypertension and DHD. In Aim 2 we determine the influence of DHD ECM on cardiomyocyte structure and function. By maturing cardiac stem cells in decellularized ECM from normal, hypertensive and DHD hearts, we determine the influence of the DHD ECM on cardiomyocyte structure and function. With a custom-adapted mounting system, we will be able to measure diastolic performance of cardiac organoids grown in either normal or DHD ECM. Consistent with our preliminary data, we expect to observe that DHD ECM drives cardiomyocyte hypertrophy, enhanced contractility, and impaired relaxation. These results indicate that the DHD ECM can signal cardiomyocytes to adopt characteristics of diastolic heart disease.