Carol Act Supplement to Data-driven Optimization of Therapy for Heart Failure

ABSTRACT This proposal is submitted in response to NOT-HL-23-078 “Administrative supplements to encourage research in valvular heart disease” and seeks 12 months of additional support for HL163977, Data-driven optimization of therapy for heart failure. The parent R01 is active until 2026. The overarching goal of HL163977 is to develop a computer model of the heart that can be used to test therapeutic strategies and optimize treatments for patients who have heart failure. Aim 1 develops a system called MyoVent as a test-bed for implementing baroreflex control and myocardial growth. Aims 2 and 3 use the techniques developed with MyoVent and deploy them in a more sophisticated 3D framework called MyoFE to create patient-specific personalized models. The team has made rapid progress and Aim 1 is now mostly complete. The breakthrough was accomplished by developing algorithms that modulate concentric (wall thickening / thinning) and eccentric (chamber dilation / constriction) growth in response to physiologic signals. Specifically, the model assumes that hearts grow concentrically to stabilize the intracellular ATP concentration while eccentric growth is sensitive to the passive intracellular stress sensed by titin filaments. These growth laws reproduce the patterns of cardiac growth observed in clinically-relevant conditions including hypertension, exercise, and destabilization of the myosin super-relaxed state. This supplement will extend the simulations to valvular heart disease. The objective is focused. The team will test whether the growth laws predict the patterns of eccentric and concentric growth observed clinically in patients with mitral valve insufficiency (prolapse) and stenosis, and aortic valve insufficiency and stenosis. This can be accomplished in a single year by a highly-qualified and experienced post-doc.