COBRE Pilot: Myofilament Relaxation in Heart Failure with Preserved Ejection Fraction

Abstract Heart Failure with preserved Ejection Fraction (HFpEF) develops when a patient’s heart cannot fill properly between beats. The condition is associated with diastolic dysfunction and impaired relaxation. Better therapies for HFpEF have been described as America’s most pressing clinical need. HFpEF is difficult to study in animals. Several murine and pig models have been developed but none fully replicates the human disease. Human samples have been difficult to obtain because patients with HFpEF rarely undergo cardiac surgery. Last year, the University of Kentucky Division of Cardiovascular Medicine started a specialist clinic for cardiac amyloidosis. Some of the patients undergo endocardial biopsy as part of their clinical workup. If the biopsies test negative for amyloid, the patients’ symptoms are attributed to HFpEF. Additional ‘add-on’ samples were collected for research during these clinical procedures. The first step in this pilot project is to isolate myofibrils (~20 sarcomeres in series) from these biopsies and test whether myofilament-level relaxation is slower in human HFpEF. Myofibrils isolated from the same regions of hearts from organ donors without cardiac disease will serve as “controls”. These experiments will be performed using highly specialized apparatus that has just been installed in PI Campbell’s laboratory. Sub-group analyses will determine the impact of risk factors including female sex, diabetes, and obesity, and the influence of prior treatment with SGLT2 inhibitors. State of the art computer models at sarcomere and cell to organ-level scales will then be deployed to help interpret the data and identify contractile mechanisms that are modulated in HFpEF. Further modeling will predict novel therapeutic targets by determining interventions that reduce cardiac filling pressures without compromising cardiac output. The data from this pilot project will support new R01 applications. Aim1: Test the hypothesis that HFpEF slows myofilament relaxation in humans. Aim2: Deploy computer modeling at molecular to system-level scales to predict therapies that improve cardiac function in HFpEF.