Therapeutic activation of AMPK for the aging right heart

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PROJECT SUMMARY/ABSTRACT The overarching goal of this application is to understand sex differences right ventricular (RV) function and how these differences change across the life-course. Dr. Bruns is a current K01 awardee (K01 AG058819) with growing expertise in cardiac aging and a strong interest in how sex differences contribute to cardiac aging. In age-related left-sided heart failure as well as other clinical contexts, right ventricular (RV) dysfunction is the strongest predictor of mortality. However, despite the clear link between right heart function and survival, very little is known about RV function with age and no RV-directed therapies exist. Through ongoing work as part of the parent K01, we have identified preliminary sex differences in RV pathogenesis and in the RV response to therapeutic interventions. However, the parent award is underpowered to mechanistically understand the differences in male and female RV function and how it changes with advanced age. Therefore, the aim of this supplement is to mechanistically investigate RV sex differences using a translationally relevant pre-clinical model of RV-centric disease. We will assess myofilament-mediated mechanisms of age- and sex differences in RV function- a primary focus of the training and scientific training of the parent award. Therefore, the experiments we propose are well within the scope of the parent award. We will achieve this goal by increasing sample sizes to increase power to statistically analyze sex differences. The outcomes achieved by this supplement will advance the ORWH strategic goal of promoting rigorous research that improves fundamental understanding of how sex influences the aging RV and RV disease.