Abstract P2035: Rad Reduction Improves Heart Failure

Abstract

Background: Heart failure with reduced ejection fraction (HFrEF) entails depressed systolic function. Targeting calcium handling provides a direct, restorative treatment for the loss of systolic function. We recently showed that induced, cardiomyocyte-restricted Rad knockout mice (cRadKO) show increased trigger Ca 2+ with improved contractility and no signs of pathological remodeling. Hypothesis: In the present study we tested the hypothesis that cRadKO provides inotropic support to hearts subjected to chronic pressure overload. Results: We first show that Rad-reduction in human myocardial slices provides an inotropic boost. We then performed transverse aortic constriction (TAC) in mice. cRadKO imposed either before TAC or 1-month after TAC promoted survival and attenuated cardiac remodeling. cRadKO induced after TAC reflects an interventional proof-of-principle that Rad reduction can attenuate heart failure progression. The intervention timeline group was further probed using bulk RNA sequencing. cRadKO attenuated key fetal gene program transcripts including NPPA, NPPB, and MYH7. RCAN1 levels were decreased with cRadKO consistent with reduced calcineurin-NFAT signaling, and BIN1 levels were restored in cRadKO, suggesting improved cardiac remodeling despite ongoing pressure overload. Conclusions: The prevention (cRadKO before TAC) and intervention (cRadKO after TAC) studies demonstrate that reduced Rad levels can provide an inotropic boost in HFrEF and stimulate transcriptional effects consistent with reparative remodeling.