Abstract 11418: Fibrosis and Calcium Signaling Regulation Are Critical Mechanisms in a Three-Hit HFpEF Mouse Model

Abstract

Introduction: There is a lack of animal models of heart failure with preserved ejection fraction (HFpEF). Hypothesis: A mouse model with increased Ca2+ influx receiving a high-fat diet (HFD) and L-NAME (3 hits) could be a model for HFpEF to help reveal the mechanism. Methods: Cardiomyocyte (CM) specific, inducible Cavβ2a low expression transgenic (Cavβ2a LE TG) and their control littermate mice were fed with either chow diet (LC and CC), HFD+L-NAME (LHLn, CHLn), or HFD+L-NAME+SAHA (LHLnS, CHLnS) since the age of 4months for 6 months. Echocardiography had been done monthly. Hemodynamic analysis, histological analyses, and Western blotting (WB) had been used to figure out the possible mechanisms after euthanization. Results: LHL (3 hits) mice had preserved left ventricular ejection fraction (LVEF) but the highest levels of ANP/BNP and the lowest strain rate. 3-Hit led to obvious diastolic dysfunction indicated by a higher ratio of mitral E wave to mitral annulus e’ velocity (E/e’ ratio), ventricular stiffness index, end-diastolic pressure, and left atrial (LA) dilation rate (90% in LHL mice). LA and LV fibrosis were more severe in the LHL group. Fibrosis-related molecules, including lysyl oxidase, Periostin, transforming growth factor-beta and its downstream transcription factor SMAD2/3 were higher in the LHL group. LHL mice also had lower PLB phosphorylation at Thr17, less SERCA, more NCX, and increased TnI phosphorylation. SAHA treatment could significantly reverse the HFpEF phenotype. Conclusions: 3-Hit is a model for HFpEF, which can be reversed by SAHA treatment. Fibrosis and altered Ca2+ signaling are critical underlying mechanisms for HFpEF.