Reverse electrical remodeling in rats with heart failure and preserved ejection fraction

Abstract

Sudden death is the most common mode of exodus in patients with heart failure and preservedejection fraction (HFpEF). Cardiosphere-derived cells (CDCs) reduce inflammation and fbrosis in arat model of HFpEF, improving diastolic function and prolonging survival. We tested the hypothesisthat CDCs decrease ventricular arrhythmias (VAs) and thereby possibly contribute to prolongedsurvival. Dahl salt-sensitive rats were fed a high-salt diet to induce HFpEF. Allogeneic rat CDCs (orphosphate-buffered saline as placebo) were injected in rats with echo-verifed HFpEF. CDC-injectedHFpEF rats were less prone to VA induction by programmed electrical stimulation. Action potentialduration (APD) was shortened, and APD homogeneity was increased by CDC injection. Transientoutward potassium current density was upregulated in cardiomyocytes from CDC rats relativeto placebo, as were the underlying transcript (Kcnd3) and protein (Kv4.3) levels. Fibrosis wasattenuated in CDC-treated hearts, and survival was increased. Sudden death risk also trended down,albeit nonsignifcantly. CDC therapy decreased VA in HFpEF rats by shortening APD, improving APDhomogeneity, and decreasing fbrosis. Unlike other stem/progenitor cells, which often exacerbatearrhythmias, CDCs reverse electrical remodeling and suppress arrhythmogenesis in HFpEF.