Abstract 16222: Abnormal Repolarization and Increased Susceptibility to Ventricular Arrhythmias in a Rat Model of Heart Failure With Preserved Ejection Fraction
Introduction: Unlike heart failure (HF) with reduced ejection fraction, where numerous pharmacological and device options are available, no treatments have been proven to be effective in heart failure with preserved ejection fraction (HFpEF). Sudden death is the leading cause of mortality in HFpEF, but arrhythmia mechanisms have not been investigated.
Methods: To induce HFpEF, Dahl salt-sensitive rats (n=38) were fed high-salt diet (8% NaCl) from 7 weeks of age. Rats fed a normal-salt diet (0.3% NaCl; n=13) served as controls. At 14 weeks of age, we performed echocardiography to assess systolic and diastolic function and programmed electrical stimulation (PES) to assess ventricular tachycardia (VT) or ventricular fibrillation (VF) inducibility. We recorded action potentials (AP) using whole-cell patch clamp. We checked the expression of transient outward potassium current (Ito) genes (Kcnd2 and Kcnd3) using reverse transcription PCR.
Results: At 14 weeks of age (7 weeks of diet), high-salt rats showed decreased E/A ratio (1.25±0.24 vs. 1.56±0.13, p<0.001) and increased E/E’ ratio (16.60±2.97 vs. 13.53±1.87, p=0.001) compared to normal-salt rats, indicative of diastolic dysfunction, but ejection fraction (EF) was equal (~67%) in the two groups. PES demonstrated increased susceptibility to VT/VF in HFpEF compared to control rats (84.2% vs. 23.1%, p<0.001). Single-cell recordings revealed prolonged AP duration in HFpEF rats (APD90 152±17 ms, n=5 cells) compared to controls (90±13 ms, n=14 cells, p<0.02), indicating abnormal repolarization. Reverse transcription PCR confirmed the decreased expression of Kcnd2 (55±12% reduction, p=0.021, n=4 each group) and Kcnd3 (40±13% reduction, p=0.021, n=4 each group) in HFpEF rats compared to control rats, consistent with patch clamp recordings showing reduced Ito density (p=0.036) in high-salt myocytes.
Conclusions: This rat model of HFpEF shows increased susceptibility to ventricular arrhythmias; cardiomyocytes from HFpEF rats have delayed repolarization, with underlying down-regulation of Ito genes. The findings provide novel insights into the mechanisms of sudden cardiac death and arrhythmias in HFpEF, revealing abnormal repolarization as a likely contributory mechanism.
Author Disclosures: J. Cho: None. R. Zhang: None. R. Gallet: None. G. de Couto: None. E. Marbán: Ownership Interest; Significant; Capricor Inc. Consultant/Advisory Board; Significant; Capricor Inc. J. Goldhaber: None. E. Cingolani: None.
- © 2016 by American Heart Association, Inc.