Abstract 16851: Sinus Node Dysfunction Underlies Chronotropic Incompetence in Rats With Heart Failure and Preserved Ejection Fraction

Abstract

Introduction: Chronotropic incompetence is a major limiting factor of exercise capacity in patients with heart failure and preserved ejection fraction (HFpEF) but little is known about the mechanisms. Hypothesis: We tested the hypothesis that sinus node dysfunction underlies chronotropic incompetence in rats with HFpEF. Methods: Dahl salt-sensitive rats were fed high-salt diet (8% NaCl) to induce HFpEF. Rats fed normal-salt diet (0.3% NaCl) served as controls. Echocardiography was used to confirm the development of diastolic dysfunction in high-salt-fed rats. Telemetry devices were implanted to echo-verified HFpEF rats and treadmill exercise test was performed to assess heart rate response to exercise and exercise capacity. Sinus node recovery time (SNRT) was measured in vivo and ex vivo optical mapping was performed in isolated sinus node tissues to measure heart rate response to isoproterenol. Reverse transcriptase PCR was performed in RNA samples isolated from sinus node tissues. Results: HFpEF rats showed decreased E/A ratio (1.30±0.07 vs. 1.58±0.13, p<0.05) and increased E/E’ ratio (19.17±2.63 vs. 13.78±2.58, p<0.05) compared to controls, indicative of diastolic dysfunction. Ejection fractions were normal (71±7% vs. 73±3%, p=ns) in both groups. Resting blood pressure were elevated in HFpEF rats compared to controls (209±30/120±38 vs. 151±12/88±17 mmHg, p<0.05) and serum catecholamine levels were elevated in HFpEF rats (38.4±5.6 vs. 25.6±1.5 ng/ml, p<0.05). Heart rate at peak exercise was decreased in HFpEF rats compared to controls (496±21 vs. 538±20 bpm, p<0.05) and exercise capacity was reduced in HFpEF rats (170±99 vs. 289±120 meters, p<0.05). Corrected SNRT was prolonged in HFpEF rats (86±34 vs. 58±10 ms, p<0.05), indicative of sinus node dysfunction. Ex vivo sinus node preparations showed decreased heart rate response to isoproterenol (119±12 vs. 163±27 bpm, p<0.05). Beta-1 receptors gene expression ( Adrb1 ) were not decreased in HFpEF sinus node (93% in HFpEF vs. 100% in control, p=ns) nor were L-type Ca channels gene expression ( Cacna1c ) (95% in HFpEF vs. 100% in control, p=ns). However, pacemaker channels gene expression ( Hcn4 ) showed a trend toward reduction in HFpEF sinus nodes (60% in HFpEF vs. 100% in control, p=0.1). Conclusions: Sinus node dysfunction underlies chronotropic incompetence in rats with HFpEF. Further investigation is warranted to elucidate the mechanism and design potential therapeutic strategies for this condition.