Abstract 812: Mechanisms of Sinus Node Dysfunction and Chronotropic Incompetence in Rats with Heart Failure and Preserved Ejection Fraction

Introduction: Chronotropic incompetence is a common feature in patients afflicted by heart failure with preserved ejection fraction (HFpEF). However, the specific mechanisms remain unknown. Aim: To probe the mechanisms of chronotropic incompetence in HFpEF. Methods: Dahl salt-sensitive rats were fed high-salt diet (8% NaCl). Rats fed normal-salt diet (0.3% NaCl) served as controls. Echocardiography was used to confirm the development of diastolic dysfunction and preserved EF. Telemetry devices were implanted and treadmill exercise tests were performed to assess heart rate response to exercise. Sinus node recovery time (SNRT) was measured in vivo, and ex vivo optical mapping was performed in isolated sinoatrial node (SAN) tissue to measure heart rate response to isoproterenol. Results: HFpEF rats showed decreased E/A ratio (17%, p<0.05) and increased E/E’ ratio (40%, p<0.05) compared to controls, indicative of diastolic dysfunction, while EF remained unchanged in both groups. Resting mean blood pressure was elevated in HFpEF rats compared to controls (75%, p<0.05). HFpEF rats exhibited low chronotropic response to maximal exercise, in association with prolonged cSNRT (46%, p<0.05), indicative of abnormal SAN function. Despite unchanged baseline heart rate, ex vivo high-resolution optical mapping in isolated SAN tissue revealed delayed slow diastolic depolarization of spontaneous action potentials underlying the lower β-AR responsiveness, as well as slowed conduction (in association with histologically-evident increases in SA fibrosis). Next-generation RNA sequencing revealed that SAN from HFpEF rats shows numerous changes in transcripts associated with ion channels, protein kinases, and tissue remodeling. At the single SAN cell level, HFpEF rats showed decreased abundance of L-type Ca 2+ channels (Ca v 1.3, 55%) and hyperpolarization-activated "pacemaker" channels (HCN4, 67%) by western blot; such protein changes were associated with remarkable reductions of both currents. Conclusions: Chronotropic incompetence in HFpEF is due, in large measure, to intrinsic abnormalities of the SAN. Among these, a depressed membrane “clock” features prominently in the underlying mechanism.