INCREASED VULNERABILITY OF FAILING HEARTS TO SYMPATHETIC STIMULATION INDUCED ATRIAL FIBRILLATION: THE ROLE OF RYANODINE RECEPTOR DYSFUNCTION
Youhua Zhang, M.D., Ph.D.,
New York Institute of Technology College of Osteopathic Medicine,
Old Westbury, NY, USA
Autonomic nervous system plays a critical role in atrial fibrillation (AF) arrhythmogenesis. Current experimental data regarding autonomic stimulation in AF are mainly derived from normal animals, indicating that vagal nerve stimulation (VS) is more arrhythmogenic than sympathetic stimulation (SS) in AF arrhythmogenesis. Heart failure (HF) results in sympathetic activation and vagal withdrawal, and is associated with an increased AF incidence. In this study, we specifically investigated whether failing hearts, compared to normal controls, respond differently to autonomic stimulation in AF arrhythmogenesis. By using a rat myocardial infarction (MI)-HF model, HF was induced in 9 rats 2 months after MI surgery. Sham-operated animals (n=10) served as controls. AF inducibility was augmented in both groups by autonomic stimulation. However, the increased magnitude was less in the MI-HF group (49±31% in MI-HF versus 80±33% in control, P=0.029) under VS, but was significantly more in MI-HF hearts under SS (53±24% versus 6±21%, P<0.001), compared with sham-controls. In light of the presence of ryanodine receptor dysfunction in HF, we further investigated whether stabilizing ryanodine receptors with dantrolene can decrease SS enhanced AF inducibility in HF. This part was done in 17 MI-HF animals, randomized into 2 groups: control (vehicle treated, n=9) and dantrolene (10mg/kg, IP, n=8) groups. AF inducibility under SS were studied in all animals 30-min after the respective treatments. Compared with controls, dantrolene treatment significantly reduced AF inducibility and AF duration under SS. Thus, in contrast to normal controls, failing hearts are less sensitive to VS, but more vulnerable to SS induced AF. Dantrolene treatment, by stabilizing ryanodine receptor, can significantly attenuate SS enhanced AF inducibility in HF, indicating that ryanodine receptor dysfunction may play a critical role in enhancing AF in HF under SS, and stabilizing ryanodine receptor may be a new treatment option in reducing AF in HF.