Testosterone replacement increases aged pulmonary vein and left atrium arrhythmogenesis with enhanced adrenergic activity

•We studied the electrophysiological effects of testosterone in aging rabbits.•Testosterone-treated aged rabbits had higher sympathetic index.•Testosterone-treated aged rabbits had poor cardiac function.•Isoproterenol induced more arrhythmogenesis in testosterone-treated PVs and LAs.•Testosterone induced atrial arrhythmias by adrenergic and mechanical dysregulation.

BackgroundAging and testosterone deficiency contribute to the pathogenesis of atrial fibrillation (AF). We determine the effects of testosterone replacement on the electrophysiology and arrhythmogenesis of pulmonary vein (PV) and left atrium (LA) in aged rabbits.MethodsElectrocardiography, heart rate variability, echocardiography, Western blot and conventional microelectrodes were used in aged rabbits (age, > 2 years) with and without (control) testosterone treatment (10 mg/kg, 12 weeks).ResultsTestosterone-treated aged rabbits had longer corrected QT interval, higher low frequency/high frequency, greater left ventricle (LV) mass but lower LA total emptying fraction and LV ejection fraction than control rabbits. In tissue preparations, the spontaneous rate was faster for testosterone-treated PVs than for control PVs. Angiotensin II concentration-dependently increased the amplitude of delayed afterdepolarizations (DADs) in testosterone-treated PVs but only did so at the highest angiotensin II concentration (100 nM) in control PVs. Isoproterenol increased the incidence of early afterdepolarizations (EADs) and DADs in testosterone-treated PVs but not in control PVs. Testosterone-treated PVs had more H2O2-induced burst firing and EADs than control PVs. Testosterone-treated LAs had more isoproterenol-induced DADs and spontaneous activity than did control LAs. However, acetylcholine infusion and rapid atrial pacing (10-20 Hz) induced AF in control LAs but not in testosterone-treated LAs. In addition, as compared with control LAs, testosterone-treated LAs expressed more androgen receptor, β1-adrenergic receptor, and Cav 1.2 and less G protein-coupled receptor kinase-2 and Kv 4.2.ConclusionsTestosterone replacement increased arrhythmogenesis in PV and LA by enhancing adrenergic activity in aged rabbits.