Testosterone replacement increases aged pulmonary vein and left atrium arrhythmogenesis with enhanced adrenergic activity. BACKGROUND: Aging 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. METHODS: Electrocardiography, heart rate variability, echocardiography, Western blot and conventional microelectrodes were used in aged rabbits (age, >2 years) with and without (control) testosterone treatment (10mg/kg, 12 weeks). RESULTS: Testosterone-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 th