Background - This study tested the hypothesis that the high incidence of ventricular arrhythmias caused by hypothalamic stimulation during acute myocardial ischemia could be attenuated by afferent nerve stimulation and investigated the cardiac mechanisms for those effects. Methods and Results - In 18 anesthetized dogs, stimulating electrodes were implanted in the hypothalamus and in the isolated left peroneal nerve. The chest was opened and approximately 100 plunge needles were inserted into the ventricles for 3- D activation mapping. Each animal underwent 4 episodes of 2.5 minutes of acute myocardial ischemia. The first and fourth episodes served as controls. During the second and third episodes, animals received either hypothalamic stimulation, peroneal nerve stimulation, or both. Hypothalamic stimulation significantly increased the incidence of ventricular arrhythmias. This high incidence was reduced 34% by simultaneous stimulation of the hypothalamus and peroneal nerve. 3-D mapping showed a focal origin for all ventricular arrhythmias. Hypothalamic stimulation increased the number of arrhythmic beats and decreased the coupling interval between each arrhythmic beat and the preceding beat. These effects were reduced by peroneal nerve stimulation. Conclusions - Alteration in autonomic tone by hypothalamic stimulation causes a high incidence of ventricular arrhythmias during acute myocardial ischemia that can be decreased by afferent nerve stimulation.