Beta-blockers are the only antiarrhythmic drug proven to improve mortality post myocardial infarction and in chronic congestive heart failure where sympathetic drive to the heart is high. We have previously demonstrated that high-level sympathetic stimulation causes the release of additional sympathetic neurotransmitters in addition to norepinephrine, such as neuropeptide-y and galanin (1) (2). In this presentation I will present preliminary data suggesting that even in the presence of beta-blockers, the release of additional sympathetic co-transmitters, can have deleterious consequences for cardiac function.In the isolated Langendorf perused rat heart with intact innervation from both stellate ganglia, the susceptibility of the heart to ventricular fibrillation is increased following direct stimulation of either the right or left stellate ganglia, even in the presence of high dose beta-blockade. However, combining beta-blockade with an antagonist of the neuropeptide-Y Y1 receptor can abolish the antiarrhythmic effect of sympathetic stimulation. Exogenous neuropeptide-Y also directly lowers ventricular fibrillation threshold and steepens the action potential restitution curve measured using optical mapping techniques.Exogenous neuropeptide Y also acts as a potent vasoconstrictor increasing coronary vascular resistance in a Y1 receptor dependent manor in the Langendorf rat heart. Immunohistochemical staining of human coronary arterioles obtained from appendage samples in patients undergoing coronary artery by-pass, demonstrates dense Y1 receptor staining in vascular smooth muscle cells in the media of these vessels. We have also recently demonstrated a strong correlation between plasma neuropeptide-Y levels and coronary microvascular function in patients with ST-elevation myocardial infarctions being treated by primary percutaneous coronary intervention (3). Targeting neuropeptide-Y receptors pharmacologically may therefore be a useful therapeutic strategy both acutely during myocardial infarction to improve microvascular function and prevent coronary “no reflow” after stenting and also during chronic heart failure as an antiarrhythmic agent. Such medications would be expected to act synergistically with beta-blockers, ACE inhibitors, and implantable cardiac devices such as defibrillators and vagus nerve stimulators.