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The heart is under constant regulation to maintain cardiac output to meet different needs of tissue perfusion under different conditions. Acutely, the regulation is mediated by the sympathetic/ β-adrenergic system (SAS) and the vagal/parasympathetic system. The SAS system is activated to exert positive chronotropic, inotropic, and lusitropic effects on the heart when a greater need of cardiac output is imposed. Chronic activation of SAS contributes to the development of cardiac dysfunction and arrhythmias. Although the roles of the SAS system in cardiac physiology and pathophysiology have been studied for decades, many questions remain and new discoveries have been made during the past decade.