739 Heart Failure Compendium © 2013 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.113.300308 Abstract: Heart failure (HF), the leading cause of death in the western world, develops when a cardiac injury or insult impairs the ability of the heart to pump blood and maintain tissue perfusion. It is characterized by a complex interplay of several neurohormonal mechanisms that become activated in the syndrome to try and sustain cardiac output in the face of decompensating function. Perhaps the most prominent among these neurohormonal mechanisms is the adrenergic (or sympathetic) nervous system (ANS), whose activity and outflow are enormously elevated in HF. Acutely, and if the heart works properly, this activation of the ANS will promptly restore cardiac function. However, if the cardiac insult persists over time, chances are the ANS will not be able to maintain cardiac function, the heart will progress into a state of chronic decompensated HF, and the hyperactive ANS will continue to push the heart to work at a level much higher than the cardiac muscle can handle. From that point on, ANS hyperactivity becomes a major problem in HF, conferring significant toxicity to the failing heart and markedly increasing its morbidity and mortality. The present review discusses the role of the ANS in cardiac physiology and in HF pathophysiology, the mechanisms of regulation of ANS activity and how they go awry in chronic HF, methods of measuring ANS activity in HF, the molecular alterations in heart physiology that occur in HF, along with their pharmacological and therapeutic implications, and, finally, drugs and other therapeutic modalities used in HF treatment that target or affect the ANS and its effects on the failing heart. (Circ Res. 2013;113:739-753.) Key Words: β-blockers ■ adrenal glands ■ adrenergic nervous system ■ cardiac sympathetic nerve terminals ■ catecholamine ■ heart failure ■ hyperactivation ■ myocytes, cardiac ■ receptors, adrenergic ■ synaptic transmission Adrenergic Nervous System in Heart Failure Pathophysiology and Therapy Anastasios Lymperopoulos, Giuseppe Rengo, Walter J. Koch Circulation Research Compendium on Heart Failure Research Advances in Heart Failure: A Compendium Epidemiology of Heart Failure Genetic Cardiomyopathies Causing Heart Failure Non-coding RNAs in Cardiac Remodeling and Heart Failure Mechanisms of Altered Ca 2+ Handling in Heart Failure Cardiac Metabolism in Heart Failure: Implications Beyond ATP Production Integrating the Myocardial Matrix Into Heart Failure Recognition and Management Adrenergic Nervous System in Heart Failure: Pathophysiology and Therapy Emerging Paradigms in Cardiomyopathies Associated With Cancer Therapies Electromechanical Dyssynchrony and Resynchronization of the Failing Heart Molecular Changes After Left Ventricular Assist Device Support for Heart Failure Heart Failure Gene Therapy: The Path to Clinical Practice Cell Therapy for Heart Failure: A Comprehensive Overview of Experimental and Clinical Studies, Current Challenges, and Future Directions Eugene Braunwald, Editor Original received January 30, 2013; revision received March 27, 2013; accepted March 28, 2013. From the Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Ft. Lauderdale, FL (A.L.); Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy (G.R.); Division of Cardiology, Fondazione Salvatore Maugeri, Telese Terme, Italy (G.R.); and Center for Translational Medicine, Temple University, Philadelphia, PA (W.J.K.). Correspondence to Anastasios Lymperopoulos, PhD, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, 3200 S. University Dr, HPD (Terry) Bldg/Room 1338, Fort Lauderdale, FL 33328-2018 (e-mail al806@nova.edu); or Walter J. Koch, PhD, Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, 3500 North Broad St, MERB Room 941, Philadelphia, PA 19140 (e-mail Walter.Koch@Temple.edu).