Adrenergic nervous system in heart failure: pathophysiology and therapy

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.

Keywords: adrenal glands; adrenergic nervous system; cardiac sympathetic nerve terminals; catecholamine; heart failure; hyperactivation; myocytes, cardiac; receptors, adrenergic; synaptic transmission; β-blockers.

Figure 1. Overview of the ANS innervation of the cardiovascular system

Note that, in contrast to the ANS which innervates both atria and ventricles of the heart, the cholinergic (parasympathetic) nervous system mainly innervates cardiac atria only. See text for more details. CSAR: Cardiac Sympathetic Afferent Reflex. (Illustration Credit: Ben Smith).

Figure 2. ANS input to the heart and its regulation

See text for details. G_i/o: inhibitory or other G protein; G_s: stimulatory G protein; ACh: Acetylcholine; NET: NE transporter; Aldo: Aldosterone; MR: Mineralocorticoid Receptor. (Illustration Credit: Ben Smith).

Figure 3. Signal transduction of cardiac myocyte contraction and its regulation by cardiac ARs

See text for details. LTCC: L-type Calcium Channel; NKA: Na⁺, K⁺-ATPase; PLM: Phospholemman; PLB: Phospholamban; SERCA: Sarcoplasmic/Endoplasmic Reticulum Ca²⁺-ATPase; RyR: Ryanodine Receptor; IP₃R: IP₃ Receptor; PKC: Protein Kinase C; TRPV: Transient Receptor Potential Vanilloid. (Illustration Credit: Ben Smith).