Molecular Mechanisms of Sympathetic Remodeling and Arrhythmias

A variety of pathological conditions can increase risk for development of ventricular arrhythmias in humans including diabetes mellitus, obesity, myocardial infarction (MI), and heart failure. Many of these diseases involve global disruption of the autonomic nervous system, including increased sympathetic drive and parasympathetic withdrawal, but another common factor among these disorders is sympathetic dysfunction within the heart. Treatments that target cardiac sympathetic transmission, including β-blockers and ganglionectomy, prolong life and decrease arrhythmias.1–5 Sympathetic control of the heart under normal conditions occurs primarily via norepinephrine acting on β adrenergic receptors (β-AR) to stimulate increases in heart rate (chronotropy), conduction velocity (dromotropy), and contractility (inotropy). These positive effects of sympathetic stimulation allow myocytes to meet increased cardiac demands during stress or exercise, serving to maintain homeostasis. The nervous system adapts to changing conditions, however, and sympathetic neurons undergo structural and functional alterations in response to injury and disease. There are at least 4 types of sympathetic remodeling that occur during conditions of increased arrhythmia susceptibility: hyperinnervation (increased nerve density), denervation (decreased nerve density), altered neurotransmitter or neuropeptide production and increased neuronal excitability. Rubart and Zipes6 proposed a model to explain how these diverse changes in sympathetic transmission might contribute to arrhythmia generation, suggesting that inappropriate heterogeneity of norepinephrine release within the heart leads to differential electric remodeling of cardiac myocytes and predisposes the heart to electric instability. Many studies now support the hypothesis that heterogeneity of noradrenergic transmission increases the risk of arrhythmia and have identified some of the mechanisms that underlie neuronal remodeling. This review will examine the mechanisms of sympathetic remodeling and will connect neural changes to increased arrhythmia susceptibility. We will focus on ventricular arrhythmias because atrial arrhythmias were reviewed recently.7 Regional hyperinnervation was the first type of neural remodeling linked to arrhythmia generation …