Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death

Abstract

The purpose of this article is to review the nerve sprouting hypothesis of sudden cardiac death. It is known that sympathetic stimulation is important in the generation of sudden cardiac death. For example, there is a diurnal variation of sudden death rate in patients with myocardial infarction. Beta blockers, or drugs with beta blocking effects, are known to prevent sudden cardiac death. It was unclear if the cardiac nerves in the heart play only a passive role in the mechanisms of sudden death. To determine if nerve sprouting and neural remodeling occur after myocardial infarction, we performed immunocytochemical studies of cardiac nerves in explanted native hearts of transplant recipients. We found that there was a positive correlation between nerve density and a clinical history of ventricular arrhythmia. Encouraged by these results, we performed a study in dogs to determine whether or not nerve growth factor (NGF) infusion to the left stellate ganglion can facilitate the development of ventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death (SCD). The results showed that augmented myocardial sympathetic nerve sprouting through NGF infusion plus atrioventricular (AV) block and MI result in a 44% incidence (four of nine dogs) of SCD and a high incidence of VT in the chronic phase of MI. In contrast, none of the six dogs (with AV block and MI) without NGF infusion died suddenly or had frequent VT episodes. Based on these findings, we propose the nerve sprouting hypothesis of ventricular arrhythmia and SCD. The hypothesis states that MI results in nerve injury, followed by sympathetic nerve sprouting and regional (heterogeneous) myocardial hyperinnervation. The coupling between augmented sympathetic nerve sprouting with electrically remodeled myocardium results in VT, VF and SCD. Modification of nerve sprouting after MI may provide a novel opportunity for arrhythmia control.

Age-related regional differences in cardiac nerve growth factor expression

“…NGF plays a pivotal role in sympathetic nerve sprouting and sudden cardiac death (Chen et al 2001). An early rise of NGF can be observed rapidly after myocardial infarction (hours) and may possibly reflect an early rescue response to support myocardial healing (Meloni et al 2010).…”

Genomics, heart failure and sudden cardiac death

“…Considerable amount of basic and clinical data attests to the critical role of the autonomic nervous system in SCD mechanisms [15][16][17]. One potential trigger for fatal arrhythmias in patients with ischemic heart disease or HF may come from an imbalance of the parasympathetic and sympathetic nervous systems, the latter being mediated by Cardiac β 1 -and β 2 -adrenergic receptors.…”

Expression and function of integrin α4β1 and vascular cell adhesion molecule‐1 (VCAM‐1) during sympathetic innervation of the heart

“…Perhaps ␣4 is used for maintaining the axon terminals within the myocardium, or it may function in regeneration. The adult sympathetic nervous system retains the ability to reinnervate areas after injury, and sprout into new areas of cardiac tissue (Cao et al, 2000;Chen et al, 2001;Zhou et al, 2001). These sprouting events have been linked to pathological conditions where scar tissue supports hyperinnervation of sympathetic nerves.…”

“…Hyperinnervation of small regions of the heart can lead to an abnormal amount of NE influence over the myocardium in the small region. This regional hyperinnervation can cause a small portion of the heart to beat faster and stronger than the surrounding myocardium, leading to fatal arrhythmias and sudden cardiac failure (Cao et al, 2000;Chen et al, 2001;Zhou et al, 2001).…”

“…␣4 may also play a role in the maintenance of the adult sympathetic nervous system. This possibility makes the ␣4 integrin a possible candidate for drug development aimed at fighting heart disease by blocking sympathetic sprouting after a myocardial infarction (Cao et al, 2000;Chen et al, 2001;Zhou et al, 2001). …”