Cardiac innervation and sudden cardiac death

Abstract

The heart is extensively innervated and its performance is tightly controlled by the nervous system. Cardiac innervation density varies in diseased hearts leading to unbalanced neural activation and lethal arrhythmia. Diabetic sensory neuropathy causes silent myocardial ischemia, characterized by loss of pain perception during myocardial ischemia, which is a major cause of sudden cardiac death in diabetes mellitus (DM). Despite its clinical importance, the mechanisms underlying the control and regulation of cardiac innervation remain poorly understood.We found that cardiac innervation is determined by the balance between neural chemoattractants and chemorepellents within the heart. Nerve growth factor (NGF), a potent chemoattractant, is induced by endothelin-1 upregulation during development and is highly expressed in cardiomyocytes. By comparison, Sema3a, a neural chemorepellent, is highly expressed in the subendocardium of early stage embryos, and is suppressed during development. The balance of expression between NGF and Seme3a leads to epicardial-to-endocardial transmural sympathetic innervation patterning. We also found that downregulation of cardiac NGF leads to diabetic neuropathy, and that NGF supplementation rescues silent myocardial ischemia in DM. Cardiac innervation patterning is disrupted in Sema3a-deficient and Sema3a-overexpressing mice, leading to sudden death or lethal arrhythmias. The present review focuses on the regulatory mechanisms underlying cardiac innervation and the critical role of these processes in cardiac performance.

Keywords: Cardiac nerve; Sema3a; arrhythmia; nerve growth factor; silent myocardial ischemia; sudden cardiac death..

Fig. (1). NGF gene transfer restores impaired sensory innervation in diabetic hearts.

Recording of impulse activity from cardiac sympathetic afferent nerves. Myocardial ischemia was induced at the time point indicated by arrows. Note that the response of cardiac afferent nerves was reduced in DM injected with p-con (control). The gene transfer of 50 μg p-NGF preserved cardiac sensory nerve function in DM.

Fig. (2). Cardiac-specific overexpression of NGF overcomes the defects of cardiac sympathetic nervous system in Edn1^-/- mice.

Immunostaining for TH in the hearts of Edn1^+/+, Edn1^-/- and Edn1^-/-/MHC-NGF mice. The reduced sympathetic innervation in Edn1^-/- hearts is rescued in Edn1^-/-/MHC-NGF hearts. Scale bar, 100 µm.

Fig. (3). Inverse expression pattern of Sema3a and sympathetic innervation in mouse hearts.

Double staining with TH (brown) and X-gal (blue) in P1 and P42 Sema3a^lacZ/+ hearts. Sympathetic nerves are restricted to the subepicardium at P1, but extend into the myocardium, coincident with downregulation of Sema3a at P42. Scale bar, 100 µm.

Fig. (4). Various arrhythmias occurred in Sema3a gene-modified mice.

(a) ECG in WT and Sema3a^–/– mice. Note the abrupt sinus-slowing in Sema3a^–/– mice. (b) Epinephrine administration revealed sustained VT only in SemaTG mice.

Fig. (5). Cardiac innervation patterning and lethal arrhythmias.

The crosstalk between cardiomyocytes and sympathetic neurons. Neurons synthesize norepinephrine, and cardiomyocytes secret NGF and Sema3a to control cardiac performance. (b) Appropriate Sema3a-mediated sympathetic innervation patterning is critical for the maintenance of an arrhythmia-free heart. SemaTG mice are highly susceptible to ventricular tachyarrhythmias.