The heart is extensively innervated, and its performance is tightly regulated by the autonomic nervous system. To maintain cardiac function, innervation density is stringently controlled, being high in the subepicardium and the central conduction system. In diseased hearts, cardiac innervation density varies, which in turn leads to sudden cardiac death. After myocardial infarction, sympathetic denervation is followed by reinnervation within the heart, 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 molecular mechanism underlying innervation density remains poorly understood. We found that cardiac sympathetic innervation is determined by the balance between neural chemoattraction and chemorepulsion, both of which occur in the heart. Nerve growth factor (NGF), which is a potent chemoattractant, is synthesized abundantly by cardiomyocytes and is induced by endothelin-1 upregulation in the heart. In contrast, Sema3a, which is a neural chemorepellent, is expressed strongly in the trabecular layer in early stage embryos and at a lower level after birth, leading to epicardial-to-endocardial transmural sympathetic innervation patterning. We also found that cardiac NGF downregulation is a cause of diabetic neuropathy, and that NGF supplementation rescues silent myocardial ischemia in DM. Both Sema3a-deficient and Sema3a-overexpressing mice showed sudden death or lethal arrhythmias due to disruption of innervation patterning. The present review focuses on the regulatory mechanisms involved in neural development in the heart and their critical roles in cardiac performance.
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