The heart is extensively innervated, and its electrical and mechanical performance is controlled by the autonomic nervous system. The cardiac nervous system comprises the sympathetic, parasympathetic, and sensory nervous systems that together regulate heart function on demand. The density of cardiac innervation varies in diseased hearts, leading to unbalanced neural activation and lethal arrhythmia. Diabetic sensory neuropathy causes silent myocardial ischemia, which is characterized by loss of pain perception during myocardial ischemia and 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. Nerve growth factor (NGF), a potent chemoattractant, is highly expressed in cardiomyocytes during development. In contrast, Sema3a, a neural chemorepellent, is highly expressed in the subendocardium of early-stage embryos, but is suppressed during development. The balance between NGF and Sema3a expression leads to epicardial to endocardial transmural sympathetic innervation patterning. Downregulation of NGF leads to diabetic neuropathy, whereas NGF supplementation rescues silent myocardial ischemia in DM. In this review, we summarize the molecular mechanisms underlying cardiac autonomic innervation, with a particular focus on DM and the clinical implications of cardiac autonomic neuropathy.
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