Noradrenergic and cholinergic innervation of the normal human heart and changes associated with cardiomyopathy

Abstract

Autonomic nerves are crucial in cardiac function and pathology. However, data on the distribution of cholinergic and noradrenergic nerves in normal and pathologic human hearts is lacking. Nonfailing donor hearts were pressure-perfusion fixed, imaged, and dissected. Left ventricular cardiomyopathy samples were also obtained. Fixed frozen sections were immunostained for nerves, and adjacent tissue underwent clearing for 3D visualization. Cholinergic and noradrenergic nerves were evenly abundant in both atria, except the sinoatrial node, where vesicular acetylcholine transporter (VAChT) nerves were dominant. Noradrenergic consistently outnumbered cholinergic nerves in right (RV) and left ventricular (LV) regions. Noradrenergic innervation of LV regions varied between donors. Cholinergic innervation was higher in RV compared to LV samples, which generally had reduced VAChT nerves. Marked neural remodeling occurred in three cardiomyopathy cases. Tyrosine hydroxylase (TH) nerve density was increased in the right atrial appendage, and all nerves showed a trend to decrease in the left atrial appendage. Cholinergic innervation was reduced in the LV, and TH innervation was heterogeneous. Noradrenergic nerves were present in granulation tissue but absent in regions of dense scar. Some border zone regions had reduced TH innervation but no hyperinnervation. Dual innervation of most atrial regions supports balanced regulation of atrial function. Higher cholinergic input to the sinoatrial node favors vagal dominance in heart rate regulation. Innervation patterns support a significant role of noradrenergic input to the ventricle, especially on the left. Both atrial and ventricular nerves remodel in cardiomyopathy, providing a foundation for asymmetric neural input and dysregulation of cardiac electromechanical function.

Keywords: cardiac innervation; cardiomyopathy; cholinergic; immunohistochemistry; intrinsic cardiac nervous system; neuronal remodeling; noradrenergic.