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The mouse heart is a popular model to study the function and autonomic control of the specialized cardiac conduction system (CCS). However, the precise identity and anatomical distribution of the intrinsic cardiac nerves that modulate the function of the mouse CCS have not been adequately studied. We aimed at determining the organization and distribution of the intrinsic cardiac nerves that supply the CCS of the mouse. In whole mouse heart preparations, intrinsic neural structures were revealed by histochemical staining for acetylcholinesterase (AChE). Adrenergic, cholinergic and peptidergic neural components were identified, respectively, by immunohistochemical labeling for tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), calcitonin gene related peptide (CGRP), substance P (SP), and protein gene product 9.5 (PGP 9.5). Myocytes of the CCS were identified by immunolabeling of hyperpolarization activated cyclic nucleotide-gated potassium channel 4 (HCN4). In addition, the presence of CCS myocytes in atypical locations was verified using fluorescent immunohistochemistry performed on routine paraffin sections. The results demonstrate that four microscopic epicardial nerves orientated toward the sinuatrial nodal (SAN) region derive from both the dorsal right atrial and right ventral nerve subplexuses. The atrioventricular nodal (AVN) region is typically supplied by a single intrinsic nerve derived from the left dorsal nerve subplexus at the posterior interatrial groove. SAN myocytes positive for HCN4 were widely distributed both on the medial, anterior, lateral and even posterior sides of the root of the right cranial (superior caval) vein. The distribution of HCN4-positive myocytes in the AVN region was also wider than previously considered. HCN4-positive cells and thin slivers of the AVN extended to the roots of the ascending aorta, posteriorly to the orifice of the coronary sinus, and even along both atrioventricular rings. Notwithstanding the fact that cholinergic nerve fibers and axons clearly predominate in the mouse CCS, adrenergic nerve fibers and axons are abundant therein as well. Altogether, these results provide new insight into the anatomical basis of the neural control of the mouse CCS., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Atrial ectopic discharges originating in the pulmonary veins (PVs) are known to initiate atrial fibrillation (AF), which may be terminated by catheter-based PV isolation. Because a functional relationship exists between cardiac autonomic effects and PVs in arrhythmogenesis, it has been suggested that discharges of the nerves that proceed to the PVs and interconnect with intrinsic ganglionated nerve plexuses are potential triggers of AF in man., Objective: This study sought to determine the characteristics and distribution of neural routes by which autonomic nerves supply the human PVs., Methods: We examined the intrinsic neural structures of 35 intact (nonsectioned) left atrial (LA)-PV complexes stained transmurally for acetylcholinesterase using a stereomicroscope., Results: The epicardial ganglionated nerves pass onto the extrapulmonary segments of the human PVs from the middle, left dorsal, and dorsal right atrial subplexuses. The left and right inferior PVs involved a lesser number of ganglia than the left and right superior PVs. Abundant extensions of epicardial nerves penetrate transmurally the PV walls and form a patchy neural network beneath the endothelium of PVs. The subendothelial neural meshwork with numerous free nerve endings, which appeared to be typical sensory compact nerve endings, was mostly situated at the roots of the 4 PVs. No ganglia were identified beneath the endothelium of the human PVs., Conclusion: The richest areas containing epicardial ganglia, from which intrinsic nerves extend to the human PVs, are concentrated at the inferior surface of both the inferior and left superior PVs. Therefore, these locations might be considered as potential targets for focal pulmonary vein ablation in catheter-based therapy of AF.