The Extrinsic and Intrinsic CANS

The CANS regulates vascular tone, contractility, and electrophysiology by transducing and integrating afferent and efferent autonomic trafficking.2,3 Autonomic control of the heart is mediated by a highly integrated intrinsic and extrinsic CANS.^2,3 The extrinsic CANS mainly consists of ganglia and their axons located outside the heart. The nucleus ambiguus, the dorsal vagal nucleus, and the vagus nerves constitute most of the parasympathetic limb of the extrinsic CANS, whereas the neurons in the intermediolateral column of the spinal cord, the stellate ganglia, and their axons en route to the heart make up most of the sympathetic limb of the extrinsic CANS. The intrinsic CANS is composed mainly of sympathetic and parasympathetic nerves, as well as ganglionated plexi (GP) on the heart itself or along the great vessels in the thorax such as the pulmonary artery, aorta, superior vena cava, and pulmonary veins (PVs). The stellate ganglia serve as the “head stage” for the sympathetic innervation of the heart. The postganglionic sympathetic fibers, mainly from the stellate ganglia, constitute the vast majority of the sympathetic innervation to both the atrium and the ventricle. The GP embedded in the epicardial fat pads contain up to several hundred autonomic neurons. The distribution of the major ventricular GP is limited to the proximal segments of the coronary arteries; they are in general small and not as extensive on the ventricles.^2–5

The major atrial GP are located adjacent to the pulmonary vein (PV)-atrial junction, or the junction of the right atrium and the superior or inferior vena cava. Chiou et al discovered that the efferent parasympathetic fibers in the vagus nerves converge at a GP before innervating the heart.⁶ This GP, at the junction of the right pulmonary artery, aorta, and superior vena cava (SVC), was coined as the “head stage” GP because the bradycardia response induced by vagal stimulation in canine hearts was nearly abolished if the RPA-Ao GP was ablated.⁶

The different nomenclature used by anatomists introduced a great deal of confusion for scientific communication.2–5 In this chapter, we use the nomenclature based on clinical anatomy, for example, GP’s relation to PVs (Figure 47-1). The superior left GP (SLGP) and the inferior left GP (ILGP) are located adjacent to the PV-atrial junction of the left superior PV and the left inferior PV, respectively.⁷ The anterior right GP (ARGP) is situated at the caudal end of the sinoatrial node, near the right superior PV-atrial junction. The inferior right GP (IRGP) extends from the inferior right PV-atrial junction to the crux of the heart near the junction of the right atrium and inferior vena cava.

It was once thought that the ARGP specifically innervates the sinus node, while the IRGP at the crux of the heart innervates only the AV node. Recent studies indicate that the intrinsic CANS forms a complex neural network, and GP serve as “integration centers” to control the physiological functions of the heart.2,3,8 For example, high-frequency stimulation (HFS; 20 Hz) to the SLGP also markedly slowed the sinus rate (SR), proving that the ARGP is not the only GP that innervates the sinus node. Ablation of the ARGP greatly attenuated, but did not eliminate, the SR slowing response induced by SLGP stimulation, indicative of the role of ARGP as the gateway GP for the sinus node and the presence of other neural pathways bypassing the ARGP. Ablation of the four major atrial GP and the ligament of Marshall (LOM) exerts potent inhibitory effects on the activity of the CANS, supporting clinical implications targeting these GP to treat AF.⁹

The interplay between the intrinsic and extrinsic CANS is not well understood. The intrinsic CANS appears to function interdependently with as well as independently from the extrinsic CANS, as evidenced by its retaining nearly full control of cardiac physiology after autotransplantation.2,3 Armour elegantly described the intrinsic CANS as “the little brain on the heart.” Cooperative interaction between the extrinsic and intrinsic CANS maintains a homeostasis that facilitates balanced cardiac physiological functions.

Noncholinergic, Nonadrenergic Neurotransmitters in the Intrinsic CANS

Until the past two decades, it was believed that the sympathetic component of the intrinsic CANS is composed exclusively of postganglionic sympathetic fibers, and that all of the cardiac autonomic neurons are parasympathetic neurons expressing cholinergic markers. With advances in immunohistochemistry, subpopulations of cardiac autonomic neurons expressing various neurotransmitter markers have been identified.¹⁰ The presence of peptidergic, nitrergic, and noradrenergic neurons, along with their associated neurotransmitters such as neuropeptide-Y, vasoactive intestinal peptide (VIP), nitric oxide synthase, and angiotensin II, strongly indicates that autonomic control of cardiac physiology involves a milieu of neurotransmitters beyond acetylcholine and norepinephrine.^10–12 Neuropeptide-Y co-released by prolonged sympathetic activation reduces acetylcholine release from the neighboring vagal nerve ending; this is a good example of sympathovagal cross-talk.¹¹ These noncholinergic, nonadrenergic neurotransmitters often exert effects similar to those of cholinergic or adrenergic agonists or antagonists. Using cholinergic and adrenergic blockers to “eliminate” CANS control is an oversimplified approach.^13,14 Liu et al demonstrated that until an antagonist of VIP ([Ac-Tyr1,D-phe2]-VIP) was administered, vagal stimulation continued to induce atrial fibrillation (AF) in canine hearts despite GP ablation+atropine+esmolol.¹² A better understanding of the arrhythmogenic potential of these noncholinergic, nonadrenergic neurotransmitters may facilitate the development of new antiarrhythmic agents for treatment of AF.

The “Ca²⁺ Transient Triggering” Hypothesis

Clinical studies demonstrated that activation of both the sympathetic and the parasympathetic nervous system commonly preceded the initiation of paroxysmal AF.19,20 This finding was later corroborated by multiple basic studies.^21–23 Patterson et al proposed a “Ca²⁺ transient triggering” hypothesis to explain the initiation of rapid PV firing (see Figure 47-1). This hypothesis states that norepinephrine (by sympathetic activation) augments the Ca²⁺ transient, and acetylcholine (by parasympathetic activation) shortens the PV activation potential duration (APD). The abbreviated APD makes the Ca²⁺ transient relatively prolonged, and the myocytes even more Ca²⁺ overloaded. This leads to activation of the forward mode of the Na⁺/Ca²⁺ exchanger, the formation of early afterdepolarization, and subsequent triggered firing from the PVs (Figure 47-1D