Cardiac Innervation and the Autonomic Nervous System in Sudden Cardiac Death

Abstract

Neural remodeling in the autonomic nervous system contributes to sudden cardiac death. The fabric of cardiac excitability and propagation is controlled by autonomic innervation. Heart disease predisposes to malignant ventricular arrhythmias by causing neural remodeling at the level of the myocardium, the intrinsic cardiac ganglia, extracardiac intrathoracic sympathetic ganglia, extrathoracic ganglia, spinal cord, and the brainstem, as well as the higher centers and the cortex. Therapeutic strategies at each of these levels aim to restore the balance between the sympathetic and parasympathetic branches. Understanding this complex neural network will provide important therapeutic insights into the treatment of sudden cardiac death.

Keywords: Autonomic; Innervation; Parasympathetic; Sudden death; Sympathetic; Ventricular fibrillation; Ventricular tachycardia.

Figure 1

Cardiac neural control occurs at multiple levels, and each level has the capability to receive afferent neurotransmission and control efferent outflow to the heart (directly or indirectly). Level I represents the intrinsic cardiac ganglia, located in the fat pads of the epicardium. Level II includes the stellate, middle cervical, and thoracic ganglia. Level III includes the spinal cord, vagal nerve and brainstem nuclei. Level IV represents cortex and higher centers. Each level also demonstrates parallel processing of neural information.

Figure 2

Sympathetic nervous system activation in the setting of myocardial infarction increases the risk of VT/VF by modulating the two primary criteria needed for initiation of arrhythmias, including conduction velocity and repolarization. Therefore, sympathetic activation creates both more excitable myocardium by initiating EADs and DADs and creates a substrate that is more likely to promote reentry. SNS: Sympathetic Nervous System, APD: action potential duration, ARI: activation recovery interval, VERP: ventricular effective refractory period, EAD: early after depolarization, DAD: delayed after depolarization

Figure 3

Effects of myocardial infarction on the cardiac sympathetic system. Infarcted myocardium stimulates release of signaling molecules including NGF that promote remodeling of the afferent and efferent nervous system such that sympathetic nervous activity is amplified. Remodeling of the nervous system occurs at all levels, including the intrinsic cardiac ganglia, the thoracic ganglia, and the higher centers. This along with denervation and nerve sprouting at the myocardial level further amplify the substrate heterogeneity and ultimately increases risk of VT and VF. Adapted from Dilsizian V. Atlas of cardiac innervation. New York, NY: Springer Science+Business Media; 2016 (with permission).

Figure 4

Neuraxial modulation can be targeted at multiple levels of the cardiac autonomic nervous system, from the central nervous system to neuro-myocardial junction. Therapeutic goals generally include decreasing sympathetic activity and augmenting parasympathetic activity. BB: Beta blocker, ACEI: angiotensin converting enzyme inhibitor, ARB: angiotensin receptor blocker, AA: aldosterone antagonist, CRT: cardiac resynchronization therapy

Figure 5

Autonomic modulation therapies have translated from basic research to animal studies and human studies, though in clinical trials, some therapies have had mixed results. VF: ventricular fibrillation, EF: ejection fraction, HF: heart failure, HTN: hypertension, AF: atrial fibrillation