The Role of the Autonomic Nervous System in Sudden Cardiac Death
Section snippets
Cardiac Autonomic Innervation: Neuroanatomy
Both branches of the autonomic nervous system are composed of both afferent and efferent as well interneuronal fibers (Fig 1). Sympathetic innervation originates mainly in the right and left stellate ganglia. These fibers travel along the epicardial vascular structures of the heart and penetrate into the underlying myocardium similar to coronary vessels and end as sympathetic nerve terminals reaching the endocardium. Based on norepinephrine content studies, a gradient exists in sympathetic
Effects of the Sympathetic Nervous System on the Normal Myocardium: Activity and Signaling Mechanisms
The major neurotransmitter mediating sympathetic response is norepinephrine; of note, epinephrine release during activation is negligible (Fig 2).3 Along the length of terminal axons are a series of localized swellings known as “varicosities,” around 1 to 3 μm and up to 4 μm in length. Most of the norepinephrine storage vesicles in a terminal axon are concentrated in these varicosities. Each individual varicosity acts as a specialized site of norepinephrine storage and release.4
The source of
Effects of the Parasympathetic Nervous System on the Normal Myocardium: Activity and Signaling Mechanisms
Acetylcholine, the transmitter of the parasympathetic system, is synthesized by transport of choline into the cytosol of the nerve terminal through high-affinity choline transporter and acetylation by choline acetyl transferase.22, 23 Acetylcholine is stored in vesicles and is released by parasympathetic stimulation, activating primarily postsynaptic muscarinic and preganglionic nicotinic receptors.24, 25 The effects are terminated by rapid degradation by acetylcholinerases.26
Increased
The Cardiac Nervous System
Data collected over the past 3 decades indicate that the intrinsic cardiac nervous system, including the intrinsic cardiac ganglia, are not simply “relay stations” of parasympathetic or sympathetic efferent input to the heart. Extensive amounts of processing occur in the intrinsic cardiac nervous system that forms a plexus at the base of heart, involving the afferent neurons, interconnecting interneurons and local circuits, as well as both sympathetic and parasympathetic efferent postganglionic
Myocardial Infarction, Heart Failure, and Sympathetic Innervation
It has been known for decades that sympathetic activation can trigger malignant arrhythmias, whereas vagal activity may exert a protective effect (Fig 3, Fig 4). Transmural myocardial infarction (MI) causes denervation and death of sympathetic fibers within the scar. Areas of dense scar do not respond to either sympathetic nerve stimulation or norepinephrine infusion. In the early 1980s, in a canine model of MI, sites apical (distal) to the infarct were shown to demonstrate an abnormal response
Effect of Sympathetic Stimulation on Action Potential Duration Restitution
Substantial evidence links enhanced sympathetic activation with ventricular arrhythmias and sudden cardiac death.59, 60, 61 Destabilization of ventricular wave fronts leading to degeneration ventricular tachycardia into ventricular fibrillation appears to be related to the restitution properties of action potential duration.61, 62 Restitution is described as the change in APD in response to the preceding diastolic interval, and steeply sloped restitution curves with large changes in APD for
Cardiac Parasympathetic Nervous System Dysfunction as Manifested by Baroreflex Sensitivity and Heart Rate Variability
As mentioned earlier, the loss of protective vagal reflexes is associated with ventricular tachycarrhythmias in heart failure and MI. Depressed baroreflex sensitivity (BRS) and heart rate variability (HRV), reflections of parasympathetic innervations, have been associated in humans and animal models of MI with a greater susceptibility to ventricular fibrillation during and after ischemic episodes.66 Heart rate variability primarily reflects tonic vagal activity, whereas BRS measures
Heart Rate Variability
Beat to beat, heart rate is not completely regular and is based in part on the autonomic innervation of the sinus node. This can serve as noninvasive marker of autonomic input to the heart, and the analysis can be accomplished in time or frequency domains. High frequencies are thought to be represent the parasympathetic component of the autonomic nervous system, whereas low frequencies are mediated by both the sympathetic and parasympathetic nervous system and are affected by BRS. Very low
Baroreflex Sensitivity
The arterial baroreceptor control of heart is generally studied using 3 techniques: (1) increasing blood pressure with vasoconstrictors such as phenylephrine and analyzing heart rate response—this method is used most commonly; (2) lowering blood pressure with vasodilators such as nitroprusside to test reflex sympathetic tone; (3) direct stimulation of carotid baroreceptors with neck suction.67 Just as in HRV, BRS was shown to be reduced after MI and to predispose to ventricular fibrillation
Parasympathetic Modulation of Sudden Death: BRS vs HRV
Although both HRV and BRS have been shown to be abnormal in heart failure and in post-MI patients, the correlation between the two is only moderate (R = 0.63).78, This is consistent with the fact that HRV and BRS are different measures of parasympathetic activity, with HRV measuring tonic vagal activity over a 24-hour period, whereas BRS is equivalent to a vagal response or variability stress test. Furthermore, BRS in some studies has been a stronger predictor of ventricular tachyarrhythmias
Therapies That Reduce Sudden Cardiac Death Modulate Neurohormonal Remodeling
As sympathetic tone is known to be increased and parasympathetic innervation decreased in cardiomyopathy patients, interventions that aim to reduce sympathetic tone and, therefore, increase parasympathetic tone, should reduce the risk of sudden cardiac death and ventricular tachyarrhythmias (Fig 5). This, has in fact, been shown to be true.
Conclusions
Both the sympathetic and parasympathetic nervous systems are intricately involved in the modulation of cardiac excitability and arrhythmias. Neural remodeling with decrease in parasympathetic input, along with heterogeneous sympathetic denervation followed by hyperinnervation in addition to the observed structural remodeling of the diseased heart, creates the electrophysiologic substrate necessary to initiate and maintain arrhythmias. Only by a better understanding of the cellular and
Acknowledgments
This study was supported by a grant from the NHLBI: R01HL084261 (Dr Shivkumar).
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