The Role of the Autonomic Nervous System in Sudden Cardiac Death

https://doi.org/10.1016/j.pcad.2008.01.003Get rights and content

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).

First page preview

First page preview
Click to open first page preview

References (116)

  • Y. Okuyama et al.

    Nerve sprouting induced by radiofrequency catheter ablation in dogs

    Heart Rhythm

    (2004)
  • H.V. Barron et al.

    Autonomic nervous system and sudden cardiac death

    J Am Coll Cardiol

    (1996)
  • S.S. Hull et al.

    Heart rate variability before and after myocardial infarction in conscious dogs at high and low risk of sudden death

    J Am Coll Cardiol

    (1990)
  • T.G. Farrell et al.

    Risk stratification for arrhythmic events in postinfarction patients based on heart rate variability, ambulatory electrocardiographic variables and the signal-averaged electrocardiogram

    J Am Coll Cardiol

    (1991)
  • R.E. Kleiger et al.

    Decreased heart rate variability and its association with increased mortality after acute myocardial infarction

    Am J Cardiol

    (1987)
  • P.J. Schwartz et al.

    Baroreflex sensitivity and its evolution during the first year after myocardial infarction

    J Am Coll Cardiol

    (1988)
  • G.M. De Ferrari et al.

    Baroreflex sensitivity predicts long-term cardiovascular mortality after myocardial infarction even in patients with preserved left ventricular function

    J Am Coll Cardiol

    (2007)
  • O. Odemuyiwa et al.

    Influence of thrombolytic therapy on the evolution of baroreflex sensitivity after myocardial infarction

    Am Heart J

    (1993)
  • J.T. Bigger et al.

    Comparison of baroreflex sensitivity and heart period variability after myocardial infarction

    J Am Coll Cardiol

    (1989)
  • G.M. De Ferrari et al.

    Prevention of life-threatening arrhythmias by pharmacologic stimulation of the muscarinic receptors with oxotremorine

    Am Heart J

    (1992)
  • G.M. De Ferrari et al.

    Scopolamine increases vagal tone and vagal reflexes in patients after myocardial infarction

    J Am Coll Cardiol

    (1993)
  • T. Eliasson et al.

    Spinal cord stimulation in severe angina pectoris—presentation of current studies, indications, and clinical experience

    Pain

    (1996)
  • Z.F. Issa et al.

    Intrathecal clonidine reduces the incidence of ischemia-provoked ventricular arrhythmias in a canine postinfarction heart failure model

    Heart Rhythm

    (2005)
  • A. Mahajan et al.

    Use of thoracic epidural anesthesia for management of electrical storm: a case report

    Heart Rhythm

    (2005)
  • A. Hjalmarson

    Effects of beta blockade on sudden cardiac death during acute myocardial infarction and the postinfarction period

    Am J Cardiol

    (1997)
  • E. Angelakos et al.

    Regional distribution of catecholamines in the heart of various species

    Ann N Y Acad Sci

    (1969)
  • R.M. Berne et al.

    Cardiovascular physiology

    (2001)
  • M. Esler et al.

    Overflow of catecholamine neurotransmitters to the circulation: source, fate, and functions

    Physiol Rev

    (1990)
  • G. Gabella

    Fine structure of post-ganglionic nerve fibers and autonomic neuroeffector junctions

  • R.A. Samson et al.

    Electrophysiological effects of alpha 2-adrenergic stimulation in canine cardiac Purkinje fibers

    Am J Physiol

    (1995)
  • J.J. Cai et al.

    Alpha 2–Adrenergic stimulation is protective against ischemia-reperfusion-induced ventricular arrhythmias in vivo

    Am J Physiol Heart Circ Physiol

    (2002)
  • D.O. Arnar et al.

    alpha-2 adrenergic antagonism enhances risk of ventricular tachycardia during acute ischemia

    Scand Cardiovasc J

    (2007)
  • M. Bristow

    Changes in myocardial and vascular receptors in heart failure

    J Am Coll Cardiol

    (1993)
  • B. Riemann et al.

    Radioligands for imaging myocardial alpha- and beta-adrenoreceptors

    Nuklearmedizin

    (2003)
  • C. Gauthier et al.

    The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle

    J Clin Invest

    (1998)
  • C. Gauthier et al.

    The negative inotropic action of catecholamines: role of beta3-adrenoceptors

    Can J Physiol Pharmacol

    (2000)
  • M. Rubart et al.

    Mechanisms of sudden cardiac death

    J Clin Invest

    (2005)
  • S. Marx et al.

    Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel

    Science

    (2002)
  • C. Terrenoire et al.

    Autonomic control of cardiac action potentials: role of potassium channel kinetics in response to sympathetic stimulation

    Circ Res

    (2005)
  • I.T. Meredith et al.

    Cardiac sympathetic nervous activity in congestive heart failure. Evidence for increased neuronal norepinephrine release and preserved neuronal uptake

    Circulation

    (1993)
  • W. Xiong et al.

    Transmural heterogeneity of Na+-Ca2+ exchange: evidence for differential expression in normal and failing hearts

    Circ Res

    (2005)
  • C. Zhang et al.

    Effect of autonomic nervous system on the transmural dispersion of ventricular repolarization in intact canine

    J Huazhong Univ Sci Technolog Med Sci

    (2004)
  • D.P. Zipes et al.

    Autonomic neural control of cardiac excitable properties

  • I. Ducis

    The high affinity choline uptake system

  • H. Zimmerman

    Cholinergic synaptic vesicles

  • T. Kubo et al.

    Cloning, sequencing and expression of complementary DNA encoding the muscarinic acetylcholine receptor

    Nature

    (1986)
  • Z.W. Hall

    Multiple forms of acetylcholinesterase and their distribution in endplate and non-endplate regions of rat diaphragm muscle

    J Neurobiol

    (1973)
  • J.A. Armour

    Myocardial ischaemia and the cardiac nervous system

    Cardiovasc Res

    (1999)
  • D.H. Pauza et al.

    Morphology, distribution, and variability of the epicardiac neural ganglionated subplexuses in the human heart

    Anat Rec

    (2000)
  • D.P. Zipes et al.

    Influence of the autonomic nervous system on the genesis of cardiac arrhythmias

    Pacing Clin Electrophysiol

    (1983)
  • Cited by (0)

    View full text