Elsevier

Heart Rhythm

Volume 7, Issue 12, December 2010, Pages 1900-1906
Heart Rhythm

Viewpoint
Novel insights into the role of the sympathetic nervous system in cardiac arrhythmogenesis

https://doi.org/10.1016/j.hrthm.2010.06.003Get rights and content

It has long been recognized that increased sympathetic nerve activity during physiologic stress (exercise, swimming, emotion, arousal, loud noise, etc.) has profound influences on the electrical and contractile functions of the heart. In the severely predisposed heart, these stressors may lead to ventricular tachyarrhythmias and sudden death. Still little is known about the temporal relationship between instantaneous autonomic nerve activity and arrhythmias. There is a large variety of autonomically-driven arrhythmias, from serious ventricular tachycardia in pathological conditions to single supraventricular and ventricular extrasystolic beats in the healthy heart. The latter are considered harmless if occurring at low frequency. In the atria, mounting data indicate the presence of a sophisticated network of ganglionated plexi with major influences on cardiac function. The ablation of multiple such ganglia can suppress pulmonary vein potentials and atrial fibrillation. At the cellular level, recent studies have focused on the spatiotemporal details of cyclic nucleotide signaling influencing ion channel function during neurohumoral stimulation. We have come to understand that sarcolemmal ion channels and other electrogenic transporters are macromolecular complexes that interact with structural elements (other than the phospholipid bilayer) to promote regionalization and targeting by regulatory proteins. Compartmentation of these regulatory proteins in subdomains of the myocyte is increasingly recognized and thought to segregate the functional (including electrogenic) responses induced by different neuromediators and hormones. In this article, contemporary issues are discussed regarding arrhythmias that are triggered by influences from the neurocardiac interface, covering the field from the molecular genetic to the intact integrated level. Actual questions are listed per topic, and viewpoints are expressed.

Section snippets

The atria

The heart is a sensory organ with an intrinsic nervous system that is so extensive and sophisticated that it readily qualifies as a “little brain.”1 Through a complex hierarchy of feedback control circuits, sensory afferent and adrenergic and cholinergic efferent neurons communicate in ganglia. These reside in the heart (intrinsic cardiac ganglia) and outside the heart in the chest cavity (intrathoracic extracardiac ganglia). At least 7 regions with intrinsic ganglia have been identified in the

Current questions

Many questions emerge from the insights contained in the previous sections. To what extent, and in which balance, can autonomic stimulation of local versus remote ganglionated plexi determine the focal initiation of atrial tachycardias, including AF, in the human heart? Which anatomic and/or genetic variations exist among patients that predispose to atrial autonomic hypersensitivity or bluntness? Does autonomic remodeling contribute to the domestication of AF, and if so, how is neurophysiology

Current questions

To what extent, and in which balance, is sympathetic stimulation of the ventricles dictated by extracardiac versus intracardiac ganglia? Which are the extremes of ventricular autonomic innervation among normal human individuals?

It has recently been found that autonomic regulation itself is an arrhythmia risk modifier that can be genetically determined.34 This raises the question of which genetic variants of autonomic neural function, receptors,35 and neurotransmitters36 exist that can influence

Current questions

With the advances of molecular–genetic techniques and fluorescence microscopy, the compartmentation of signal proteins in subdomains of the cardiac myocyte is increasingly recognized. This compartmentation is thought to segregate the functional (including electrogenic) responses induced by different neuromediators and hormones. A major question is to what extent compartmentalized segregation of autonomic signal pathways is altered by cardiac overload. In hypertrophied cardiac myocytes from rats

Acknowledgments

Roel L. H. M. G. Spätjens, BSc, Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, The Netherlands, assisted in the figure making.

References (50)

  • H. Kanki et al.

    A structural requirement for processing the cardiac K+ channel KCNQ1

    J Biol Chem

    (2004)
  • C. Terrenoire et al.

    The cardiac IKs potassium channel macromolecular complex includes the phosphodiesterase PDE4D3

    J Biol Chem

    (2009)
  • K. Piippo et al.

    A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics

    J Am Coll Cardiol

    (2001)
  • J.A. Armour

    Potential clinical relevance of the 'little brain' on the mammalian heart

    Exp Physiol

    (2008)
  • D.A. Murphy et al.

    Capacity of intrinsic cardiac neurons to modify the acutely autotransplanted mammalian heart

    J Heart Lung Transplant

    (1994)
  • Z. Lu et al.

    Autonomic mechanism for initiation of rapid firing from atria and pulmonary veins: evidence by ablation of ganglionated plexi

    Cardiovasc Res

    (2009)
  • A.Y. Tan et al.

    Neural mechanisms of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia in ambulatory canines

    Circulation

    (2008)
  • R.C. Arora et al.

    Intrinsic cardiac nervous system in tachycardia induced heart failure

    Am J Physiol Regul Integr Comp Physiol

    (2003)
  • T. Opthof et al.

    Dispersion of refractoriness in canine ventricular myocardiumEffects of sympathetic stimulation

    Circ Res

    (1991)
  • M.W. Dae et al.

    Heterogeneous sympathetic innervation in German shepherd dogs with inherited ventricular arrhythmia and sudden cardiac death

    Circulation

    (1997)
  • J.M. Cao et al.

    Relationship between regional cardiac hyperinnervation and ventricular arrhythmia

    Circulation

    (2000)
  • F. Yanowitz et al.

    Functional distribution of right and left stellate innervation to the ventricles: production of neurogenic electrocardiographic changes by unilateral alteration of sympathetic tone

    Circ Res

    (1966)
  • S.G. Priori et al.

    Delayed afterdepolarizations elicited in vivo by left stellate ganglion stimulation

    Circulation

    (1988)
  • R.F. Hanich et al.

    Autonomic modulation of ventricular arrhythmia in cesium chloride-induced long QT syndrome

    Circulation

    (1988)
  • J. Ben-David et al.

    Differential response to right and left ansae subclaviae stimulation of early afterdepolarizations and ventricular tachycardia induced by cesium in dogs

    Circulation

    (1988)
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    Supported by a Vidi grant from the Netherlands Organization for Scientific Research (ZonMw 91710365).

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