Review Article | Published:

The autonomic nervous system and cardiac arrhythmias: current concepts and emerging therapies

Abstract

Research into cardiac autonomic control has received great interest in the past 20 years, and we are now at a critical juncture with regard to the clinical translation of the experimental findings. A rush to develop clinical interventions and implant a range of devices aimed at cardiac neuromodulation therapy has occurred. This interest has been driven by research, superimposed on commercial opportunities and perhaps the more relaxed regulatory framework governing implantable devices and interventions compared with that for pharmacotherapy. However, many of the results of the clinical trials into these therapies have been disappointing or conflicting. This lack of positive results is partly attributable to a scramble to find simple solutions for complex problems that we do not yet fully understand. Are there reasons to be optimistic? In this Review, we highlight areas in the field of cardiac autonomic control that we feel show the most promise for clinical translation and areas in which our current range of blunt tools need to be refined to bring about long-term success in treating arrhythmias.

Key points

  • Many primary cardiovascular diseases, such as hypertension, acute myocardial infarction and heart failure, are also diseases of the autonomic nervous system.

  • Sympathetic overactivity and vagal impairment are powerful negative prognostic indicators for morbidity and mortality associated with arrhythmia and sudden cardiac death.

  • Emerging evidence suggests that neuromodulation therapy might be clinically important in the management and prevention of lethal arrhythmia.

  • Neuromodulation device therapy has yielded conflicting and disappointing results in clinical trials, which might be related to stimulation parameters and/or the lack of site-specific targeting and appreciation of the complex neural circuitry driving postsynaptic excitability.

  • Surgical resection or ablation of specific ganglia, in particular the stellate ganglion, has produced encouraging therapeutic benefits in patients with sympathetic hyperactivity, who are prone to arrhythmia.

  • Understanding the relationship between neural circuitry and the molecular pathways underpinning abnormal neurotransmission to cardiac electrophysiology is essential to improve neuromodulation therapy.

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Acknowledgements

N.H. is a British Heart Foundation (BHF) Intermediate Fellow (FS/15/8/3115). D.J.P. acknowledges the NIH Stimulating Peripheral Activity to Relieve Conditions (SPARC) award OT2OD023848 and BHF programme grant RG/17/14/33085. N.H., M.K. and D.J.P. also acknowledge support from the BHF Centre of Research Excellence (RE/08/004), Oxford, UK.

Reviewer information

Nature Reviews Cardiology thanks P. J. Schwartz, M.Vaseghi and R. L. Verrier for their contribution to the peer review of this work.

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N.H. and D.J.P. developed the idea of the Review. All authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

Correspondence to Neil Herring or David J. Paterson.

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Fig. 1: Neuromodulation targets for treating cardiac arrhythmia.
Fig. 2: Cardiac electrophysiological and autonomic responses after neuromodulation therapy.
Fig. 3: The cardio–neural hierarchy.
Fig. 4: Cardiac autonomic innervation and cardiac disease progression.
Fig. 5: Targeting the cardiac sympathetic nervous system with surgical denervation.
Fig. 6: Transcriptomics for the discovery of novel neuronal targets.
Fig. 7: Neurotransmitter switching in sympathetic neurons in prehypertension.
Fig. 8: Gene therapy to target presynaptic and postsynaptic sites involved in long QT syndrome.