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  • Review Article
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Innovative approaches to anti-arrhythmic drug therapy

Nature Reviews Drug Discovery volume 5, pages 1034–1049 (2006)Cite this article

Key Points

  • The drug treatment of cardiac arrhythmias has been limited by the potential for serious adverse effects, particularly by the risk of causing serious arrhythmias ('pro-arrhythmia'). Pro-arrhythmic potential is largely due to drug actions that are not sufficiently selective for the arrhythmias targeted.

  • The two most important arrhythmias that present unmet therapeutic needs are atrial and ventricular fibrillation.

  • Atrial selective ionic-current targets (such as the ultra-rapid and the cholinergic potassium currents) might allow for new drugs that suppress atrial fibrillation with little or no risk of ventricular pro-arrhythmia.

  • The pathophysiology of acute myocardial ischaemia presents targets for novel and selective therapeutic development, such as adenosine triphosphate-regulated potassium current and connexin proteins, which might present practical new targets for drugs that selectively prevent potentially lethal arrhythmias arising in acutely ischaemic ventricular tissues.

  • Currents involved in generating focal arrhythmic activity, such as hyperpolarization-activated cyclic nucleotide binding channels, stretch-activated channels and sarcoplasmic reticulum calcium-release channels, might all have significant roles in specific forms of arrhythmias. Drugs that suppress arrhythmias by acting on each of these ion-handling systems have been developed and are in various stages of development.

  • Our understanding of the genetic basis of cardiac arrhythmias at the molecular level is in rapid evolution. Improved knowledge in this area could permit much safer targeting of drug therapy on an individualized, pathophysiological and pharmacogenetic basis.

  • Evolving technologies in cell and gene therapy could allow for gene-transfer approaches that deliver highly specific therapeutic interventions directly to the arrhythmic cardiac tissue.

Abstract

Normal cardiac function requires an appropriate and regular beating rate (cardiac rhythm). When the heart rhythm is too fast or too slow, cardiac function can be impaired, with derangements that vary from mild symptoms to life-threatening complications. Irregularities, particularly those involving excessively fast or slow rates, constitute cardiac 'arrhythmias'. In the past, drug treatment of cardiac arrhythmias has proven difficult, both because of inadequate effectiveness and a risk of serious complications. However, a variety of recent advances have opened up exciting possibilities for the development of novel and superior approaches to arrhythmia therapy. This article will review recent progress and future prospects for treating two particularly important cardiac arrhythmias: atrial fibrillation and ventricular fibrillation.

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Figure 1: Electrical functioning of the heart.
Figure 2: Cellular mechanisms of abnormal impulse formation and arrhythmia.
Figure 3: Re-entry.
Figure 4: Ion currents, ion channel subunits and ion transporters implicated in arrhythmogenesis.
Figure 5: Promising targets for ischaemia-selective anti-arrhythmics.
Figure 6: Examples of genetically based arrhythmia syndromes.

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Article 07 April 2022

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Acknowledgements

Supported by the Canadian Institutes of Health Research, the Quebec Heart and Stroke Foundation and the Mathematics of Complex Systems and Information Technology (MITACS) Network of Centers of Excellence.

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  1. Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, 5000 Belanger Street, Montreal, H1T 1C8, Quebec, Canada

    Stanley Nattel

  2. AstraZeneca Research & Development, Integrative Pharmacology, Pepparedsleden 1, Mölndal, S-431 83, Sweden

    Leif Carlsson

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Correspondence to Stanley Nattel.

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L.C. is an employee and shareholder of AstraZeneca Corp. S.N. has received research funding in the past 2 years from Xention, Inotek, Daiichi Asubi and AstraZeneca. S.N. is listed as inventor on patents pending for which intellectual property belongs to Montreal Heart Institute and the University of Montreal, regarding: (1) blockers of cholinergic potassium current for atrial fibrillation therapy; and (2) statins to prevent atrial fibrillation.

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Nattel, S., Carlsson, L. Innovative approaches to anti-arrhythmic drug therapy. Nat Rev Drug Discov 5, 1034–1049 (2006). https://doi.org/10.1038/nrd2112

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