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  • Review Article
  • Published:

Electrophysiological and molecular mechanisms of paroxysmal atrial fibrillation

Nature Reviews Cardiology volume 13, pages 575–590 (2016)Cite this article

Subjects

Key Points

  • Paroxysmal atrial fibrillation (pAF) has discrete clinical features from persistent forms, including greater relative pathophysiological importance of the pulmonary vein sleeves and greater susceptibility to both medical and ablation therapy

  • Evidence indicates that both focal ectopic activity and re-entry can have a role in pAF, and that the pulmonary veins have structural and electrophysiological features that favour both mechanisms

  • The mechanisms underlying pAF are likely to vary between patients, depending on factors such as genetic background, cardiovascular risk factors, and concomitant heart disease

  • Ca2+-dependent triggered activity seems to underlie atrial ectopy in pAF, and has complex underlying molecular mechanisms that increase both cellular Ca2+ load and the leakiness of the sarcoplasmic reticulum Ca2+-release channel (ryanodine receptor)

  • Molecular mechanisms promoting re-entrant activity in patients with pAF include ionic properties (such as larger left atrial inward-rectifier background current) and structural properties (such as atrial fibrosis)

  • Fairly little attention has been paid in the literature to the specific mechanistic basis of pAF; more work is needed to provide insights with translational potential

Abstract

Atrial fibrillation (AF) is an extremely prevalent arrhythmia that presents a wide range of therapeutic challenges. AF usually begins in a self-terminating paroxysmal form (pAF). With time, the AF pattern often evolves to become persistent (nonterminating within 7 days). Important differences exist between pAF and persistent AF in terms of clinical features, in particular the responsiveness to antiarrhythmic drugs and ablation therapy. AF mechanisms have been extensively reviewed, but few or no Reviews focus specifically on the pathophysiology of pAF. Accordingly, in this Review, we examine the available data on the electrophysiological basis for pAF occurrence and maintenance, as well as the molecular mechanisms forming the underlying substrate. We first consider the mechanistic insights that have been obtained from clinical studies in the electrophysiology laboratory, noninvasive observations, and genetic studies. We then discuss the information about underlying molecular mechanisms that has been obtained from experimental studies on animal models and patient samples. Finally, we discuss the data available from animal models with spontaneous AF presentation, their relationship to clinical findings, and their relevance to understanding the mechanisms underlying pAF. Our analysis then turns to potential factors governing cases of progression from pAF to persistent AF and the clinical implications of the basic mechanisms we review. We conclude by identifying and discussing questions that we consider particularly important to address through future research in this area.

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Figure 1: General mechanistic concepts of atrial fibrillation.
Figure 2: Mechanisms of atrial fibrillation initiation at the pulmonary veins.
Figure 3: Molecular mechanisms of focal ectopic firing in paroxysmal atrial fibrillation (pAF).
Figure 4: Molecular mechanisms governing re-entry in paroxysmal atrial fibrillation (pAF).
Figure 5: Mechanisms of progression from paroxysmal atrial fibrillation (AF) to persistent forms.

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Acknowledgements

The authors were supported by grants from the Canadian Institutes of Health Research (S.N.), Quebec Heart and Stroke Foundation (S.N.), the European-North American Atrial Fibrillation Research Alliance (07CVD03) grant from Fondation Leducq (S.N., D.D.), the European Network for Translational Research in Atrial Fibrillation (EUTRAF, No. 261057; D.D.), the DZHK (German Center for Cardiovascular Research; D.D.), and the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH RO1HL131517; D.D.).

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  1. Stanley Nattel and Dobromir Dobrev: These authors contributed equally to this work.

Authors and Affiliations

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

    Stanley Nattel & Dobromir Dobrev

  2. Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, H3G 1Y6, Quebec, Canada

    Stanley Nattel

  3. Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Hufeland Strasse 55, Essen, 45122, Germany

    Stanley Nattel & Dobromir Dobrev

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  1. Stanley Nattel
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Both authors researched data for the article, discussed its content, wrote the manuscript, and reviewed/edited it before submission.

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Correspondence to Stanley Nattel.

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Competing interests

D.D. declares that he has received consultancy fees and research grants from OMEICOS Therapeutics GmbH and Xention. S.N. declares no competing interests.

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Nattel, S., Dobrev, D. Electrophysiological and molecular mechanisms of paroxysmal atrial fibrillation. Nat Rev Cardiol 13, 575–590 (2016). https://doi.org/10.1038/nrcardio.2016.118

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