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Mechanisms of Disease: genetic mechanisms of atrial fibrillation

Nature Clinical Practice Cardiovascular Medicine volume 3, pages 276–282 (2006)Cite this article

Abstract

Atrial fibrillation is the most common cardiac arrhythmia, and it increases in prevalence with advancing age to about 6% in people older than 65 years. The chance of developing atrial fibrillation at age 40 years or older is about 25% in men and women. This arrhythmia accounts for about one-third of all strokes, and 30% of all patients with atrial fibrillation have a family history of the disease. In 1997, Brugada et al. identified the first locus for familial atrial fibrillation on chromosome 10q22–24 in three different Spanish families. Since that time, seven further loci have been mapped and four relevant genes identified. All these genes encode potassium-channel subunits. The mechanism of action by which all four genes induce atrial fibrillation is via shortening of the action potential duration and atrial effective refractory period. The consistency of the mechanism of action beckons the development of therapy specifically targeted to prevent these molecular events. In addition to monogenic diseases, patients with structural heart disease are predisposed to atrial fibrillation by inherited DNA polymorphisms. The development of chips with hundreds of thousands of single-nucleotide polymorphisms to perform genome-wide scans will elucidate over the next few years the single-nucleotide polymorphisms that predispose to atrial fibrillation. Within the next decade, most of the genes responsible for atrial fibrillation and the single-nucleotide polymorphisms that confer predisposition will probably be identified, and therapies will be developed on the basis of individuals' genomic profiles. In this review I provide an overview of the understanding of the relevant genetic mutations that have been identified so far, and briefly discuss what implications this information might have for practice.

Key Points

  • Atrial fibrillation is the most common atrial arrhythmia and accounts for over one-third of all strokes

  • A significant proportion of atrial fibrillation has a genetic origin or predisposition

  • Four genes have been identified to be responsible for atrial fibrillation and the loci (chromosomal position) of three other genes have been mapped, but they have not yet been identified

  • The four genes currently identified as responsible for familial atrial fibrillation encode for a cardiac potassium channel and the defect is due to a missense mutation

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Figure 1: Diagram of a typical potassium α subunit.
Figure 2: Diagram of the KirBac1.1 potassium channel, which closely resembles the structure of a mammalian potassium channel.

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Acknowledgements

The assistance of Susan Slater and Fran Baas on the preparation of this manuscript is greatly appreciated. This work is supported by grants from the National Heart, Lung and Blood Institute; Specialized Centers of Research; the National Institutes of Health Training Center in Molecular Cardiology; and the Canadian Institutes of Health Research.

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  1. University of Ottawa Heart Institute, ON, Canada

    Robert Roberts

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  1. Robert Roberts
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Correspondence to Robert Roberts.

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Roberts, R. Mechanisms of Disease: genetic mechanisms of atrial fibrillation. Nat Rev Cardiol 3, 276–282 (2006). https://doi.org/10.1038/ncpcardio0509

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