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  • Review Article
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Genetic mechanisms of atrial fibrillation: impact on response to treatment

Nature Reviews Cardiology volume 10, pages 317–329 (2013)Cite this article

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Abstract

Atrial fibrillation (AF) is the most-common sustained arrhythmia observed in clinical practice, but response to therapy is highly variable between patients. Current drug therapies to suppress AF are incompletely and unpredictably effective and carry substantial risk of proarrhythmia and noncardiac toxicities. The limited success of therapy for AF is partially the result of heterogeneity of the underlying substrate, interindividual differences in disease mechanisms, and our inability to predict response to therapies in individual patients. In this Review, we discuss the evidence that variability in response to drug therapy is also conditioned by the underlying genetic substrate for AF. Increased susceptibility to AF is mediated through diverse genetic mechanisms, including modulation of the atrial action-potential duration, conduction slowing, and impaired cell-to-cell communication, as well as novel mechanisms, such as regulation of signalling proteins important in the pathogenesis of AF. However, the translation of genetic data to the care of the patients with AF has been limited because of poor understanding of the underlying mechanisms associated with common AF-susceptibility loci, a dearth of prospective, adequately powered studies, and the challenges associated with determining efficacy of antiarrhythmic drugs. What is apparent, however, is the need for appropriately designed, genotype-directed clinical trials.

Key Points

  • The incidence of atrial fibrillation (AF) is rising, with approximately 16 million of the US population projected to develop AF by 2050

  • Limitations of current therapies for AF have spurred research into understanding the genetic basis of this arrhythmia

  • Positional cloning and candidate-gene approaches have linked rare genetic variants in ion channels, gap-junction proteins, and signalling molecules with the development of AF

  • Genome-wide association studies have identified nine commonly occurring AF-susceptibility loci associated with cardiopulmonary development, cardiac ion channels, and cell-signalling molecules that might be important in the pathogenesis of AF

  • Both common and rare genetic variants have provided insights into AF genetic mechanisms, but the direct impact of this understanding on the management of patients has been limited

  • Exploiting the genetic mechanisms of AF to prescribe personalized therapy is an important goal, but clinical trials are needed to determine whether genotype-directed treatment of AF is viable

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Figure 1: The relationship between ionic currents and the duration of the atrial action potential.
Figure 2
Figure 3: Allele frequencies and risk in families and populations.

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Article 07 April 2022

Bianca J. J. M. Brundel, Xun Ai, … Natasja M. S. de Groot

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Acknowledgements

This work was supported by NIH grants (U19 HL65962 and R01 HL092217), and an AHA Established Investigator Award (0940116N).

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  1. Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville, 37323–6602, TN, USA

    Dawood Darbar & Dan M. Roden

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Both authors researched data for the article and contributed substantially to discussions of its content. D. Darbar wrote the manuscript, and both authors reviewed/edited it before submission.

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Correspondence to Dawood Darbar.

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Competing interests

Dawood Darbar has received grant or research support from the AHA and the NIH. Dan M. Roden receives royalties from Clinical Data, Inc. on a patent to predict drug-induced arrhythmias.

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Darbar, D., Roden, D. Genetic mechanisms of atrial fibrillation: impact on response to treatment. Nat Rev Cardiol 10, 317–329 (2013). https://doi.org/10.1038/nrcardio.2013.53

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