Genetic mechanisms of atrial fibrillation: impact on response to treatment

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.

Figure 1

The relationship between ionic currents and the duration of the atrial action potential. The action potential is initiated by a rapid influx of Na⁺ ions (phase 0), followed by early (phases 1 and 2) and late (phase 3) stages of repolarization, before returning to the resting membrane potential (phase 4). Repolarization is controlled by a balance between inward (red) and outward (blue) currents. The genes encoding the major currents of the atrial action potential are shown. *Function-modifying subunit. ^‡Mutation in this gene associated with atrial fibrillation.

Figure 2

The ‘two-hit’ hypothesis states that a combination of a genetic (blue) and an acquired (green) risk factor is required for the development of atrial fibrillation.

Figure 3

Allele frequencies and risk in families and populations. The combination of rare and common variants of atrial fibrillation susceptibility genes might have a large aggregate risk for the development of this arrhythmia.