title: 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.
authors.affiliation: Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, 2215B Garland Avenue, Nashville, TN 37323-6602, USA. dawood.darbar@vanderbilt.edu
authors.forename: Dawood
authors.initials: D
authors.lastname: Darbar
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D018579:Patient Selection; D010597:Pharmacogenetics; D010641:Phenotype; D057285:Precision Medicine / Q000379:methods; D011237:Predictive Value of Tests; D016896:Treatment Outcome
chemical_list: D000889:Anti-Arrhythmia Agents