CLINICAL MANAGEMENT CONSIDERATIONS
Given the growing repository of causative rare genes and linked SNPs with AF, multiple studies have analyzed the role of specific genetic variants on outcomes by AF management strategy (rate vs rhythm control; AAD trial vs ablation). However, outcomes remain variable by variant analyzed (Table 1 ). Additionally, many published studies on this topic are retrospective, observational studies, and there is a dearth of prospective, randomized controlled trials to inform the universal utility of genetic testing and to inform AF care. For example, there is a paucity of data for surgical treatment in genetically linked AF. Given lone AF is a well-established clinical phenotype, multiple studies have analyzed post-operative rhythm-free survival after Cox-Maze surgery in this population.84,85 Among these patients, Cox-Maze is associated with durable freedom from AF without the use of AAD.86 Although there is a strong genetic association with lone AF, there have been no direct analyses of genetic variants on outcomes in surgical AF management.
In contrast, there are some emerging data for the effect of genetic variation on AF pharmacotherapy response. In acute AF with rapid ventricular response, it is currently recommended to utilize atrioventricular nodal blocking agents for symptomatic and heart rate management.86 Only one analysis has evaluated the response to intravenous diltiazem in rapid ventricular response in European patients with AF. However, multiple AF susceptibility SNPs combined into a susceptibility score, including those at 4q25, did not appear to alter response to acute rate control methods in an emergency room AF population.87 In contrast, the Vanderbilt AF Registry identified that the wildtype SNP rs10033464 at 4q25 was associated with a favorable response to anti-arrhythmic drug therapy, compared to matched controls with a variant allele.88
More supporting evidence has identified that genetic variability influences outcomes after AF catheter ablation. A variety of SNPs associated with AF susceptibility have been shown to be associated with modulation of response to catheter ablation.89-93Additionally, SNPs associated with electrical remodeling in lone AF have also been associated with AF recurrence post ablation,94 and there is some emerging data concerning the effects of atrial cardiomyopathy95 and DCM related variants on post-ablation outcomes.96 By far, SNPs at locus 4q25 have consistently been associated with AF susceptibility, and there are a number of analyses indicating this locus’ role in response to AF therapy. The SNP rs2200733, which was one of the first SNPs associated with increased AF susceptibility at 4q25 has been demonstrated to lead to decreased likelihood of arrhythmia-free survival and increased likelihood of AAD therapy post catheter ablation, possibly due to altered left atrial conduction patterns.97-99However, other SNPs, including rs10033464 (which is associated with increased left atrial diameter)100, at this locus have not been consistently associated with AF recurrence post-ablation, including in a predominantly Turkish-based population101 and in meta-analysis.102 There is some conflicting data in another European population the rs10033464 SNP was associated with AF recurrence post ablation103 and in meta-analysis.100,104 This variability may be explained in part by variation in increased levels of circulating biomarkers of myocardial fibrosis in patients with paroxysmal AF.105 Of note, there is emerging evidence that other SNPs at 4q25 may increase left atrial scar formation and increase non-pulmonary vein triggers for AF recurrence, which may help inform future risk stratification when selecting patients for catheter ablation.106 However, prospective analyses of these and other SNPs are still needed.
While most studies in this space rely on observational data, the Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Metoprolol Succinate for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter (AFL) in Patients with Heart Failure (GENETIC-AF) trial was one of the first trials to interrogate the genotype-outcome relationship. This trial investigated the role of genotype-guided use of bucindolol versus metoprolol succinate in reducing the recurrence of symptomatic AF/AFL events and/or mortality in a population of heart failure with reduced ejection fraction. This trial was founded on the principle that bucindolol is a non-selective beta-blocker with particular efficacy in patients with ADRB1Arg389Arg genotype.107 Patients managed with bucindolol had 55% reduction in AF burden compared to metoprolol and a 32% reduction in necessity of rhythm control strategies for those with recurrent AF/AFL.108 This trial represents a major advance in the use of genotyping to inform therapy selection in AF/AFL patients and may help inform further trial design surrounding AF outcomes and other genetic variants.