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.