Symptomatic Response to Antiarrhythmic Drug Therapy Is Modulated by a Common Single Nucleotide Polymorphism in Atrial Fibrillation

Abstract

Objectives This study tested the hypothesis that response to antiarrhythmic drugs (AADs) is modulated by 3 common loci associated with atrial fibrillation (AF). Background Recent genome wide association studies (GWAS) have identified 3 loci, on chromosomes 4q25 (near PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3), that associate with either typical or lone AF. These findings indicate that variable mechanisms contribute to AF susceptibility, and suggest that response to therapy may be genotype-dependent. Methods We studied 478 and 198 Caucasian patients respectively in the discovery cohort and validation cohort, prospectively enrolled in the Vanderbilt AF Registry. Response was defined prospectively as successful rhythm control if the patient remained on the same AAD therapy for a minimum of 6 months with ≥ 75% reduction in symptomatic AF burden. We also evaluated AF recurrence by 12 lead ECG at 3, 6 and 12 months. Symptomatic patients were also given 24-48-hour Holter monitor or 30-days event recorder when AF recurrence was not captured by 12 lead ECG. Results In the discovery cohort, 399 (83%) were successfully rhythm-controlled. Multiple clinical variables (including age, hypertension, lone AF) failed to significantly predict response to AADs. By contrast single nucleotide polymorphism (SNP) rs10033464 at 4q25 was an independent predictor of successful rhythm control in patients with Typical AF carrying the ancestral allele (wild type) vs. carriers of variant allele (odds ratio [OR] 4.7, [95% confidence interval [CI] 1.83-12, P=0.0013. In the validation cohort, 143 (72%) patients met the criteria for successful rhythm control and rs10033464 was again an independent predictor of successful rhythm control, OR: 1.5, 95% CI: 1.02-3.06, P = 0.04. This SNP (rs10033464) was an independent predictor of AF recurrence in the discovery (39% AF recurrence) and validation cohort (38% AF recurrence); OR: 3.27, 95% CI: 1.7–6, P<0.001 and OR: 4.3, 95% CI: 1.98–9.4, P<0.001 respectively. Conclusions These results suggest that a common SNP on chromosome 4q25 associated with AF modulates response to AAD therapy and points to a potential role for stratification of therapeutic approaches by genotype.

Pharmacokinetic and pharmacodynamic profile of dronedarone, a new antiarrhythmic agent for the treatment of atrial fibrillation

“…It should be noted that recent works have hypothesized that the response to antiarrhytmic drug therapy is influenced by a common polymorphism on chromosome 4q25 near PITX2 gene [37] and that the risk of proarrhythmic effect is modulated by common variants in nitric oxide synthase 1 adaptor protein [38], thus explaining the patient-to-patient variations in response and proarrhtmic effect.…”

“…Only study with head-to-head comparison of dronedarone with active control, better tolerability, lower efficacy PALLAS (2011) [36] 3236 Permanent AF (> 6 months), age > 65 years; additional cardiovascular risk factor 3,5 months Prematurely halted for increased primary cardiovascular endpoints HESTIA (2012) [37] 112 Paroxysmal AF; AF burden > 1%, dualchamber pacemaker with AF detection 12 weeks Reduction of AF burden by 59%…”

“…The recent observation that the response to antiarrhythmic drug therapy in patients with AF and the risk of proarrhythmic events are modulated by genetic polymorphisms [37,38] suggest that genetic information, if supported by data of randomized pharmacogenetic trials or by the incorporation of genetic testing in all future AF therapy trials, may also play a role in the identification of patients who may benefit or have harmful effects from dronedarone therapy.…”

Can Polymorphisms Predict Response to Antiarrhythmic Drugs in Atrial Fibrillation?

“…With the rationale that the multiple genetic variants associated with AF might indicate variable mechanisms contributing to AF susceptibility, or variable sub-types of AF, Parvez et al (11) hypothesized that response to AAD therapy might also be genotype-dependent. Testing first in a discovery cohort of 478 patients, the authors identified an association between a response to AAD therapy and the rs10033464 SNP, but not with the other SNPs tested.…”

Not everything about atrial fibrillation is a hot topic: drug-induced atrial fibrillation is an exception

“…Certain variations of these genes will alter the metabolism of warfarin, subsequently the dose requirement of warfarin [7,8]. Similarly, the SNP of cardiac ionic channel genes has been associated with the susceptibility to different arrhythmias including AF and the efficacy of antiarrhythmic drugs [9][10][11]. It is possible that patients carrying an AF-predisposing polymorphic genetic variation are more likely to develop AF compared to the "non-carriers" after taking a specific drug.…”