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.

Background Randomized studies have shown that ventricular rate-control is an acceptable treatment strategy in patients with atrial fibrillation (AF). However, identification of patients who will adequately respond to rate control therapy remains a challenge. Objectives In this study, we evaluated the impact of two common β1-adrenergic receptor (β1-ADR) polymorphisms (G389R and S49G) on response to ventricular rate control therapy in patients with AF. Methods We studied 543 subjects (63% men; age 61.8 ± 14) prospectively enrolled in the Vanderbilt AF registry and managed with rate control strategy. A ‘responder’ displayed adequate ventricular rate control based on the AFFIRM criteria: 1. Average heart rate (HR) at rest ≤80 bpm and 2. Maximum HR during 6-min walk test ≤110 bpm or average HR during 24-hr Holter ≤100 bpm. Result 295 (54.3%) met the AFFIRM criteria. Baseline clinical characteristics were similar in responders and non-responders except for mean resting heart rate (76 ± 20 vs. 70 ± 15; P <0.01) and smoking (6% vs. 1%; P <0.01). Multiple clinical variables (age, gender, HTN) failed to predict response to rate-control therapy. By contrast, carriers of Gly variant at 389 were more likely to respond favorably to rate control therapy; 60% vs. 51% in Arg389Arg genotype, P = 0.04. This association persisted after correction for multiple clinical factors (OR 1.42, 95% CI 1.00–2.03, P<0.05). Among responders, subjects carrying the Gly389 variant required the lowest doses of rate-control meds; atenolol 92 mg vs. 68 mg; carvedilol 44 mg vs. 20 mg; metoprolol 80 mg vs. 72mg; diltiazem 212 mg vs. 180 mg and verapamil 276 mg vs. 200 mg respectively (P < 0.01 for all comparisons). Conclusion We have identified a common β1-ADR polymorphism, G389R that is associated with adequate response to rate control therapy in AF patients. Gly389 is a ‘loss of function’ variant, consequently, for the same adrenergic stimulation it produces reduced levels of adenyl cyclase and hence attenuates the β-adrenergic cascade. Mechanistically, the effect of rate-control drugs will be synergistic with that of the Gly389 variant, which could possibly explain our findings. These findings represent a step forward in development of a long-term strategy of selecting treatment options in AF based on genotype.

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