A Common β1-Adrenergic Receptor Polymorphism Predicts Favorable Response to Rate-Control Therapy in Atrial Fibrillation

Abstract

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.

Status of Antiarrhythmic Drug Development for Atrial Fibrillation

“…A study by Nia et al demonstrated that the conversion rate of AF with flecainide was highest in patients with the Arg/Arg genotype and lower in glycine carriers. 73 Patients who were glycine carriers did, however, have lower heart rates during AF, corroborating the findings by Parvez et al 77 B 1 AR polymorphisms may alter the efficacy of flecainide because adrenoceptor stimulation induces sodium channel inhibition; 73 therefore, the enhanced adrenergic signaling associated with the Arg/Arg polymorphism may synergistically inhibit sodium channels with flecainide. This adrenergic influence on sodium channels might also explain why the ACT I trial found that patients who had their AF successfully cardioverted with the sodium channel blocker vernakalant had a higher baseline heart rate, which is associated with the Arg/Arg polymorphism.…”

“…Interestingly, a study by Parvez et al 77 demonstrated that the loss of function glycine 389 polymorphism is associated with a significantly better response to rate-controlling therapies in patients with AF. This may be explained because the rate-control therapies can work synergistically with the attenuated β 1 -adrenergic cascade caused by this genotype.…”

A Physiologic Approach to the Pharmacogenomics of Hypertension

“…Several small studies have revealed positive results with the C allele corresponding to an improved response to beta-blockade as defined by reduction in BP or heart failure endpoints [47][48][49][50][51] . Studies have also illustrated contradictory results where the G allele is associated with more favorable rate control with verapamil and multiple beta-blockers 52 .…”

Do we need an individual approach to atrial fibrillation and adrenergic overload in the critically ill?

“…Interestingly, the loss of function glycine 389 polymorphism is associated with a significantly better response to rate-controlling therapies in patients with AF. (43) This may be explained because the rate-control therapies can work synergistically with the attenuated β1-adrenergic cascade caused by this genotype. β1-AR polymorphisms could also influence the efficacy of amiodarone because it possesses antiadrenergic effects.…”