Impact of the β1-Adrenoceptor Arg389Gly Polymorphism on Heart-Rate Responses to Bisoprolol and Carvedilol in Heart-Failure Patients

Abstract

This pharmacogenetic substudy of the prospective, double-blind, randomized CIBIS-ELD trial determined the impact of the β1-adrenoceptor Arg189Gly polymorphism on heart-rate responses to bisoprolol or carvedilol in elderly patients with heart failure (421 with sinus rhythm, 107 with atrial fibrillation). Patients were randomized 1:1 to bisoprolol or carvedilol with a fortnightly dose-doubling scheme and guideline target doses. Patients with sinus rhythm responded essentially identically to bisoprolol and carvedilol, independent of genotype. Atrial fibrillation patients homozygous for Arg389 had a much smaller response to carvedilol than carriers of at least one Gly389 allele (mean difference 12 bpm, P < 0.00001). Carvedilol up to 2 × 12.5 mg did not reduce heart rate in Arg389Arg homozygotes at all. Interestingly, the immediate response to carvedilol did not differ between genotypes. The Arg389Gly polymorphism has a major impact on the heart-rate response to carvedilol (but not bisoprolol) in patients with heart failure plus atrial fibrillation.

A Physiologic Approach to the Pharmacogenomics of Hypertension

“…However, negative studies, including larger, well-powered investigations, predominate suggesting that rs1801253 cannot reliably predict antihypertensive response, rate control, or heart failure outcomes 11,17,[53][54][55][56][57][58] .…”

A frequent Gene Polymorphism Affecting the Heart-rate Response to Carvedilol

“…Instead, the data show slowly developing genotype-specific regulation of atrioventricular node (AVN) conduction, but not of pacemaking in the sinoatrial node. Catecholamines accelerate AVN conduction by stimulating the main depolarizing inward current, I Ca , and shorten the effective refractory period by stimulating I Kur (see review in [16]). b-blockers antagonize these effects and thereby slow AVN conduction velocity.…”

Cardiovascular Pharmacogenomics—Implications for Patients With CKD

“…For example, among elderly patients with AF, the Arg389Gly polymorphism did not impact heart rate response to bisoprolol, whereas the Arg/Arg genotype was associated with a lesser heart rate response to carvedilol. 64 …”