Impact of the β-1 adrenergic receptor polymorphism on tolerability and efficacy of bisoprolol therapy in Korean heart failure patients: association between β adrenergic receptor polymorphism and bisoprolol therapy in heart failure (ABBA) study

Abstract

Background/aims: We evaluated the association between coding region variants of adrenergic receptor genes and therapeutic effect in patients with congestive heart failure (CHF).

Methods: One hundred patients with stable CHF (left ventricular ejection fraction [LVEF] < 45%) were enrolled. Enrolled patients started 1.25 mg bisoprolol treatment once daily, then up-titrated to the maximally tolerable dose, at which they were treated for 1 year.

Results: Genotypic analysis was carried out, but the results were blinded to the investigators throughout the study period. At position 389 of the β-1 adrenergic receptor gene (ADRB1), the observed minor Gly allele frequency (Gly389Arg + Gly389Gly) was 0.21, and no deviation from Hardy-Weinberg equilibrium was observed in the genotypic distribution of Arg389Gly (p = 0.75). Heart rate was reduced from 80.8 ± 14.3 to 70.0 ± 15.0 beats per minute (p < 0.0001). There was no significant difference in final heart rate across genotypes. However, the Arg389Arg genotype group required significantly more bisoprolol compared to the Gly389X (Gly389Arg + Gly389Gly) group (5.26 ± 2.62 mg vs. 3.96 ± 2.05 mg, p = 0.022). There were no significant differences in LVEF changes or remodeling between two groups. Also, changes in exercise capacity and brain natriuretic peptide level were not significant. However, interestingly, there was a two-fold higher rate of readmission (21.2% vs. 10.0%, p = 0.162) and one CHF-related death in the Arg389Arg group.

Conclusions: The ADRB1 Gly389X genotype showed greater response to bisoprolol than the Arg389Arg genotype, suggesting the potential of individually tailoring β-blocker therapy according to genotype.

Keywords: Beta-blocker; Heart failure; Polymorphism; Receptors, adrenergic, beta.

Figure 1.

Study design.

Figure 2.

Study flow chart. ITT, intention-to-treat; LVEF, left ventricular ejection fraction; PP, per-protocol.

Figure 3.

Bisoprolol response on heart rate according to β-1 adrenergic receptor gene 1 (ADRB1) genotype. (A) Up-titration curve of bisoprolol according to ADRB1 genotype. (B) Final bisoprolol dose after 12 weeks of up-titration. The p values are computed from two sample t test. (C) Heart rate change after 6 months of bisoprolol treatment according to ADRB1 genotype. The p values are computed from paired t test between baseline and week 24. bpm, beats per minute.

Figure 4.

Left ventricular remodeling following bisoprolol treatment according to β-1 adrenergic receptor gene 1 (ADRB1) genotype. The p values are computed from paired t test between baseline and week 24. (A) Left ventricular ejection fraction (LVEF) change following bisoprolol treatment. (B) Left ventricular volume change following bisoprolol treatment. (C) Left ventricular E/e’ ratio change following bisoprolol treatment. LVEDV, left ventricular end-diastolic volume.

Figure 5.

Short-term and long-term functional improvements according to β-1 adrenergic receptor gene 1 (ADRB1) genotype. (A) Six-minute walk test before and 24 weeks after bisoprolol therapy. The p values are computed from paired t test between baseline and week 24. (B) B-natriuretic peptide (BNP) level before 24 weeks after bisoprolol therapy. As BNP level showed a skewed distribution, the results were compared after log-transformation. The p values are computed from paired t test between baseline and week 24. (C) Cardiovascular event for 1 year after bisoprolol treatment. The p values are computed from chi-square test. LogBNP, log-transformed B-natriuretic peptide.