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 beta-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 beta-blocker therapy according to genotype.
Adrenergic beta-1 Receptor Antagonists/adverse effects/*therapeutic use ; Adult ; Aged ; Bisoprolol/adverse effects/*therapeutic use ; Female ; Gene Frequency ; Genotype ; Heart Failure/diagnosis/*drug therapy/*genetics/physiopathology ; Heart Rate/drug effects ; Humans ; Male ; Maximum Tolerated Dose ; Middle Aged ; Pharmacogenomic Testing ; Phenotype ; *Polymorphism, Genetic ; Precision Medicine ; Receptors, Adrenergic, beta-1/*drug effects/*genetics ; Republic of Korea ; Stroke Volume/drug effects ; Time Factors ; Treatment Outcome ; Ventricular Function, Left/drug effects ; Ventricular Remodeling/drug effects

The purpose of this study was to investigate the effect of the overexpression of &beta;(1)-adrenoceptor (&beta;(1)-AR) on the contractile function and cell survival of rat cardiomyocytes injured by isoprenaline (ISO). The rat cardiomyocytes were isolated using the collagenase perfusion method and then transfected with &beta;(1)-AR gene using adenoviruses vector. Four hours after the infection, the rat cardiomyocytes were treated with ISO for 24 h to imitate the high catecholamine levels of chronic heart failure. Western blot was performed to measure the protein expression of &beta;(1)-AR. The percentages of rod cells were measured to test cell survival. Video-based edge-detection system was used to measure the contractile function of the cardiomyocytes. The results indicated that the expression of &beta;(1)-AR in &beta;(1)-AR-transfected cardiomyocytes was significantly increased compared with that in control group (P<0.01). Meanwhile, &beta;(1)-AR transfection also increased &beta;(1)-AR protein levels in ISO-injured cardiomyocytes. The cardiomyocyte survival was significantly decreased in ISO group compared with that in control group. &beta;(1)-AR-transfection alone had no effect on cardiomyocyte survival in &beta;(1)-AR group, but it further decreased cardiomyocyte survival in &beta;(1)-AR+ISO group. Contractile amplitudes of ISO-injured cardiomyocytes were significantly decreased regardless of whether they were transfected with &beta;(1)-AR or not, although &beta;(1)-AR-transfected cardiomyocytes showed significantly increased contractile function compared with control group (P<0.05). These results suggest that the overexpression of &beta;(1)-AR has no significant protective effect on rat cardiomyocytes injured by ISO.
Animals ; Cell Survival ; Cells, Cultured ; Female ; Heart Failure ; metabolism ; Isoproterenol ; pharmacology ; Male ; Myocardial Contraction ; drug effects ; Myocytes, Cardiac ; cytology ; metabolism ; pathology ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic, beta-1 ; genetics ; metabolism ; Transfection