比索洛尔治疗心力衰竭疗效和β_1受体多态性的相关性研究

β_1-adrenergic receptor(Arg389Gly)polymorphism and response to bisoprolol in patients with chronic heart failure

目的探讨β_1受体(Arg389Gly)基因多态性和靶剂量比索洛尔治疗慢性心力衰竭(心衰)疗效的相关性,预测心衰的预后。方法 110例心衰患者,靶剂量比索洛尔治疗3个月后作β_1受体 Arg389Gly 多态性测定,将患者分成 CC 组(Arg389Arg)、CG 组(Arg389Gly)、GG 组(Gly389Gly),观察治疗前后各项心功能指标变化的组间差异。另选取100例正常健康人群,比较正常人群和心衰患者之间基因型频率。结果本试验测定的上海地区健康人群和心衰患者β_1受体 Arg389Arg、Arg389Gly、Gly389Gly 基因型频率分别为0.53、0.40和0.07,0.51、0.40和0.09,均符合 Hardy-Weinberg 定律(x^2=0.135,P=0.713;x^2=0.002,P=0.966)。心衰患者三种基因型之间一般临床特征、心脏结构和心功能情况差异无统计学意义(P>0.05)。比索洛尔治疗后,左室射血分数在 CC 组和 GG 组分别升高了(7.37±6.72)%和(1.33±2.87)%,脑利钠肽在 CC 组和 GG 组分别下降了(177.67±111.87)ng/L 和(75.67±123.63)ng/L,两组间差异有统计学意义(均为 P<0.01)。结论上海地区健康人群和心衰患者β_1受体389位点基因型频率分布相似,β_1受体 Arg389Gly 多态性和心衰的严重程度无关。CC 组心衰患者对β_1受体阻滞剂治疗更为敏感,预后也较 GG 组好。

Objective The purpose of this study was to investigate the relation between the Arg389Gly polymorphism of the β1-AR gene and chronic heart faihire（CHF） and to evaluate the effect of this polymorphism on clinieal response to β-adrenoceptor blockade （bisoprolol） in patients with CHF. Methods One hundred and ten patients with stable CHF receiving basic therapy for heart faihire were included. Before initiation and 3 months after the maximal tolerated dose of bisoprolol was reached, all indices （ineluding BP, HR, LAD, LVEDD, LVESD, LVEF, BNP level, 6 min walk distance ） were measured and compared with the Arg389Gly genotypes, which identified by PCR-restrietion fragment length polymorphism analysis. We also determined the Arg389Gly genotypes in 100 healthy control subjects, and compared the distribution of Arg389Gly genotypes with that in CHF. Results No difference was observed between the two groups in any of the three genotypes （ CC, CG and GG）. The prevalenees of the three genotypes in normal subjects and patients with CHF were Arg389Arg 0. 53 vs. 0.51, Arg389Gly 0. 40 vs. 0. 40, Gly38Gly 0. 07 vs. 0. 09, respectively. After 3 months of biseprolol usage, a significant improvement in LVEF was observed in CC group, which increased from （36. 7 ± 8. 63 ） % to （44. 1 ± 9. 53 ） %, CG group, from （35.76±8.39）% to （42.90 ±9.41）%, but not GG group, from （36.00 ±5.66）% to （37. 33±5.64）%. The improvement in BNP was also observed in CC [from （502. 93 ±160. 80） ng/L to （325.26 ± 135. 63） ng/L], CG [from （525.76 ± 157.66） ng/L to （331.79 ± 133.97） ng/L], but not GG [from （505. 33 ± 125.07） ng/L to （429. 67 ± 182. 39） ng/L]. Arg389-homozygous patients showed a substantially greater improvement in LVEF and BNP, compared with Gly389-homozygous patients （all P 〈 0. 01 ）. Conclusions There was no difference in the prevalence of the three genotypes between healthy and CHF subjects. The Gly389 polymorphism of the β1-AR gene was not associated with an increased risk of CHF. The Arg389 variant of the β1-AR gene was associated with a greater response to biseprolol than that of the Gly389 variant in patients with CHF.