Kaye David M, Smirk Belinda, Williams Carolyn, Jennings Garry, Esler Murray, Holst Dianne
Heart Centre, Alfred Hospital and Baker Medical Reserach Insititute, Melbourne, Victoria, Australia.
Pharmacogenetics. 2003 Jul;13(7):379-82. doi: 10.1097/00008571-200307000-00002.
Although the widespread introduction of beta-adrenoceptor antagonists into the management of congestive heart failure (CHF) has led to significant improvements in morbidity and mortality, it is also apparent that clinical responses to this therapy vary substantially. With the recognition that functionally significant genetic polymorphisms of the beta2-adrenoceptor exist with clinically relevant allelic frequency, we hypothesized that beta2-adrenoceptor genotype may affect the response to carvedilol. The clinical response, influence on left ventricular function and beta2-adrenoceptor (beta2AR) genotype was determined in 80 patients treated with carvedilol. A clinically significant improvement in left ventricular function (good responder) was defined as an absolute improvement of 10% in the left ventricular ejection fraction or 5% in the fractional shortening. Consistent with studies performed in vitro on the influence of beta2AR genotype and receptor desensitization, subjects who were homozygous for the allele encoding the Gln27 polymorphism displayed a significantly lower proportion of good responders than patients who were homozygous or heterozygous for the Glu27 polymorphism (26% versus 63%, P=0.003). These data demonstrate a significant influence of beta2AR genotype in the response to carvedilol in CHF patients. Accordingly, determination of beta2AR status may be of value in the tailoring of individual therapy in patients with CHF.
尽管β肾上腺素能受体拮抗剂广泛应用于充血性心力衰竭(CHF)的治疗,显著改善了发病率和死亡率,但显然这种治疗的临床反应差异很大。鉴于已认识到β2肾上腺素能受体存在具有临床相关等位基因频率的功能显著的基因多态性,我们推测β2肾上腺素能受体基因型可能影响对卡维地洛的反应。对80例接受卡维地洛治疗的患者测定了临床反应、对左心室功能的影响以及β2肾上腺素能受体(β2AR)基因型。左心室功能的临床显著改善(良好反应者)定义为左心室射血分数绝对提高10%或缩短分数提高5%。与体外进行的关于β2AR基因型和受体脱敏影响的研究一致,编码Gln27多态性的等位基因纯合子受试者的良好反应者比例显著低于Glu27多态性纯合子或杂合子患者(26%对63%,P = 0.003)。这些数据表明β2AR基因型对CHF患者对卡维地洛的反应有显著影响。因此,测定β2AR状态可能对CHF患者个体化治疗的调整有价值。