Chen Lu, Meyers Deborah, Javorsky George, Burstow Darryl, Lolekha Pakorn, Lucas Margaret, Semmler Annalese B T, Savarimuthu Santiyagu M, Fong Kwun M, Yang Ian A, Atherton John, Galbraith Andrew J, Parsonage William A, Molenaar Peter
Department of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
Pharmacogenet Genomics. 2007 Nov;17(11):941-9. doi: 10.1097/FPC.0b013e3282ef7354.
Administration of the beta-adrenergic receptor blocker carvedilol to patients with chronic heart failure leads to clinically significant benefits, including improvement in left ventricular systolic function in some, but not all, patients. We sought to determine the basis of the variable effect obtained with carvedilol in patients with heart failure. Carvedilol blocks both beta1-adrenergic and beta2-adrenergic receptors, and both receptors exist as polymorphisms. We aimed to determine whether these polymorphisms contribute to variability in response to carvedilol in patients with chronic heart failure.
We retrospectively and prospectively investigated 135 patients with nonischemic cardiomyopathy and chronic stable heart failure (New York Heart Association class II, III) treated with carvedilol. Baseline echocardiography was obtained before introduction of carvedilol and repeated after stabilization of a maximally tolerated dose of carvedilol (50-100 mg/day) for at least 1 year. Polymerase chain reaction and restriction fragment length polymorphism analysis were used to genotype beta1-adrenergic and beta2-adrenergic receptor polymorphisms.
When grouped according to receptor polymorphisms patients were well matched for severity of heart failure, comorbidity and treatment. No significant difference was observed in baseline left ventricular ejection fraction (LVEF) between groups (P>0.05). After 1.5 years of treatment with carvedilol patients with Arg389Arg-beta1-adrenergic receptors had a significantly greater improvement in LVEF compared with Gly389 carriers (Arg389Arg 18.8%; Arg389Gly 9.4%; Gly389Gly 6.0%; P<0.001) whereas there were no differences attributable to other beta1-adrenergic and beta2-adrenergic receptor polymorphisms (P>0.05).
In patients with nonischemic dilated cardiomyopathy, carvedilol leads to a significantly greater improvement in LVEF in patients with the Arg389Arg-beta1 adrenergic receptor phenotype.
对慢性心力衰竭患者使用β-肾上腺素能受体阻滞剂卡维地洛可带来显著的临床益处，包括部分（而非全部）患者左心室收缩功能的改善。我们试图确定卡维地洛在心力衰竭患者中产生不同效果的原因。卡维地洛可阻断β1-肾上腺素能受体和β2-肾上腺素能受体，且这两种受体均存在基因多态性。我们旨在确定这些基因多态性是否会导致慢性心力衰竭患者对卡维地洛的反应存在差异。
我们对135例接受卡维地洛治疗的非缺血性心肌病和慢性稳定心力衰竭（纽约心脏协会II级、III级）患者进行了回顾性和前瞻性研究。在开始使用卡维地洛前进行基线超声心动图检查，并在最大耐受剂量（50 - 100毫克/天）的卡维地洛稳定治疗至少1年后重复检查。采用聚合酶链反应和限制性片段长度多态性分析对β1-肾上腺素能受体和β2-肾上腺素能受体基因多态性进行基因分型。
根据受体基因多态性分组时，患者在心力衰竭严重程度、合并症和治疗方面匹配良好。各组间基线左心室射血分数（LVEF）无显著差异（P>0.05）。使用卡维地洛治疗1.5年后，与携带Gly389的患者相比，具有Arg389Arg-β1-肾上腺素能受体的患者LVEF改善更为显著（Arg389Arg为18.8%；Arg389Gly为9.4%；Gly389Gly为6.0%；P<0.001），而其他β1-肾上腺素能受体和β2-肾上腺素能受体基因多态性无差异（P>0.05）。
在非缺血性扩张型心肌病患者中，卡维地洛可使具有Arg389Arg-β1肾上腺素能受体表型的患者LVEF得到更显著的改善。
