University of Colorado Health Sciences Center, Aurora, CO 80045, USA.
Circ Heart Fail. 2010 Jan;3(1):21-8. doi: 10.1161/CIRCHEARTFAILURE.109.885962. Epub 2009 Oct 30.
Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional alpha(2C)-adrenergic receptors (ARs), which exhibit genetic variation in humans. Bucindolol is a novel beta-AR blocking agent that also lowers systemic norepinephrine and thus is also a sympatholytic agent. This study investigated whether alpha(2C)-AR polymorphisms affect sympatholytic effects of bucindolol in patients with heart failure.
In the beta-Blocker Evaluation of Survival Trial, adrenergic activation was estimated by systemic venous norepinephrine measured at baseline, 3 months, and 12 months posttreatment in patients treated with placebo or bucindolol. In the beta-Blocker Evaluation of Survival Trial AR polymorphism substudy, DNA was collected from 1040 of the 2708 randomized patients, and alpha(2C)-AR gene polymorphisms (alpha(2C) Del322-325 or the wild-type counterpart) were measured by polymerase chain reaction and gel electrophoresis. Patients who were alpha(2C) Del carriers (heterozygotes or homozygotes) exhibited a much greater sympatholytic response to bucindolol (decrease in norepinephrine at 3 months of 153+/-57 pg/mL, P=0.012 compared with placebo versus decrease of 50+/-13 pg/mL in alpha(2C) wild type, P=0.0005 versus placebo; P=0.010 by interaction test). alpha(2C) Del carriers had no evidence of a favorable survival benefit from bucindolol (mortality compared with placebo hazard ratio, 1.09; 95% CI, 0.57 to 2.08; P=0.80), whereas bucindolol-treated subjects who were wild type for the alpha(2C)-AR had a 30% reduction in mortality (hazard ratio, 0.70; 95% CI, 0.51 to 0.96; P=0.025).
In the beta-Blocker Evaluation of Survival Trial AR polymorphism substudy, the norepinephrine lowering and clinical therapeutic responses to bucindolol were strongly influenced by alpha(2C) receptor genotype.
肾上腺素能激活是慢性心力衰竭患者预后的一个重要决定因素。肾上腺素能活性部分受神经前α2C-肾上腺素能受体（AR）调节，人类α2C-AR 存在基因变异。比索洛尔是一种新型的β-AR 阻断剂，也能降低全身去甲肾上腺素，因此也是一种交感神经抑制剂。本研究探讨α2C-AR 多态性是否影响心力衰竭患者比索洛尔的交感神经抑制作用。
在β-受体阻滞剂心力衰竭生存试验中，通过测定基线、治疗后 3 个月和 12 个月时的静脉血去甲肾上腺素来评估治疗患者的肾上腺素能激活情况。在β-受体阻滞剂心力衰竭生存试验 AR 多态性亚研究中，从 2708 名随机患者中采集了 1040 名患者的 DNA，并用聚合酶链反应和凝胶电泳法测定α2C-AR 基因多态性（α2C-Del322-325 或野生型）。α2C-Del 携带者（杂合子或纯合子）对比索洛尔的交感神经抑制反应更大（3 个月时去甲肾上腺素下降 153+/-57 pg/mL，与安慰剂相比，p=0.012；与安慰剂相比，α2C 野生型下降 50+/-13 pg/mL，p=0.0005；交互检验，p=0.010）。α2C-Del 携带者没有从比索洛尔治疗中获益的证据（与安慰剂相比，死亡率的危险比为 1.09；95%CI，0.57 至 2.08；p=0.80），而α2C-AR 野生型的比索洛尔治疗患者死亡率降低 30%（危险比，0.70；95%CI，0.51 至 0.96；p=0.025）。
在β-受体阻滞剂心力衰竭生存试验 AR 多态性亚研究中，比索洛尔的去甲肾上腺素降低和临床治疗反应受α2C 受体基因型的强烈影响。
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