Klinik III für Innere Medizin, Herzzentrum der Universität zu Köln, Kerpener Str. 62, 50937, Cologne, Germany.
Clin Res Cardiol. 2011 Aug;100(8):641-7. doi: 10.1007/s00392-011-0288-1. Epub 2011 Feb 11.
The β(1)-adrenoceptor (β(1)AR) mediates cardiostimulatory effects of catecholamines in the heart. The Arg389Gly polymorphism of the β(1)AR gene has recently been shown to determine the responsiveness to catecholamines in vitro, and we previously reported that dobutamine induced an augmented contractile response in humans homozygous for the Arg389 allele. The aim of the present study was to evaluate whether the Arg389Gly β(1)AR gene polymorphism influences the responsiveness to β-blocker treatment on cardiac contractility.
We investigated 30 healthy male volunteers who were genotyped for the Arg389Gly polymorphism and subjected to modified dobutamine stress-echocardiography (DSE) with and without pretreatment with metoprolol controlled release/extended release (CR/XL). Fractional shortening (FS) as a parameter for left-ventricular contractility and heart rate were measured. To control for pre- and afterload effects, rate corrected velocity of circumferential fiber shortening (Vcfc) was calculated.
Homozygous Arg389 carriers had a significantly higher increase in contractility upon dobutamine stimulation than individuals carrying the Gly389 allele. Pretreatment with metoprolol CR/XL prior to DSE blunted the dobutamine-induced increase of FS and Vcfc in homozygous Arg389 carriers to the level of subjects carrying the Gly389 allele. In the latter group, metoprolol had a modest effect on the dobutamine-induced increase in FS at low concentrations of dobutamine, and no significant effect at peak stress (40 μg/kg/min of dobutamine).
The responsiveness to β-blockers with respect to cardiac contractility is determined by the Arg389Gly β(1)AR gene polymorphism. These findings offer a molecular explanation for interindividual differences in the responsiveness to β-blocker treatment in humans.
β(1)-肾上腺素能受体（β(1)AR）介导儿茶酚胺在心脏中的心脏刺激作用。β(1)AR 基因的 Arg389Gly 多态性最近已被证明决定儿茶酚胺在体外的反应性，我们先前报道过，多巴酚丁胺诱导 Arg389 等位基因纯合子的人类收缩反应增强。本研究的目的是评估 Arg389Gly β(1)AR 基因多态性是否影响心脏收缩对β-阻滞剂治疗的反应性。
我们调查了 30 名健康男性志愿者，他们的 Arg389Gly 多态性进行了基因分型，并接受了美托洛尔控释/缓释（CR/XL）预处理前后的改良多巴酚丁胺应激超声心动图（DSE）检查。左心室收缩功能的参数为缩短分数（FS），心率。为了控制前负荷和后负荷的影响，计算了圆周纤维缩短速度（Vcfc）的速率校正值。
Arg389 纯合子在多巴酚丁胺刺激下的收缩力增加明显高于携带 Gly389 等位基因的个体。在 DSE 前用美托洛尔 CR/XL 预处理，使 Arg389 纯合子的多巴酚丁胺诱导的 FS 和 Vcfc 增加减弱到携带 Gly389 等位基因的个体的水平。在后一组中，美托洛尔在低浓度多巴酚丁胺诱导的 FS 增加中对多巴酚丁胺有适度的作用，在峰值应激（40μg/kg/min 多巴酚丁胺）时无明显作用。
β-阻滞剂对心脏收缩的反应性取决于 Arg389Gly β(1)AR 基因多态性。这些发现为人类对β-阻滞剂治疗反应性的个体差异提供了分子解释。
