Wagoner Lynne E, Craft Laura L, Zengel Paul, McGuire Nancy, Rathz Deborah A, Dorn Gerald W, Liggett Stephen B
Department of Cardiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0564, USA.
Am Heart J. 2002 Nov;144(5):840-6. doi: 10.1067/mhj.2002.125325.
Exercise performance in patients with congestive heart failure is partially dependent on cardiac beta1-adrenergic receptor (beta1AR) function. There are 2 common polymorphisms of the beta1AR gene that alter the encoded amino acids at positions 49 (Ser or Gly) and 389 (Gly or Arg) and alter receptor function in vitro. Their relevance to modification of cardiac function in heart failure is not known.
Exercise testing was performed in 263 patients with idiopathic or ischemic cardiomyopathy (left ventricular ejection fraction approximately 25%). Potential associations were sought between beta1AR genotypes and the primary outcome variables of peak oxygen consumption (VO2), heart rate response, and exercise time.
The major determinants of exercise capacity were the polymorphisms at position 389, where patients homozygous for Gly389 had significantly lower peak VO2 compared with those with Arg389 (14.5 +/- 0.6 vs 17.7 +/- 0.4 mL/kg/min, P =.006), despite similar clinical characteristics including left ventricular ejection fraction. Consistent with a gene dose-response, heterozygosity was associated with an intermediate response (16.9 +/- 0.6 mL/kg/min, P <.05). When position 49 genotypes were included, a graded relationship between the 5 2-locus haplotypes and VO2 was found. Two haplotypes displayed the most divergent peak VO2: homozygous Gly389/Ser49, and homozygous Arg389/Gly49 carriers (14.4 +/- 0.5 vs 18.2 +/- 0.8 mL/kg/min, P =.001). Genotype did not predict the heart rate response. The above results were independent of beta-blocker or other medication use, left ventricular ejection fraction, beta2AR genotype, or other demographic and clinical characteristics.
beta1AR polymorphisms are a significant determinant of exercise capacity in patients with congestive heart failure. Early identification, by genetic testing for these polymorphisms, of heart failure patients at risk for development of depressed exercise capacity may be useful for initiation of specific therapy tailored to genotype.
充血性心力衰竭患者的运动能力部分取决于心脏β1 - 肾上腺素能受体（β1AR）功能。β1AR基因存在两种常见的多态性，它们会改变第49位（丝氨酸或甘氨酸）和第389位（甘氨酸或精氨酸）编码的氨基酸，并在体外改变受体功能。它们与心力衰竭时心脏功能改变的相关性尚不清楚。
对263例特发性或缺血性心肌病患者（左心室射血分数约为25%）进行运动测试。研究β1AR基因多态性与峰值耗氧量（VO2）、心率反应和运动时间等主要结局变量之间的潜在关联。
运动能力的主要决定因素是第389位的多态性，与携带精氨酸389的患者相比，甘氨酸389纯合子患者的峰值VO2显著降低（14.5±0.6 vs 17.7±0.4 mL/kg/min，P = 0.006），尽管包括左心室射血分数在内的临床特征相似。与基因剂量反应一致，杂合子与中间反应相关（16.9±0.6 mL/kg/min，P < 0.05）。当纳入第49位基因型时，发现5种双位点单倍型与VO2之间存在分级关系。两种单倍型的峰值VO2差异最大：甘氨酸389/丝氨酸49纯合子和精氨酸389/甘氨酸49纯合子携带者（14.4±0.5 vs 18.2±0.8 mL/kg/min，P = 0.001）。基因型不能预测心率反应。上述结果与β受体阻滞剂或其他药物使用、左心室射血分数、β2AR基因型或其他人口统计学和临床特征无关。
β1AR多态性是充血性心力衰竭患者运动能力的重要决定因素。通过对这些多态性进行基因检测，早期识别有运动能力下降风险的心力衰竭患者，可能有助于启动针对基因型的特异性治疗。
