The Arg389Gly β1-adrenoceptor gene polymorphism determines contractile response to catecholamines

Objectives Recently, the Arg389Gly beta(1)-adrenoceptor (beta(1)AR) gene polymorphism has been detected. The Arg variant exhibited increased responsiveness to agonist-induced stimulation in vitro. Functional studies in isolated human atrial muscle strips and in-vivo studies revealed contradictory results regarding the functional relevance of this polymorphism. We sought to characterize the functional consequences of the Arg389Gly beta(1)-AR polymorphism in 30 consecutive healthy male volunteers in vivo. Methods beta(1)-AR genotype was determined by PCR and restriction analysis, which was confirmed by DNA sequencing. We compared heart rate, blood pressure, and contractile response of the various genotype carriers with a modified dobutamine stress echocardiography protocol. Results Subjects homozygous for the Arg389 beta(1)AR showed a significantly higher increase in fractional shortening upon cumulative doses of dobutamine as compared to subjects carrying one or two copies of the Gly389 allele. A statistically significant difference was observed at a dobutamine dose of 10 mug/kg/min (46.5 +/- 1.3 vs. 41.8 +/- 1.0%; P = 0.023) and was maximal at 40 mug/kg/min (61.9 +/- 1.4 vs. 52.8 +/- 1.6; P = 0.001). As a result, the systolic blood pressure response to dobutamine was significantly enhanced in individuals homozygous for the Arg389 allele, whereas the effect on heart rate did not differ between the two groups. Normalization for changing afterload conditions by calculating the pressure-dimension ratio revealed similar effects, indicating that the beta(1)AR-mediated effects are mainly a result of increased myocardial inotropy. Conclusion These data indicate that the Arg389Gly beta(1)AR polymorphism is functionally relevant in vivo and determines contractile responsiveness to catecholamines in humans. (C) 2004 Lippincott Williams Wilkins.