Blunted Cardiac Responses to Receptor Activation in Subjects With Thr164Ile β 2 -Adrenoceptors

Abstract

Background—Recent evidence indicates that certain genotypes of β₂-adrenoceptors (AR) may indicate an increased risk of cardiovascular disease or an increased rate of disease progression. Of particular importance, the Thr164Ile polymorphism, which is found in ≈4% of humans, shows decreased receptor signaling, blunted cardiac response when expressed in transgenic mice, and is associated with a decreased survival rate in patients with congestive heart failure. Methods and Results—In this study, we compared functional activity, ie, chronotropic (heart rate increases) and inotropic (duration of the electromechanical systole) responses to intravenously administered terbutaline, in 6 subjects (4 women and 2 men) who were heterozygous for Thr164Ile with the responses in 12 volunteers (6 women and 6 men) who were homozygous for wild-type (WT) β₂-AR (ie, Arg16, Gln27, and Thr164). The β₂AR polymorphism significantly affected the dose-response curves for terbutaline-induced inotropic and chronotropic responses: compared with WT individuals, subjects with the Thr164Ile receptor had substantial blunting in maximal increases in heart rate (WT, 29.7±3.9 beats/min; Ile164, 20.7±1.9 beats/min; P=0.016) and a shortening of the duration of electromechanical systole (WT, 51.9±4.5 ms; Ile164, 37.9±4.6 ms; P=0.02). Conclusions—These data show that humans with the Ile164 genotype show blunted cardiac β₂-AR responsiveness, which may help explain the decreased survival of patients with this genotype in the setting of congestive heart failure.