Blunted Cardiac Responses to Receptor Activation in Subjects With Thr164Ile β₂-Adrenoceptors

BACKGROUND: Recent evidence indicates that certain genotypes of beta(2)-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 approximately 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) beta(2)-AR (ie, Arg16, Gln27, and Thr164). The beta(2)AR 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 beta(2)-AR responsiveness, which may help explain the decreased survival of patients with this genotype in the setting of congestive heart failure.