(Circulation. 2001;103:1048.)
© 2001 American Heart Association, Inc.
Brief Rapid Communications |
Blunted Cardiac Responses to Receptor Activation in Subjects With Thr164Ile ß2-Adrenoceptors
From the Departments of Pharmacology (O.-E.B., S.D.) and Anesthesiology (R.T., J.R.), University of Halle, Germany; the Department of Pediatric Nephrology (R.B.), University of Essen, Germany; and the Department of Pharmacology (P.A.I.), University of California at San Diego, La Jolla, Calif.
Correspondence to Paul A. Insel, MD, Department of Pharmacology, University of California at San Diego, 9500 Gilman Drive, MC 0636, La Jolla, CA 92093-0636. E-mail pinsel{at}ucsd.edu
Background—Recent
evidence indicates that certain genotypes of
ß2-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) ß2-AR (ie, Arg16, Gln27, and Thr164). The ß2AR 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 ß2-AR responsiveness, which may help explain the decreased survival of patients with this genotype in the setting of congestive heart failure.
Key Words: receptors, adrenergic, beta • myocardial contraction • heart rate • terbutaline • genetics
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