Blunted cardiac responses to receptor activation in subjects with Thr164Ile beta(2)-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.


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.
Department of Pharmacology, University of Halle, Germany.
O E
OE
Brodde
R
R
Büscher
R
R
Tellkamp
J
J
Radke
S
S
Dhein
P A
PA
Insel
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D019943:Amino Acid Substitution; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006334:Heart Function Tests / Q000187:drug effects; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D013726:Terbutaline / Q000494:pharmacology*; D013912:Threonine / Q000235:genetics
D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D007532:Isoleucine; D013912:Threonine; D013726:Terbutaline