title: Beta-adrenoceptor genotype influences the response to carvedilol in patients with congestive heart failure.
abstract: Although the widespread introduction of beta-adrenoceptor antagonists into the management of congestive heart failure (CHF) has led to significant improvements in morbidity and mortality, it is also apparent that clinical responses to this therapy vary substantially. With the recognition that functionally significant genetic polymorphisms of the beta2-adrenoceptor exist with clinically relevant allelic frequency, we hypothesized that beta2-adrenoceptor genotype may affect the response to carvedilol. The clinical response, influence on left ventricular function and beta2-adrenoceptor (beta2AR) genotype was determined in 80 patients treated with carvedilol. A clinically significant improvement in left ventricular function (good responder) was defined as an absolute improvement of 10% in the left ventricular ejection fraction or 5% in the fractional shortening. Consistent with studies performed in vitro on the influence of beta2AR genotype and receptor desensitization, subjects who were homozygous for the allele encoding the Gln27 polymorphism displayed a significantly lower proportion of good responders than patients who were homozygous or heterozygous for the Glu27 polymorphism (26% versus 63%, P=0.003). These data demonstrate a significant influence of beta2AR genotype in the response to carvedilol in CHF patients. Accordingly, determination of beta2AR status may be of value in the tailoring of individual therapy in patients with CHF.
authors.affiliation: Heart Centre, Alfred Hospital and Baker Medical Reserach Insititute, Melbourne, Victoria, Australia. d.kaye@alfred.org.au
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
authors.forename: Belinda
authors.initials: B
authors.lastname: Smirk
authors.forename: Carolyn
authors.initials: C
authors.lastname: Williams
authors.forename: Garry
authors.initials: G
authors.lastname: Jennings
authors.forename: Murray
authors.initials: M
authors.lastname: Esler
authors.forename: Dianne
authors.initials: D
authors.lastname: Holst
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006333:Heart Failure / Q000188:drug therapy*; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011412:Propanolamines / Q000627:therapeutic use*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D000077261:Carvedilol