Arg389Gly-beta1-adrenergic receptors determine improvement in left ventricular systolic function in nonischemic cardiomyopathy patients with heart failure after chronic treatment with carvedilol.
OBJECTIVE
Administration of the beta-adrenergic receptor blocker carvedilol to patients with chronic heart failure leads to clinically significant benefits, including improvement in left ventricular systolic function in some, but not all, patients. We sought to determine the basis of the variable effect obtained with carvedilol in patients with heart failure. Carvedilol blocks both beta1-adrenergic and beta2-adrenergic receptors, and both receptors exist as polymorphisms. We aimed to determine whether these polymorphisms contribute to variability in response to carvedilol in patients with chronic heart failure.


METHODS
We retrospectively and prospectively investigated 135 patients with nonischemic cardiomyopathy and chronic stable heart failure (New York Heart Association class II, III) treated with carvedilol. Baseline echocardiography was obtained before introduction of carvedilol and repeated after stabilization of a maximally tolerated dose of carvedilol (50-100 mg/day) for at least 1 year. Polymerase chain reaction and restriction fragment length polymorphism analysis were used to genotype beta1-adrenergic and beta2-adrenergic receptor polymorphisms.


RESULTS
When grouped according to receptor polymorphisms patients were well matched for severity of heart failure, comorbidity and treatment. No significant difference was observed in baseline left ventricular ejection fraction (LVEF) between groups (P>0.05). After 1.5 years of treatment with carvedilol patients with Arg389Arg-beta1-adrenergic receptors had a significantly greater improvement in LVEF compared with Gly389 carriers (Arg389Arg 18.8%; Arg389Gly 9.4%; Gly389Gly 6.0%; P<0.001) whereas there were no differences attributable to other beta1-adrenergic and beta2-adrenergic receptor polymorphisms (P>0.05).


CONCLUSIONS
In patients with nonischemic dilated cardiomyopathy, carvedilol leads to a significantly greater improvement in LVEF in patients with the Arg389Arg-beta1 adrenergic receptor phenotype.
Chen
Lu
L
Department of Medicine, The University of Queensland, Brisbane, Queensland, Australia. lchen@somc.uq.edu.au
Meyers
Deborah
D
Javorsky
George
G
Burstow
Darryl
D
Lolekha
Pakorn
P
Lucas
Margaret
M
Semmler
Annalese B T
AB
Savarimuthu
Santiyagu M
SM
Fong
Kwun M
KM
Yang
Ian A
IA
Atherton
John
J
Galbraith
Andrew J
AJ
Parsonage
William A
WA
Molenaar
Peter
P
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D002227:Carbazoles / Q000627:therapeutic use*; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000503:physiopathology; D000077261:Carvedilol; D004452:Echocardiography; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011412:Propanolamines / Q000627:therapeutic use*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*; D013599:Systole / Q000502:physiology; D016277:Ventricular Function, Left / Q000502:physiology*
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D000077261:Carvedilol