Arg389Gly-β1-adrenergic receptors determine improvement in left ventricular systolic function in nonischemic cardiomyopathy patients with heart failure after chronic treatment with carvedilol

Lu Chen, Deborah Meyers, George Javorsky, Darryl Burstow, Pakorn Lolekha, Margaret Lucas, Annalese B.T. Semmler, Santiyagu M. Savarimuthu, Kwun M. Fong, Ian A. Yang, John Atherton, Andrew J. Galbraith, William A. Parsonage, Peter Molenaar

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

OBJECTIVE: Administration of the β-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 β1-adrenergic and β2-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 β1-adrenergic and β2-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-β1-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 β1-adrenergic and β2-adrenergic receptor polymorphisms (P>0.05). CONCLUSION: In patients with nonischemic dilated cardiomyopathy, carvedilol leads to a significantly greater improvement in LVEF in patients with the Arg389Arg-β1 adrenergic receptor phenotype.

Original languageEnglish (US)
Pages (from-to)941-949
Number of pages9
JournalPharmacogenetics and Genomics
Volume17
Issue number11
DOIs
StatePublished - Nov 2007
Externally publishedYes

Keywords

  • Beta-adrenergic receptor-blocking drugs
  • Beta1-adrenergic and beta2-adrenergic receptors
  • Cardiomyopathy
  • Carvedilol
  • Genetic polymorphisms
  • Heart failure

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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