Elsevier

American Heart Journal

Volume 144, Issue 5, November 2002, Pages 840-846
American Heart Journal

Congestive Heart Failure
Polymorphisms of the β1-adrenergic receptor predict exercise capacity in heart failure,☆☆,

https://doi.org/10.1067/mhj.2002.125325Get rights and content

Abstract

Background Exercise performance in patients with congestive heart failure is partially dependent on cardiac β1-adrenergic receptor (β1AR) function. There are 2 common polymorphisms of the β1AR gene that alter the encoded amino acids at positions 49 (Ser or Gly) and 389 (Gly or Arg) and alter receptor function in vitro. Their relevance to modification of cardiac function in heart failure is not known. Methods Exercise testing was performed in 263 patients with idiopathic or ischemic cardiomyopathy (left ventricular ejection fraction ~25%). Potential associations were sought between β1AR genotypes and the primary outcome variables of peak oxygen consumption (VO2), heart rate response, and exercise time. Results The major determinants of exercise capacity were the polymorphisms at position 389, where patients homozygous for Gly389 had significantly lower peak VO2 compared with those with Arg389 (14.5 ± 0.6 vs 17.7 ± 0.4 mL/kg/min, P =.006), despite similar clinical characteristics including left ventricular ejection fraction. Consistent with a gene dose-response, heterozygosity was associated with an intermediate response (16.9 ± 0.6 mL/kg/min, P <.05). When position 49 genotypes were included, a graded relationship between the 5 2-locus haplotypes and VO2 was found. Two haplotypes displayed the most divergent peak VO2: homozygous Gly389/Ser49, and homozygous Arg389/Gly49 carriers (14.4 ± 0.5 vs 18.2 ± 0.8 mL/kg/min, P =.001). Genotype did not predict the heart rate response. The above results were independent of β-blocker or other medication use, left ventricular ejection fraction, β2AR genotype, or other demographic and clinical characteristics. Conclusion β1AR polymorphisms are a significant determinant of exercise capacity in patients with congestive heart failure. Early identification, by genetic testing for these polymorphisms, of heart failure patients at risk for development of depressed exercise capacity may be useful for initiation of specific therapy tailored to genotype. (Am Heart J 2002;144:840-6.)

Section snippets

Patients

The study was approved by the Institutional Review Board of the University of Cincinnati College of Medicine. The group consisted of 263 unrelated sequential white patients with ischemic (n = 111) or idiopathic dilated cardiomyopathy (n = 152) (aged 48.9 ± 1.0 years, New York Heart Association functional class II-IV, left ventricular ejection fraction 26.0% ± 0.8%, 74.5% male) referred to the University of Cincinnati Heart Failure/Transplant Program. At the time of entry into the study,

Results

Table I shows the clinical characteristics of the patients stratified by β1AR genotypes.At position 389, there were 23 homozygous Gly389 patients, 105 heterozygotes, and 135 patients who were homozygous for Arg 389. Table II and Figure 1 show the results from the exercise studies in the 3 groups.

. β1AR polymorphisms at position 389 are associated with differential exercise responses in heart failure. Shown are results from graded exercise studies as described in Methods. Asterisk, P =.006; dagger

Discussion

In this work we found that patients with heart failure with the homozygous Gly389 β1AR polymorphism have significantly depressed exercise performance compared with those with the Arg389 β1AR. Heterozygotes had an intermediate level of performance. A smaller contribution to exercise performance in these patients were the polymorphisms at amino acid position 49. The greatest predictive β1AR genotypes were those that included position 49 and 389 polymorphisms. Importantly, these patients could not

Acknowledgements

We thank Esther Getz for assistance in manuscript preparation.

References (31)

  • A Wellstein et al.

    Beta adrenoceptor subtype binding activity in plasma and beta blockade by propranolol and beta-1 selective bisoprolol in humans: evaluation with Schild-plots

    J Pharmacol Exp Ther

    (1988)
  • E Bulbring et al.

    Catecholamine action on smooth muscle

    Pharmacol Rev

    (1987)
  • SB Liggett

    β-adrenergic receptors in the failing heart: the good, the bad, and the unknown

    J Clin Invest

    (2001)
  • MR Bristow et al.

    β1- and β2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium

    Mol Pharmacol

    (1988)
  • WW Parmley

    Cost-effective cardiology: cost-effective management of heart failure

    Clin Cardiol

    (1996)
  • Cited by (0)

    Supported by NIH grants HL52318, HD07463, and ES06096.

    ☆☆

    Reprint requests: Stephen B. Liggett, MD, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Room G167, Cincinnati, OH 45267-0564.

    E-mail: [email protected]

    View full text