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(Circulation Research. 2000;86:834.)
© 2000 American Heart Association, Inc.

Clinical Research

Polymorphisms of the ß₂-Adrenergic Receptor Determine Exercise Capacity in Patients With Heart Failure

Lynne E. Wagoner, Laura L. Craft, Balkrishna Singh, Damodhar P. Suresh, Paul W. Zengel, Nancy McGuire, William T. Abraham, Thomas C. Chenier, Gerald W. Dorn, II, Stephen B. Liggett

From the Department of Medicine, Divisions of Cardiology (L.E.W., L.L.C., B.S., D.P.S., P.W.Z., N.M., W.T.A., G.W.D.) and Pulmonary Medicine (S.B.L.), and the Institute for Health Policy and Health Services Research (T.C.C.), University of Cincinnati College of Medicine, Cincinnati, Ohio.

Correspondence to Lynne E. Wagoner, MD, University of Cincinnati College of Medicine, 231 Bethesda Ave, PO Box 670542, Cincinnati, OH 45267-0542. E-mail Wagonele{at}ucmail.uc.edu

Abstract—The ß₂-adrenergic receptor (ß₂AR) exists in multiple polymorphic forms with different characteristics. Their relevance to heart failure (HF) physiology is unknown. Cardiopulmonary exercise testing was performed on 232 compensated HF patients with a defined ß₂AR genotype. Patients with the uncommon Ile164 polymorphism had a lower peak O₂ (15.0±0.9 mL · kg^-1 · min^-1) than did patients with Thr164 (17.9±0.9 mL · kg^-1 · min^-1, P<0.0001). The percentage achieved of predicted peak O₂ was also lower in patients with Ile164 (62.3±4.5% versus 71.5±5.1%, P=0.045). The relative risk of a patient having a O₂ 14 mL · kg^-1 · min^-1 who had Ile164 was 8.0 (P=0.009). Catheterization-based invasive exercise testing revealed depressed changes in the exercise-induced cardiac index, systemic vascular resistance, stroke volume, and O₂ in patients with Ile164. The polymorphisms at position 16 also impacted exercise capacity: peak O₂ for Arg16 versus Gly16 was 17.0±0.8 versus 15.6±0.5 mL · kg^-1 · min^-1, respectively (P=0.03). Because the polymorphisms at loci 16 and 27 can occur together, 4 homozygous combinations exist. Patients with Arg16/Glu27 had the highest percentage achieved of predicted peak O₂ (75.7±6.4%), whereas those with Gly16/Gln27 had the lowest (55.3±2.8%, P=0.0032). The above findings were not confounded by baseline clinical characteristics, including ß-blocker usage. We conclude that the ß₂AR polymorphisms Ile164, Gly16, and the combination of Gly16 and Gln27 are associated with depressed exercise performance in HF and represent a genetically determined factor in the pathophysiology of HF.

Key Words: exercise • heart failure • ß-adrenergic receptors • genetics

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