Polymorphisms of the β₂-adrenergic receptor determine exercise capacity in patients with heart failure

The β₂-adrenergic receptor (β₂AR) 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 β₂AR genotype. Patients with the uncommon Ile164 polymorphism had a lower peak V̇O₂ (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 V̇O₂ 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 V̇O₂ ≤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 V̇O₂ in patients with Ile164. The polymorphisms at position 16 also impacted exercise capacity: peak V̇O₂ 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 V̇O₂ (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 β-blocker usage. We conclude that the β₂AR 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.