Polymorphisms of the β 2 -Adrenergic Receptor Determine Exercise Capacity in Patients With Heart Failure

Abstract

Abstract —The β 2 -adrenergic receptor (β 2 AR) 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 β 2 AR genotype. Patients with the uncommon Ile164 polymorphism had a lower peak V̇ o 2 (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 V̇ o 2 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 V̇ o 2 ≤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 V̇ o 2 in patients with Ile164. The polymorphisms at position 16 also impacted exercise capacity: peak V̇ o 2 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 V̇ o 2 (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 β 2 AR 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.