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

The beta(2)-adrenergic receptor (beta(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 beta(2)AR genotype. Patients with the uncommon lie 164 polymorphism had a lower peak (V) over dot 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 (V) over dot 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 (V) over dot O-2 less than or equal to 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 (V) over dot O-2 in patients with Ile164. The polymorphisms at position 16 also impacted exercise capacity: peak (V) over dot 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, 3 homozygous combinations exist. Patients with Arg16/Glu27 had the highest percentage achieved of predicted peak (V) over dot 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 beta-blocker usage. We conclude that the beta(2)AR polymorphisms Ile164, Gly16, and the combination of Gly 16 and Gln27 are associated with depressed exercise performance in HF and represent a genetically determined factor in the pathophysiology of HF.