Polymorphisms of the beta(2)-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 Ile164 polymorphism had a lower peak VO(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 VO(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 VO(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 VO(2) in patients with Ile164. The polymorphisms at position 16 also impacted exercise capacity: peak VO(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 VO(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 Gly16 and Gln27 are associated with depressed exercise performance in HF and represent a genetically determined factor in the pathophysiology of HF.