THE ILE164 BETA(2)-ADRENERGIC RECEPTOR POLYMORPHISM ADVERSELY AFFECTSTHE OUTCOME OF CONGESTIVE-HEART-FAILURE

The beta(2)-adrenergic receptor (beta(2)AR), an important modulator of cardiac inotropy and chronotropy, has significant genetic heterogenei ty in the population. Because dysfunctional beta ARs play a role in th e pathogenesis of the failing ventricle, we tested the hypothesis that beta(2)AR polymorphisms alter the outcome of congestive heart failure . 259 patients with NYHA functional class Ill-IV heart failure due to ischemic or dilated cardiomyopathy were genotyped and prospectively fo llowed, with the endpoint defined as death or cardiac transplantation. The allele frequencies between this group and those of 212 healthy co ntrols also were compared and did not differ between the groups. Howev er, those with the Ile164 polymorphism displayed a striking difference in survival with a relative risk of death or cardiac transplant of 4. 81 (P < 0.001) compared with those with the wild-type Thr at this posi tion. Age, race, gender, functional class, etiology, ejection fraction , and medication use did not differ between these individuals and thos e with the wildtype beta(2)AR, and thus the beta(2)AR genotype at posi tion 164 was the only clear distinguishing feature between the two gro ups. The 1-yr survival for Ile164 patients was 42% compared with 76% f or patients harboring wild-type beta(2)AR. In contrast, polymorphisms at amino acid positions 16 (Arg or Gly) or 27 (Gln or Glu), which also alter receptor phenotype, did not appear to have an influence on the course of heart failure. Taken together with cell-based and transgenic mouse results, this study establishes a paradigm whereby genetic vari ants of key signaling elements can have patho-physiologic consequences within the context of a disease. Furthermore, patients with the Ile16 4 polymorphism and heart failure may be candidates for earlier aggress ive intervention or cardiac transplantation.