Abstract 2174: G Protein Beta 3 Subunit (GNB3) Genotype Predicts Enhanced Benefit of Fixed-Dose Isosorbide Dinitrate and Hydralazine: Results of the A-HeFT Trial
Introduction: The G protein beta 3-subunit (GNB3) plays an important role in alpha adrenergic signaling. A polymorphism (C825T) exists and the T haplotype is linked to enhanced alpha adrenergic tone. We examined the impact of the GNB3 T haplotype on heart failure (HF) outcomes and the effect of therapy with isosorbide dinitrate and hydralazine (I-H) for subjects in the African American Heart Failure Trial (A-HeFT).
Method: 350 subjects enrolled in the genetic sub-study of A-HeFT (GRAHF) were genotyped for the C825T polymorphism and followed to an endpoint of death or heart failure hospitalization. In addition, a composite score (CS) which incorporates death, HF hospitalization and change in functional status (QOL) was assessed. The impact of I-H on event-free survival (EFS) was assessed overall in GRAHF and in GNB3 genotype subsets.
Results: The GRAHF GNB3 cohort was 60% male, 25% ischemic, 97% class III with a mean age of 57.4 years and a qualifying LVEF of 23.9%. For GNB3 genotype, 184 subjects were TT (53%), 137 (39%) were CT, and 29 (8%) were CC homzygotes. Overall in GRAHF, treatment with I-H was associated with a trend toward improved CS (p=0.06). In subjects with the GNB3 TT genotype, I-H vs placebo improved CS (0.50 vs −0.11, p=0.02), QOL (0.69 vs 0.24, p=0.04) and EFS (HR=0.512, p=0.047, figure⇓), but not in subjects with the C haplotype (CS= −0.05 vs −0.09, p-0.87, QOL-0.28 vs 0.14, p= 0.56, EFS p=0.35).
Conclusion: The GNB3 TT genotype prevalent in African Americans and associated with increased alpha adrenergic signaling was associated with greater therapeutic effect of I-H in A-HeFT. The mechanism of this effect and the role of GNB3 genotype in targeting therapy deserve further study.