G-protein beta-3 subunit genotype predicts enhanced benefit of fixed-dose isosorbide dinitrate and hydralazine: Results of A-HeFT

Objectives: The purpose of this study was to evaluate the influence of the guanine nucleotide-binding proteins (G-proteins), beta-3 subunit (GNB3) genotype on the effectiveness of a fixed-dose combination of isosorbide dinitrate and hydralazine (FDC I/H) in A-HeFT (African American Heart Failure Trial). Background: GNB3 plays a role in alpha₂-adrenergic signaling. A polymorphism (C825T) exists, and the T allele is linked to enhanced alpha-adrenergic tone and is more prevalent in African Americans. Methods: A total of 350 subjects enrolled in the genetic substudy (GRAHF [Genetic Risk Assessment of Heart Failure in African Americans]) were genotyped for the C825T polymorphism. The impact of FDC I/H on a composite score (CS) that incorporated death, hospital stay for heart failure, and change in quality of life (QoL) and on event-free survival were assessed in GNB3 genotype subsets. Results: The GRAHF cohort was 60% male, 25% ischemic, 97% New York Heart Association functional class III, age 57 ± 13 years, with a mean qualifying left ventricular ejection fraction of 0.24 ± 0.06. For GNB3 genotype, 184 subjects were TT (53%), 137 (39%) CT, and 29 (8%) were CC. In GNB3 TT subjects, FDC I/H improved the CS (FDC I/H= 0.50 ± 1.6; placebo=-0.11 ± 1.8, p= 0.02), QoL (FDC I/H= 0.69 ± 1.4; placebo= 0.24 ± 1.5, p= 0.04), and event-free survival (hazard ratio: 0.51, p= 0.047), but not in subjects with the C allele (for CS, FDC I/H=-0.05 ± 1.7; placebo=-0.09 ± 1.7, p= 0.87; for QoL, FDC I/H= 0.28 ± 1.5; placebo= 0.14 ± 1.5, p= 0.56; and for event-free survival, p= 0.35). Conclusions: The GNB3 TT genotype was associated with greater therapeutic effect of FDC I/H in A-HeFT. The role of the GNB3 genotype for targeting therapy with FDC I/H deserves further study.