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G-Protein Beta-3 Subunit Genotype Predicts Enhanced Benefit of Fixed-Dose Isosorbide Dinitrate and Hydralazine: Results of A-HeFT | Journal Scan
Study Questions:
Was there an 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 the A-HeFT study (African American Heart Failure Trial)?
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 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 the GNB3 genotype, 184 subjects (53%) were TT, 137 (39%) were CT, and 29 (8%) were CC. In GNB3 TT subjects, FDC I/H improved the composite score (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 composite score, 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 the A-HeFT study. The authors concluded that the role of the GNB3 genotype for targeting therapy with FDC I/H deserves further study.
Perspective:
G-proteins beta-3 subunit GNB3 plays a role in alpha2-adrenergic signaling. A polymorphism (C825T) exists; the T allele is linked to enhanced alpha-adrenergic tone, and is more prevalent in African Americans. This study suggests that the TT genotype is associated with greater clinical benefit from therapy with a FDC I/H in addition to standard therapy among African Americans with heart failure resulting from systolic left ventricular dysfunction.
Keywords: African Americans, Disease-Free Survival, Drug Combinations, Genotype, GTP-Binding Proteins, Heart Failure, Ventricular Dysfunction, Left, Hydralazine, Isosorbide Dinitrate, Length of Stay, Quality of Life, Risk Assessment, Stroke Volume
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