Endothelial Nitric Oxide Synthase (NOS3) Polymorphisms in African Americans With Heart Failure : Results From the A-HeFT Trial

Abstract Background Genetic heterogeneity at the endothelial nitric oxide synthase (NOS3) locus influences heart failure outcomes. The prevalence of NOS3 variants differs in black and white cohorts, but the impact of these differences is unknown. Methods and Results Subjects (n = 352) in the Genetic Risk Assessment of Heart Failure (GRAHF) substudy of the African-American Heart Failure Trial were genotyped for NOS3 polymorphisms: –786 T/C promoter, intron 4a/4b, and Glu298Asp and allele frequencies and compared with a white heart failure cohort. The effect of treatment with fixed-dose combination of isosorbide dinitrates and hydralazine (FDC I/H) on event-free survival and composite score (CS) of survival, hospitalization, and quality of life (QoL) was analyzed within genotype subsets. In GRAHF, NOS3 genotype frequencies differed from the white cohort ( P P = .01), whereas the intron 4a allele was linked to lower diastolic blood pressure and higher LVEF ( P = .03). Only the Glu298Asp polymorphism influenced treatment outcome; therapy with FDC I/H improved CS ( P = .046) and QoL ( P = .03) in the Glu298Glu subset only. Conclusions In black subjects with heart failure, NOS3 genotype influences blood pressure and left ventricular remodeling. The impact of genetic heterogeneity on treatment with FDC I/H requires further study.