Abstract 20316: Nitric Oxide Synthase (NOS3) Asp298Glu Polymorphism and Survival in Pulmonary Arterial Hypertension
Introduction: For subjects with pulmonary arterial hypertension (PAH), differences in genetic background may influence outcomes and the impact of therapeutic interventions. Nitric oxide (NO) is an important modulator of vascular tone and endothelial nitric oxide synthase (NOS3) is the primary source of vascular NO. Therapies which increase the impact of NO, such as the PDE5 inhibitors, improve outcomes in PAH. A common polymorphism exists in exon 7 of NOS3, Asp298Glu, and the Asp298Asp genotype has been associated with poor outcomes in subjects with coronary disease. Its impact on outcomes in PAH and the interaction with PDE5 inhibitor therapy has not been previously studied.
Methods: We enrolled 138 patients with PAH in a single center genetic study at University of Pittsburgh Medical Center from 2001-2008. At the time of enrollment demographics, clinical phenotype and medical therapy were noted and blood obtained for genotyping of the NOS3 Asp298Glu polymorphism. Subjects were followed for at least five years post enrollment. Survival was compared by genotype overall and by treatment with PDE5 inhibitors.
Results: For the cohort the mean age was 54±13, 68% F, 81% group 1, 54% class III/IV and PA mean 49±13 mm Hg. At entry 41% were on a prostacyclin derivative, 37% endothelin receptor antagonist and 23% PDE5 inhibitor. %NOS3 genotype AspAsp/AspGlu/GluGlu =9/48/43. The NOS3 Asp-Asp genotype was associated with a trend toward poorer survival overall (1,3,5 yr % survival AspAsp= 85/53/44; Glu=88/72/61, p=0.16). For subjects not treated with PDE5 inhibitors, the AspAsp genotype was linked to significantly poorer outcomes (p=0.01, Figure). This impact was not evident in patients on PDE5 inhibitor therapy (p=0.86).
Conclusions: The NOS3 Asp-Asp genotype was associated with poor survival in subjects with PAH not treated with PDE5 inhibitors, but this impact was eliminated by therapy. Further studies are needed to evaluate the potential for genomic targeting of PAH therapy.
Author Disclosures: A. Klein: None. D. Ishizawar: None. K. Hanley-Yanez: None. D.M. McNamara: None.
- © 2016 by American Heart Association, Inc.