title: Effect of the Asp298 variant of endothelial nitric oxide synthase on survival for patients with congestive heart failure.
abstract: BACKGROUND
  Significant variation exists within the endothelial nitric oxide synthase (NOS3) gene that may influence cardiovascular risk. The Asp298 variant of NOS3 has a shorter half-life in endothelial cells. Given the importance of nitric oxide in the heart failure syndrome, we evaluated the effect of this variant on event-free survival in a population with systolic dysfunction.
  
  
  RESULTS
  Four hundred sixty-nine patients (72% male, 49% ischemic; mean age, 56+/-12 years) with systolic dysfunction (left ventricular ejection fraction < or =0.45) were enrolled in a study of Genetic Risk Assessment of Cardiac Events (GRACE). The polymorphism in exon 7 of NOS3, a G-T transition at position 894 that results in a Glu to Asp amino acid substitution for codon 298, was genotyped and subjects were followed prospectively to the end point of death or heart transplantation. Event-free survival was compared on the basis of the presence (group 1, n=266) or absence (group 2, n=203) of the Asp298 variant. Event-free survival was significantly poorer in patients with the Asp298 variant (percent event-free survival group 1 at 1/2/3 years=78/65/54; group 2=82/72/64, P=0.03). In subset analysis, the adverse impact of the Asp298 variant was primarily in patients with nonischemic cardiomyopathy (group 1=82/73/63; group 2=87/79/71, P=0.03) and was not apparent among patients with ischemic heart disease (group 1=75/59/47; group 2=74/62/54, P=0.71).
  
  
  CONCLUSIONS
  For patients with heart failure caused by systolic function, the Asp298 variant of NOS3 is associated with poorer event-free survival, particularly in patients with nonischemic cardiomyopathy.
authors.affiliation: Heart Failure Section, Cardiovascular Institute, University of Pittsburgh Medical Center, 558 Scaife Hall, 200 Lothrop St, Pittsburgh, Pa 15213, USA. mcnamaradm@msx.upmc.edu
authors.forename: Dennis M
authors.initials: DM
authors.lastname: McNamara
authors.forename: Richard
authors.initials: R
authors.lastname: Holubkov
authors.forename: Lisa
authors.initials: L
authors.lastname: Postava
authors.forename: Ravi
authors.initials: R
authors.lastname: Ramani
authors.forename: Karen
authors.initials: K
authors.lastname: Janosko
authors.forename: Michael
authors.initials: M
authors.lastname: Mathier
authors.forename: Guy A
authors.initials: GA
authors.lastname: MacGowan
authors.forename: Srinivas
authors.initials: S
authors.lastname: Murali
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Feldman
authors.forename: Barry
authors.initials: B
authors.lastname: London
mesh_terms: D000328:Adult; D000368:Aged; D001224:Aspartic Acid / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006333:Heart Failure / Q000175:diagnosis*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies
chemical_list: D001224:Aspartic Acid; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III