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(Circulation. 2003;107:1598.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Effect of the Asp²⁹⁸ Variant of Endothelial Nitric Oxide Synthase on Survival for Patients With Congestive Heart Failure

Dennis M. McNamara, MD; Richard Holubkov, PhD; Lisa Postava, MBA; Ravi Ramani, MD; Karen Janosko, MSN; Michael Mathier, MD; Guy A. MacGowan, MD; Srinivas Murali, MD; Arthur M. Feldman, MD, PhD; Barry London, MD, PhD

From the Cardiovascular Institute, University of Pittsburgh Medical Center (D.M.M., L.P., R.R., K.J., M.M., G.A.M., S.M., B.L.), Pittsburgh, Pa; the Department of Family and Preventive Medicine, School of Medicine, University of Utah (R.H.), Salt Lake City, Utah; and the Department of Medicine, Thomas Jefferson Medical Center (A.M.F.), Philadelphia, Pa.

Correspondence to Dennis M. McNamara, MD, Heart Failure Section, Cardiovascular Institute, University of Pittsburgh Medical Center, 558 Scaife Hall, 200 Lothrop St, Pittsburgh, PA 15213. E-mail mcnamaradm{at}msx.upmc.edu

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.

Methods and Results— Four hundred sixty-nine patients (72% male, 49% ischemic; mean age, 56±12 years) with systolic dysfunction (left ventricular ejection fraction 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.

Key Words: heart failure • cardiomyopathy • nitric oxide synthase • genetics • survival

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