Journal of Cardiac Failure
Volume 15, Issue 3 , Pages 191-198, April 2009

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

  • Dennis M. McNamara, MD

      Affiliations

    • University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
    • Corresponding Author InformationReprint requests: Dennis M McNamara, MD, Heart Failure/Transplantation Program, University of Pittsburgh Medical Center, 566 Scaife Hall, 200 Lothrop Street, Pittsburgh, PA 15241. Tel: 412-648-6598; Fax: 412-648-6101.
    • ,
  • S. William Tam, PhD

      Affiliations

    • NitroMed Inc, Lexington, Massachusetts
    • ,
  • Michael L. Sabolinski, MD

      Affiliations

    • NitroMed Inc, Lexington, Massachusetts
    • ,
  • Page Tobelmann, BS

      Affiliations

    • University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
    • ,
  • Karen Janosko, MSN

      Affiliations

    • University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
    • ,
  • Lakshmi Venkitachalam, PhD

      Affiliations

    • University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
    • ,
  • Elizabeth Ofili, MD

      Affiliations

    • Morehouse School of Medicine, Atlanta, Georgia
    • ,
  • Clyde Yancy, MD

      Affiliations

    • Baylor University Medical Center, Dallas, Texas
    • ,
  • Arthur M. Feldman, MD, PhD

      Affiliations

    • Thomas Jefferson Medical College, Philadelphia, Pennsylvania
    • ,
  • Jalal K Ghali, MD

      Affiliations

    • Wayne State University School of Medicine, Detroit, Michigan
    • ,
  • Anne L. Taylor, MD

      Affiliations

    • Columbia University Medical Center, New York, New York
    • ,
  • Jay N. Cohn, MD

      Affiliations

    • University of Minnesota, Minneapolis, Minnesota
    • ,
  • Manuel Worcel, MD

      Affiliations

    • NitroMed Inc, Lexington, Massachusetts

Received 14 December 2007; received in revised form 14 October 2008; accepted 23 October 2008. published online 24 December 2008.

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 < .001). The –786 T allele was associated with lower left ventricular ejection fraction (LVEF) (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.

Key Words: Pharmacogenetics, left ventricular ejection fraction, isosorbide dinitrate and hydralazine, nitric oxide

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 Supported in part by a research grant from NitroMed Inc. and grants from the National Heart, Lung and Blood Institute, contracts K24 HL 69912 and RO1 HL75038. Additonal support was received from the National Center for Research Resources, contract 5P20RR011104.

 Conflict of interest: None.

PII: S1071-9164(08)01052-X

doi:10.1016/j.cardfail.2008.10.028

Journal of Cardiac Failure
Volume 15, Issue 3 , Pages 191-198, April 2009

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