Endothelial Nitric Oxide Synthase (NOS3) Polymorphisms in African Americans With Heart Failure

Results From the A-HeFT Trial

Dennis M. McNamara, S. William Tam, Michael L. Sabolinski, Page Tobelmann, Karen Janosko, Lakshmi Venkitachalam, Elizabeth Ofili, Clyde Yancy, Arthur M. Feldman, Jalal K. Ghali, Anne L. Taylor, Jay N. Cohn, Manuel Worcel

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)191-198
Number of pages8
JournalJournal of cardiac failure
Volume15
Issue number3
DOIs
StatePublished - Apr 1 2009

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Nitric Oxide Synthase Type III
African Americans
Heart Failure
Genetic Heterogeneity
Genotype
Blood Pressure
Stroke Volume
Introns
Alleles
Quality of Life
Ventricular Remodeling
Gene Frequency
Disease-Free Survival
Hospitalization
Therapeutics
isosorbide-hydralazine combination

Keywords

  • Pharmacogenetics
  • isosorbide dinitrate and hydralazine
  • left ventricular ejection fraction
  • nitric oxide

Cite this

McNamara, D. M., Tam, S. W., Sabolinski, M. L., Tobelmann, P., Janosko, K., Venkitachalam, L., ... Worcel, M. (2009). Endothelial Nitric Oxide Synthase (NOS3) Polymorphisms in African Americans With Heart Failure: Results From the A-HeFT Trial. Journal of cardiac failure, 15(3), 191-198. https://doi.org/10.1016/j.cardfail.2008.10.028

Endothelial Nitric Oxide Synthase (NOS3) Polymorphisms in African Americans With Heart Failure : Results From the A-HeFT Trial. / McNamara, Dennis M.; Tam, S. William; Sabolinski, Michael L.; Tobelmann, Page; Janosko, Karen; Venkitachalam, Lakshmi; Ofili, Elizabeth; Yancy, Clyde; Feldman, Arthur M.; Ghali, Jalal K.; Taylor, Anne L.; Cohn, Jay N.; Worcel, Manuel.

In: Journal of cardiac failure, Vol. 15, No. 3, 01.04.2009, p. 191-198.

Research output: Contribution to journalArticle

McNamara, DM, Tam, SW, Sabolinski, ML, Tobelmann, P, Janosko, K, Venkitachalam, L, Ofili, E, Yancy, C, Feldman, AM, Ghali, JK, Taylor, AL, Cohn, JN & Worcel, M 2009, 'Endothelial Nitric Oxide Synthase (NOS3) Polymorphisms in African Americans With Heart Failure: Results From the A-HeFT Trial', Journal of cardiac failure, vol. 15, no. 3, pp. 191-198. https://doi.org/10.1016/j.cardfail.2008.10.028
McNamara, Dennis M. ; Tam, S. William ; Sabolinski, Michael L. ; Tobelmann, Page ; Janosko, Karen ; Venkitachalam, Lakshmi ; Ofili, Elizabeth ; Yancy, Clyde ; Feldman, Arthur M. ; Ghali, Jalal K. ; Taylor, Anne L. ; Cohn, Jay N. ; Worcel, Manuel. / Endothelial Nitric Oxide Synthase (NOS3) Polymorphisms in African Americans With Heart Failure : Results From the A-HeFT Trial. In: Journal of cardiac failure. 2009 ; Vol. 15, No. 3. pp. 191-198.
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AU - Venkitachalam, Lakshmi

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AU - Yancy, Clyde

AU - Feldman, Arthur M.

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N2 - 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.

AB - 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.

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