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

doi: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

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

Medicine - Cardiology Division

Research output: Contribution to journal › Article › peer-review

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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 language	English (US)
Pages (from-to)	191-198
Number of pages	8
Journal	Journal of cardiac failure
Volume	15
Issue number	3
DOIs	https://doi.org/10.1016/j.cardfail.2008.10.028
State	Published - Apr 2009

Bibliographical note

Funding Information:
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.

Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.

Keywords

Pharmacogenetics
isosorbide dinitrate and hydralazine
left ventricular ejection fraction
nitric oxide

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McNamara, D. M., Tam, S. W., Sabolinski, M. L., Tobelmann, P., Janosko, K., Venkitachalam, L., Ofili, E., Yancy, C., Feldman, A. M., Ghali, J. K., Taylor, A. L., Cohn, J. N., & 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

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

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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.",

keywords = "Pharmacogenetics, isosorbide dinitrate and hydralazine, left ventricular ejection fraction, nitric oxide",

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

note = "Funding Information: 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. Copyright: Copyright 2009 Elsevier B.V., All rights reserved.",

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AU - Sabolinski, Michael L.

AU - Tobelmann, Page

AU - Janosko, Karen

AU - Venkitachalam, Lakshmi

AU - Ofili, Elizabeth

AU - Yancy, Clyde

AU - Feldman, Arthur M.

AU - Ghali, Jalal K.

AU - Taylor, Anne L.

AU - Cohn, Jay N.

AU - Worcel, Manuel

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

Abstract

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