G-protein beta-3 subunit genotype predicts enhanced benefit of fixed-dose isosorbide dinitrate and hydralazine

Results of A-HeFT

Dennis M. McNamara, Anne L. Taylor, S. William Tam, Manuel Worcel, Clyde W. Yancy, Karen Hanley-Yanez, Jay N. Cohn, Arthur M. Feldman

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Objectives: The purpose of this study was to evaluate the influence of the guanine nucleotide-binding proteins (G-proteins), beta-3 subunit (GNB3) genotype on the effectiveness of a fixed-dose combination of isosorbide dinitrate and hydralazine (FDC I/H) in A-HeFT (African American Heart Failure Trial). Background: GNB3 plays a role in alpha2-adrenergic signaling. A polymorphism (C825T) exists, and the T allele is linked to enhanced alpha-adrenergic tone and is more prevalent in African Americans. Methods: A total of 350 subjects enrolled in the genetic substudy (GRAHF [Genetic Risk Assessment of Heart Failure in African Americans]) were genotyped for the C825T polymorphism. The impact of FDC I/H on a composite score (CS) that incorporated death, hospital stay for heart failure, and change in quality of life (QoL) and on event-free survival were assessed in GNB3 genotype subsets. Results: The GRAHF cohort was 60% male, 25% ischemic, 97% New York Heart Association functional class III, age 57 ± 13 years, with a mean qualifying left ventricular ejection fraction of 0.24 ± 0.06. For GNB3 genotype, 184 subjects were TT (53%), 137 (39%) CT, and 29 (8%) were CC. In GNB3 TT subjects, FDC I/H improved the CS (FDC I/H= 0.50 ± 1.6; placebo=-0.11 ± 1.8, p= 0.02), QoL (FDC I/H= 0.69 ± 1.4; placebo= 0.24 ± 1.5, p= 0.04), and event-free survival (hazard ratio: 0.51, p= 0.047), but not in subjects with the C allele (for CS, FDC I/H=-0.05 ± 1.7; placebo=-0.09 ± 1.7, p= 0.87; for QoL, FDC I/H= 0.28 ± 1.5; placebo= 0.14 ± 1.5, p= 0.56; and for event-free survival, p= 0.35). Conclusions: The GNB3 TT genotype was associated with greater therapeutic effect of FDC I/H in A-HeFT. The role of the GNB3 genotype for targeting therapy with FDC I/H deserves further study.

Original languageEnglish (US)
Pages (from-to)551-557
Number of pages7
JournalJACC: Heart Failure
Volume2
Issue number6
DOIs
StatePublished - Jan 1 2014

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Isosorbide Dinitrate
Hydralazine
Guanine Nucleotides
African Americans
Carrier Proteins
Heart Failure
Genotype
Placebos
Disease-Free Survival
Quality of Life
Adrenergic Agents
Alleles
isosorbide-hydralazine combination
Therapeutic Uses
Stroke Volume
Length of Stay

Keywords

  • Heart failure
  • Outcomes
  • Pharmacogenetics
  • Race

Cite this

McNamara, D. M., Taylor, A. L., Tam, S. W., Worcel, M., Yancy, C. W., Hanley-Yanez, K., ... Feldman, A. M. (2014). G-protein beta-3 subunit genotype predicts enhanced benefit of fixed-dose isosorbide dinitrate and hydralazine: Results of A-HeFT. JACC: Heart Failure, 2(6), 551-557. https://doi.org/10.1016/j.jchf.2014.04.016

G-protein beta-3 subunit genotype predicts enhanced benefit of fixed-dose isosorbide dinitrate and hydralazine : Results of A-HeFT. / McNamara, Dennis M.; Taylor, Anne L.; Tam, S. William; Worcel, Manuel; Yancy, Clyde W.; Hanley-Yanez, Karen; Cohn, Jay N.; Feldman, Arthur M.

In: JACC: Heart Failure, Vol. 2, No. 6, 01.01.2014, p. 551-557.

Research output: Contribution to journalArticle

McNamara, Dennis M. ; Taylor, Anne L. ; Tam, S. William ; Worcel, Manuel ; Yancy, Clyde W. ; Hanley-Yanez, Karen ; Cohn, Jay N. ; Feldman, Arthur M. / G-protein beta-3 subunit genotype predicts enhanced benefit of fixed-dose isosorbide dinitrate and hydralazine : Results of A-HeFT. In: JACC: Heart Failure. 2014 ; Vol. 2, No. 6. pp. 551-557.
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abstract = "Objectives: The purpose of this study was to evaluate the influence of the guanine nucleotide-binding proteins (G-proteins), beta-3 subunit (GNB3) genotype on the effectiveness of a fixed-dose combination of isosorbide dinitrate and hydralazine (FDC I/H) in A-HeFT (African American Heart Failure Trial). Background: GNB3 plays a role in alpha2-adrenergic signaling. A polymorphism (C825T) exists, and the T allele is linked to enhanced alpha-adrenergic tone and is more prevalent in African Americans. Methods: A total of 350 subjects enrolled in the genetic substudy (GRAHF [Genetic Risk Assessment of Heart Failure in African Americans]) were genotyped for the C825T polymorphism. The impact of FDC I/H on a composite score (CS) that incorporated death, hospital stay for heart failure, and change in quality of life (QoL) and on event-free survival were assessed in GNB3 genotype subsets. Results: The GRAHF cohort was 60{\%} male, 25{\%} ischemic, 97{\%} New York Heart Association functional class III, age 57 ± 13 years, with a mean qualifying left ventricular ejection fraction of 0.24 ± 0.06. For GNB3 genotype, 184 subjects were TT (53{\%}), 137 (39{\%}) CT, and 29 (8{\%}) were CC. In GNB3 TT subjects, FDC I/H improved the CS (FDC I/H= 0.50 ± 1.6; placebo=-0.11 ± 1.8, p= 0.02), QoL (FDC I/H= 0.69 ± 1.4; placebo= 0.24 ± 1.5, p= 0.04), and event-free survival (hazard ratio: 0.51, p= 0.047), but not in subjects with the C allele (for CS, FDC I/H=-0.05 ± 1.7; placebo=-0.09 ± 1.7, p= 0.87; for QoL, FDC I/H= 0.28 ± 1.5; placebo= 0.14 ± 1.5, p= 0.56; and for event-free survival, p= 0.35). Conclusions: The GNB3 TT genotype was associated with greater therapeutic effect of FDC I/H in A-HeFT. The role of the GNB3 genotype for targeting therapy with FDC I/H deserves further study.",
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T2 - Results of A-HeFT

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AU - Taylor, Anne L.

AU - Tam, S. William

AU - Worcel, Manuel

AU - Yancy, Clyde W.

AU - Hanley-Yanez, Karen

AU - Cohn, Jay N.

AU - Feldman, Arthur M.

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N2 - Objectives: The purpose of this study was to evaluate the influence of the guanine nucleotide-binding proteins (G-proteins), beta-3 subunit (GNB3) genotype on the effectiveness of a fixed-dose combination of isosorbide dinitrate and hydralazine (FDC I/H) in A-HeFT (African American Heart Failure Trial). Background: GNB3 plays a role in alpha2-adrenergic signaling. A polymorphism (C825T) exists, and the T allele is linked to enhanced alpha-adrenergic tone and is more prevalent in African Americans. Methods: A total of 350 subjects enrolled in the genetic substudy (GRAHF [Genetic Risk Assessment of Heart Failure in African Americans]) were genotyped for the C825T polymorphism. The impact of FDC I/H on a composite score (CS) that incorporated death, hospital stay for heart failure, and change in quality of life (QoL) and on event-free survival were assessed in GNB3 genotype subsets. Results: The GRAHF cohort was 60% male, 25% ischemic, 97% New York Heart Association functional class III, age 57 ± 13 years, with a mean qualifying left ventricular ejection fraction of 0.24 ± 0.06. For GNB3 genotype, 184 subjects were TT (53%), 137 (39%) CT, and 29 (8%) were CC. In GNB3 TT subjects, FDC I/H improved the CS (FDC I/H= 0.50 ± 1.6; placebo=-0.11 ± 1.8, p= 0.02), QoL (FDC I/H= 0.69 ± 1.4; placebo= 0.24 ± 1.5, p= 0.04), and event-free survival (hazard ratio: 0.51, p= 0.047), but not in subjects with the C allele (for CS, FDC I/H=-0.05 ± 1.7; placebo=-0.09 ± 1.7, p= 0.87; for QoL, FDC I/H= 0.28 ± 1.5; placebo= 0.14 ± 1.5, p= 0.56; and for event-free survival, p= 0.35). Conclusions: The GNB3 TT genotype was associated with greater therapeutic effect of FDC I/H in A-HeFT. The role of the GNB3 genotype for targeting therapy with FDC I/H deserves further study.

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