Aldosterone Synthase Promoter Polymorphism Predicts Outcome 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, Anne L. Taylor, Jay N. Cohn, Arthur M. Feldman, Manuel Worcel

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Objectives: We sought to evaluate the effect of the aldosterone synthase promoter polymorphism on heart failure outcomes for subjects in the African American Heart Failure Trial (A-HeFT). Background: Genetic heterogeneity modulates clinical outcomes in subjects with heart failure (HF); however, little data exist in African American populations. A common polymorphism exists in the promoter region of the aldosterone synthase gene (CYP11B2) at position -344 (T/C). The -344C allele, associated with higher aldosterone synthase activity, has been linked to hypertension; however, its impact on outcomes in HF is unknown. Methods: A total of 354 subjects from A-HeFT participated in the GRAHF (Genetic Risk Assessment of Heart Failure in African Americans) substudy and were genotyped for the aldosterone synthase polymorphism. Patients were followed prospectively, and event-free survival (freedom from death and HF hospitalization) compared by CYP11B2 genotype. Results: Of the cohort, 218 patients were TT, 114 CT, and 22 patients were CC. Baseline etiology, blood pressure, and functional class were not significantly different among the 3 cohorts. The C allele was associated with significantly poorer HF hospitalization-free survival with the best survival among TT subjects, intermediate for heterozygotes, and the poorest for CC homozygotes (p = 0.018), and a higher rate of death (% death TT/TC/CC = 1.8/3.5/18.2, p = 0.001). The TT genotype, more prevalent in blacks, was associated with greater impact of fixed combination of isosorbide dinitrate and hydralazine on the primary composite end point (p = 0.01). Conclusions: The aldosterone synthase promoter -344C allele linked to higher aldosterone levels is associated with poorer event-free survival in blacks with HF. The role of aldosterone receptor antagonists in diminishing this apparent genetic risk remains to be explored.

Original languageEnglish (US)
Pages (from-to)1277-1282
Number of pages6
JournalJournal of the American College of Cardiology
Volume48
Issue number6
DOIs
StatePublished - Sep 19 2006

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Cytochrome P-450 CYP11B2
African Americans
Heart Failure
Alleles
Disease-Free Survival
Hospitalization
Genotype
Mineralocorticoid Receptor Antagonists
Survival
Genetic Heterogeneity
Homozygote
Heterozygote
Aldosterone
Genetic Promoter Regions
Blood Pressure
Hypertension

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Aldosterone Synthase Promoter Polymorphism Predicts Outcome 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; Taylor, Anne L.; Cohn, Jay N.; Feldman, Arthur M.; Worcel, Manuel.

In: Journal of the American College of Cardiology, Vol. 48, No. 6, 19.09.2006, p. 1277-1282.

Research output: Contribution to journalArticle

McNamara, Dennis M. ; Tam, S. William ; Sabolinski, Michael L. ; Tobelmann, Page ; Janosko, Karen ; Taylor, Anne L. ; Cohn, Jay N. ; Feldman, Arthur M. ; Worcel, Manuel. / Aldosterone Synthase Promoter Polymorphism Predicts Outcome in African Americans With Heart Failure. Results From the A-HeFT Trial. In: Journal of the American College of Cardiology. 2006 ; Vol. 48, No. 6. pp. 1277-1282.
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abstract = "Objectives: We sought to evaluate the effect of the aldosterone synthase promoter polymorphism on heart failure outcomes for subjects in the African American Heart Failure Trial (A-HeFT). Background: Genetic heterogeneity modulates clinical outcomes in subjects with heart failure (HF); however, little data exist in African American populations. A common polymorphism exists in the promoter region of the aldosterone synthase gene (CYP11B2) at position -344 (T/C). The -344C allele, associated with higher aldosterone synthase activity, has been linked to hypertension; however, its impact on outcomes in HF is unknown. Methods: A total of 354 subjects from A-HeFT participated in the GRAHF (Genetic Risk Assessment of Heart Failure in African Americans) substudy and were genotyped for the aldosterone synthase polymorphism. Patients were followed prospectively, and event-free survival (freedom from death and HF hospitalization) compared by CYP11B2 genotype. Results: Of the cohort, 218 patients were TT, 114 CT, and 22 patients were CC. Baseline etiology, blood pressure, and functional class were not significantly different among the 3 cohorts. The C allele was associated with significantly poorer HF hospitalization-free survival with the best survival among TT subjects, intermediate for heterozygotes, and the poorest for CC homozygotes (p = 0.018), and a higher rate of death ({\%} death TT/TC/CC = 1.8/3.5/18.2, p = 0.001). The TT genotype, more prevalent in blacks, was associated with greater impact of fixed combination of isosorbide dinitrate and hydralazine on the primary composite end point (p = 0.01). Conclusions: The aldosterone synthase promoter -344C allele linked to higher aldosterone levels is associated with poorer event-free survival in blacks with HF. The role of aldosterone receptor antagonists in diminishing this apparent genetic risk remains to be explored.",
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T1 - Aldosterone Synthase Promoter Polymorphism Predicts Outcome in African Americans With Heart Failure. Results From the A-HeFT Trial

AU - McNamara, Dennis M.

AU - Tam, S. William

AU - Sabolinski, Michael L.

AU - Tobelmann, Page

AU - Janosko, Karen

AU - Taylor, Anne L.

AU - Cohn, Jay N.

AU - Feldman, Arthur M.

AU - Worcel, Manuel

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Y1 - 2006/9/19

N2 - Objectives: We sought to evaluate the effect of the aldosterone synthase promoter polymorphism on heart failure outcomes for subjects in the African American Heart Failure Trial (A-HeFT). Background: Genetic heterogeneity modulates clinical outcomes in subjects with heart failure (HF); however, little data exist in African American populations. A common polymorphism exists in the promoter region of the aldosterone synthase gene (CYP11B2) at position -344 (T/C). The -344C allele, associated with higher aldosterone synthase activity, has been linked to hypertension; however, its impact on outcomes in HF is unknown. Methods: A total of 354 subjects from A-HeFT participated in the GRAHF (Genetic Risk Assessment of Heart Failure in African Americans) substudy and were genotyped for the aldosterone synthase polymorphism. Patients were followed prospectively, and event-free survival (freedom from death and HF hospitalization) compared by CYP11B2 genotype. Results: Of the cohort, 218 patients were TT, 114 CT, and 22 patients were CC. Baseline etiology, blood pressure, and functional class were not significantly different among the 3 cohorts. The C allele was associated with significantly poorer HF hospitalization-free survival with the best survival among TT subjects, intermediate for heterozygotes, and the poorest for CC homozygotes (p = 0.018), and a higher rate of death (% death TT/TC/CC = 1.8/3.5/18.2, p = 0.001). The TT genotype, more prevalent in blacks, was associated with greater impact of fixed combination of isosorbide dinitrate and hydralazine on the primary composite end point (p = 0.01). Conclusions: The aldosterone synthase promoter -344C allele linked to higher aldosterone levels is associated with poorer event-free survival in blacks with HF. The role of aldosterone receptor antagonists in diminishing this apparent genetic risk remains to be explored.

AB - Objectives: We sought to evaluate the effect of the aldosterone synthase promoter polymorphism on heart failure outcomes for subjects in the African American Heart Failure Trial (A-HeFT). Background: Genetic heterogeneity modulates clinical outcomes in subjects with heart failure (HF); however, little data exist in African American populations. A common polymorphism exists in the promoter region of the aldosterone synthase gene (CYP11B2) at position -344 (T/C). The -344C allele, associated with higher aldosterone synthase activity, has been linked to hypertension; however, its impact on outcomes in HF is unknown. Methods: A total of 354 subjects from A-HeFT participated in the GRAHF (Genetic Risk Assessment of Heart Failure in African Americans) substudy and were genotyped for the aldosterone synthase polymorphism. Patients were followed prospectively, and event-free survival (freedom from death and HF hospitalization) compared by CYP11B2 genotype. Results: Of the cohort, 218 patients were TT, 114 CT, and 22 patients were CC. Baseline etiology, blood pressure, and functional class were not significantly different among the 3 cohorts. The C allele was associated with significantly poorer HF hospitalization-free survival with the best survival among TT subjects, intermediate for heterozygotes, and the poorest for CC homozygotes (p = 0.018), and a higher rate of death (% death TT/TC/CC = 1.8/3.5/18.2, p = 0.001). The TT genotype, more prevalent in blacks, was associated with greater impact of fixed combination of isosorbide dinitrate and hydralazine on the primary composite end point (p = 0.01). Conclusions: The aldosterone synthase promoter -344C allele linked to higher aldosterone levels is associated with poorer event-free survival in blacks with HF. The role of aldosterone receptor antagonists in diminishing this apparent genetic risk remains to be explored.

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