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EXPEDITED REVIEW

Aldosterone Synthase Promoter Polymorphism Predicts Outcome in African Americans With Heart Failure

Results From the A-HeFT Trial

Dennis M. McNamara, MD^_*,2,_*, S. William Tam, PhD^,1, Michael L. Sabolinski, MD^,1, Page Tobelmann, BS^_*, Karen Janosko, MSN^_*, Anne L. Taylor, MD^,2, Jay N. Cohn, MD^,2, Arthur M. Feldman, MD, PhD^,2 and Manuel Worcel, MD^,1

^_* University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
NitroMed Inc., Lexington, Massachusetts
University of Minnesota, Rochester, Minnesota
Thomas Jefferson Medical College, Philadelphia, Pennsylvania.

Manuscript received February 7, 2006; revised manuscript received June 12, 2006, accepted July 10, 2006.

^_* Reprint requests and correspondence: Dr. Dennis M. McNamara, Heart Failure/Transplantation Program, University of Pittsburgh Medical Center, 566 Scaife Hall, 200 Lothrop Street, Pittsburgh, Pennsylvania 15241. (Email: mcnamaradm{at}upmc.edu).

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.

Abbreviations and Acronyms   A-HeFT = African-American Heart Failure Trial   CYP11B2 = aldosterone synthase gene locus   GRACE = Genetic Risk Assessment of Cardiac Events trial   GRAHF = Genetic Risk Assessment of Heart Failure in African Americans substudy   I/H = isosorbide dinitrate and hydralazine   LVDD = left ventricular end-diastolic diameter   LVEF = left ventricular ejection fraction   MLHFQ = Minnesota Living with Heart Failure Questionnaire   NO = nitric oxide   QoL = quality of life   SF-1 = steroidogenic transcription factor-1

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