Aldosterone synthase promoter polymorphism predicts outcome in African Americans with heart failure: results from the A-HeFT Trial.
OBJECTIVE
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.
McNamara
Dennis M
DM
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. mcnamaradm@upmc.edu
Tam
S William
SW
Sabolinski
Michael L
ML
Tobelmann
Page
P
Janosko
Karen
K
Taylor
Anne L
AL
Cohn
Jay N
JN
Feldman
Arthur M
AM
Worcel
Manuel
M
D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000483:Alleles; D002303:Cardiac Output, Low / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000503:physiopathology; D015331:Cohort Studies; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006760:Hospitalization; D006801:Humans; D006830:Hydralazine / Q000627:therapeutic use*; D007548:Isosorbide Dinitrate / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016019:Survival Analysis; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000627:therapeutic use; D020257:Ventricular Remodeling
D014665:Vasodilator Agents; D006830:Hydralazine; D019405:Cytochrome P-450 CYP11B2; D007548:Isosorbide Dinitrate