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Journal of the American College of Cardiology
© 2006 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 48, No. 6, 2006
ISSN 0735-1097/06/$32.00
doi:10.1016/j.jacc.2006.07.030
EXPEDITED REVIEW
Aldosterone Synthase Promoter
Polymorphism Predicts Outcome in
African Americans With Heart Failure
Results From the A-HeFT Trial
Dennis M. McNamara, MD,* S. William Tam, PHD,† Michael L. Sabolinski, MD,† Page Tobelmann, BS,*
Karen Janosko, MSN,* Anne L. Taylor, MD,‡ Jay N. Cohn, MD,‡ Arthur M. Feldman, MD, PHD,§
Manuel Worcel, MD†
Pittsburgh and Philadelphia, Pennsylvania; Lexington, Massachusetts; and Rochester, Minnesota
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. (J Am Coll
Cardiol 2006;48:1277– 82) © 2006 by the American College of Cardiology Foundation
OBJECTIVES
Activation of aldosterone may play an important role in the
progression of heart failure. Stimulation of myocardial
aldosterone receptors increases apoptosis, resulting in fibrosis and ventricular remodeling (1). Blockade of the aldosterone receptor has been shown to improve heart failure
outcomes. In the RALES (Randomized Aldactone Evaluation Study), the addition of the aldosterone receptor
antagonist spironolactone improved survival in subjects with
severe heart failure (2). Aldosterone antagonists also reduce
left ventricular remodeling, and the addition of the selective
From the *University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;
†NitroMed Inc., Lexington, Massachusetts; ‡University of Minnesota, Rochester,
Minnesota; and §Thomas Jefferson Medical College, Philadelphia, Pennsylvania.
The GRAHF substudy of the A-HeFT study was supported, in part, by a research
grant from NitroMed Inc. Drs. Tam, Worcel, and Sabolinski are employees of the
NitroMed Corporation. Drs. McNamara, Feldman, Taylor, and Cohn have received
research support and/or consulting fees from NitroMed. NitroMed produces a fixed
combination of isosorbide dinitrate and hydralazine which was evaluated in the
GRAHF and AHeFT studies.
Manuscript received February 7, 2006; revised manuscript received June 12, 2006,
accepted July 10, 2006.
antagonist eplerenone post-myocardial infarction improves
survival (3).
Significant clinical heterogeneity exists in heart failure
outcomes, and much of this variability is genetically based.
Aldosterone synthase (CYP11B2) is a 9-exon gene occurring on chromosome 8q22 (4). A common single nucleotide
polymorphism, C to T transition for position ⫺344, occurs
within the promoter region of CYP11B2 (5). The ⫺344C
allele binds the steroidogenic transcription factor 1 (SF-1) 4
times more than the T allele (6), and has been linked to
increased aldosterone production (7,8). The CYP11B2
promoter polymorphism has been linked to hypertension
(9 –12) and the ⫺344C allele in particular to the risk of
coronary disease (13,14). Despite the central role of aldosterone in heart failure progression, the impact of the
⫺344C allele on clinical outcomes is unknown.
The heart failure phenotype differs in African American
and white cohorts (15). Hypertension is a more frequent
etiology in blacks, while, despite significant risk factors,
coronary disease is less common. Angiotensin-converting
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McNamara et al.
Aldosterone Synthase Polymorphism in Heart Failure
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
enzyme inhibitors are less effective in African Americans
(16); however, racial differences in the impact of aldosterone
antagonists have not been investigated. In contrast with
angiotensin-converting enzyme inhibitors, the nitric oxide
(NO) donor combination, isosorbide dinitrate and hydralazine (I/H), appears to be more efficacious in blacks. In the
A-HeFT (African-American Heart Failure Trial), I/H in
fixed combination markedly improved survival in a cohort
with systolic dysfunction (17).
While the impact of genetic heterogeneity on heart
failure outcomes has been extensively studied in predominantly white cohorts, few studies have investigated the
impact of genomic variation in blacks. The GRAHF study
(Genetic Risk of Heart Failure in African Americans) was a
genetic substudy of the A-HeFT study. This substudy was
initiated to explore the impact of functional genomic variation of heart failure mediators in an African-American
cohort. We investigated the impact of the ⫺344 T/C
polymorphism of the aldosterone synthase promoter in the
GRAHF cohort.
JACC Vol. 48, No. 6, 2006
September 19, 2006:1277–82
Minnesota). The aldosterone synthase (CYP11B2) promoter ⫺344 T/C polymorphism was assessed using a
TaqMan SNP Genotyping Assay with tagged primers
(ABI, Norwalk, Connecticut), and products were read using
the Applied Biosystems 7000 (Applied Biosystems, Foster
City, California).
Outcomes analysis. Subjects were followed to an end point
of death or heart failure hospitalization. Quality-of-life
(QoL) assessment was performed by the Minnesota Living
with Heart Failure Questionnaire (MLHFQ) at baseline
and at the 6-month visit. Left ventricular function was
assessed by transthoracic echocardiography at baseline and 6
months in a subset (n ⫽ 273 at baseline, n ⫽ 268 at 6
months) of the GRAHF study subjects. The primary end
point for the A-HeFT study was a composite weighted
score with 3 components: mortality, heart failure hospitalization, and change in QoL at 6 months (19). HardyWeinberg equilibrium was evaluated by chi-square analysis.
Event-free survival was compared by genotype class by
Kaplan-Meier log rank analysis. The impact of the ⫺344C
allele on aldosterone levels is predicted to be additive, with
homozygous CC subjects having the highest levels, TT
subjects the lowest, with heterozygous subjects being intermediate. Therefore, a priori a linear model was utilized that
predicts an intermediate phenotype for heterozygotes. Continuous variables such as left ventricular ejection fraction
(LVEF) and composite score were compared by genotype
class by linear analysis of variance (ANOVA). For the
interaction of aldosterone genotype and the impact of
therapy, ANOVA was used to compare outcomes (composite score and QoL score) by treatment subset (I/H vs.
placebo) within genotype subsets. For this pharmacogenetic
analysis, subjects with the C allele (CC and TC genotypes)
were pooled and compared with the TT genotype subset
given the limited number of CC subjects.
METHOD
Study population. A total of 354 subjects in the A-HeFT
study were enrolled in a genetic substudy, the GRAHF
substudy. Inclusion criteria for the A-HeFT study (17)
include self designation as African Americans, heart failure
due to systolic dysfunction, and standard background therapy for heart failure with neurohormonal blockade, including angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, and beta-blockers. Subjects were
randomized to either I/H in fixed combination or placebo in
addition to standard therapy. The white heart failure cohort
from the GRACE (Genetic Risk Assessment of Cardiac
Events) trial, a single-center investigation based at the heart
failure clinic at the University of Pittsburgh (18), was
utilized for comparisons of allele frequencies by race.
Genotyping. Subjects were enrolled in the GRAHF study
at the A-HeFT study 6-month visit. Deoxyribonucleic acid
was isolated from peripheral blood by leukocyte centrifugation and cell lysis (PureGene, Gentra Systems, Minneapolis,
RESULTS
The GRAHF study population was 60% men, 25% ischemic, and 98% New York Heart Association functional class
III, with a mean age of 57. Over the course of follow-up,
there were 60 (17%) heart failure hospitalizations and 12
deaths (3.4%). In terms of the CYP11B2 ⫺344 T/C
promoter polymorphism, 218 subjects (62%) were TT, 114
CT (32%), and 22 patients were CC (6%). The observed
distribution was consistent with Hardy-Weinberg equilibrium (allele frequency T/C ⫽ 0.78/0.22, expected genotype
frequencies % TT/TC/CC ⫽ 61%/34%/5%, chi-square
expected vs. observed, p ⫽ 0.63). Comparisons of baseline
etiology, medical therapy, blood pressure, and functional
class were not significantly different among the 3 genotype
subsets (Table 1). The allele frequencies differed markedly
by race, as the T allele was much more prevalent in the black
cohort in the A-HeFT study when compared with the white
cohort from the GRACE study (p ⬍ 0.001) (Fig. 1).
McNamara et al.
Aldosterone Synthase Polymorphism in Heart Failure
JACC Vol. 48, No. 6, 2006
September 19, 2006:1277–82
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Table 1. Baseline Characteristics by CYP11B2 ⫺344 Genotype*
Age (yrs)
Female (%)
NYHA functional class, % (III/IV)
Ischemic (%)
LVEF core entry (n ⫽ 270)
Systolic BP
Diastolic BP
Therapy
ACE inhibitor (%)
Aldosterone receptor antagonist
Beta-blocker (%)
CC (n ⴝ 22)
TC (n ⴝ 114)
TT (n ⴝ 218)
All Patients (n ⴝ 354)
56.6 ⫾ 12.2
31.8
95.5/4.5
22.7
0.31 ⫾ 0.07
125 ⫾ 20
79 ⫾ 14
57.9 ⫾ 11.8
34.2
96.5/3.5
26.3
0.35 ⫾ 0.08
128 ⫾ 17
78 ⫾ 11
57.2 ⫾ 13.5
44.5
96.8/3.2
25.2
0.35 ⫾ 0.09
127 ⫾ 17
76 ⫾ 10
57.4 ⫾ 12.8
40.4
96.6/3.4
25.4
0.35 ⫾ 0.09
127 ⫾ 17
77 ⫾ 10
72.7
45.5
77.3
74.6
33.3
86.8
77.1
36.5
82.6
76.0
36.1
83.6
*No significant differences in characteristics by CYP11B2 genotype.
ACE ⫽ angiotensin-converting enzyme; BP ⫽ blood pressure; CC ⫽ ⫺344 CC genotype; LVEF ⫽ left ventricular ejection fraction; NYHA ⫽ New York Heart Association;
TC ⫽ ⫺344 TC genotype; TT ⫽ ⫺344 TT genotype.
Event-free survival. The event-free survival of overall
subjects in the GRAHF study at 90, 180, and 360 days was
94%, 91%, and 81%, respectively. The C allele was associated with significantly poorer hospitalization-free survival
(Fig. 2) (p ⫽ 0.018) with the best survival among TT
subjects (% event-free survival at 90/180/360 days ⫽ 94/93/
85), intermediate for heterozygotes (% event-free ⫽ 93/90/
77), and the poorest for CC homozygotes (% event-free ⫽
96/81/63). Mortality in the overall GRAHF study cohort
was significantly greater in subjects with the C allele (%
deaths TT/TC/CC ⫽ 1.8%, 3.5%, 18.2%; p ⫽ 0.001).
Aldosterone synthase genotype, outcomes and I/H. In
the GRAHF study subpopulation, treatment with I/H was
associated with a trend towards improved composite score
(placebo ⫽ ⫺0.09 ⫾ 1.7, I/H ⫽ 0.22 ⫾ 1.8, p ⫽ 0.08).
When analyzed in genotype subset, I/H markedly improved
the composite score among TT homozygotes (placebo ⫽
⫺0.17 ⫾ 1.7, I/H ⫽ 0.38 ⫾ 1.4, p ⫽ 0.01) (Fig. 3A), but
had no impact among subjects with the ⫺344C allele
(placebo ⫽ 0.01 ⫾ 1.8; I/H ⫽ ⫺0.07 ⫾ 2.0) (Fig. 3A).
Change in MLHFQ QoL score also suggested marked
improvement in TT subjects, but not among those with the
C allele (change in MLHFQ score at 6 months from
baseline, TT subset: placebo ⫽ ⫺0.6 ⫾ 22.6; I/H ⫽ ⫺7.4
Figure 1. Genotype frequencies for the aldosterone synthase (CYP11B2)
⫺344 T/C polymorphism in the white heart failure cohort in the GRACE
trial and the African American heart failure cohort from GRAHF
substudy. The prevalence of the T allele is significantly higher (p ⬍ 0.001)
in African Americans.
⫾ 17.0, p ⫽ 0.038; CC ⫹ TC subset: placebo ⫽ ⫺7.7 ⫾
19.0; I/H ⫽ ⫺7.3 ⫾ 20.4, p ⫽ NS) (lower scores represents
better QoL) (Fig. 3B).
Aldosterone genotype and left ventricular remodeling.
Baseline ejection fraction did not differ at baseline among
groups; however, there was a trend toward lower LVEF at
6 months for subjects with the ⫺344C allele (LVEF % for
genotype subsets: TT/TC/CC ⫽ 38/37/33, p ⫽ 0.10)
(Table 2). Aldosterone receptor antagonists did not limit
the impact of the C allele on 6-month LVEF, as in fact the
impact was more pronounced for subjects on antagonists
(⫺344C allele linked to lower LVEF, subjects on aldosterone receptor antagonists: TT/TC/CC ⫽ 39/36/32, p ⫽
0.03). In contrast with the impact of aldosterone antagonists, treatment with I/H appeared to eliminate the impact
of the C allele on remodeling, as the impact on LVEF was
evident among subjects treated with placebo (LVEF: TT/
TC/CC ⫽ 37/36/32, p ⫽ 0.05) but not for subjects on I/H
(LVEF: TT/TC/CC ⫽ 38/38/40, p ⫽ 0.79). Consistent
with the impact of genotype on LVEF, subjects on placebo
Figure 2. Event-free survival by CYP11B2 ⫺344 genotype subsets. Freedom from heart failure hospitalization was significantly poorer (p ⫽ 0.018)
in subjects with the C allele, with the worst outcomes in CC homozygotes,
best outcomes in TT subjects, and intermediate in heterozygotes.
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Aldosterone Synthase Polymorphism in Heart Failure
JACC Vol. 48, No. 6, 2006
September 19, 2006:1277–82
Figure 3. Impact of therapy with isosorbide dinitrate and hydralazine
(I/H) on outcomes in heart failure. (A) Effect on composite score in ⫺344
genotype subsets. Treatment associated with marked improvement in the
⫺344TT subset (n ⫽ 218, p ⫽ 0.01), but minimal effect in subjects with
the ⫺344 C allele (CC ⫹ TC, n ⫽ 136, p ⫽ NS). (B) Effect on change
in quality-of-life scores from baseline to 6 months in ⫺344 genotype
subsets.
with the C allele had a greater left ventricular end-diastolic
diameter (LVDD) at 6 months (LVDD [cm] TT/TC/CC
⫽ 6.0/6.3/6.8, p ⫽ 0.01) (Table 2).
DISCUSSION
In the GRAHF study, the CYP11B2 promoter ⫺344C
allele linked to higher expression of aldosterone synthase
was associated with an increased risk of death and hospitalization for African American subjects with heart failure.
Analysis by treatment subset suggests the C allele also
worsens left ventricular remodeling. Of interest, the impact
of the NO donor strategy I/H was greatest in subjects with
the TT genotype, a genotype predominant in African
Americans and previously linked to low-renin hypertension.
The results of this investigation suggest that genetic variation in aldosterone production plays an important role in left
ventricular remodeling and disease progression in African
Americans with heart failure, a population underrepresented
in previous genetics outcomes investigations.
While the ⫺344C allele in vitro has increased binding of
SF-1 (6), the impact on transcriptional activity and aldosterone levels in vivo remains controversial. In clinical
studies in essential hypertension, the C allele was associated
with higher circulating levels of aldosterone in a geneordered fashion with the highest levels in the CC genotype
subset, intermediate in heterozygotes, and lowest in TT
homozygotes (20). However, the linkage of the ⫺344
genotype with aldosterone levels has been inconsistent as
several reports actually associate the ⫺344T allele with
higher levels (21,22). An analysis from the Framingham
study suggests the variance in aldosterone levels in populations is primarily due to non-genetic factors (23). The
impact of the CYP11B2 genotype on aldosterone levels may
be dependent on a subject’s overall level of neurohormonal
activation. While these previous studies have been done in
normal subjects or in those with hypertension, little data
exist on the interaction of the ⫺344 T/C polymorphism
with aldosterone levels in heart failure cohorts.
As demonstrated in the GRAHF study, the ⫺344T allele
is consistently more prevalent in black cohorts (21,24). The
heart failure phenotype differs in African American and
white cohorts (15), with a much greater prevalence of
hypertensive cardiomyopathy. Low-renin hypertension, in
which the aldosterone/renin ratio is elevated, is particularly
more prevalent in African Americans (25,26) and has been
linked to the T allele (21,27). In a hypertension study
comparing the aldosterone antagonist eplerenone to angiotensin receptor antagonists, eplerenone was more effective
than angiotensin receptor antagonists in black cohorts
Table 2. Left Ventricular Ejection Fraction (LVEF) and Left Ventricular Diastolic Diameter (LVDD) at 6 Months by ⫺344
Genotype and Treatment
LVEF (%)
LVDD (cm)
LVEF on spironolactone (%)
LVDD (cm) on spironolactone
LVEF on placebo (%)
LVDD (cm) on placebo
LVEF on I/H (%)
LVDD (cm) on I/H
n
TT
TC
CC
p Value*
262
268
99
101
136
137
126
131
38 ⫾ 9
6.1 ⫾ 1.3
39 ⫾ 10
6.2 ⫾ 1.4
37 ⫾ 10
6.0 ⫾ 1.3
38 ⫾ 9
6.2 ⫾ 1.4
37 ⫾ 9
6.2 ⫾ 1.3
36 ⫾ 9
6.3 ⫾ 1.5
36 ⫾ 10
6.3 ⫾ 1.2
38 ⫾ 8
6.0 ⫾ 1.4
33 ⫾ 8
6.5 ⫾ 1.3
32 ⫾ 6
6.5 ⫾ 0.8
32 ⫾ 7
6.8 ⫾ 0.9
40 ⫾ 6
5.6 ⫾ 1.9
NS (0.10)
NS
0.03
NS
0.05
0.01
NS
NS
*Comparisons of means by linear ANOVA.
I/H ⫽ isosorbide dinitrate and hydralazine in fixed combination; other abbreviations as in Table 1.
JACC Vol. 48, No. 6, 2006
September 19, 2006:1277–82
(28,29). Whether aldosterone antagonists are more effective
as heart failure therapy in African Americans will require
further investigation.
Stimulation of the myocardium by aldosterone induces
left ventricular remodeling, hypertrophy, and fibrosis (1). In
a Finnish cohort free of cardiac disease, the ⫺344C allele
was associated with increased left ventricular size and mass
(30). In a study of 995 members of 229 families, the
CYP11B2 haplotype was linked to left ventricular cavity size
and wall thickness (31). In the current GRAHF study
cohort, the C allele was associated with a trend towards
lower LVEF at 6 months. This was particularly significant
for the subset on placebo and was not evident for subjects
randomized to I/H. Of note, the impact of the C allele was
also more pronounced for subjects on aldosterone receptor
antagonists. Aldosterone receptor antagonists were not
randomized in the GRAHF study, and their use may
represent a marker for higher-risk subjects rather than a
pharmacogenetic interaction. Overall, the current study is
consistent with previous reports of an increased risk of
remodeling with the ⫺344C allele, and this may be the
mechanism of its adverse effect on heart failure outcomes.
Low-renin hypertension is associated with endothelial
dysfunction (32) and has been linked to the ⫺344TT
genotype (33). Aldosterone excess in low-renin states is
associated with impaired NO-mediated vasodilation (34).
Treatment with aldosterone antagonists enhance endothelial nitric oxide synthase (NOS3) expression (35), which
may help to restore endothelial function and contribute to
their therapeutic effects in subjects with heart failure. In
V-HeFT I, the therapeutic impact of treatment with I/H
was greater in the African American cohort (36), and this
finding was confirmed by the marked benefits in heart
failure survival with treatment in the A-HeFT study (17).
In the GRAHF study, the impact of I/H was primarily in
subjects with the ⫺344TT genotype predominant in African Americans. Whether NO donor strategies are more
effective in low-renin states remains to be determined.
While this study suggests the TT genotype subjects
received greater benefit from I/H, this finding was driven by
improvements in the QoL score and reevaluated in a
prospective trial of pharmacogenetic targeting. Indeed,
though treatment with I/H did not affect composite score in
subjects with the C allele, therapy did appear to limit the
adverse impact of the C allele on 6-month LVEF, particularly among CC subjects (LVEF 32% placebo vs. 40% on
I/H). However, this impact of treatment on left ventricular
remodeling must be viewed with caution given the small
number of CC subjects.
The design of the A-HeFT and the GRAHF studies
imposed several limitations on this analysis. Circulating
mediators were not evaluated as part of the GRAHF study,
so the impact of the ⫺344 T/C polymorphism on aldosterone level was not investigated. The mortality rate for
subjects in GRAHF (3.4%) was lower than in the A-HeFT
study itself, and therefore the ability to evaluate the impact
McNamara et al.
Aldosterone Synthase Polymorphism in Heart Failure
1281
of genotype on survival as a single end point was limited.
Treatment with aldosterone receptor antagonists was not
randomized and was utilized in a minority of subjects (39%
in A-HeFT and 36% in the GRAHF cohort), so the impact
of CYP11B2 genotype on treatment designed to block
aldosterone could not be evaluated. Future studies should
evaluate the influence of CYP11B3 genotype on treatment
response to both aldosterone receptor antagonists.
The current investigation demonstrates that the ⫺344
T/C promoter polymorphism of CYP11B2 influences clinical outcomes in an African American cohort with heart
failure, and provides evidence for the importance of aldosterone in heart failure progression. The heart failure
phenotype for African Americans differs from whites, and
the allele frequencies of this functional polymorphism differ
markedly in black and white cohorts. These results from the
GRAHF study suggest that genetic variation in aldosterone
production may contribute to these phenotypic differences.
In determining optimal heart failure treatment for an
individual, race is likely a surrogate marker for differences in
genetic background. Future investigations will determine
the role of genomic markers for tailoring therapy for
individuals with heart failure.
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. E-mail: [email protected]
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