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

1278

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

1279

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.

1280

McNamara et al. 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]

REFERENCES 1. White PC. Aldosterone: direct effects on and production by the heart. J Clin Endocrinol Metab 2003;88:2376 – 83. 2. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341:709 –17. 3. Pitt B, Remme W, Zannad F, et al., Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309 –21. 4. Bassett MH, White PC, Rainey WE. The regulation of aldosterone synthase expression. Mol Cell Endocrinol 2004;217:67–74. 5. White PC, Hautanen A, Kupari M. Aldosterone synthase (CYP11B2) polymorphisms and cardiovascular function. J Steroid Biochem Mol Biol 1999;69:409 –12. 6. White PC, Slutsker L. Haplotype analysis of CYP11B2. Endocr Res 1995;21:437– 42. 7. Brand E, Chatelain N, Mulatero P, et al. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension 1998;32:198 –204. 8. White PC, Rainey WE. Polymorphisms in CYP11B genes and 11-hydroxylase activity (editorial). J Clin Endocrinol Metab 2005;90: 1252–5. 9. Connell JMC, Fraser R, MacKenzie SM, et al. The impact of polymorphisms in the gene encoding aldosterone synthase (CYP11B2) on steroid synthesis and blood pressure regulation. Mol Cell Endocrinol 2004;217:243–7. 10. Lim PO, MacDonald TM, Holloway C, et al. Variation at the aldosterone synthase (CYP11B2) locus contributes to hypertension in subjects with a raised aldosterone-to-renin ratio. J Clin Endocrinol Metab 2002;87:4398 – 402.

1282

McNamara et al. Aldosterone Synthase Polymorphism in Heart Failure

11. Tsukada K, Ishimitsu T, Teranishi M, et al. Positive association of CYP11B2 gene polymorphism with genetic predisposition to essential hypertension. J Hum Hypertens 2002;16:789 –93. 12. Kumar NN, Benjafield AV, Lin RC, et al. Haplotype analysis of aldosterone synthase gene (CYP11B2) polymorphisms shows association with essential hypertension. J Hypertens 2003;21:1249 –53. 13. Patel S, Steeds R, Channer K, et al. Analysis of promoter region polymorphism in the aldosterone synthase gene (CYP11B2) as a risk factor for myocardial infarction. Am J Hypertens 2000;13: 134 –9. 14. Hautanen A, Toivanen P, Manttari M, et al. Joint effects of an aldosterone synthase (CYP11B2) gene polymorphism and classic risk factors on risk of myocardial infarction. Circulation 1999;100:2213– 8. 15. Yancy CW. Heart failure in African Americans. Am J Cardiol 2005;96:3i–12i. 16. Taylor JS, Ellis GR. Racial differences in responses to drug treatment: implications for pharmacotherapy of heart failure. Am J Cardiovasc Drugs 2002;2:389 –99. 17. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049 –57. 18. McNamara DM, Holubkov R, Postava L, et al. Phamacogenetic interactions between ACE inhibitor therapy and the angiotensinconverting enzyme deletion polymorphism in patients with congestive heart failure. J Am Coll Cardiol 2004;44:2019 –26. 19. Taylor AL. The African-American Heart Failure Trial (A-HeFT): rationale and methodology. J Card Fail 2003;9 Suppl 5:S216 –9. 20. Pojoga L, Gautier S, Blanc H, et al. Genetic determination of plasma aldosterone levels in essential hypertension. Am J Hypertens 1998;11: 856 – 60. 21. Barbato A, Russo P, Siani A, et al. Aldosterone synthase gene (CYP11B2) C⫺344T polymorphism, plasma aldosterone, renin activity and blood pressure in a multi-ethnic population. J Hypertens 2004;22:1895–901. 22. Paillard F, Chansel D, Brand E, et al. Genotype-phenotype relationships for the renin-aldosterone system in a normal population. Hypertension 1999;34:423–9. 23. Kathiresan S, Larson MG, Benjamin EJ, et al. Clinical and genetic correlates of serum aldosterone in the community: the Framingham heart study. Am J Hypertens 2005;18:657– 65.

JACC Vol. 48, No. 6, 2006 September 19, 2006:1277–82 24. Zhu H, Sagnella GA, Dong Y, et al. Contrasting associations between aldosterone synthase gene polymorphisms and essential hypertension in blacks and in whites. J Hypertens 2003;21:87–95. 25. Price D, Fisher ND. The renin-angiotensin system in blacks: active, passive of what? Curr Hypertens Rep 2003;5:225–30. 26. Preston RA, Matersn BJ, Reda DJ, et al. Age-race subgroup compared with renin profile as predictors of blood pressure response to antihypertensive therapy. JAMA 1998;280:1168 –72. 27. Henderson SO, Haiman CA, Mack W. Multiple polymorphisms in the renin-angiotensin-aldosterone system (ACE, CYP11B2, AGTR1) and their contribution to hypertension in African Americans and Latinos in the multiethnic cohort. Am J Med Sci 2004;328:266 –73. 28. Flack JM, Oparil S, Pratt JH, et al. Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients. J Am Coll Cardiol 2003;41:1148 –55. 29. Ben-Yehuda O. Hypertension, angiotensin II, aldosterone and race. J Am Coll Cardiol 2003;41:1156 – 8. 30. Kupari M, Hautanen A, Lankinen L, et al. Associations between human aldosterone synthase (CYP11B2) gene polymorphisms and left ventricular size, mass, and function. Circulation 1998;97:569 –75. 31. Mayosi BM, Keavney B, Watkins H, et al. Measured haplotype analysis of the aldosterone synthase gene and heart size. Eur J Hum Genet 2003;11:395– 401. 32. Ergul A. Hypertension in black patients. An emerging role of the endothelial system in salt sensitive hypertension. Hypertension 2000; 36:62–7. 33. Komiya I, Yamada T, Takara M, et al. Lys173Arg and ⫺334T/C variants of CYP11B2 in Japanese patients with low-renin hypertension. Hypertension 2000;35:699 –703. 34. Duffy SJ, Biegelsen ES, Eberhardt RT, et al. Low-renin hypertension with relative aldosterone excess is associated with impaired NOmediated vasodilation. Hypertension 2005;46:707–13. 35. Sanz-Rosa D, Oubina MP, Cediel E, et al. Eplerenone reduces oxidative stress and enhances eNOS in SHR: vascular functional and structural consequences. Antioxid Redox Signal 2005;7:1294 –301. 36. Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail 1999;5:178 – 87.

Table 1

6, 2006. © 2006 by the American College of Cardiology Foundation ... City, California). ..... correlates of serum aldosterone in the community: the Framingham.

142KB Sizes 0 Downloads 344 Views

Recommend Documents

Table 1
Local Effect. U.S.-Mexico. Border. 230.5 39.0. 37.5. 487.0. 52.5. 39.2. 67.4. 52.6. El Paso. 7.6 16.6. -5.1. -52.0. 2.5. 18.9. 9.0. 53.6. Brownsville 18.6 52.4. -0.2.

Table 1
Department of Economics and Finance, College of Business. Administration ..... (5) by maximum likelihood within the system framework of Johansen (1988). 10. 4. Results ..... Reserve Bank of Dallas, El Paso Business Frontier 1. Chang-Hee ...

Alien Periodic Table 1.pdf
Sign in. Loading… Whoops! There was a problem loading more pages. Retrying... Whoops! There was a problem previewing this document. Retrying.

Table of Equivalents (1).pdf
Loading… Page 1. Whoops! There was a problem loading more pages. Table of Equivalents (1).pdf. Table of Equivalents (1).pdf. Open. Extract. Open with.

November 1963 table (1).pdf
There was a problem previewing this document. Retrying... Download. Connect more apps... Try one of the apps below to open or edit this item. November 1963 table (1).pdf. November 1963 table (1).pdf. Open. Extract. Open with. Sign In. Main menu.

Page 1 TABLE 1. GENERAL FUND REVENUE OF SCHOOL ...
Sep 16, 2016 - 3/ This increase in the "other revenue" category is attributable primarily to a change in the method of compiling the data. In prior years, funds reported in the category "miscellaneous revenue" were distributed to other categories whe

Page 1 Page 2 TABLE 1 CHEMICAL COMPOSITION ...
TABLE 1. CHEMICAL COMPOSITION REQUIREMENTS FOR SOLID ... Copper due to any coating on the electrode or rod plus the copper content of the filler ...

Table 1: Demonstration of a simple table. Right Left Center ... - GitHub
Page 1. Table 1: Demonstration of a simple table. Right Left Center Default. 12 12. 12. 12. 123 123. 123. 123. 1 1. 1. 1. Table 1 is from the Pandoc User's Guide. A simpler table is given by table 2: Table 2: Even simpler. A B. 0. 1. 1.

Prorated CPE Hours - Table #1 and Table #2.pdf
There was a problem previewing this document. Retrying... Download. Connect more apps... Try one of the apps below to open or edit this item. Prorated CPE ...

Prorated CPE Hours - Table #1 and Table #2.pdf
September 30 even years 50 10 2. October 1 –. December 31 even years. 40 8 2. January 1 –. March 31 odd years 30 6 2. April 1 –. June 30 odd years 20 4 2. July 1 –. September 30 odd years 10 2 2. October 1 –. December 31 odd years 0 0 0. Pa

Change in Time table Revised (1).pdf
There was a problem previewing this document. Retrying... Download. Connect more apps... Try one of the apps below to open or edit this item. Change in Time table Revised (1).pdf. Change in Time table Revised (1).pdf. Open. Extract. Open with. Sign I

WAEC May-June Time-Table 2018 (1).pdf
Mathematics/Mathematics. (Core) 1 (Objective). 2hrs 30mins. 1hr 30mins. 08:30 hrs. – 11:00. hrs. 14:00 hrs. – 15:30. hrs. Page 3 of 9. WAEC May-June Time-Table 2018 (1).pdf. WAEC May-June Time-Table 2018 (1).pdf. Open. Extract. Open with. Sign In

2014 prayer time table (1).pdf
There was a problem previewing this document. Retrying... Download. Connect more apps... Try one of the apps below to open or edit this item. 2014 prayer ...

2014 prayer time table (1).pdf
4:33 5:50 12:48 4:31 7:44 9:02. 4:32 5:50 12:48 4:31 ... 4:22 5:43 12:48 4:33 7:53 9:14. 4:22 5:42 12:48 4:33 ..... 2014 prayer time table (1).pdf. 2014 prayer time ...

January Exam time table (1).pdf
There was a problem previewing this document. Retrying... Download. Connect more apps... Try one of the apps below to open or edit this item. Main menu.

Table 1: List of SLAM / VO algorithms Name References Code ...
JoanSola/objectes/curs{\_}SLAM/SLAM2D/SLAMcourse.pdf. [29] Zeyneb Kurt-Yavuz ..... sensor network distributed SEIF range-only SLAM”. In: Proceedings ... In: Computer Vision - ECCV 2014 Workshops: Zurich, Switzer- land, September 6-7 ...

TABLE OF CONTENTS Grade 1.pdf
ST. KITTS AND NEVIS. MINISTRY OF EDUCATION .... 17. Subtopic: My Family History. ..... TABLE OF CONTENTS Grade 1.pdf. TABLE OF CONTENTS Grade ...

Data 8R Table Methods and Functions Summer 2017 1 ... - GitHub
Jul 18, 2017 - Data 8R. Table Methods and Functions. Summer 2017. Discussion 7: ... its range - the difference between the highest value in the array and.

Table 1. Corporate Welfare Grant & Loan Programs Spending ...
Sep 19, 2016 - Agricultural Promotion, Education and Exports. $275. Alternative Fuels Funding ... Food Marketing and Research. $494. Grants to the Arts.

Data 8R Table Methods and Functions Summer 2017 1 ... - GitHub
Jul 18, 2017 - We have the dataset trips, which contains data on trips taken as part ofa ... def num_long_trips(cutoff): ... We want to see what the distribution of.

Warrants Table
Warrants Table. 20-Oct-16. Warrant. Stocks Price .... Stocks Price. Warrant Price trade Exercise Exercise Ratio .... 82 NEWS-W4. 0.12. 0.01. 31-Mar-19. 0.2848.

1-4-17 Spring 2017 Qualifications Table .pdf
There was a problem previewing this document. Retrying... Download. Connect more apps... Try one of the apps below to open or edit this item. 1-4-17 Spring ...

2016 Term 1 Time Table [Sec 3].pdf
Winnie Yap / Huang. Mei / Lee Pick Siew. Koh Dee Yong / A. Periasamy / Tay Tze. Hoon / Tan Puay Hock. SR 7,SR 8,Comp. Lab 3. MTL. Tay Tze Hoon / Winnie.

Table 1. Corporate Welfare Grant & Loan Programs Spending ...
Sep 19, 2016 - Corporate Welfare Grant & Loan. Programs ... Infrastructure and Facilities Improvement Grants. $19,000 ... Keystone Innovation Zone. $25,000.