Research ArticleModulation of aldosterone levels by −344 C/T CYP11B2 polymorphism and spironolactone use in resistant hypertension
Introduction
The effects of aldosterone in the cardiovascular system are mediated by mineralocorticoid receptors (MR) activation, promoting extracellular volume expansion, cardiac remodeling, endothelial dysfunction, arterial stiffness, inflammation, and production of reactive oxygen species.1, 2, 3 Higher circulating aldosterone levels were associated with risk of hypertension in normotensive subjects4 and with target-organ damage in essential and resistant hypertension.5, 6 Moreover, about 30% of patients with resistant hypertension (RH), defined as lack of blood pressure (BP) control despite the use of three antihypertensive drugs or any BP level requiring four or more antihypertensive drugs,7 have elevated plasma aldosterone concentration and intravascular volume expansion.8 The optimal fourth-line drug in the treatment of resistant hypertension has been extensively discussed, and the efficacy of MR antagonists was demonstrated in observational and prospective studies.9, 10
Genetic polymorphisms in aldosterone synthase gene (CYP11B2) were associated with BP and hypertension.11, 12 Also, higher urinary aldosterone excretion was observed in T carriers for −344 C/T polymorphism in CYP11B2.13 Recently, functional analysis revealed that haplotypes that include allele C reduce aldosterone synthase transcription.14
Therefore, the aim of this cross-sectional study was to evaluate the impact of −344 C/T polymorphism in CYP11B2 on plasma aldosterone concentration (PAC) in patients with resistant hypertension (RH).
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Study Subjects
A total of 62 resistant hypertensive subjects from Outpatient Resistant Hypertension Clinic of the University of Campinas (Campinas, Brazil) were enrolled in this study. RH was defined according to American Heart Association Statement.7 Patients with a systolic BP ≥140 mm Hg and/or a diastolic BP ≥90 mm Hg in spite of the use of three antihypertensive drugs including a diuretic were considered resistant hypertensive. Also, patients who use four or more drugs, regardless of BP control, are
Results
General characteristics of resistant hypertensive subjects enrolled in the study are listed in Table 1. No differences were observed in demographic and laboratorial variables among −344 C/T CYP11B2 genotype groups (CC, CT, and TT). Left ventricular mass index and microalbuminuria were similar among genotype groups. There were no differences in number of antihypertensive drugs used by the three groups (CC, 4.2 ± 1.1; CT, 4.5 ± 0.9; and TT, 4.2 ± 0.9 [mean ± SD]). Moreover, all patients were
Discussion
The main findings of this study were: (1) −344 C/T CYP11B2 polymorphism shows an additive effect on aldosterone levels in subjects with resistant hypertension, with crescent levels in CC, CT, and TT genotypes; (2) TT homozygous under use of spironolactone have higher aldosterone compared with C carriers (CT and CC) and compared with TT homozygous that were not under use of that drug; (3) both TT genotype and mineralocorticoid receptor antagonist are independent predictors of aldosterone
References (31)
- et al.
Aldosterone and cardiovascular disease: the heart of the matter
Trends Endocrinol Metab
(2013) - et al.
Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease
Am J Cardiol
(2006) - et al.
Association between increased plasma levels of aldosterone and decreased systemic arterial compliance in subjects with essential hypertension
Am J Hypertens
(1997) - et al.
Characteristics and predictors of obstructive sleep apnea in patients with systemic hypertension
Am J Cardiol
(2010) - et al.
Clinical and genetic correlates of serum aldosterone in the community: the Framingham Heart Study
Am J Hypertens
(2005) - et al.
Efficacy of low-dose spironolactone in subjects with resistant hypertension
Am J Hypertens
(2003) - et al.
Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension
Ann Int Med
(2009) - et al.
Serum aldosterone and the incidence of hypertension in nonhypertensive persons
N Engl J Med
(2004) - et al.
Hypoadiponectinemia and aldosterone excess are associated with lack of blood pressure control in subjects with resistant hypertension
Hypertens Res
(2013) - et al.
Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research
Hypertension
(2008)
Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion
Arch Int Med
Efficacy of spironolactone therapy in patients with true resistant hypertension
Hypertension
Aldosterone excess or escape: Treating resistant hypertension
J Clin Hypertens (Greenwich)
Reevaluation of the association of seven candidate genes with blood pressure and hypertension: a replication study and meta-analysis with a larger sample size
Hypertens Res
Association of the C-344T aldosterone synthase gene variant with essential hypertension: a meta-analysis
J Hypertens
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This work was supported by Sao Paulo Research Foundation (FAPESP) and National Council for Scientific and Technological Development (CNPq).
All authors have declared no financial or other relationship that might lead to a conflict of interest.