Research Article
Modulation of aldosterone levels by −344 C/T CYP11B2 polymorphism and spironolactone use in resistant hypertension

https://doi.org/10.1016/j.jash.2013.12.001Get rights and content

Abstract

Interindividual variability in plasma aldosterone levels comprises environmental and genetic sources. Increased aldosterone levels have been associated with higher risk of hypertension and target-organ damage related to hypertension. Aldosterone excess and intravascular volume expansion are implicated in pathophysiology of resistant hypertension (RH). We sought to investigate whether −344 C/T polymorphism (rs1799998) in aldosterone synthase gene (CYP11B2) is associated with plasma aldosterone levels in patients with resistant hypertension. Sixty-two patients with resistant hypertension were enrolled in this cross-sectional study. Genotypes were obtained by allelic discrimination assay using real time polymerase chain reaction. Multivariable linear regression was used to identify whether TT genotype was a predictor of aldosterone levels. No differences in clinical and laboratorial parameters were found among genotype groups. We found an additive effect of the T allele on plasma aldosterone concentration in RH. Also, there was higher aldosterone levels in TT homozygous under use of spironolactone compared with C carriers and compared with TT subjects who was not under use of spironolactone. TT genotype and the use of spironolactone were significant predictors of aldosterone levels in RH subjects. Plasma aldosterone concentration is significantly associated with −344 C/T CYP11B2 polymorphism and with the treatment with spironolactone in resistant hypertensive subjects.

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).

Section snippets

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

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  • Cited by (0)

    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.

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