Low Renin Essential Hypertension Research Articles

Mild primary aldosteronism (PA) followed by overt PA are possibly the most common forms of low renin hypertension: a single-center retrospective study.

Low renin hypertension (LRH) is a common condition in hypertensive patients, and mainly includes primary aldosteronism (PA) and low renin essential hypertension. To investigate the distributions and clinical manifestations of the main LRH forms, we reviewed 1267 hypertensive patients who underwent assessment for plasma renin activity (PRA) and plasma aldosterone concentration (PAC) by standardized protocols in our specialized center. LRH was defined as PRA < 1.0 ng/mL/h. A saline infusion test (SIT) was performed when LRH patients showed positive screening results for PA. The main LRH forms were defined as follows: post-SIT PAC > 10 ng/dL as 'overt PA', post-SIT PAC 5-10 ng/dL as 'mild PA', and post-SIT PAC < 5 ng/dL or negative screening results as 'non-PA'. Overall, 760 patients were defined as LRH, with 160 classified as overt PA, 268 as mild PA, and 332 as non-PA. The total proportion of PA amounted to 56.3% with 21.0% overt PA and 35.3% mild PA. Compared with the mild PA, patients with overt PA had higher systolic and diastolic blood pressures, lower serum potassium, higher urine potassium excretion, more frequent incidence of stage 3 hypertension, hypokalemia, diabetes mellitus, and classical unilateral adenoma on computerized tomography (P < 0.05). PA including overt and mild forms is indeed a major form of LRH. Clinical manifestations in mild PA are less severe than those in overt PA. Nevertheless, mild PA is more prevalent than overt PA in LRH and should be recognized.

SUN-366 The Optimal Cutoff Value for Basal Plasma Aldosterone Concentration Suspected as Primary Aldosteronism Distributed According to Aldosterone-Renin Ratio and Confirmatory Tests Response

Aldosterone/renin ratio (ARR) >200 [(pg/mL)/(ng/mL/hr)] is a widely accepted threshold to screen for primary aldosteronism (PA) (1). Because using ARR as a sole index leads to excessive inclusion of cases with low renin essential hypertension, it may be desirable to combine ARR with a minimum plasma aldosterone concentration (PAC) value to increase diagnostic accuracy, but currently there is no consensus on the minimum PAC value. Therefore, we carried out a single-center, retrospective study to investigate optimal PAC cutoff to be used with ARR >200. The subjects were 385 individuals (240 female and 145 male) with ARR >200 who underwent PA screening tests between 2010 and 2015. They were diagnosed according to the Japan Endocrine Society guideline (2) with either PA or essential hypertension (EH). The optimal cutoff value for baseline PAC that best distinguished between PA and EH was calculated. Of the 385 subjects, 297 were diagnosed with PA and 88 with EH. Of 194 PA patients who underwent adrenal venous sampling, 141 exhibited aldosterone hypersecretion from both adrenal glands, and 53 were diagnosed with aldosterone-producing adenoma (APA) on the basis of adrenalectomy. There was no difference between the PA (n = 194) and EH (n = 88) groups in terms of age, body mass index, or glucose and lipid profiles. Receiver operating characteristic curve analysis found that the optimal baseline PAC for distinguishing between PA and EH was 171 pg/mL, which provided a sensitivity of 0.75 and a specificity of 0.65 (area under the curve 0.718 and 95% confidence interval 0.656-0.780). Baseline PAC was ≥171 pg/mL for all 53 subjects with APA (minimum 171 pg/mL, maximum 943 pg/mL, and median 341 pg/mL), and if the cutoff value for baseline PAC is set at 171 pg/mL, it is unlikely that significant cases of APA will be overlooked in PA screening using ARR >200. Combining PAC ≥171 pg/mL with ARR >200 increases diagnostic accuracy for PA without compromising APA detection. Reference: (1)Hiramatsu et al., Arch Intern Med. 1981 Nov;141(12):1589-93. (2) Nishikawa et al., Endocr J. 2011;58(9):711-21.

Microalbuminuria in primary aldosteronism

Background. Primary aldosteronism (PA) is an adrenal disorder which is characterized by the overproduction of the mineralocorticoid hormones by the adrenal glands when not as a result of excessive renin secretion. Different studies report the prevalence of PA in from 7 to 15 % patients with hypertension. Nowadays PA is considered to be the most frequent cause of secondary hypertension taking up to 30% of it. The importance of case detection of PA among hypertensive patients is not a matter of controversy presently. It has been demonstrated recently that patients with PA are more prone to cardiovascular events and target organ damage than essential hypertensive patients.Aim: to establish renal dysfunction in PA.Methods. We evaluated 192 low-renin hypertensive patients and 30 normotensive subjects. The mean age of the hypertensives was 47,5±3,4 years. The control group was 51,8±4,2 years old. PA was established in 57 patients, all the others were classified as low-renin essential hypertensives (LREH). Both groups were similar with respect to age (44,7±4,2 in PA, 48,3±3,9 in LREH), sex (female 63% of PA and 67% of LREH) and blood pressure (158±16/96±8 mm Hg in PA, 164±21/99±13 mm Hg in LREH). There were slight differences in BMI (31,4±4,3 in PA and 28,7±3,5 in LREH, p&lt;0,05). PA and LREH patients significantly differed with respect to prevalence of diabetes mellitus (26,3% in PA and 9,6% in LREH, p&lt;0,01) and duration of hypertension (7±5 years in PA and 13±4 in LREH, p&lt;0,05).Results. We observed an increase in urinary protein excretion in both group. But in group of patients with PA it was higher than in LREH (0,14±0,06 vs. 0,05±0,03 g/24 h, p&lt;0,05). In addition, patients with PA had higher serum creatinine concentrations (101,7±13,2 vs. 83,4±9,1 mkmol/l, p&lt;0,05). Subgroup analyses of normoglycemic subjects showed that PA patients still had a higher creatinine concentration (84,3±11,8 vs. 81,9±10,5 mkmol/l) but the difference was no longer statistically significant. Although, microalbuminuria was significantly higher in non-diabetic PA patients (0,12±0,04 vs. 0,05±0,07 g/24 h, p&lt;0,05). Diabetic subjects in both groups did not differ significantly with respect to microalbuminuria.Conclusions. Cross-sectional Primary Aldosteronism Prevalence in Italy (PAPY) study showed an increased prevalence of microalbuminuria in PA. The data from German Conn’s Registry showed a significant increase of serum creatinine concentrations in patients with PA but they did not observe any significant differences in protein excretion. In our study the differences in creatinine concentration were diabetes-dependent. Although, we suppose an increase of microalbuminuria in patients with PA to be aldosterone-dependent. However, this hypothesis should be confirmed in wider populations.

Abstract P211: Normo-aldosteronemic Aldosterone-producing Adenoma: Immunochemical Characterization and Diagnostic Implications

Background: Primary Aldosteronism (PA), the most common form of endocrine hypertension, is usually identified by a high aldosterone-renin ratio (ARR) alongside elevated plasma aldosterone concentration (PAC) values. Normo-aldosteronemic PA is also being diagnosed when only the high ARR was driven by low renin because PAC was normal. However, whether this entity truly exists remains contentious since most such cases did not undergo surgical confirmation and even when adrenalectomy was performed no demonstration of an aldosterone-producing adenoma (APA) could be obtained at immunohistochemistry. Case Description: In 2003 a young lady presented with severe hypertension, low plasma renin activity (PRA), but consistently normal PAC values. She undertook a magnetic resonance that revealed a small adenoma on the right side, but adrenal vein sampling (AVS) showed left lateralization of aldosterone secretion. Therefore, she underwent left laparoscopic adrenal surgery, which determined complete normalization of blood pressure and PRA long term follow up (12 years). In 2014 the development of novel monoclonal antibodies for the human aldosterone synthase CYP11B2 and 11β-hydroxylase CYP11B1, allowed us to immunochemically characterize the resected adrenal gland. Double immunostaining for CYP11B2 and CYP11B1 showed a small CYP11B2-positive adenoma, thus unequivocally proving the presence of an APA. Conclusions: This case provides compelling evidence for the existence of normo-aldosteronemic APA and suggests that many cases that we dismiss as “low renin-essential hypertension” might instead have an undetected surgically curable APA.

Pathophysiological functions of adrenomedullin and natriuretic peptides in patients with primary aldosteronism.

To measure the plasma concentrations of adrenomedullin (ADM),atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP), and investigate their pathophysiological functions in patients with primary aldosteronism (PA). Between June 2006 and December 2012, we recruited 25 patients with untreated PA, 30 patients with untreated low-renin essential hypertension (EH), and 35 healthy control subjects. The plasma concentrations of ADM, ANP, and BNP were measured in all the subjects. After 4 weeks of effective antihypertensive therapy with slow-release nifedipine, the three peptides were measured again in the PA and low-renin EH subjects. Unilateral laparoscopic adrenalectomy was performed in all the PA patients; 2 weeks after surgery, the three peptides were measured again. The PA patients had significantly higher plasma concentrations of ADM, ANP, and BNP than the low-renin EH and control subjects. The low-renin EH and control subjects significantly differed in the concentrations of the three peptides between low-renin EH and control subjects. ADM was the most important peptide associated with aldosterone or blood pressure in the PA patients. Plasma ADM concentration was not only correlated with plasma aldosterone concentrations, but also with systolic and diastolic blood pressures, and plasma ANP and BNP concentrations in the PA patients. By contrast, ADM concentration was not related to blood urea nitrogen levels, serum creatinine levels, and glomerular filtration rates. After antihypertensive treatment, the concentrations of the three peptides significantly decreased in the low-renin EH patients, but remained unchanged in the PA subjects. However, these concentrations significantly decreased 2 weeks after laparoscopic adrenalectomy in the PA subjects. ADM, ANP, and BNP possibly participate in the mechanisms counteracting further elevation of blood pressure or plasma volume expansion resulting from aldosterone hypersecretion in PA patients. An ADM/aldosterone local regulatory mechanism may be involved in regulating adrenal adenoma functions.

Left ventricle remodeling in men with moderate to severe volume-dependent hypertension

We evaluated the influence of increased intravascular volume on the heart anatomy in salt-sensitive types of hypertension, represented by primary aldosteronism (PA) and low-renin essential hypertension (LREH). Echocardiography was performed in 128 males with moderate to severe or resistant hypertension: 44 patients had PA, 40 patients had LREH and 44 patients had normal-renin essential hypertension (NREH). Groups were comparable in demographic characteristics, blood pressure, duration of hypertension and previous antihypertensive treatment. Patients with PA and LREH, in comparison with NREH patients, showed both greater end-systolic (37.6±5.4 and 35.6±4.5 vs 32.6±4.4 mm, p<0.001 and p<0.05) and end-diastolic (56.1±4.5 and 54.0±4.8 vs 50.4±5.1 mm; p<0.001 and p<0.01) left ventricle (LV) diameter. There were no significant differences either in LV wall thicknesses or LV mass, although a higher percentage of patients with PA and LREH met the criteria of eccentric hypertrophy (p<0.001 and p<0.05 respectively). Aldosterone concentration was positively related to LV cavity dimensions, whether wall thicknesses were rather associated with blood pressure levels. In conclusion, plasma volume overload was identified as an important factor influencing LV remodeling in PA and LREH, whether due to excessive aldosterone levels in PA or other pathophysiological mechanisms.

TASK-3 Channel Deletion in Mice Recapitulates Low-Renin Essential Hypertension

Idiopathic primary hyperaldosteronism (IHA) and low-renin essential hypertension (LREH) are common forms of hypertension, characterized by an elevated aldosterone-renin ratio and hypersensitivity to angiotensin II. They are suggested to be 2 states within a disease spectrum that progresses from LREH to IHA as the control of aldosterone production by the renin-angiotensin system is weakened. The mechanism(s) that drives this progression remains unknown. Deletion of Twik-related acid-sensitive K(+) channels (TASK) subunits, TASK-1 and TASK-3, in mice (T1T3KO) produces a model of human IHA. Here, we determine the effect of deleting only TASK-3 (T3KO) on the control of aldosterone production and blood pressure. We find that T3KO mice recapitulate key characteristics of human LREH, salt-sensitive hypertension, mild overproduction of aldosterone, decreased plasma-renin concentration with elevated aldosterone:renin ratio, hypersensitivity to endogenous and exogenous angiotensin II, and failure to suppress aldosterone production with dietary sodium loading. The relative differences in levels of aldosterone output and aldosterone:renin ratio and in autonomy of aldosterone production between T1T3KO and T3KO mice are reminiscent of differences in human hypertensive patients with LREH and IHA. Our studies establish a model of LREH and suggest that loss of TASK channel activity may be one mechanism that advances the syndrome of low renin hypertension.

18-Hydroxycorticosterone, 18-Hydroxycortisol, and 18-Oxocortisol in the Diagnosis of Primary Aldosteronism and Its Subtypes

Diagnosis of primary aldosteronism (PA) is made by screening, confirmation testing, and subtype diagnosis (computed tomography scan and adrenal vein sampling). However, some tests are costly and unavailable in most hospitals. The aim of the study was to evaluate the role of serum 18-hydroxycorticosterone (s18OHB), urinary and serum 18-hydroxycortisol (u- and s18OHF), and urinary and serum 18-oxocortisol (u- and s18oxoF) in the diagnosis of PA and its subtypes, aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). The study included 62 patients with low-renin essential hypertension (EH), 81 patients with PA (20 APA, 61 BAH), 24 patients with glucocorticoid-remediable aldosteronism, 16 patients with adrenal incidentaloma, and 30 normotensives. We measured s18OHB, s18OHF, and s18oxoF before and after saline load test (SLT) and 24-h u18OHF and u18oxoF. PA patients displayed significantly higher levels of s18OHB, u18OHF, and u18oxoF compared to EH and normal subjects; APA patients displayed s18OHB, u18OHF, and u18oxoF levels significantly higher than BAH patients. Similar results were obtained for s18OHF and s18oxoF. SLT significantly reduced s18OHB, s18OHF, and s18oxoF in all groups, but steroid reduction was much less for APA patients compared to BAH and EH. The s18OHB/aldosterone ratio after SLT more than doubled in EH but remained unchanged in APA patients. u18OHF, u18oxoF, and s18OHB measurements in patients with a positive aldosterone/plasma renin activity ratio correlate with confirmatory tests and adrenal vein sampling in PA patients. If verified, these steroid assays would refine the diagnostic workup for PA.

低レニン性本態性高血圧症:―特に降圧剤の効果について―第1報 安静時の血漿レニン活性についての検討

低レニン性本態性高血圧症:―特に降圧剤の効果について―第1報 安静時の血漿レニン活性についての検討

COMPLEX ANALYSIS OF GENETIC PREDISPOSITION TO DIFFERENT FORMS OF LOW-RENIN ARTERIAL HYPERTENSION: PP.21.338

Objective: Comparison of distribution of alleles and genotypes of polymorphic loci of RAAS genes: CYP11B2 (C-344T), REN (C-5434T, C-5312T, and A BglI G), CMA (G–1903A), ACE (I/D) and AT2R1 (A1166C) and their combinations in patients with low-renin forms of arterial hypertension (AH). Design and Method: 87 hypertensive pts aged 50 ± 13 years with low-renin forms of AH were studied. PAC and PRA were determined in the supine position and following 4-hour upright posture. Complex statistic analysis of differences in allele and genotype patterns distribution between different forms of low-renin AH was carried out by means of recently developed by our group software APSampler, which used a Bayesian Markov chain Monte Carlo-based method and provided an independent validation by means of Fisher's exact test. The differences were considered significant at p values < 0.05. RESULTS: According to clinical data and comparison with PAC, PRA and instrumental analysis pts were divided into 3 groups: group Ia (n = 41) with primary hyperaldosteronism (HA) associated with adenoma; group Ib (n = 18) with idiopathic HA -adrenocortical hyperplasia; combined group I included all 59 HA cases; and group II (n = 28) cases with low-renin essential hypertension with a normal PAC and the absence of structural adrenal changes. The analysis of carriership of allele and genotypes combinations showed significant differences between groups Ia, Ib and II. A comparison of groups II and Ia identified assemblage associated with predisposition only to primary HA: (–344T) CYP11B2 + BglI G REN + I ACE (p = 0.009, OR = 5.4 (95% CI 1.4 to 21.2)) and a comparison of groups II with group Ib identified assemblage as predisposing only to IHA: (–5312 T) REN + D ACE (p = 0.004, OR = 10.7 (95% CI 1.9 to 60.1)). Conclusions: Assemblage (–344T) CYP11B2 + BglI G REN + I ACE is factor of genetic predisposition only to PHA and assemblage (–5312 T) REN + D ACE - only to IHA, thereby indicating that these assemblages are risk factors for different forms of low-renin HA.

Aldosterone to Renin Ratio – A Reliable Screening Tool for Primary Aldosteronism?

Primary aldosteronism (PA) is defined as inappropriately high and (relatively or absolutely) autonomous aldosterone secretion, which is not adequately suppressible by sodium loading. Recent evidence shows that the PA prevalence ranges from 3 to 32%. This high prevalence of PA is suggested to be the result of both more intense screening for PA and improvement of laboratory procedures. Inappropriate high aldosterone secretion is paralleled by severe target organ damage, underlining the importance for the identification of PA at an early stage. The aldosterone to renin ratio (ARR), which reflects aldosterone hypersecretion in regard to its principal trophin renin, is currently considered the most reliable tool for PA screening. Accumulating evidence, however, points to a considerable intra-individual variation of this ratio, emphasizing the importance of standardized screening procedures. In particular, laboratory methods, posture, antihypertensive medication, and dietary salt intake are significant effectors of ARR variation. Furthermore, differentiation between low-renin essential hypertension and PA is difficult and probably arbitrary. It is the purpose of the present review to issue the reliability of the ARR as a screening tool for PA. This review also provides an overview about the physiology of the renin-angiotensin-aldosterone system, highlights current laboratory methods for aldosterone and renin determination, and addresses potential influence factors on the ARR.

Nonalcoholic Fatty Liver Disease in Primary Aldosteronism: A Pilot Study

An impairment of glucose metabolism, contributing to the increased cardiovascular risk, has been shown in primary aldosteronism (PA). Insulin resistance is associated with nonalcoholic fatty liver disease (NAFLD) and may play a role in its pathophysiology. The aim of this study was to investigate the association between NAFLD and PA, and to identify determinants of NAFLD in this condition. A total of 40 patients with PA, 40 sex-, age-, and body mass index matched patients with low-renin essential hypertension (LREH) and 40 normotensive subjects were studied. According to ultrasound detection of fatty liver, each group was subdivided in two subsets: with NAFLD and without NAFLD. Patients with diabetes, obesity, and hyperlipidemia were excluded. Prevalence of NAFLD in PA was similar to that observed in LREH patients, and higher (P < 0.01) than in normotensive controls. Serum potassium was lower in PA than in LREH patients with NAFLD (P < 0.001), while it was similar in PA and LREH patients without NAFLD. At univariate analysis, plasma aldosterone, homeostasis model assessment (HOMA) index and hypokalemia were determinants of NAFLD in PA (P < 0.05), while HOMA index was associated with NAFLD in LREH (P < 0.05). At multivariable analysis, only hypokalemia remained associated with NAFLD in PA (P = 0.02). The results of this pilot study suggest that, in the absence of major risk factors for liver disease, NAFLD is a frequent finding in PA. Patients with PA and hypokalemia are more insulin resistant and have higher prevalence of NAFLD than those with normokalemia, indicating greater risk for metabolic and liver disease in this subgroup.

Some considerations about evolution of idiopathic primary aldosteronism

The prevalence of primary aldosteronism has increased since many patients who were previously considered as being affected by low renin essential hypertension are actually satisfying the new diagnostic criteria using plasma aldosterone/ plasma renin activity (PRA) ratio. Many of these cases could be classified as subclinical hyperaldosteronism, having normal aldosterone and low PRA, or in alternative the normal range of aldosterone should be revised. Idiopathic hyperaldosteronism can, in many cases, be considered as an evolutive disease: it can be hypothesized that the biochemical picture can be preceded by essential hypertension and that, after several years, primary aldosteronism can evolve back to essential hypertension due to age-related reduced vascular and adrenal sensitivity to angiotensin II. This effect is also evident after longterm treatment with aldosterone receptors blockers and therefore it possible that aldosterone-receptors blockers are able to normalize the sensitivity of glomerulosa to angiotensin II even after long-term withdrawal. The use of aldosterone receptors blockers prevents cardiovascular complications due to local aldosterone effect at the level of endothelium and mononuclear leukocytes; therefore, these drugs should be also considered for therapy of patients with hypertension. It is not excluded that aldosterone receptor blockers could prevent the onset of idiopathic hyperaldosteronism and its complications in patients with hypertension without primary hyperaldosteronism. From all these considerations it follows that the concept of normal range of aldosterone should be revised and the use of aldosterone receptor blockers should be revisited.

Adiponectin and Insulin Sensitivity in Primary Aldosteronism

A high prevalence of metabolic syndrome has been reported in primary aldosteronism. Low levels of adiponectin, an adipokine with insulin-sensitizing properties, are considered a hallmark of the metabolic syndrome. We evaluated the relationship between adiponectin and insulin sensitivity in primary aldosteronism, with and without metabolic syndrome, compared with essential hypertension. Forty patients with primary aldosteronism and 40 matched patients with low-renin essential hypertension (LREH) were studied. Patients with type 2 diabetes were excluded. Each group was divided into two subsets: one including patients with metabolic syndrome and one including patients without metabolic syndrome (ie, hypertension alone or associated with another component of the syndrome). Insulin resistance, defined by increased homeostasis model assessment (HOMA index), was higher in patients with primary aldosteronism than in those with LREH only in the absence of metabolic syndrome (P<.01), whereas in the subsets bearing the syndrome it was similar. Adiponectin levels were lower in primary aldosteronism than in patients with LREH (P<.01). Like HOMA index, the difference was maintained (P<.01) only in the subsets without metabolic syndrome. Adiponectin levels were inversely correlated with HOMA index and positively correlated with potassium levels both in primary aldosteronism (P<.001) or in LREH (P<.05) groups. Lower adiponectin as well as lower insulin sensitivity in primary aldosteronism compared with LREH seem to result from both direct (aldosterone excess) and indirect (hypokalemia) mechanisms. Therapeutic interventions aimed at correcting both potassium and adiponectin levels by specific antihypertensive agents might improve insulin sensitivity, providing better cardiovascular protection in primary aldosteronism.

Diagnosis and treatment of low‐renin hypertension

Plasma renin levels can be used to classify hypertension. A significant proportion of hypertensive individuals display a low-renin profile and thus low-renin hypertension (LRH) requires appropriate diagnosis and treatment. LRH includes essential, secondary and genetic forms, the most common of which are low-renin essential hypertension and primary aldosteronism. Several studies have investigated the relationship between PRA status and clinical response to different antihypertensive therapies. The present review will discuss the differential diagnosis of LRH subtypes and the most appropriate treatment options based on the pathophysiological background of this condition.

A Polymorphic GT Short Tandem Repeat Affecting β-ENaC mRNA Expression Is Associated With Low Renin Essential Hypertension

The epithelial sodium channel (ENaC) is a candidate gene associated with the development of essential hypertension. A potentially polymorphic repetitive region (GT dinucleotide short tandem repeat [STR]) was identified in intron 8 of beta-ENaC gene (SCNN1B). The aim of this study was to identify the prevalence and distribution of a polymorphic GT-STR in SCNN1B in Chilean essential hypertensive (EH) patients and to analyze the correlation between the different genotypes with plasma renin activity (PRA) and serum aldosterone (SA), and furthermore, to evaluate the beta-ENaC gene expression in vitro. We studied 133 patients with EH and 69 normotensive (NT). In both EH and NT subjects we measured PRA, SA, urine sodium, and genotyped them according to the GT-STR length using sequencing analysis. We detected 11, 13 and 14 GT alleles in EH and NT subjects. Both groups were classified according to genotype: 14/14, 14/13, 13/13, 13/11, and 11/11. Influence of the GT-STR on beta-ENaC minigene expression was evaluated by real-time polymerase chain reaction. In EH, PRA decreased with the length of the STR region 11/13, 1.40 +/- 0.69; 13/13, 1.16 +/- 0.61; 13/14, 0.90 +/- 0.56; 14/14, 0.32 +/- 0.09 ng/mL/h; P < .01. Likewise, PRA in patients with EH with 14/14 or 14/13 genotypes were lower than EH with 13/13 or 13/11 genotypes (0.77 +/- 0.5 v 1.24 +/- 0.6 ng/mL/h; P < .01). Real-time polymerase chain reaction demonstrated an increased beta-ENaC expression in minigenes containing 14 GT-STR. We have identified a polymorphic GT-STR in the beta-ENaC gene, which is present in the EH and NT Chilean population. Biochemical analysis showed a possible linkage between this polymorphic region and low renin hypertension. The in vitro assay suggests that GT-STR could regulate the beta-ENaC expression.

QT Interval in Patients with Primary Aldosteronism and Low-Renin Essential Hypertension

QT Interval in Patients with Primary Aldosteronism and Low-Renin Essential Hypertension

QT interval in patients with primary aldosteronism and low-renin essential hypertension

QT interval prolongation increases the risk of sudden death in several medical conditions. Patients with primary aldosteronism and salt-sensitive hypertension experience more cardiovascular events than those with normal-renin essential hypertension. QT interval prolongation might represent one of the risk factors for cardiovascular events in these patients. The aim of the present study was to evaluate the QT interval in patients with primary aldosteronism and low-renin essential hypertension (LREH). Twenty-seven patients with primary aldosteronism, 17 patients with LREH, 117 patients with essential hypertension and 25 healthy individuals were studied. Plasma aldosterone, plasma renin activity, and aldosterone to plasma renin activity ratio (ARR) were determined. Corrected QT intervals (QTcs) were measured from a 12-lead electrocardiogram. The QTc was longer in primary aldosteronism (434 +/- 23 ms) and LREH (430 +/- 18 ms) compared with essential hypertension (419 +/- 22 ms) and healthy controls (412 +/- 19 ms) (P = 0.0004). The prevalence of QTc longer than 440 ms was higher in primary aldosteronism (48%) and LREH (23%) compared with essential hypertension (11%) and healthy controls (4%) (P < 0.0001). QTc correlated with plasma aldosterone (P = 0.01), ARR (P = 0.02), and diastolic blood pressure (P = 0.01). ARR (P = 0.01) and systolic blood pressure (P = 0.01) were identified as independent predictors of QTc. We postulate that the elevated aldosterone secretion contributes to the prolongation of the QT interval in patients with primary aldosteronism and LREH through both a depletion of intracellular potassium concentration and higher blood pressure values. QTc measurement might represent one simple, non-invasive and reproducible index to characterize the cardiovascular risk in patients with primary aldosteronism and LREH.

Association between Aldosterone Production and Variation in the 11β-Hydroxylase (CYP11B1) Gene

Variation in the region of chromosome 8 including the genes steroid 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) influences mineralocorticoid and glucocorticoid metabolism. However, the relative importance of polymorphisms in CYP11B1 and CYP11B2 in determining these phenotypes is unknown. Our objective was to investigate genetic influences of the CYP11B1 and CYP11B2 genes on mineralocorticoid metabolism. We measured 24-h urinary excretion of the key metabolites of the principal mineralocorticoids, glucocorticoids and androgens secreted by the adrenal cortex. We genotyped polymorphisms spanning the CYP11B1 and CYP11B2 genes, which together capture all common variations at the locus. Participants included 573 members of 105 British Caucasian families ascertained on a hypertensive proband. We assessed heritability of urinary tetrahydroaldosterone (THAldo) excretion and association of THAldo excretion with genotype. The heritability of THAldo excretion was 52% (P < 10(-6)). There was significant association between THAldo and genotype at several of the CYP11B1/B2 polymorphisms. The strongest association was observed at the rs6387 (2803A/G) polymorphism in intron 3 of CYP11B1 (P = 0.0004). Association followed a codominant model with a 21% higher THAldo excretion per G allele. Genotype at rs6387 accounted for 2.1% of the total population variability of THAldo. We found significant association between THAldo excretion and urinary total androgen excretion, urinary tetrahydrodeoxycortisol level, and urinary cortisol metabolites (all P < 0.001). Aldosterone synthesis is highly heritable and is affected by genotype at CYP11B1. Our findings support the hypothesis that genetically determined differences in 11-hydroxylation efficiency can have downstream effects on mineralocorticoid synthesis. Such effects may be of relevance to the development of low-renin essential hypertension.

Aldosterone and the Pathogenesis of Hypertension

Hypertension remains a major public health problem, affecting up to 20% of the adult population in Western societies. Despite progress in treatment, the rates of blood pressure control remain suboptimal. Hypertension is a heterogeneous disorder, and in the majority of cases, with so-called essential hypertension, no clear single identifiable cause is found. Syndromes of excessive mineralocorticoid production or activity are among the important causes of secondary hypertension. Aldosterone is the principal mineralocorticoid in humans, and primary aldosterone excess, when associated with an aldosterone secreting adenoma (Conns tumor), is amenable to surgical cure. Classically, patient with Conns tumor present with spontaneous hypokalemia and have a relative excess of aldosterone production with suppression of plasma levels of renin (a proxy for angiotensin II, the major trophic substance regulating aldosterone secretion). This combination of a high aldosterone and a low renin is however more commonly associated with nodular hyperplasia of the adrenal glands, a condition not improved by surgery and variably responsive to the effects of mineralocorticoid antagonists such as spironolactone. Although primary aldosteronism was previously considered to be rare, recent studies have reported prevalence rates of up to 20% among hypertensive patients. This reflects the increasing use of the plasma aldosterone concentration to renin activity ratio (ARR), rather than spontaneous hypokalemia, as a screening tool for aldosteronism. Many patients with high ARR have normokalemia and, although renin activity is low, the level of aldosterone is usually within the normal range. This group of patients may thus include those who were previously classified as having low-renin essential hypertension. Recent data suggest that disturbances in aldosterone metabolism and regulation may not be uncommon in patients with essential hypertension. Thus, relatively high serum aldosterone levels within the reference range in normotensive individuals are associated with a substantially increased risk of developing hypertension, highlighting the potential role for aldosterone in the etiology of essential hypertension. The present review addresses the physiology of aldosterone action and its role in the pathogenesis of hypertension.