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Aldosterone modulates the activity of both epithelial (specifically renal) and non-epithelial cells. Binding to the mineralocorticoid receptor (MR), activates two pathways: the classical genomic and the rapidly activated non-genomic that is substantially modulated by the level of striatin. We hypothesized that disruption of MR’s non-genomic pathway would alter aldosterone-induced cardiovascular/renal damage. To test this hypothesis, wild type (WT) and striatin heterozygous knockout (Strn+/−) littermate male mice were fed a liberal sodium (1.6% Na+) diet and randomized to either protocol one: 3 weeks of treatment with either vehicle or aldosterone plus/minus MR antagonists, eplerenone or esaxerenone or protocol two: 2 weeks of treatment with either vehicle or L-NAME/AngII plus/minus MR antagonists, spironolactone or esaxerenone. Compared to the WT mice, basally, the Strn+/− mice had greater (~26%) estimated renal glomeruli volume and reduced non-genomic second messenger signaling (pAkt/Akt ratio) in kidney tissue. In response to active treatment, the striatin-associated-cardiovascular/renal damage was limited to volume effects induced by aldosterone infusion: significantly increased blood pressure (BP) and albuminuria. In contrast, with aldosterone or L-NAME/AngII treatment, striatin deficiency did not modify aldosterone-mediated damage: in the heart and kidney, macrophage infiltration, and increases in aldosterone-induced biomarkers of injury. All changes were near-normalized following MR blockade with spironolactone or esaxerenone, except increased BP in the L-NAME/AngII model. In conclusion, the loss of striatin amplified aldosterone-induced damage suggesting that aldosterone’s non-genomic pathway is protective but only related to effects likely mediated via epithelial, but not non-epithelial cells.

Context Arterial hypertension (AHT) is one of the most frequent pathologies in the general population. Subtypes of essential hypertension characterized by low renin levels allowed the identification of 2 different clinical entities: aldosterone-mediated mineralocorticoid receptor (MR) activation and cortisol-mediated MR activation. Evidence Acquisition This review is based upon a search of Pubmed and Google Scholar databases, up to August 2019, for all publications relating to endocrine hypertension, apparent mineralocorticoid excess (AME) and cortisol (F) to cortisone (E) metabolism. Evidence Synthesis The spectrum of cortisol-mediated MR activation includes the classic AME syndrome to milder (nonclassic) forms of AME, the latter with a much higher prevalence (7.1%) than classic AME but different phenotype and genotype. Nonclassic AME (NC-AME) is mainly related to partial 11βHSD2 deficiency associated with genetic variations and epigenetic modifications (first hit) and potential additive actions of endogenous or exogenous inhibitors (ie, glycyrrhetinic acid-like factors [GALFS]) and other factors (ie, age, high sodium intake) (second hit). Subjects with NC-AME are characterized by a high F/E ratio, low E levels, normal to elevated blood pressure, low plasma renin and increased urinary potassium excretion. NC-AME condition should benefit from low-sodium and potassium diet recommendations and monotherapy with MR antagonists. Conclusion NC-AME has a higher prevalence and a milder phenotypical spectrum than AME. NC-AME etiology is associated to a first hit (gene and epigene level) and an additive second hit. NC-AME subjects are candidates to be treated with MR antagonists aimed to improve blood pressure, end-organ damage, and modulate the renin levels.

The renin-angiotensin-aldosterone system modulates volume, sodium and potassium homeostasis. In the setting of a high sodium diet, up to 30% of patients with hypertension have a low or suppressed renin and increased volume. This phenotype of low renin hypertension (LRH) is multifactorial and includes infrequent inherited genetic syndromes, milder phenotypes of classic diseases and environmental exposures. All these conditions have in common a higher cardiovascular risk mediated by the over activation of the mineralocorticoid receptor (MR), present not only in the kidney, but also in vasculature, myocardium and adipocytes. Consequently, the aim of LRH treatment goes beyond the control of blood pressure and requires antagonizing MR with specific pharmacologic agents, pursuing normalization of renin as a clinical objective. Due to the unusual evaluation of renin status by non-endocrinologists and lack of disease awareness, only a minority of hypertensive patients receive this pathophysiologically-driven treatment that should reduce cardiovascular outcomes.

Purpose Latin American reports on pheochromocytomas and paragangliomas (PPGLs) are scarce. Recent studies demonstrate changes in clinical presentation and management of these patients. Herein, we assessed the main characteristics of PPGL patients in our academic center over the past 4 decades. Methods Demographic, clinical, biochemical, and perioperative data from 105 PPGL patients were retrospectively and prospectively collected over the 1980–2019 period. Data were organized into 4 periods by decade. Results Age at diagnosis, gender, tumor size and percentage of bilaterality, percentage of paragangliomas, and metastases remained stable across the 4 decades. The proportion of genetic testing and incidentalomas increased in recent decades (all P < 0.001). Therefore, we compared PPGLs diagnosed as incidentalomas (36%) with those clinically suspected (64%). Incidentalomas had fewer adrenergic symptoms (38 vs. 62%; P < 0.001) and lower rates of hypertension (64% vs. 80%; P = 0.01) and hypertensive crisis (28% vs. 44%; P = 0.02); also, they had lower functionality (79% vs. 100%; P = 0.01) and lower catecholamines levels (8.4-fold vs. 12.5-fold above upper cutoffs; P = 0.04). Regarding management of all PPGLs over the decades, we observed significant increases in both perioperative doxazosin dose (P = 0.003) and laparoscopic approach rates (P < 0.001), along with a decrease in the length of hospital stays (P = 0.007). Conclusions We observed a change in the clinical presentation of PPGL in recent decades, with a marked increase in incidental cases and milder symptoms. The implementation of a multidisciplinary program for adrenal disorders in our institution has translated into more timely diagnoses, more genetic testing, and improvements in perioperative management.

BACKGROUND We aimed to study the associations of adipocytokines, endothelial damage markers, and high-sensitivity C-reactive protein (hs-CRP) with metabolic syndrome (MetS) components. METHODS This cross-sectional study included 202 subjects categorized into MetS and No-MetS according to Harmonizing Adult Treatment Panel III. RESULTS Subjects with MetS showed higher levels of proinflammatory molecules but significantly lower adiponectin levels than subjects with No-MetS. Among the studied adipocytokines, plasminogen activator inhibitor-1 (PAI-1) and adiponectin showed the strongest associations with most MetS components. PAI-1 was associated with MetS (odds ratio (OR) 1.107 (1.065–1.151), P < 0.0001), whereas adiponectin was inversely associated with MetS (OR 0.710 (0.610–0.825), P < 0.0001). Following adjustment by sex, age, body mass index, and 24-hour urinary sodium excretion in a multivariate analysis, the association of PAI-1 (OR 1.090 (1.044–1.137), P < 0.0001) and adiponectin (OR 0.634 (0.519–0.775), P < 0.0001) with MetS remained significant. Multivariate analyses supported a model in which systolic blood pressure (BP) could be predicted by PAI-1, hs-CRP, and matrix metalloproteinase 2 (R2 = 0.125; P = 0.04); diastolic BP (R2 = 0.218; P = 0.0001) and glucose (R2 = 0.074; P = 0.0001) could be predicted by PAI-1; waist circumference could be predicted by PAI-1 and hs-CRP (R2 = 0.28; P = 0.016). Receiver operating characteristic curve analysis showed that a PAI-1 concentration had the best sensitivity and specificity for discriminating subjects with MetS. CONCLUSION PAI-1 and adiponectin rendered the most robust associations with MetS components in a general population, indicating that unfavorable adipose tissue performance is a key contributor to these metabolic anomalies. Further prospective analyses should allow establishing whether these adipocytokines can anticipate the progress of MetS and cardiovascular risk.

Introduction and Objectives Nonalcoholic-fatty-liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome (MetS). Mineralocorticoid receptor (MR) activation is associated with increased risk of MetS but few studies have assessed the role of liver MR on NAFLD. We aimed to evaluate the effect of MR modulation by sodium intake in liver injury in experimental models of NAFLD. Materials and Methods C57BL/6J mice were fed either a high-fat-diet (HFD) or a choline/methionine deficient (MCD) diet with different sodium concentrations. Hepatic concentration of lipid species, serum aldosterone levels, expression of MR, proinflammatory and profibrotic markers and liver histology were assessed. Results Mice fed with High-Na+/HFD showed a lower MR expression in liver (p = 0.01) and less steatosis on histology (p = 0.04). Consistently, animals from this group exhibited lower levels of serum aldosterone (p = 0.028) and lower hepatic triglyceride content (p = 0.008). This associated to a reduced expression of lipogenic genes, significant changes in lipid subspecies, lower HOMA-IR (p < 0.05), and lower expression of pro-inflammatory and profibrotic markers compared to those mice fed a Low-Na+/HFD. Additionally, mice fed a High-Na+/HFD showed higher expression of salt-inducible kinase (SIK)-1 and lower expression of serum-and-glucocorticoid-inducible kinase (SGK)-1. Similar results were observed with the MCD diet model. Conclusion We identified in two experimental models of NAFLD that High-Na+ diet content is associated to lower serum aldosterone levels and hepatic MR downregulation, associated to decreased steatosis and reduced de novo hepatic lipogenesis, proinflammatory and profibrotic markers. Decreased activation of hepatic MR seems to generate beneficial downstream inhibition of lipogenesis in experimental NAFLD. This work was funded, in part, by grants from the Chilean Government [FONDECYT #1150327 and #1191145 to M.A.; #1200227 to JPA; #1190419 to R.B and #1191183 to F.B.; #1211879 to D.C.) and the Comisión Nacional de Investigación Científica y Tecnológica (CONICYT, AFB170005, CARE Chile UC)]. MA is part of the European- Latin American ESCALON consortium funded by the European Union’s Horizon 2020 Research and Innovation Program under grant agreement no. 825510. Funding from Ayudas para apoyar grupos de investigación del sistema Universitario Vasco (IT971-16 to P.A.), MCIU/AEI/FEDER, UE (RTI2018-095134-B-100 to P.A) is also acknowledged.

Objective: Latin American reports on pheochromocytomas and paragangliomas (PPGL) are scarce. Recent studies have shown changes in both clinical presentation and management of these patients. We aimed to assess the main characteristics of PPGL patients in a single academic center over the last four decades. Experimental design: Cohort study. Patients and methods: Demographic, clinical, biochemical, genetic and perioperative data from 105 PPGL patients were retrospectively and prospectively collected over the 1980–2019 period. Patients were categorized into four groups (14 patients in the 1st, 25 patients in the 2nd, 27 patients in the 3th and 39 patients in the 4th decade) according to the date of diagnosis. Results: The mean age at diagnosis was 46±19 years, and the tumor size was 5.3±2.2 cm, female gender was 63%, bilateral tumor of 15%, paragangliomas 9% and metastatic disease in 15%. The aforementioned parameters remained stable across the four decades. During the study period we observed significant increases in doxazosin dosing (2.7±2.6 mg vs. 8.0±4.5 p marked increase in incidental cases, which highlights the importance of early diagnosis and treatment.

We aimed to study the associations of 5 adipocytokines, two endothelial damage markers, and hs-CRP with the MetS components to distinguish the most significant cytokines likely related to distinct metabolic profiles. Methods: Cross-sectional study with 202 Chilean subjects (18–65 years old), categorized by MetS, and No-MetS according to Harmonizing ATP III. Adipocytokines profiling included adiponectin, leptin, hs-CRP, CTRP-1, PAI-1, FABP4, and metalloproteinase (MMP)-9 and MMP-2 activity. Results: Subjects with MetS showed higher levels of the most proinflammatories molecules but significantly lower adiponectin than subjects with No-MetS. Among the studied adipocytokines, PAI-1 and adiponectin showed the strongest associations with most of MetS components. PAI-1 was associate with MetS OR 1.107 [1.065–1.151], p< 0.0001, and adiponectin inversely associated with MetS OR 0.710 [0.610 -0.825], p< 0.0001). Following adjustment by sex, age, BMI, and 24 h sodium urinary excretion in a multivariate analysis, the association of PAI-1 OR 1.090 [1.044–1.137], p< 0.0001) and adiponectin OR 0.634 [0.519 - 0.775], p < 0.0001) with MetS remained significant. Multivariate analyses support a model where PAI-1associate to waist_hip, SBP, DBP, and glucose (all p< 0.0001) and adiponectin associate to TG (p=0.03) and HDL-cholesterol (p=0.0001). Conclusion: PAI-1 and Adiponectin rendered the most robust associations with MetS components in a general population, indicating that unfavourable adipose tissue performance is a key contributor to these metabolic anomalies. Further prospective analyses should allow establishing whether these adipocytokines can anticipate the progress of MetS and cardiovascular risk. Conflict of interest: The authors declared no conflict of interest. Funding: This work was supported by Chilean grants CONICYT Fondo Nacional de Desarrollo Científico y Tecnológico, (FONDECYT) 1160695(CEF) and 1190419(RB); FONDECYT Post-doctorado 3200646(ATC); Millenium Institute of Immunology and Immunotherapy - ICM (P09/16-F)(AK-CEF).

Mindfulness-based Stress Reduction (MBSR) has shown good efficacy for improving wellbeing in employees experiencing occupational stress. However, comparisons with other interventions, longer-term follow-up, and data from varying sociocultural contexts are lacking. This three-arm, parallel randomised controlled trial (RCT) examined the effects of MBSR on psychological distress in non-physician health workers in direct contact with patients. 105 participants were randomly allocated to either: (1) MBSR (N = 35), (2) Stress Management Course (SMC; N = 34) or (3) wait-list (N = 36). Participants and those assessing outcomes were blinded to group assignment. Participants completed questionnaires pre- and post-intervention and four months after the intervention. Psychological distress was measured using the General Health Questionnaire (GHQ-12) and Outcome Questionnaire (OQ-45). Secondary outcomes included perceived stress, job satisfaction, mindfulness skills and changes in salivary cortisol. 77 participants completed measures post-intervention and 52 at 4-month follow-up. MBSR showed a post-intervention effect in reducing GHQ-12 (ß = -0.80 [SE = 1.58] p 0.01) and OQ-45 (ß = -0.72, [SE = 5.87] p 0.05) psychological distress, compared to SMC and in reducing GHQ-12 (ß = -1.30 [SE = 1.38] p 0.001) and OQ-45 (ß = -0.71, [SE = 5.58] p 0.01) psychological distress compared to wait-list condition. In our secondary outcome, only MBSR was associated with a decrease in the cortisol awaking response by 23% (p 0.05). At follow-up, only effects of MBSR on the psychological distress 'social role' subscale (ß = -0.76 [SE = 1.31] p 0.05) remained significant, compared to SMC. In conclusion, MBSR appears useful in reducing short-term psychological distress in healthcare workers, but these effects were not maintained at follow-up. Trial registration: ISRCTN12039804.

Statin use is associated with lower aldosterone levels. We hypothesized that caveolin-1 may be important for the uptake of statins into the adrenal gland and would affect statin’s aldosterone-lowering effects. The aim of this study was to test whether the caveolin-1 risk allele (rs926198) would affect aldosterone levels associated with statin use. The Hypertensive Pathotype database includes healthy and hypertensive individuals who have undergone assessment of adrenal hormones. Individuals were studied off antihypertensive medications but were maintained on statins if prescribed by their personal physician. Adrenal hormones were measured at baseline and after 1 hour of angiotensin II stimulation on both high- and low-sodium diets. A mixed-model repeated-measures analysis was employed with a priori selected covariates of age, sex, body mass index, and protocol (low versus high sodium, baseline versus angiotensin II stimulated aldosterone). A total of 250 individuals were included in the study; 31 individuals were taking statins (12.4%) and 219 were not. Among statin users, carrying a caveolin-1 risk allele resulted in a 25% (95% CI, 1–43.2) lower aldosterone level ( P =0.04). However, among nonstatin users, carrying a caveolin-1 risk allele resulted in no significant effect on aldosterone levels ( P =0.38). Additionally, the interaction between caveolin-1 risk allele and statin use on aldosterone levels was significant ( P =0.03). These findings suggest caveolin-1 risk allele carrying individuals are likely to receive the most benefit from statin’s aldosterone-lowering properties; however, due to the observational nature of this study, these findings need further investigation.

Adrenal incidentalomas are common with a prevalence of 3-10% and in up to 30% of cases may have probable autonomous cortisol secretion. Hypercortisolism is associated with substantial cardiometabolic morbimortality and can physiologically decrease ACTH levels. Objective: To determine the sensitivity, specificity, and positive and negative predictive values of ACTH levels in evaluating autonomous cortisol secretion in a prospective cohort of incidentally discovered adrenal adenomas. Methods: We prospectively evaluated 224 consecutive adult subjects with incidentally discovered adrenal masses on computed tomography. Finally, 168 participants with radiographic adenoma criteria underwent systematic hormonal assessment, including measurements of morning cortisol and ACTH on day 1, and a 1 mg dexamethasone suppression test (DST) on day 2. Hypercortisolism was excluded if the DST was < 1.8 mcg/dL. Autonomous cortisol secretion was defined as a DST > 5.0 mcg/dL and DST levels of 1.8-5.0 mcg/dL were considered to be possibly autonomous hypercortisolism. We evaluated the correlation of ACTH levels with clinical, radiographic, and endocrine variables. In order to identify the most sensitive threshold value for diagnosing autonomous cortisol secretion, we determined ROC curves and negative likelihood ratio (NLR). Concordance of repeated ACTH was assessed using Bland Altman analysis. Results: The characteristics of the cohort were mean age 56 (+/- 11.8) years, 76% female, adenoma size 19 (+/- 7) mm, and 13% bilateral adenomas. Mean ACTH was 15 (+/- 11) pg/ml (range 5-72) and the mean DST was 2.2 (+/- 3.0) ug/dL (range 0.4-25.9). Fifty-four (32%) participants had a DST ≥1.8mcg/dL and 13 (8%) a DST≥5.0 mcg/dL. We found no correlation between ACTH levels and age, gender or body mass index. ACTH was inversely associated with adrenal adenoma diameter (r=-3.3 p=0.002) and volume (r=-2.9 p=0.008). There was an inverse association between ACTH and DST values (r=-3.1 p=0.01). In the subgroup of patients with a second ACTH measurement we found high concordance, with mean difference of 0.16+/-3.6 pg/ml (p=0.83). ROC analysis showed that an ACTH ≥20 pg/ml had a sensitivity of 98% to exclude hypercortisolism, with a negative predictive value of 97% and a negative likelihood ratio of 0.06. The only case with DST≥1.8 and ACTH≥20 had Cushing′s phenotype with both an adrenal adenoma and a pituitary ACTH-producing adenoma. Systematic evaluation of morning cortisol and ACTH allowed the detection of 5 cases of false negative low DST values due to the use of non-oral corticosteroids. Conclusion: In this cohort, an ACTH ≥20pg/ml excluded autonomous cortisol secretion with excellent sensitivity and negative predictive value, providing strong reassurance that there is no clinically relevant hypercortisolism. Therefore, subjects with a normal DST and ACTH ≥20pg/ml should be candidates for relaxed surveillance.

OBJECTIVES To identify associations among the plasma renin concentration (PRC), plasma aldosterone and urinary sodium (Na)/potassium (K) ratio, and to integrate these variables into a nomogram with the aim of estimating the expected versus observed aldosterone concentration. METHODS We studied 40 healthy normotensive children (5-8 years old, 57.5% girls) who were born at term and were adequate for their gestational age. Following overnight fasting, the PRC and plasma aldosterone in blood samples were measured, and the Na/K ratio was calculated from a simultaneously obtained urinary spot sample. A mathematical function was defined with these three variables, and a nomogram was built that would return the expected aldosterone concentration from the obtained plasma renin and urinary Na/K ratio values. RESULTS The PRC (B = 5.9, P

Primary aldosteronism is characterized by aldosterone secretion that is independent of renin and angiotensin II and sodium status. The deleterious effects of primary aldosteronism are mediated by excessive activation of the mineralocorticoid receptor that results in the well-known consequences of volume expansion, hypertension, hypokalemia, and metabolic alkalosis, but it also increases the risk for cardiovascular and kidney disease, as well as death. For decades, the approaches to defining, diagnosing, and treating primary aldosteronism have been relatively constant and generally focused on detecting and treating the more severe presentations of the disease. However, emerging evidence suggests that the prevalence of primary aldosteronism is much greater than previously recognized, and that milder and nonclassical forms of renin-independent aldosterone secretion that impart heightened cardiovascular risk may be common. Public health efforts to prevent aldosterone-mediated end-organ disease will require improved capabilities to diagnose all forms of primary aldosteronism while optimizing the treatment approaches such that the excess risk for cardiovascular and kidney disease is adequately mitigated. In this review, we present a physiologic approach to considering the diagnosis, pathogenesis, and treatment of primary aldosteronism. We review evidence suggesting that primary aldosteronism manifests across a wide spectrum of severity, ranging from mild to overt, that correlates with cardiovascular risk. Furthermore, we review emerging evidence from genetic studies that begin to provide a theoretical explanation for the pathogenesis of primary aldosteronism and a link to its phenotypic severity spectrum and prevalence. Finally, we review human studies that provide insights into the optimal approach toward the treatment of primary aldosteronism.

The majority of tumor-induced osteomalacia cases have been reported in the Northern Hemisphere and Asia. In this first series of South American patients, we show that the clinical presentation and sensitivity of plasmatic fibroblast growth factor 23 and somatostatin analog-based imaging are similar to those described in other populations. Describe the experience of clinical presentation, diagnostic study, and treatment of patients with tumor-induced osteomalacia (TIO) in a South American academic center in comparison to literature. Analysis of the records of patients diagnosed with TIO. The clinical presentation, diagnostic studies, and treatment were analyzed. Fibroblast growth factor 23 (FGF23) was measured by ELISA. Six patients were diagnosed with TIO during the studied period. The patients’ median age was 53 years (range 22–64). All patients presented with weakness and pain in the extremities. Four experienced fractures during their evolution. The median time to diagnosis was 4.5 years (1–20). Biochemical studies showed hypophosphatemia, median of 1.4 mg/dL (1.2–1.6), with low maximum rates of tubular reabsorption of phosphate adjusted for glomerular filtration rate. FGF23 was elevated in 4/6 patients and inappropriately normal in the other two. In three patients, the location of the tumor was clinically evident and confirmed with anatomical imaging. In the remaining patients, two tumors were located with 68Ga DOTATATE-PET/CT and one with OctreoScan. The causal tumors were located in the lower extremities in five patients and invading the frontal sinus in one patient. In all patients, tumors were successfully removed. Within 14 days, there was normalization of phosphate and FGF23 levels and resolution of clinical symptoms in all patients. In all cases, the histopathology was compatible with a phosphaturic mesenchymal tumor. The clinical presentation, delay time to diagnosis, FGF23 diagnostic sensitivity and histopathology in this first series of South American patients is similar to those described in other populations. The success of localization by somatostatin analog-based imaging, suggests this may the optimal imaging modality.

Item does not contain fulltext BACKGROUND: Although unilateral primary aldosteronism is the most common surgically correctable cause of hypertension, no standard criteria exist to classify surgical outcomes. We aimed to create consensus criteria for clinical and biochemical outcomes and follow-up of adrenalectomy for unilateral primary aldosteronism and apply these criteria to an international cohort to analyse the frequency of remission and identify preoperative determinants of successful outcome. METHODS: The Primary Aldosteronism Surgical Outcome (PASO) study was an international project to develop consensus criteria for outcomes and follow-up of adrenalectomy for unilateral primary aldosteronism. An international panel of 31 experts from 28 centres, including six endocrine surgeons, used the Delphi method to reach consensus. We then retrospectively analysed follow-up data from prospective cohorts for outcome assessment of patients diagnosed with unilateral primary aldosteronism by adrenal venous sampling who had undergone a total adrenalectomy, consecutively included from 12 referral centres in nine countries. On the basis of standardised criteria, we determined the proportions of patients achieving complete, partial, or absent clinical and biochemical success in accordance with the consensus. We then used logistic regression analyses to identify preoperative factors associated with clinical and biochemical outcomes. FINDINGS: Consensus was reached for criteria for six outcomes (complete, partial, and absent success of clinical and biochemical outcomes) based on blood pressure, use of antihypertensive drugs, plasma potassium and aldosterone concentrations, and plasma renin concentrations or activities. Consensus was also reached for two recommendations for the timing of follow-up assessment. For the international cohort analysis, we analysed clinical data from 705 patients recruited between 1994 and 2015, of whom 699 also had biochemical data. Complete clinical success was achieved in 259 (37%) of 705 patients, with a wide variance (range 17-62), and partial clinical success in an additional 334 (47%, range 35-66); complete biochemical success was seen in 656 (94%, 83-100) of 699 patients. Female patients had a higher likelihood of complete clinical success (odds ratio [OR] 2.25, 95% CI 1.40-3.62; p=0.001) and clinical benefit (complete plus partial clinical success; OR 2.89, 1.49-5.59; p=0.002) than male patients. Younger patients had a higher likelihood of complete clinical success (OR 0.95 per extra year, 0.93-0.98; p

21-hydroxylase deficiency (21-OHD) is a congenital adrenal disease with more than 200 mutations published to date. The aim of this report is to describe a severe novel mutation of the CYP21A2 gene. We describe a case of a 39-year-old male diagnosed with a salt wasting congenital adrenal hyperplasia (SWCAH) due to 21-OHD. The genetic testing was done using a combination of three methods (PCR XL, SALSA-MLPA, and bidirectional sequencing) and finally an in silico analysis. The genetic testing demonstrated three severe mutations of the CYP21A2 gene (p.Gln318*; c.290-13C>G; and p.Trp86*), being the last one a novel mutation not previously reported. The in silico modeling of the p.Trp86* (c.258G>A) showed a truncated CYP21A2 protein that loses all the main structural features required for activity, such as the HEM binding domain and the hormone binding site. We present an adult man with an SWCAH due to 21-OHD who carried three severe mutations of the CYP21A2 gene, one of them, p.Trp86* (c.258G>A) has not been previously described.

Mineralocorticoid arterial hypertension has risen as one of the most prevalent causes of secondary hypertension, where 11β-hydroxysteroid dehydrogenase type-2 partial deficiency (also known as non-classical AME (NC-AME)), could reach a prevalence of 7% in Chilean subjects. The phenotype of NC-AME is associated to high serum cortisol (F) to cortisone (E) ratio &low E, high potassium excretion and low-renin activity (Tapia-Castillo et al, JCEM 2018). However, local metabolic changes in NC-AME affecting protein, RNA and miRNA expression have not been studied. Nowadays, exosomes technology allows to identify those biomolecules in specific biofluids. Aim: To identify the transcriptomic (miRNA) and proteomic profile in urinary exosomes of subjects with non-classical AME and healthy subjects. Subjects and methods: A cross-sectional study was carried out in 24 subjects (10-65 years). The subjects were classified as NC-AME (F/E ratio> percentile 75th, and E < percentile 25th) and healthy controls. The levels of F, E, aldosterone and plasma renin activity were quantified. The exosomes were obtained from morning urine samples by differential ultracentrifugation and were characterized with the NS300 nanoparticle analyzer, electron microscopy and western-blot for CD63 and TSG101. The total exosomal RNA was isolated with Trizol reagent. The Illumina TruSeq Small RNA kit was used and sequenced by Illumina NextSeq-500. Additionally, an exosomal proteomic profile was obtained by LC-MS/MS 5600 Triple TOF (ABSciex, Framingham, USA). Bioinformatic analyzes were performed with miRdeep2, PANTHER and STRING. Results: In urinary exosomes, we found355 from 2822 predicted miRNAs , of which 170 miRNA were found to be upregulated and 185 miRNA were dowregulated in subjects with NC-AME vs controls. We also found miR-204-5p (change times = 0.115; p = 0.001) and have miR-192-5p (change times = 0.246; p = 0.03), present a significantly lower expression in NC-AME subjects vs controls, both confirmed by Taqman PCR. Genetic ontology analyses indicate that both miRNAs would have a role in steroid biosynthesis (hsa00100). We identified around 350 exosomal proteins, of which 79 proteins were commonly expressed in both groups and 23 proteins were exclusively expressed in subjects with NC-AME, highlighting the 14-3-3 (YWHAE, YWHAZ), RHOA and CDC42 protein. Conclusion: This is the first study on urinary exosomes showing the differential expression of miRNA (miR-204 and miR-192) and proteins (14-3-3, RHOA and CDC42) which highlight its potential role as biomarkers and regulators of the high mineralocorticoid activity in NC-AME subjects. Acknowledgements: This study was supported by grants CONICYT-FONDECYT 1150437, 1160695, 1160836, CONICYT-FONDEQUIP EQM150023, IMII P09/16-F, & CETREN-UC. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

BACKGROUND Aldosterone has been linked with obesity, metabolic syndrome (MetS), pro-inflammatory, and prothrombotic states; however, most studies relate these indicators with primary aldosteronism (PA), excluding non-PA patients. OBJECTIVE To determine whether aldosterone, renin, or the plasma aldosterone/renin ratio (ARR) are associated with metabolic disorders and inflammatory/vascular biomarkers in a non-PA population. METHODS We studied 275 patients including adolescents and adults of both genders and measured plasma and urinary aldosterone and determined the plasma renin activity. In all subjects, the presence of MetS was determined according to Adult Treatment Panel III. Renal, vascular, inflammatory, and mineralocorticoid activity biomarkers were evaluated. RESULTS The ARR correlated with the number of variables of MetS (r = 0.191, P = 0.002), body mass index (BMI; r = 0.136, P = 0.026), systolic blood pressure (r = 0.183, P = 0.002), diastolic blood pressure (r = 0.1917, P = 0.0014), potassium excreted fraction (r = 0.174, P = 0.004), low-density lipoprotein (r = 0.156, P = 0.01), plasminogen activator inhibitor type 1 (r = 0.158, P = 0.009), microalbuminuria (r = 0.136, P = 0.029), and leptin (r = 0.142, P = 0.019). In a linear regression model adjusted by age, BMI, and gender, only the ARR was still significant (r = 0.108, P = 0.05). In a logistic regression analysis, the ARR predicted MetS index (odds ratio (OR) = 1.07 [95% confidence interval (CI) = 1.011–1.131], P= 0.02) even after adjusting for age, BMI, and gender. On the other hand, aldosterone showed no association with MetS or inflammatory markers. CONCLUSION These results suggest a continuum of cardiometabolic risk beyond the classic PA threshold screening. The ARR could be a more sensitive marker of obesity, MetS, and endothelial damage in non-PA patients than aldosterone or renin alone. Prospective studies are needed to develop future screening cutoff values.

BACKGROUND High sodium intake has been associated with various noncommunicable disease like hypertension, cardiovascular disease, or stroke. To estimate accurately sodium intake is challenging in clinical practice. We investigate the usefulness and limitations of assessing sodium intake simultaneously by dietary assessment and urinary samples in both children and adults. METHODS We used a cross-sectional study design inviting 298 Chilean subjects (74 children and 222 adults) aged between 9 and 66 years of both genders. Sodium intake by dietary assessment was obtained from Chilean food composition data, based on FAO tables. Sodium and creatinine excretion were measured in 24-hour urine samples, in all participants. RESULTS Adequate urinary collection was obtained in 81% of children (59/74) and 61% of adults (135/222). The mean sodium intake by dietary assessment was similar to the sodium excretion in 24 hours (3,121±1,153mg/d vs. 3,114±1,353mg/24h, P = nonsignificant) in children but was significantly lower (3,208±1,284mg/d vs. 4,160±1,651mg/24h, P < 0.001) in adults. In both children and adults, sodium intake correlated with urinary sodium excretion (r = 0.456, P < 0.003 and r = 0.390, P < 0.001, respectively). Secondary analyses also suggested that the dietary assessment was more inaccurate in overweight adult subjects. CONCLUSIONS Our results showed that average sodium intake was higher than recommended in both children and adults (WHO ≤2,000mg/d). The sodium intake estimated by dietary assessment correlated with urinary excretion in all subjects, but in obese adults was more inaccurate than in children. Future studies to validate the appropriate test to assess sodium intake by age and nutritional status are warranted.

Context Classical apparent mineralocorticoid excess (AME) is a rare recessive disorder, caused by severe 11β-hydroxysteroid dehydrogenase type 2 enzyme (11β-HSD2) deficiency. AME manifests as low-renin pediatric hypertension, hypokalemia and high cortisol/cortisone (F/E) ratio. Objective To evaluate nonclassic AME (NC-AME) due to partial 11β-HSD2 insufficiency and its association with hypertension, mineralocorticoid receptor (MR) activation, and inflammatory parameters. Design Cross-sectional study. Setting Primary care cohort. Participants We recruited 127 adolescents and adults. Subjects with secondary hypertension were excluded. We measured clinical, biochemical, renal, vascular, and inflammatory variables. Sequencing of HSD11B2 gene was performed in all subjects. Main Outcome Measure NC-AME. Results Serum F/E ratio was positively associated with systolic blood pressure (BP), microalbuminuria, and high-sensitivity C-reactive protein (hs-CRP). Serum cortisone correlated with MR activation parameters even when adjusted for age, body mass index, and sex: lower cortisone with higher potassium excretion (partial r = -0.29, P = 0.002) and with lower plasma renin activity (PRA) (partial r = 0.29, P = 0.001). Consistently, we identified 9 in 127 subjects (7.1%) with high F/E ratios (first quartile) and low cortisone (last quartile), suggestive of NC-AME. These subjects had higher systolic BP, 141.4 ± 25.7 mm Hg vs 127.3 ± 18.1 mm Hg, P = 0.03; lower PRA, 0.36 ± 0.19 ng/L*s vs 0.64 ± 0.47 ng/L*s, P < 0.0001; and greater potassium excretion, microalbuminuria, hs-CRP, and plasminogen activator inhibitor. We only found in 2 out of 9 subjects with NC-AME heterozygous mutations in the HSD11B2 gene. Conclusions These findings suggest a spectrum of partial 11β-HSD2 insufficiency in a primary care cohort without the classic phenotype and genotype of AME. NC-AME may represent a phenotype of MR activation and cardiovascular risk, suggesting that these subjects could be treated with MR antagonists.

BACKGROUND Mounting evidence has associated high sodium (HS) intake with hypertension, cardiovascular disease, and stroke. We investigated whether HS intake modulates the parameters of endothelial damage, inflammation, and oxidative stress. METHODS We used a cross-sectional study design including 223 Chilean subjects (6.9–65.0 years old). We measured aldosterone, renin activity, cortisol, cortisone, adiponectin, leptin, hsCRP, interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor type 1 (PAI-1), metalloproteinase (MMP)-9 and MMP-2 activity, and malondialdehyde. Sodium and creatinine were measured in 24-hour urine samples. The subjects were divided by sodium intake, high sodium (HS): ≥150 mEq/day, n = 118, and adequate sodium (AS): RESULTS We observed a positive correlation between urinary sodium excretion and blood pressure (r = 0.1669, P = 0.0124 for systolic and r = 0.2416, P = 0.0003 for diastolic), glycemia (r = 0.2660, P < 0.0001), and triglycerides (r = 0.1604, P = 0.0175) and a highly significant correlation between sodium excretion and PAI-1 (r = 0.2701, P < 0.0001). An inverse correlation was observed between urinary sodium and HDL-cholesterol (r = −0.2093, P = 0.0018) and adiponectin (r = −0.2679, P < 0.0001). In a linear regression model, urinary sodium excretion remained significantly associated with PAI-1 values even after adjusting for age, gender, and BMI. The HS group had higher blood pressure, glycemia, HOMA-IR, atherogenic index of plasma, and PAI-1 values than the group with AS intake. CONCLUSIONS HS intake is associated with endothelial damage (high PAI-1) and metabolic dysregulation. On the other hand, inflammation and oxidative stress parameters are not modified by sodium intake.

BACKGROUND Pathogenic variations in HSD11B2 gene triggers the apparent mineralocorticoid excess syndrome (AME). There is scarce information regarding the phenotypes of subjects carrying heterozygous pathogenic variants in HSD11B2 gene. We investigated if serum cortisol/cortisone (F/E) ratio and cortisone are useful for identifying partial 11βHSD2 deficiency in those heterozygous subjects. METHODS We studied two patients diagnosed with AME and their families carrying either D223N or R213C mutation. We also evaluated 32 healthy control subjects (13 children and 19 adults) to obtain normal references ranges for all measured variables. Case 1: A boy carrying D223N mutation in HSD11B2 gene and Case 2: A girl carrying R213C mutation. We assessed serum F/E ratio and cortisone by HPLC-MS/MS, aldosterone, plasma-renin-activity(PRA), electrolytes, and HSD11B2 genetic analyses. RESULTS The normal values (median [interquartile range]) in children for serum F/E and cortisone (µg/dl) were 2.56 [2.21–3.69] and 2.54 [2.35–2.88], and in adults were 4.42 [3.70–4.90] and 2.23 [1.92–2.57], respectively. Case 1 showed a very high serum F/E 28.8 and low cortisone 0.46 µg/dl. His mother and sister were normotensives and heterozygous for D223N mutation with high F/E (13.2 and 6.0, respectively) and low cortisone (2.0 and 2.2, respectively). Case 2 showed a very high serum F/E 175 and suppressed cortisone 0.11 µg/dl. Her parents and sister were heterozygous for the R213C mutation with normal phenotype, but high F/E and low cortisone. Heterozygous subjects showed normal aldosterone, PRA, but lower fractional excretion of sodium and urinary Na/K ratio than controls. CONCLUSION Serum F/E ratio and cortisone allow to identify partial 11βHSD2 deficiencies, as occurs in heterozygous subjects, who would be susceptible to develop arterial hypertension.

Over the last decades, our conventional understanding of aldosterone biosynthesis and signaling has been dramatically challenged. We learned that a local regulatory system modifies tissue levels of cortisol to improve aldosterone selectivity for the mineralocorticoid receptor (MR) and that steroid receptor signaling includes rapid nongenomic effects. Moreover, the MR has been identified in a wide variety of tissues beyond epithelial cells, which includes endothelial cells, vascular smooth muscle cells, fibroblasts, adipocytes, and myocytes. The function of aldosterone in these cells is different from the classic renal actions and could be explained by different signaling mechanisms and/or tissue-specific modulators. Likewise, aldosterone not only works through a classic nuclear receptor but also through a cell-surface receptor that regulate diverse intracellular events. By improving our understanding of MR signaling we have reshaped our vision of aldosterone beyond its classic role in electrolyte regulation to include newly discovered roles of MR in extrarenal tissues and a potential pathogenic role in cardiometabolic disorders.

Background: Primary aldosteronism is recognized as a severe form of renin-independent aldosteronism that results in excessive mineralocorticoid receptor (MR) activation. Objective: To investigate whether a spectrum of subclinical renin-independent aldosteronism that increases risk for hypertension exists among normotensive persons. Design: Cohort study. Setting: National community-based study. Participants: 850 untreated normotensive participants in MESA (Multi-Ethnic Study of Atherosclerosis) with measurements of serum aldosterone and plasma renin activity (PRA). Measurements: Longitudinal analyses investigated whether aldosterone concentrations, in the context of physiologic PRA phenotypes (suppressed, ≤0.50 µg/L per hour; indeterminate, 0.51 to 0.99 µg/L per hour; unsuppressed, ≥1.0 µg/L per hour), were associated with incident hypertension (defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or initiation of antihypertensive medications). Cross-sectional analyses investigated associations between aldosterone and MR activity, assessed via serum potassium and urinary fractional excretion of potassium. Results: A suppressed renin phenotype was associated with a higher rate of incident hypertension than other PRA phenotypes (incidence rates per 1000 person-years of follow-up: suppressed renin phenotype, 85.4 events [95% CI, 73.4 to 99.3 events]; indeterminate renin phenotype, 53.3 events [CI, 42.8 to 66.4 events]; unsuppressed renin phenotype, 54.5 events [CI, 41.8 to 71.0 events]). With renin suppression, higher aldosterone concentrations were independently associated with an increased risk for incident hypertension, whereas no association between aldosterone and hypertension was seen when renin was not suppressed. Higher aldosterone concentrations were associated with lower serum potassium and higher urinary excretion of potassium, but only when renin was suppressed. Limitation: Sodium and potassium were measured several years before renin and aldosterone. Conclusion: Suppression of renin and higher aldosterone concentrations in the context of this renin suppression are associated with an increased risk for hypertension and possibly also with increased MR activity. These findings suggest a clinically relevant spectrum of subclinical primary aldosteronism (renin-independent aldosteronism) in normotension. Primary Funding Source: National Institutes of Health.

BACKGROUND The impairment of 11β-hydroxysteroid dehydrogenase type 2 enzyme (11βHSD2) results in an inefficient conversion of cortisol to cortisone, which triggers hypertension. Cytosine-adenine repeat (CA repeat) microsatellite has been associated with low HSD11B2 gene expression. AIM To determine whether the CA-repeat length in intron 1 affect the serum cortisol to cortisone (F/E) ratio and/or blood pressure (BP) levels in pediatric subjects. SUBJECTS AND METHODS Eighty-one hypertensive (HT) and 117 normotensive (NT) subjects participated in this study. We measured BP levels, as well as the F and E and F/E ratio in morning sera and 12-hour urine samples. The length of CA repeats was determined through fragment analysis. We compared the allele distribution between the HT and NT groups, and the patients were dichotomized into groups with short alleles (S) (

BackgroundTherapeutic options to treat Non-alcoholic steatohepatitis (NASH) are limited. Mineralocorticoid receptor (MR) activation could play a role in hepatic fibrogenesis and its modulation could be beneficial for NASH.AimTo investigate whether eplerenone, a specific MR antagonist, ameliorates liver damage in experimental NASH.MethodsC57bl6 mice were fed a choline-deficient and amino acid-defined (CDAA) diet for 22weeks with or without eplerenone supplementation. Serum levels of aminotransferases and aldosterone were measured and hepatic steatosis, inflammation and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic, oxidative stress-associated genes and of MR were also assessed.ResultsCDAA diet effectively induced fibrotic NASH, and increased the hepatic expression of pro-inflammatory, pro-fibrotic and oxidative stress-associated genes. Hepatic MR mRNA levels significantly correlated with the expression of pro-inflammatory and pro-fibrotic genes and were significantly increased in hepatic stellate cells obtained from CDAA-fed animals. Eplerenone administration was associated to a reduction in histological steatosis and attenuation of liver fibrosis development, which was associated to a significant decrease in the expression of collagen-1, collagen type III, alpha 1 and Matrix metalloproteinase-2.ConclusionThe expression of MR correlates with inflammation and fibrosis development in experimental NASH. Specific MR blockade with eplerenone has hepatic anti-steatotic and anti-fibrotic effects. These data identify eplerenone as a potential novel therapy for NASH. Considering its safety and FDA-approved status, human studies are warranted.

Striatin is a novel protein that interacts with steroid receptors and modifies rapid, nongenomic activity in vitro. We tested the hypothesis that striatin would in turn affect mineralocorticoid receptor function and consequently sodium, water, and blood pressure homeostasis in an animal model. We evaluated salt sensitivity of blood pressure in novel striatin heterozygote knockout mice. Compared with wild type, striatin heterozygote exhibited a significant increase in blood pressure when sodium intake was increased from restricted (0.03%) to liberal (1.6%) sodium. Furthermore, renal expression of mineralocorticoid receptor and its genomic downstream targets serum/glucocorticoid-regulated kinase 1, and epithelial sodium channel was increased in striatin heterozygote versus wild-type mice on liberal sodium intake while the pAkt/Akt ratio, readout of mineralocorticoid receptor’s rapid, nongenomic pathway, was reduced. To determine the potential clinical relevance of these findings, we tested the association between single nucleotide polymorphic variants of striatin gene and salt sensitivity of blood pressure in 366 white hypertensive subjects. HapMap-derived tagging single nucleotide polymorphisms identified an association of rs2540923 with salt sensitivity of blood pressure (odds ratio, 6.25; 95% confidence interval, 1.7–20; P =0.01). These data provide the first in vivo evidence in humans and rodents that associates striatin with markers of mineralocorticoid receptor activity. The data also support the hypothesis that the rapid, nongenomic mineralocorticoid receptor pathway (mediated via striatin) has a role in modulating the interaction between salt intake and blood pressure.

Primary aldosteronism is a severe form of autonomous aldosteronism. Milder forms of autonomous and renin-independent aldosteronism may be common, even in normotension. We characterized aldosterone secretion in 210 normotensives who had suppressed plasma renin activity (12 μg/24 hours with urinary sodium excretion >200 mmol/24 hours. Across the population, there were strong and significant associations between higher aldosterone excretion rate and higher urinary potassium excretion, higher angiotensin II–stimulated aldosterone, and lower plasma renin activity, suggesting a continuum of renin-independent aldosteronism and mineralocorticoid receptor activity. Autonomous aldosterone secretion that fulfilled confirmatory criteria for primary aldosteronism was detected in 29 participants (14%). Normotensives with evidence suggestive of confirmed primary aldosteronism had higher 24-hour urinary aldosterone excretion rate (20.2±12.2 versus 6.2±2.9 μg/24 hours; P P P =0.001); however, there were no differences in age, aldosterone-to-renin ratio, blood pressure, or renal plasma flow between the 2 groups. These findings indicate a continuum of renin-independent aldosteronism and mineralocorticoid receptor activity in normotension that ranges from subtle to overtly dysregulated and autonomous. Longitudinal studies are needed to determine whether this spectrum of autonomous aldosterone secretion contributes to hypertension and cardiovascular disease.

Aldosterone's functions and mechanisms of action are different depending on the tissue and the environmental condition. The mineralocorticoid receptor is present in tissues beyond epithelial cells, including the heart and vessels. Furthermore, aldosterone has direct adverse effects by both genomic and rapid/nongenomic actions not only through a nuclear receptor but also through caveolae-mediated intracellular events. Also, multiple environmental-genetic interactions play an important role in salt-sensitive hypertension (SSH) and aldosterone modulation. These findings have reshaped our vision of aldosterone's role in cardiovascular pathophysiology. This review describes new mediators of aldosterone's mechanisms of action: lysine-specific demethylase 1 (LSD1), caveolin 1 (cav-1) and striatin.LSD1, an epigenetic regulator, is involved in the pathogenesis of SSH in both humans and rodents. In addition, cav-1, the main component of caveolae, plays a substantial role in mediating aldosterone pathways of SSH. The mineralocorticoid receptor interacts with cav-1 and is modulated by sodium intake. Finally, striatin, a scaffolding protein, mediates a novel interaction between signalling molecules and mineralocorticoid receptor's rapid effects in the cardiovascular system.Substantial progress in aldosterone's functions and mechanisms of action should facilitate the study of cardiovascular diseases and the role of sodium intake in aldosterone-induced damage.

Context: Mild cases of autonomous aldosterone secretion may go unrecognized using current diagnostic criteria for primary aldosteronism (PA). Objective: To investigate whether the inability to stimulate renin serves as a biomarker for unrecognized autonomous aldosterone secretion and mineralocorticoid receptor (MR) activation. Participants: Six hundred sixty-three normotensive and mildly hypertensive participants, who were confirmed to not have PA using current guideline criteria and were on no antihypertensive medications. Design: Participants had their maximally stimulated plasma renin activity (PRA) measured while standing upright after sodium restriction. Tertiles of maximally stimulated PRA were hypothesized to reflect the degree of MR activation: lowest PRA tertile = “Inappropriate/Excess MR Activity;” middle PRA tertile = “Intermediate MR Activity;”; and highest PRA tertile = “Physiologic MR Activity.” All participants underwent detailed biochemical and vascular characterizations under conditions of liberalized sodium intake, and associations with stimulated PRA phenotypes were performed. Results: Participants with lower stimulated PRA had greater autonomous aldosterone secretion [higher aldosterone-to-renin ratio (P = 0.002), higher urine aldosterone excretion rate (P = 0.003), higher systolic blood pressure (P = 0.004), and lower renal plasma flow (P = 0.04)] and a nonsignificant trend toward lower serum potassium and higher urine potassium excretion, which became significant after stratification by hypertension status. Conclusions: In participants without clinical PA, the inability to stimulate renin was associated with greater autonomous aldosterone secretion, impaired vascular function, and suggestive trends in potassium handling that indicate an extensive spectrum of unrecognized MR activation.

Objective:The detection of adrenal incidentalomas is increasing. Current European guidelines suggest that all adrenal incidentalomas (AI) should be screened for excess cortisol and cathecolamines, but excess aldosterone only in the presence of hypertension and/or hypokalemia. Consistently, the repor

Background Central obesity has a higher risk of the metabolic syndrome (MetS) and cardiovascular diseases. It is estimated by measuring waist circumference (WC) and waist-to-hip ratio (WHR), which are operator-dependent. The present study aimed to validate a body composition monitor (BCM) as a tool for estimating visceral adipose tissue (VAT), as well as to assess its capacity to predict the MetS and its correlation with anthropometric parameters. Methods We measured WC, WHR and body mass index (BMI) in 60 recruited subjects. BCM estimated VAT (1–30 points). Body composition and resting energy expenditure (REE) were compared with bioelectrical impedance analysis (BIA) and indirect calorimetry, respectively. VAT was estimated by BCM (range 1–30 points), We evaluated the capability of VAT, WC, BMI and WHR to predict the MetS by ATP-III criteria. Results The mean (SD) age of subjects was 36.8 (12.9) years, 80% were female, and 47% had the MetS. Body composition and REE estimated by BCM had a significant correlation with BIA (r = 0.85–0.91, P

La hipertensión arterial (HTA) dependiente de mineralocorticoides representa actualmente una de las formas secundarias de hipertensión de mayor prevalencia. Entre las causas más prevalentes está el hiperaldosteronismo primario (HAP) cuya prevalencia es cercana al 10% de la población de hipertensos. El HAP se detecta principalmente por una elevación de la razón aldosterona a actividad renina plasmática (ARR), ya que la hipokalemia es infrecuente de encontrar. La fisiopatología del HAP se presenta como un desequilibrio en el control electrolítico a nivel renal, por mayor actividad del receptor mineralocorticoides (MR), lo cual aumenta el volumen intravascular y la presión arterial. Recientemente se ha demostrado también que el exceso de aldosterona afecta también el endotelio vascular, el tejido cardiaco entre otros. Este exceso puede ser por una alteración a nivel de la glándula suprarrenal (generalmente hiperplasia o adenoma) o formas genéticas (familiares). Por otra parte, alteraciones parciales o totales de la enzima 11β-Hidroxiesteroide deshidrogenasa tipo 2 (11β-HSD2) resulta en una metabolización total o parcial de cortisol, imitando los efectos de aldosterona sobre MR. La actividad de esta enzima se evalúa midiendo la razón cortisol a cortisona en suero por HPLC-MS/MS. La prevalencia de alteraciones parciales de la actividad de la enzima 11β-HSD2 en estudios de cohorte alcanza en alrededor del 15% en población hipertensa. El diagnóstico del HAP o deficiencias de 11BHSD2, permitiría un tratamiento específico del cuadro hipertensivo mediantes el uso de bloqueadores del receptor mineralocorticoideo y/o uso de corticoides de acción prolongada sin actividad mineralocorticoidea como dexametasona o betametasona.

Background Overactivation of the aldosterone and mineralocorticoid receptor ( MR ) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav‐1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav‐1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav‐1–null mice and humans with a prevalent variant in the CAV 1 gene. Methods and Results In mouse studies, cav‐1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high‐ to low‐density lipoprotein (all P mRNA levels for resistin, retinol binding protein 4, NADPH oxidase 4, and aldose reductase in liver and/or fat tissues. MR blockade with eplerenone significantly decreased glycemia ( P P P CAV 1 gene polymorphism rs926198 in 556 white participants; 58% were minor allele carriers and displayed higher odds of insulin resistance (odds ratio 2.26 [95% CI 1.40–3.64]) and low high‐density lipoprotein (odds ratio 1.54 [95% CI 1.01–3.37]). Aldosterone levels correlated with higher homeostatic model assessment of insulin resistance and resistin and lower high‐density lipoprotein only in minor allele carriers. CAV 1 gene expression quantitative trait loci data revealed lower cav‐1 expression in adipose tissues by the rs926198 minor allele. Conclusions Our findings in mice and humans suggested that decreased cav‐1 expression may activate the effect of aldosterone/ MR signaling on several pathways of glycemia, dyslipidemia, and resistin. In contrast, hyperinsulinemia and hypertriglyceridemia are likely mediated by MR ‐independent mechanisms. Future human studies will elucidate the clinical relevance of MR blockade in patients with genotype‐mediated cav‐1 deficiency.

We thank Dr Campbell for his interest in our study,1 and the fair and helpful comments from the accompanying editorial by Andersson and Vasan, as well.2 We are in agreement with Dr Campbell that statins may influence adrenal steroidogenesis via a multitude of effects. Our study focused mainly on the regulation of aldosterone by using a series of complex physiological maneuvers that included manipulation of angiotensin II and potassium. The subjects in our study were not taking antihypertensive therapy or were withdrawn of therapy, thus allowing investigation of their native physiology. In this context, our use of extreme sodium diets permitted the study of aldosterone when the renin-angiotensin system was maximally suppressed on high sodium and maximally stimulated on low sodium intake in the context of a fixed potassium diet. Therefore, all our assessments of aldosterone were conducted under conditions whereby the …

In the past decades, we have extended the view of aldosterone effects beyond epithelial tissues. New evidence regarding the aldosterone/mineralocorticoid receptor (MR) pathway in active metabolic tissues, including adipose tissue, has confirmed its pathogenic role in systemic inflammation, endothelial dysfunction, insulin resistance, and dyslipidemia. Obesity, a current epidemic worldwide, increases aldosterone production by several adipocyte factors such as leptin but is also associated with local aldosterone production. In addition, obesity can modulate MR activation leading to signaling dysregulation and a pro-inflammatory profile of adipocytes. Current knowledge have deciphered that this phenotypical differences of obesity may be explained, at least in part, by novel non-genomic activation of MR, new inducers of aldosterone synthesis, and probably by several epigenetic modifications. In addition, with the understanding of the complex interplay of obesity, hormones, and receptors, targeted pharmacological therapy is expected and is currently under active research.

Context: The aldosterone to renin ratio (ARR) is recommended to screen for primary aldosteronism (PA). Objective: To evaluate whether dietary sodium restriction results in misinterpretation of PA screening. Participants: Untreated hypertensives with ARR more than 20 on a high dietary sodium intake (HS) were also evaluated on a low dietary sodium intake (LS) (n = 241). Positive screening for PA was defined as: plasma renin activity (PRA) less than or equal to 1.0 ng/mL · h with serum aldosterone more than or equal to 6 ng/dL. PA was confirmed by a 24-hour urinary aldosterone excretion more than or equal to 12 mcg with urinary sodium more than 200 mmol. Results: Only 33% (79/241) of participants with an ARR more than 20 had a positive PA screen on HS. On LS, 56% (44/79) of these participants no longer met criteria for positive PA screening. When compared with participants with positive PA screening on both diets, participants with a positive screen on HS but negative on LS exhibited a significantly higher PRA on both diets. Remarkably, of the 48/79 participants who had PA confirmed, 52% had negative PA screening on LS. The distinguishing feature of these participants with “discordant” screening results was a larger rise in PRA on LS resulting in normalization of the ARR and higher Caucasian race prevalence. Conclusions: Sodium restriction is recommended in hypertension; however, it can significantly raise PRA, normalize the ARR, and result in false interpretation of PA screening. Milder phenotypes of PA, where PRA is not as suppressed, are most susceptible to dietary sodium influences on renin and ARR. Optimal screening for PA should occur under conditions of HS.

To identify novel biomarkers associated with pediatric primary hypertension.We recruited 350 participants (4-16 years). Anthropometric parameters and aldosterone, plasma renin activity, cortisol, cortisone, Homeostasis Model Assessment Insulin Resistance (HOMA-IR), high-sensitivity C-reactive protein, adiponectin, IL-6, plasminogen activator inhibitor type 1 levels and matrix metalloproteinase-9 and matrix metalloproteinase-2 (MMP-9 and MMP-2) activities were measured. Genomic DNA was isolated. Patients with altered glucose metabolism, severe obesity [BMI-SD score (BMI-SDS) 2.5], renovascular disease, primary aldosteronism and apparent mineralocorticoid excess syndrome were excluded.In selected participants (n = 320), SBP was positively correlated with BMI-SDS (r = 0.382, P 0.001), HOMA-IR (r = 0.211, P 0.001), MMP-9 activity (r = 0.215, P 0.001) and the cortisol/cortisone ratio (r = 0.231, P 0.001). DBP showed similar correlations with these variables. No correlation was observed with aldosterone or plasma renin activity. Participants were categorized as hypertensive (n = 59) or nonhypertensive (n = 261). In the univariate analysis, hypertensive patients had higher BMI-SDS (P 0.001), HOMA-IR (P 0.001), high-sensitivity C-reactive protein (P 0.001), MMP-9 activity (P 0.001), plasminogen activator inhibitor type 1 (P 0.001) and cortisol/cortisone ratio (P 0.001) than nonhypertensive patients. Multiple regression analysis showed that the variables that remained associated with hypertension were higher BMI-SDS [odds ratio (OR) = 3.74; 95% confidence interval (CI) = 1.84-7.58], a higher cortisol/cortisone ratio (OR = 3.92; 95% CI = 1.98-7.71) and increased MMP-9 activity (OR = 4.23; 95% CI = 2.15-8.32).We report that MMP-9 activity and the cortisol/cortisone ratio were higher in pediatric primary hypertensive patients, and these associations were independent of the effect of obesity. The potential role of these novel biomarkers in predicting hypertension risk and blood pressure regulation warrants further investigation.

© 2015 Elsevier Inc. Context and objective We examined whether a prevalent caveolin-1 gene (CAV1) variant, previously related to insulin resistance, is associated with metabolic syndrome (MetS). Patients and methods We included subjects genotyped for the CAV1 variant rs926198 from two cohorts: 735 Caucasians from the HyperPATH multicenter study, and 810 Hispanic participants from the HTN-IR cohort. Results Minor allele carriers from HyperPATH cohort (57% of subjects) had higher Framingham risk scores, higher odds of diabetes (10.7% vs 5.7%, p = 0.016), insulin resistance (44.3% vs 35.1%, p = 0.022), low HDL (49.3% vs 39.6%, p = 0.018) and MetS (33% vs 20.5%, p < 0.001) but similar BMI. Consistently, minor allele carriers exhibited higher odds of MetS, even when adjusted for confounders and relatedness (OR 2.83 (1.73-4.63), p < 0.001). The association with MetS was replicated in the Hispanic cohort HTN-IR (OR 1.61, [1.06-2.44], p = 0.025). Exploratory analyses suggest that MetS risk is modified by a CAV1 variant-BMI status interaction, whereby the minor allele carrier status strongly predicted MetS (OR 3.86 [2.05-7.27], p < 0.001) and diabetes (OR 2.27 [1.07-4.78], p = 0.03) in non-obese, but not in obese subjects. In addition, we observed a familial aggregation for MetS diagnosis in minor allele carriers. Conclusion The prevalent CAV1 gene variant rs926198 is associated with MetS in separate Caucasian and Hispanic cohorts. These findings appear to be driven by an interaction between the genetic marker and obesity status, suggesting that the CAV1 variant may improve risk profiling in non-obese subjects. Additional studies are needed to confirm the clinical implications of our results.

11-β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone to cortisol, mainly in the liver and visceral adipose tissue (VAT), and has been implicated in several metabolic disorders. The absence of systemic hypercortisolism in central obesity could be due to increased inactivation of cortisol to its tetrahydrometabolites by the hepatic enzymes 5α- and 5β-reductases. Our aim was to assess the expression of the reductases in the liver and of 11β-HSD1 in the liver and VAT in morbidly obese patients and to analyze their association with clinical, anthropometric, and biochemical parameters. Hepatic and VAT samples were obtained during bariatric surgery. 5α- and 5β-reductases, 11β-HSD1, and 18S expression was measured using real-time polymerase chain reaction. Anthropometric and biochemical variables were analyzed. Forty-one patients were recruited (age, 41.8 ± 10.6 years; body mass index, 42.1 ± 6.6 kg/m(2); 71% women). The expression of hepatic 5α- and 5β-reductases was positively correlated (r = +0.53, P = .004), and their expression levels were correlated with hepatic 11β-HSD1 expression (r = +0.61, P < .001 for 5α-reductase and r = +0.50, P < .001 for 5β-reductase). Hepatic 5α-reductase was associated with insulin (r = +0.34, P = .015). Visceral adipose tissue 11β-HSD1 expression was associated with glucose (r = +0.37, P = .025) and insulin (r = +0.54, P = .002). Our results showed that 5α-reductase and VAT 11β-HSD1 expressions were associated with insulinemia. These findings suggest that overexpression of 5α-reductase, through a higher inactivation of cortisol in the liver, could have a protective role in preserving hepatic sensitivity to insulin. The overexpression of liver reductases in obesity could be an adaptive response to an increase in cortisol production by the liver and visceral 11β-HSD1 to avoid systemic hypercortisolism.