Pro-Osteogenic and Anti-Inflammatory Synergistic Effect of Orthosilicic Acid, Vitamin K2, Curcumin, Polydatin and Quercetin Combination in Young and Senescent Bone Marrow-Derived Mesenchymal Stromal Cells.

During aging, bone marrow mesenchymal stromal cells (MSCs)-the precursors of osteoblasts-undergo cellular senescence, losing their osteogenic potential and acquiring a pro-inflammatory secretory phenotype. These dysfunctions cause bone loss and lead to osteoporosis. Prevention and intervention at an early stage of bone loss are important, and naturally active compounds could represent a valid help in addition to diet. Here, we tested the hypothesis that the combination of two pro-osteogenic factors, namely orthosilicic acid (OA) and vitamin K2 (VK2), and three other anti-inflammatory compounds, namely curcumin (CUR), polydatin (PD) and quercetin (QCT)-that mirror the nutraceutical BlastiMin Complex® (Mivell, Italy)-would be effective in promoting MSC osteogenesis, even of replicative senescent cells (sMSCs), and inhibiting their pro-inflammatory phenotype in vitro. Results showed that when used at non-cytotoxic doses, (i) the association of OA and VK2 promoted MSC differentiation into osteoblasts, even when cultured without other pro-differentiating factors; and (ii) CUR, PD and QCT exerted an anti-inflammatory effect on sMSCs, and also synergized with OA and VK2 in promoting the expression of the pivotal osteogenic marker ALP in these cells. Overall, these data suggest a potential role of using a combination of all of these natural compounds as a supplement to prevent or control the progression of age-related osteoporosis.

Bone Metabolism in SARS-CoV-2 Disease: Possible Osteoimmunology and Gender Implications.

Even though inflammatory conditions are known to exert adverse effects on bone metabolism, there are no published data regarding SARS-CoV-2 infection and subsequent fracture risk. We present a brief review of the molecular mechanisms linking inflammatory diseases to increased fracture risk/osteoporosis and of the therapeutic strategies that can prevent bone resorption in patients with inflammatory disease, focusing on the RANK-RANKL system. We also make some considerations on gender differences in infection response and on their implications for survival and for the consequences of COVID-19. Several inflammatory cytokines, especially IL-1, IL-6, and TNF-α, stimulate osteoclast activity, favoring bone resorption through the RANK-RANKL system. Data from the previous SARS-CoV outbreak suggest that the present disease also has the potential to act directly on bone resorption units, although confirmation is clearly needed. Even though the available data are limited, the RANK-RANKL system may provide the best therapeutic target to prevent bone resorption after COVID-19 disease. Vitamin D supplementation in case of deficiency could definitely be beneficial for bone metabolism, as well as for the immune system. Supplementation of vitamin D in case of deficiency could be further advantageous. In COVID-19 patients, it would be useful to measure the bone metabolism markers and vitamin D. Targeting the RANK-RANKL system should be a priority, and denosumab could represent a safe and effective choice. In the near future, every effort should be made to investigate the fracture risk after SARS-CoV-2 infection.

May Measure Month 2022 in Italy: A Focus on Fixed-dose Combination, Therapeutic Adherence, and Medical Inertia in a Nationwide Survey.

INTRODUCTION: Hypertension is the main risk factor for cardiovascular diseases (CVD). Notably, only about half of hypertensive patients manage to achieve the recommended blood pressure (BP) control. Main reasons for the persistence of uncontrolled BP during treatment are lack of compliance on the patients' side, and therapeutic inertia on physicians' side. METHODS: During the global BP screening campaign "May Measure Month" (MMM) (May 1st to July 31st, 2022), a nationwide, cross-sectional, opportunistic study endorsed by the Italian Society of Hypertension was conducted on volunteer adults ≥ 18 years to raise awareness of the health issues surrounding high BP. A questionnaire on demographic/clinical features and questions on the use of fixed-dose single-pills for the treatment of hypertension was administered. BP was measured with standard procedures. RESULTS: A total of 1612 participants (mean age 60.0±15.41 years; 44.7% women) were enrolled. Their mean BP was 128.5±18.1/77.1±10.4 mmHg. About half of participants were sedentary, or overweight/obese, or hypertensive. 55.5% individuals with complete BP assessment had uncontrolled hypertension. Most were not on a fixed-dose combination of antihypertensive drugs and did not regularly measure BP at home. Self-reported adherence to BP medications was similar between individuals with controlled and uncontrolled BP (95% vs 95.5%). CONCLUSIONS: This survey identified a remarkable degree of therapeutic inertia and poor patients' involvement in the therapeutic process and its monitoring in the examined population, underlining the importance of prevention campaigns to identify areas of unsatisfactory management of hypertension, to increase risk factors' awareness in the population with the final purpose of reducing cardiovascular risk.

Cortical adrenal mitochondrial morphology changes in functional state: new insights.

We compared changes in the morphology of mitochondrial cristae with those in the blood and adrenal content of steroid hormones after the stimulation or inhibition of steroidogenesis. Rats were treated with adrenocorticotrophic hormone or angiotensin II to elicit steroidogenesis and with dexamethasone to inhibit it. Blood and adrenal glands were collected after several time intervals for measurements of steroids and their main intermediates. In the zona fasciculata, mitochondrial ultrastructure was investigated by high resolution scanning electron microscopy. We found that the morphometric data correlated well with the measurements of hyper- or hypo-activity of steroidogenesis over short periods of time (4 h) but not over longer observation times. A peculiar finding was that, contrary to previous reports, 11-deoxycortisol was present in adult rat adrenal tissue.

The Effects of Polyphenols on Bone Metabolism in Postmenopausal Women: Systematic Review and Meta-Analysis of Randomized Control Trials.

Osteoporosis is a condition favored by the postmenopausal decline in estrogen levels and worsened by oxidative stress (OS). Polyphenols are natural compounds abundantly found in fruits and vegetables, and they exert antioxidant and hormonal effects that could be useful in osteoporosis prevention, as suggested by epidemiological studies showing a lower incidence of fractures in individuals consuming polyphenol-rich diets. The aim of our meta-analysis is to evaluate the effects of polyphenols on bone mineral density (BMD, primary endpoint) and bone turnover markers (BTMs, secondary endpoint) in postmenopausal women. Twenty-one randomized control trials (RCTs) were included in our analysis after in-depth search on PubMed, EMBASE, and Scopus databases. We found that supplementation with polyphenols for 3-36 months exerted no statically significant effects on BMD measured at lumbar spine (sMD: 0.21, 95% CI [-0.08 to 0.51], p = 0.16), femoral neck (sMD: 0.16, 95% CI [-0.23 to 0.55], p = 0.42), total hip (sMD: 0.05, 95% CI [-0.14 to 0.24], p = 0.61), and whole body (sMD: -0.12, 95% CI [-0.42 to 0.17], p = 0.41). Subgroup analysis based on treatment duration showed no statistical significance, but a significant effect on lumbar BMD emerged when studies with duration of 24 months or greater were analyzed separately. On the other hand, we found a significantly slight increase in bone-specific alkaline phosphatase (BALP) levels (sMD: 1.27, 95% CI [1.13 to 1.42], p < 0.0001) and a decrease in pyridinoline (PD) levels (sMD: -0.58, 95% CI [-0.77 to -0.39], p < 0.0001). High heterogeneity among studies and unclear risk of bias in one third of the included studies emerged. A subgroup analysis showed similar effects for different duration of treatment and models of dual-energy X-ray absorptiometry (DXA) scanner. More robust evidence is needed before recommending the prescription of polyphenols in clinical practice.

Remote management of osteoporosis in the first wave of the COVID-19 pandemic.

We conducted a survey during the first pandemic wave of coronavirus disease 2019 (COVID-19) on a large group of osteoporotic patients to evaluate the general conditions of osteoporotic patients and the impact of the pandemic on the management of osteoporosis, finding high compliance to treatments and low COVID-19 lethality. INTRODUCTION: During the first pandemic wave of coronavirus disease 2019 (COVID-19), 209,254 cases were diagnosed in Italy; fatalities were 26,892 and were overwhelmingly older patients. The high prevalence of osteoporosis in this age group suggests a potential relationship between SARS-CoV-2 infection and bone metabolism. METHODS: In a telephone survey conducted from April to May 2020, patients from the Osteoporosis Center, Clinic of Endocrinology and Metabolic Diseases of Umberto I Hospital (Ancona, Italy), were interviewed to evaluate the general clinical conditions of osteoporotic patients, compliance with osteoporosis medications, COVID-19 prevalence, hospitalization rate, COVID-19 mortality, and lethality. RESULTS: Among the 892 patients interviewed, 77.9% were taking osteoporosis treatment and 94.6% vitamin D supplementation as prescribed at the last visit. COVID-19-like symptoms were reported by 5.1%, whereas confirmed cases were 1.2%. A total number of 33 patients had been in hospital and the hospitalization rate of those who had not discontinued vitamin D supplementation was less than 4%. There were eight deaths, two with a concomitant COVID-19 diagnosis. The prevalence of severe osteoporosis was 50% in total COVID-19 patients and 87.5% in deceased COVID-19 patients. The overall COVID-19 mortality was 0.2%; lethality was 20%, lower than the national rate of the same age group. CONCLUSIONS: This large group of osteoporotic patients showed high compliance and lower COVID-19 lethality compared to patients of the same age. Novel approaches such as telemedicine can provide critical support for the remote follow-up of patients with chronic diseases also in the setting of routine care.

The 2020 Italian Society of Arterial Hypertension (SIIA) practical guidelines for the management of primary aldosteronism.

BACKGROUND AND AIM: Considering the amount of novel knowledge generated in the last five years, a team of experienced hypertensionlogists was assembled to furnish updated clinical practice guidelines for the management of primary aldosteronism. METHODS: To identify the most relevant studies, the authors utilized a systematic literature review in international databases by applying the PICO strategy, and then they were required to make use of only those meeting predefined quality criteria. For studies of diagnostic tests, only those that fulfilled the Standards for Reporting of Diagnostic Accuracy recommendations were considered. RESULTS: Each section was jointly prepared by at least two co-authors, who provided Class of Recommendation and Level of Evidence following the American Heart Association methodology. The guidelines were sponsored by the Italian Society of Arterial Hypertension and underwent two rounds of revision, eventually reexamined by an External Committee. They were presented and thoroughly discussed in two face-to-face meetings with all co-authors and then presented on occasion of the 36th Italian Society of Arterial Hypertension meeting in order to gather further feedbacks by all members. The text amended according to these feedbacks was subjected to a further peer review. CONCLUSIONS: After this process, substantial updated information was generated, which could simplify the diagnosis of primary aldosteronism and assist practicing physicians in optimizing treatment and follow-up of patients with one of the most common curable causes of arterial hypertension.

Management of primary aldosteronism: its complications and their outcomes after treatment.

Primary aldosteronism is the most common cause of secondary hypertension, accounting for about 10% of all forms of high blood pressure. Life-time pharmacological therapy is the treatment of choice for primary aldosteronism due to idiopathic adrenal hyperplasia (IHA), while adrenalectomy is effective in curing most patients with an aldosterone producing adenoma (APA). Far from being a benign form of hypertension, primary aldosteronism is characterized by the development of cardiovascular renal and metabolic complications, including left ventricular hypertrophy, myocardial infarction, atrial fibrillation and stroke, microalbuminuria, renal cysts as well as metabolic syndrome, glucose impairment and diabetes mellitus. We review recent clinical experience with the above mentioned complications and long-term outcomes of blood pressure normalization and cardiac, renal and gluco-metabolic complications in patients with primary aldosteronism, after medical treatment with mineralocorticoid receptor antagonists and surgical treatment. We conclude that removal of adrenal adenoma results in normalization of the renin-angiotensin-aldosterone system (RAAS) and of kalaemia and improvement of blood pressure levels in all patients. Complete resolution of hypertension is achieved in nearly half of treated patients. Moreover, unilateral adrenalectomy is the best treatment to have the regression of cardiovascular, renal and metabolic complications in patients with APA. On the other hand, targeted medical treatment with aldosterone antagonists improves blood pressure control and appears able to prevent the progression of cardiac and metabolic complications in patients with IHA.

AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: a novel mechanism in Cushing's syndrome.

Chronic exposure to glucocorticoid hormones, resulting from either drug treatment or Cushing's syndrome, results in insulin resistance, central obesity, and symptoms similar to the metabolic syndrome. We hypothesized that the major metabolic effects of corticosteroids are mediated by changes in the key metabolic enzyme adenosine monophosphate-activated protein kinase (AMPK) activity. Activation of AMPK is known to stimulate appetite in the hypothalamus and stimulate catabolic processes in the periphery. We assessed AMPK activity and the expression of several metabolic enzymes in the hypothalamus, liver, adipose tissue, and heart of a rat glucocorticoid-excess model as well as in in vitro studies using primary human adipose and primary rat hypothalamic cell cultures, and a human hepatoma cell line treated with dexamethasone and metformin. Glucocorticoid treatment inhibited AMPK activity in rat adipose tissue and heart, while stimulating it in the liver and hypothalamus. Similar data were observed in vitro in the primary adipose and hypothalamic cells and in the liver cell line. Metformin, a known AMPK regulator, prevented the corticosteroid-induced effects on AMPK in human adipocytes and rat hypothalamic neurons. Our data suggest that glucocorticoid-induced changes in AMPK constitute a novel mechanism that could explain the increase in appetite, the deposition of lipids in visceral adipose and hepatic tissue, as well as the cardiac changes that are all characteristic of glucocorticoid excess. Our data suggest that metformin treatment could be effective in preventing the metabolic complications of chronic glucocorticoid excess.

Primary aldosteronism, a major form of low renin hypertension: from screening to diagnosis.

There is general consensus on the use of (but not cut-off values for) the aldosterone/plasma renin activity ratio as a screening test for primary aldosteronism. There is also agreement on the need for subsequent confirmatory testing, but not on the protocols to be chosen. The four most common confirmatory tests in clinical practice are oral sodium loading, intravenous saline infusion, captopril challenge and fludrocortisone administration plus sodium loading. The choice of test reflects multiple variables: patient factors (including accessibility, compliance and safety), established practice and cost. Finally, subtype forms and lateralization of aldosterone production should be established by bilateral adrenal venous sampling, despite its technical difficulty and varying criteria for success.

Adipose cell-adrenal interactions: current knowledge and future perspectives.

The central role of adipose tissue in the development of cardiovascular and metabolic pathology has been highlighted by the discovery of mediators (adipokines) secreted by adipose tissue and their involvement in the regulation of various biological processes. In light of recent experimental data, cross-talk between adipose tissue and the adrenal gland, particularly via the mineralocorticoid aldosterone, has been proposed. Aldosterone can induce adipogenesis, and human white adipose tissue is reported to release as-yet-uncharacterized factors that stimulate adrenocortical steroidogenesis and aldosterone production. These data could provide new insights into the pathophysiology of obesity-related disorders, including hypertension and aldosterone excess, with further studies necessary for confirming and better defining such adipose-adrenal interactions.

Primary aldosteronism: cardiovascular, renal and metabolic implications.

For many years primary aldosteronism was considered a relatively benign form of hypertension. This assumption reflects the primacy accorded to elevated levels of angiotensin in terms of deleterious cardiovascular effects, and the fact that in primary aldosteronism renin and angiotensin levels are low. We now know that primary aldosteronism causes a constellation of cardiovascular, renal and metabolic sequelae which make it far from benign and that these are not merely effects of blood pressure elevation. In primary aldosteronism, tissue damage, on several indices, is higher than in age-, sex- and blood pressure-matched controls, reflecting the ability of inappropriately elevated aldosterone for salt status to produce structural and functional changes over and above those produced by high blood pressure.

Primary Aldosteronism and Obstructive Sleep Apnea: A Cross-Sectional Multi-Ethnic Study.

The association between primary aldosteronism (PA) and obstructive sleep apnea (OSA) has been a matter of debate. 2016 Endocrine Society guideline recommends screening for PA all hypertensive patients with OSA. We designed a multicenter, multiethnic, cross-sectional study to evaluate the prevalence of PA in patients with OSA and the prevalence of OSA in unselected patients with PA. Two hundred and three patients with OSA (102 whites and 101 Chinese) were screened for PA, and 207 patients with PA (104 whites, 100 Chinese, and 3 of African descent) were screened for OSA by cardiorespiratory polygraphy. Eighteen patients with OSA (8.9%) had PA (11.8% of white and 5.9% of Chinese ethnicity). In patients without other indications for PA screening, the prevalence of PA dropped to 1.5%. The prevalence of OSA in patients with PA was 67.6%, consistent in both white and Chinese patients. A correlation between aldosterone levels and apnea/hypopnea index was observed in white patients with PA (R2=0.225, P=0.016) but not in Chinese patients. Multinomial logistic regression confirmed a significant and independent association between plasma aldosterone levels and moderate to severe OSA diagnosis in white patients (odds ratio, 1.002; P=0.002). In conclusion, aldosterone levels may contribute to the severity of OSA in white patients with hyperaldosteronism, but patients with OSA are not at high risk of PA. Results of the present study challenge the current recommendation of the Endocrine Society guideline that all patients with OSA should be screened for PA, irrespective of the grade of hypertension.

Changes in adenosine 5'-monophosphate-activated protein kinase as a mechanism of visceral obesity in Cushing's syndrome.

OBJECTIVE: Features of the metabolic syndrome such as central obesity with insulin resistance and dyslipidemia are typical signs of Cushing's syndrome and common side effects of prolonged glucocorticoid treatment. AMP-activated protein kinase (AMPK), a key regulatory enzyme of lipid and carbohydrate metabolism as well as appetite, is involved in the development of the deleterious metabolic effects of excess glucocorticoids, but no data are available in humans. In the current study, we demonstrate the effect of high glucocorticoid levels on AMPK activity of human adipose tissue samples from patients with Cushing's syndrome. METHODS: AMPK activity and mRNA expression of genes involved in lipid metabolism were assessed in visceral adipose tissue removed at abdominal surgery of 11 patients with Cushing's syndrome, nine sex-, age-, and weight-matched patients with adrenal incidentalomas, and in visceral adipose tissue from four patients with non-endocrine-related abdominal surgery. RESULTS: The patients with Cushing's syndrome exhibited a 70% lower AMPK activity in visceral adipose tissue as compared with both incidentalomas and control patients (P = 0.007 and P < 0.001, respectively). Downstream targets of AMPK fatty acid synthase and phosphoenol-pyruvate carboxykinase were up-regulated in patients with Cushing's syndrome. AMPK activity was inversely correlated with 0900 h serum cortisol and with urinary free cortisol. CONCLUSIONS: Our data suggest that glucocorticoids inhibit AMPK activity in adipose tissue, suggesting a novel mechanism to explain the deposition of visceral adipose tissue and the consequent central obesity observed in patients with iatrogenic or endogenous Cushing's syndrome.

Body mass index predicts plasma aldosterone concentrations in overweight-obese primary hypertensive patients.

CONTEXT: Body mass index (BMI) shows a direct correlation with plasma aldosterone concentration (PAC) and urinary aldosterone excretion in normotensive individuals; whether the same applies to hypertensive patients is unknown. OBJECTIVE: Our objective was to determine if BMI predicts PAC and the PAC/plasma renin activity ratio [aldosterone renin ratio (ARR)] in hypertensive patients, and if this affects the identification of primary aldosteronism (PA). DESIGN: This was a prospective evaluation of consecutive hypertensive patients referred nationwide to specialized hypertension centers. MAIN OUTCOME MEASURES: Sitting PAC, plasma renin activity, and the ARR, baseline and after 50 mg captopril orally with concomitant assessment of parameters, including BMI and daily sodium intake, were calculated. RESULTS: Complete biochemical data and a definite diagnosis were obtained in 1125 consecutive patients. Of them 999 had primary (essential) hypertension (PH) and 126 (11.2%) PA caused by an aldosterone-producing adenoma in 54 (4.8%). BMI independently predicted PAC (beta = 0.153; P < 0.0001) in PH, particularly in the overweight-obese, but not in the PA group. Covariance analysis and formal comparison of the raw, and the BMI-, sex-, and sodium intake-adjusted ARR with receiver operator characteristic curves, showed no significant improvement for the discrimination of aldosterone-producing adenoma from PH patients with covariate-adjusted ARR. CONCLUSIONS: BMI correlated with PAC independent of age, sex, and sodium intake in PH, but not in PA patients. This association of BMI is particularly evident in overweight-obese PH patients, and suggests a pathophysiological link between visceral adiposity and aldosterone secretion. However, it does not impact on the diagnostic accuracy of the ARR for discriminating PA from PH patients.

Adrenalectomy Lowers Incident Atrial Fibrillation in Primary Aldosteronism Patients at Long Term.

Primary aldosteronism (PA) causes cardiovascular damage in excess to the blood pressure elevation, but there are no prospective studies proving a worse long-term prognosis in adrenalectomized and medically treated patients. We have, therefore, assessed the outcome of PA patients according to treatment mode in the PAPY study (Primary Aldosteronism Prevalence in Hypertension) patients, 88.8% of whom were optimally treated patients with primary (essential) hypertension (PH), and the rest had PA and were assigned to medical therapy (6.4%) or adrenalectomy (4.8%). Total mortality was the primary end point; secondary end points were cardiovascular death, major adverse cardiovascular events, including atrial fibrillation, and total cardiovascular events. Kaplan-Meier and Cox analysis were used to compare survival between PA and its subtypes and PH patients. After a median of 11.8 years, complete follow-up data were obtained in 89% of the 1125 patients in the original cohort. Only a trend (P=0.07) toward a worse death-free survival in PA than in PH patients was observed. However, at both univariate (90.0% versus 97.8%; P=0.002) and multivariate analyses (hazard ratio, 1.82; 95% confidence interval, 1.08-3.08; P=0.025), medically treated PA patients showed a lower atrial fibrillation-free survival than PH patients. By showing that during a long-term follow-up adrenalectomized aldosterone-producing adenoma patients have a similar long-term outcome of optimally treated PH patients, whereas, at variance, medically treated PA patients remain at a higher risk of atrial fibrillation, this large prospective study emphasizes the importance of an early identification of PA patients who need adrenalectomy as a key measure to prevent incident atrial fibrillation.

Computed Tomography and Adrenal Venous Sampling in the Diagnosis of Unilateral Primary Aldosteronism.

Unilateral primary aldosteronism is the most common surgically correctable form of endocrine hypertension and is usually differentiated from bilateral forms by adrenal venous sampling (AVS) or computed tomography (CT). Our objective was to compare clinical and biochemical postsurgical outcomes of patients with unilateral primary aldosteronism diagnosed by CT or AVS and identify predictors of surgical outcomes. Patient data were obtained from 18 internationally distributed centers and retrospectively analyzed for clinical and biochemical outcomes of adrenalectomy of patients with surgical management based on CT (n=235 patients, diagnosed from 1994-2016) or AVS (526 patients, diagnosed from 1994-2015) using the standardized PASO (Primary Aldosteronism Surgical Outcome) criteria. Biochemical outcomes were highly different according to surgical management approach with a smaller proportion in the CT group achieving complete biochemical success (188 of 235 [80%] patients versus 491 of 526 [93%], P<0.001) and a greater proportion with absent biochemical success (29 of 235 [12%] versus 10 of 526 [2%], P<0.001). A diagnosis by CT was associated with a decreased likelihood of complete biochemical success compared with AVS (odds ratio, 0.28; 0.16-0.50; P<0.001). Clinical outcomes were not significantly different, but the absence of a postsurgical elevated aldosterone-to-renin ratio was a strong marker of complete clinical success (odds ratio, 14.81; 1.76-124.53; P=0.013) in the CT but not in the AVS group. In conclusion, patients diagnosed by CT have a decreased likelihood of achieving complete biochemical success compared with a diagnosis by AVS.

Aldosterone as a key mediator of the cardiometabolic syndrome in primary aldosteronism: an observational study.

OBJECTIVE: Primary aldosteronism (PA) is characterized by the onset of both cardiac and gluco-metabolic alterations. The aim of this study was to evaluate the impact of aldosterone excess on the development of such complications, and the effects of surgical and pharmacological treatment on their long-term outcome. METHODS: We prospectively re-examined 61 patients: 25 with aldosterone-producing adenoma (APA), after surgery, and 36 patients with idiopathic hyperaldosteronism (IHA) on pharmacological treatment. The lipid, fasting and dynamic glucose profiles and the echocardiographic parameters were evaluated at diagnosis and at follow-up. RESULTS: After adrenalectomy all patients had normalization of aldosterone levels and were cured of hypokalaemia, and a resolution of hypertension was achieved in 12 of 25 patients. APA patients showed a significant reduction of both plasma glucose (P=0.017) and insulin levels (P=0.001) after 75 g oral glucose tolerance test. Stabilization of glucose metabolism complications was observed in IHA patients. Multiple regression analysis at diagnosis showed a positive correlation between homeostasis model assessment (HOMA) insulin resistance index and HOMA beta cell and serum aldosterone levels in both APA and IHA. Echocardiographic parameters were improved in both APA and IHA at follow-up and the difference was statistically significant for left ventricular mass index (P=0.017) and interventricular septum thickness (P=0.007) in APA patients. CONCLUSIONS: The removal of aldosterone excess in APA patients induces the regression of both cardiac and gluco-metabolic complications, indicating aldosterone as a main determinant of such alterations. In IHA patients the medical treatment seems to avoid the possible progression of the these alterations that appear to be stable.

Prospective evaluation of the saline infusion test for excluding primary aldosteronism due to aldosterone-producing adenoma.

BACKGROUND: Data on the performance of the tests used to confirm the diagnosis of primary aldosteronism (PA) are limited. OBJECTIVE: To prospectively investigate the accuracy of the saline infusion test (SIT). METHODS: Three hundred and seventeen (26.9%) out of 1125 patients screened in the PAPY study underwent measurement of plasma aldosterone, cortisol and renin activity after infusion of 2 l of isotonic saline intravenously over 4 h. They comprised patients with a baseline aldosterone/renin ratio (ARR) > 40 and one every four patients not fulfilling such criterion. The area under the receiver-operator characteristic curves (AUC) of aldosterone values after SIT was used as a measure of accuracy for diagnosing PA, aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA). RESULTS: One hundred and twenty (37.9%) patients had PA that was due to an APA in 46 (38.3%) and to IHA in 74 (61.7%). No untoward effect occurred with the SIT. The AUC (0.811 +/- 0.026, 0.878 +/- 0.040 and 0.784 +/- 0.034 for identification of PA, APA and IHA, respectively) was higher (P < 0.0001) than that under the diagonal. By sensitivity/specificity versus criterion values plot, the best aldosterone cut-off values for identifying APA and IHA were 6.75 and 6.91 ng/dl, respectively. However, even at these optimal cut-offs, sensitivity and specificity were moderate because of values overlapping between patients with and without the disease. Moreover, there were no differences of AUC and aldosterone cut-offs between APA and IHA. CONCLUSION: In a multicenter study the SIT was safe and specific for excluding PA, but had no place for discriminating between an APA and IHA.

A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness.

CONTEXT: Mineralocorticoid receptors (MR) mediate the action of aldosterone on sodium resorption in kidney tubular cells, but in brain they respond to the glucocorticoid cortisol in stress regulation and cognitive processes. OBJECTIVE: The objective of the study was to investigate the role of the MR gene variant I180V in the neuroendocrine response to a psychosocial stressor and in electrolyte regulation. DESIGN: Associations between the MRI180V and outcome variables in a healthy cohort subjected to psychosocial challenge (Trier Social Stress Test) and in a mild hypertensive cohort exposed to acute salt loading (Weinberger's test) were investigated. In vitro transactivational assays were applied to compare the effects of cortisol and aldosterone on the MRI180V. RESULTS: Carriers of the MR180V allele showed higher saliva (P < 0.01), plasma cortisol (P < 0.01), and heart rate responses (P < 0.05) to the Trier Social Stress Test than noncarriers (MR180I). After 3 d of a normal salt diet and the Weinberger's test, no association was found with urinary sodium excretion, plasma aldosterone, and plasma renin activity or with changes in blood pressure, aldosterone, and renin responses. In vitro testing of the MR180V allele revealed a mild loss of function using cortisol as a ligand, compared with the MR180I allele. Significantly higher doses of cortisol were needed for half-maximal induction on the TAT-1 (P < 0.002), TAT-3 (P < 0.03), or mouse mammary tumor virus (P < 0.02) promoters, whereas maximal induction was not different. These differences were not observed using aldosterone as a ligand. CONCLUSION: The findings reveal that cortisol and heart rate responses to a psychosocial stressor are enhanced in carriers of the MR180V variant.