Search

Background: Accumulating evidence suggests that primary aldosteronism (PA) is associated with several features of the metabolic syndrome, in particular with obesity, type 2 diabetes mellitus, and dyslipidemia. Whether these manifestations are primarily linked to aldosterone-producing adenoma (APA) or bilateral idiopathic hyperaldosteronism (IHA) remains unclear. The aim of the present study was to investigate differences in metabolic parameters between APA and IHA patients and to assess the impact of treatment on these clinical characteristics., Methods: We conducted a retrospective multicenter study including 3566 patients with APA or IHA of Caucasian and Asian origin. We compared the prevalence of metabolic disorders between APA and IHA patients at the time of diagnosis and 1-year post-intervention, with special references to sex differences. Furthermore, correlations between metabolic parameters and plasma aldosterone, renin, or plasma cortisol levels after 1 mg dexamethasone (DST) were performed., Results: As expected, APA patients were characterized by higher plasma aldosterone and lower serum potassium levels. Only female IHA patients demonstrated significantly worse metabolic parameters than age-matched female APA patients, which were associated with lower cortisol levels upon DST. One-year post-intervention, female adrenalectomized patients showed deterioration of their lipid profile, when compared to patients treated with mineralocorticoid receptor antagonists. Plasma aldosterone levels negatively correlated with the BMI only in APA patients., Conclusions: Metabolic alterations appear more prominent in women with IHA. Although IHA patients have worse metabolic profiles, a correlation with cortisol autonomy is documented only in APAs, suggesting an uncoupling of cortisol action from metabolic traits in IHA patients.

Aims: Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis which incidence, cause, and response to therapy is unreported., Methods and Results: Among 1916 patients with biopsy-proven myocarditis, 30 had NCV. Endomyocardial samples were retrospectively investigated with immunohistochemistry for toll-like receptor 4 (TLR4) and real-time polymerase chain reaction (PCR) for viral genomes. Serum samples were processed for anti-heart autoantibodies (Abs), IL-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α. Identification of an immunologic pathway (including virus-negativity, TLR4-, and Ab-positivity) was followed by immunosuppression. Myocarditis-NCV cohort was followed for 6 months with 2D-echo and/or cardiac magnetic resonance and compared with 60 Myocarditis patients and 30 controls. Increase in left ventricular ejection fraction ≥10% was classified as response to therapy. Control endomyocardial biopsy followed the end of treatment. Twenty-six Myocarditis-NCV patients presented with heart failure; four with electrical instability. Cause of Myocarditis-NCV included infectious agents (10%) and immune-mediated causes (chest trauma 3%; drug hypersensitivity 7%; hypereosinophilic syndrome 3%; primary autoimmune diseases 33%, idiopathic 44%). Abs were positive in immune-mediated Myocarditis-NCV and virus-negative Myocarditis; Myocarditis-NCV patients with Ab+ presented autoreactivity in vessel walls. Toll-like receptor 4 was overexpressed in immune-mediated forms and poorly detectable in viral. Interleukin-1β was significantly higher in Myocarditis-NCV than Myocarditis, the former presenting 24% in-hospital mortality compared with 1.5% of Myocarditis cohort. Immunosuppression induced improvement of cardiac function in 88% of Myocarditis-NCV and 86% of virus-negative Myocarditis patients., Conclusion: Necrotizing coronary vasculitis is histologically detectable in 1.5% of Myocarditis. Necrotizing coronary vasculitis includes viral and immune-mediated causes. Intra-hospital mortality is 24%. The immunologic pathway is associated with beneficial response to immunosuppression., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Context: Due to selection biases and inadequate statistical power, individual studies may fail to identify the clinical features of patients with an aldosterone-producing adenoma (APA) harboring KCNJ5 mutations. When this failure occurs, meta-analysis can provide significant outcome data., Objective: The objective was to determine the clinical features of these APA patients., Design: We systematically searched the PubMed, Scopus, Web of Science, and Cochrane databases library in January 2015 applying the Population, Intervention, Comparison, and Outcome (PICO) strategy. The standardized differences in mean and corresponding 95% confidence interval of continuous variables were computed by random-effects modeling., Setting: We performed a meta-analysis of all available studies on somatic KCNJ5 mutations in APA., Patients: We could identify 13 studies that recruited 1636 patients (age 49 ± 4 years; 55% females)., Main Outcomes and Measures: Differences between APA with and without KCNJ5 mutations in gender, plasma renin activity, plasma aldosterone, tumor size, serum potassium, and blood pressure were investigated., Results: The overall prevalence of KCNJ5 mutations was 43% (range = 12-80%). Their rate was lower (P < .003) in the studies done in Europe, the United States, and Australia (35%) than in Japan and China (63%); it correlated (r = 0.60, P = .029) with the mean daily urinary sodium excretion. Compared with the wild-type, the mutated APA patients were younger (45 ± 3 vs 52 ± 5 yrs), had higher plasma aldosterone (42 ± 8 vs 33 ± 8 ng/dl), larger tumors (16.1 ± 6.4 versus 14.9 ± 7.4 mm), and were more often females (67% vs 44%) (all P < .05)., Conclusions: Meta-analysis showed that more pronounced hyperaldosteronism, young age, female gender, and larger tumors are the phenotypic features of APA patients with KCNJ5 mutations. No significant differences in blood pressure and serum K(+) was found, which suggests that these clinical features do not help in identifying mutated APA patients.

Context: Interplay between adipose tissue and adrenal glands has been recently suggested, without well-founded actions of locally adipose tissue surrounding the adrenal glands., Objective: We hypothesized that the local expression of leptin and adiponectin can be associated with pathological changes of the adrenal glands., Patients and Main Outcome Measures: We evaluated RT-PCR of leptin and adiponectin mRNA expression from the adipose tissue surrounding adrenal glands in 30 patients, collecting adipose tissue surrounding the adrenal neoplasms, peri-renal and subcutaneous depots., Results: Leptin mRNA levels from adrenal neoplasia and peri-renal fat were significantly higher in aldosterone-producing adenoma than in nonfunctioning adenomas (P < 0.001 and P < 0.02, respectively). In patients with Cushing's syndrome leptin mRNA levels were significantly higher in adrenal fat than in peri-renal (P < 0.05) and subcutaneous adipose tissue (P < 0.001). Adiponectin mRNA expression from adrenal neoplasia was significantly lower than that from peri-renal and subcutaneous fat depots (P < 0.05). Leptin and adiponectin plasma levels significantly correlated with their mRNA expression from the fat depot surrounding the adrenal neoplasia., Conclusions: Our findings suggest an active role of the fat depot surrounding the adrenal neoplasia, with local secretion of leptin and adiponectin.

Context: Somatic mutations in the selectivity filter of KCNJ5 K(+) channel were found to be associated with higher plasma aldosterone concentrations in the patients with an aldosterone-producing adenoma (APA)., Objective: We investigated whether plasma aldosterone levels and the lateralization index are higher from the side with the APA with the mutation, as compared with those without the mutation., Design: From 170 consecutive APA patients with comprehensive clinical and KCNJ5 data and a conclusive diagnosis, we recruited 91 patients with adrenal vein sampling and follow-up data. We measured CYP11B1 and CYP11B2 mRNA in APA tissue and plasma aldosterone (PAC) and plasma cortisol concentrations (PCC) in adrenal vein blood. To determine whether KCNJ5 mutations affected aldosterone output from the APA, we calculated the lateralization index (defined as the ratio of PAC to PCC at the APA side over the PAC to PCC ratio at the contralateral side). We also calculated two indexes of the aldosterone production from the APA side and the contralateral suppression index., Results: The mRNA content of CYP11B2, but not of CYP11B1, and, accordingly, the lateralization index was higher (29.9 ± 7.4 vs. 10.3 ± 3.6, P < 0.02) in the APA with the mutation than in the APA without the mutation., Conclusions: APA patients with the somatic KCNJ5 mutations showed a higher production of aldosterone than those without such mutations, which translates in a higher lateralization index. Thus, they are more likely to be identified at adrenal vein sampling and therefore to receive adrenalectomy.

Context: Primary aldosteronism (PA) has been recently associated with an unfavorable cardiometabolic profile. However, whether pro- and antiinflammatory adipokines levels can vary in PA is unknown., Objective: We evaluated the circulating levels of resistin, leptin, and adiponectin, echocardiographic left ventricle (LV) parameters, and the prevalence of metabolic syndrome (SM) in subjects with PA., Patients: Seventy-five subjects with established diagnosis of PA and 232 consecutive individuals with known or suspected hypertension were enrolled., Main Outcome Measures: Plasma adipokine levels and echocardiographic parameters were calculated. Prevalence of SM was also estimated., Results: Among the 75 PA subjects, 37 patients were affected by aldosterone-producing adenoma and 38 by idiopathic hyperaldosteronism; 40 subjects were affected by essential hypertension (EH) and SM (EH SM+); 152 subjects were affected by EH without SM (EH SM-); and 40 subjects were normotensive (NT). Subjects with PA had the highest plasma resistin levels among the four groups (P < 0.01). Plasma resistin concentration was significantly higher in PA subjects when compared with EH SM+ individuals (P < 0.01) and EH SM- subjects (P < 0.01). PA subjects showed the higher LV mass and left atrium than EH individuals, irrespectively of the presence of SM (P < 0.01 for both). Plasma resistin levels was significantly correlated with ejection fraction and LV end-diastolic volume. The prevalence of SM was higher in PA subjects than in those with EH (25.4 vs. 20.3%)., Conclusions: Our data suggest that elevated aldosterone levels is associated with elevated circulating resistin levels and cardiac morphological changes independently of the presence of SM.

Purpose: The aim of the study was to define the frequency of hereditary forms and the genotype/phenotype correlations in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas., Design: We examined 501 consecutive patients with pheochromocytomas and/or paragangliomas (secreting or nonsecreting). Complete medical and family histories, as well as the results of clinical, laboratory, and imaging studies, were recorded in a database. Patients were divided into different groups according to their family history, the presence of lesions outside adrenals/paraganglia considered syndromic for VHL disease, MEN2, and NF1, and the number and types of pheochromocytomas and/or paragangliomas. Germ-line mutations in known susceptibility genes were investigated by gene sequencing (VHL, RET, SDHB, SDHC, SDHD) or diagnosed according to phenotype (NF1). In 160 patients younger than 50 yr with a wild-type profile, multiplex ligation-dependent probe amplification assays were performed to detect genomic rearrangements., Results: Germline mutations were detected in 32.1% of cases, but frequencies varied widely depending on the classification criteria and ranged from 100% in patients with associated syndromic lesions to 11.6% in patients with a single tumor and a negative family history. The types and number of pheochromocytomas/paragangliomas as well as age at presentation and malignancy suggest which gene should be screened first. Genomic rearrangements were found in two of 160 patients (1.2%)., Conclusions: The frequency of the hereditary forms of pheochromocytoma/paraganglioma varies depending on the family history and the clinical presentation. A positive family history and an accurate clinical evaluation of patients are strong indicators of which genes should be screened first.

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.

Background: Brain injury is a major adverse event after cardiac surgery, especially when extracorporeal circuits are used. We evaluated whether cardiopulmonary bypass (CPB) affects cerebrovascular resistance and plasma concentrations of adrenomedullin (AM), a vasoactive peptide regulating cerebral blood flow., Methods: We evaluated 50 infants (age <1 year) with congenital heart defects, matched according to a 2-year follow-up; 40 infants had no overt neurological injury, and 10 had brain damage. Blood samples were taken before surgery, during surgery before CPB, at the end of CPB, at the end of surgery, and at 12 h after surgery. Neurological outcome was evaluated before surgery, on postoperative day 7, and 2 years after surgery. We measured AM concentrations and used Doppler velocimetry to measure middle cerebral artery (MCA) pulsatility index (PI)., Results: The highest MCA PI values and lowest AM concentrations occurred at the end of CPB and of the surgical procedure. Infants who developed abnormal neurologic sequelae had significantly (P <0.001 for both) higher MCA PI values and lower AM concentrations than patients with normal neurologic outcome at the end of CPB and after surgery. As single markers for predicting neurological abnormalities, AM (cutoff: 17.4 ng/L) achieved a sensitivity of 100% and a specificity of 73.0% and MCA PI (cutoff value: 1.8) a sensitivity of 100% and a specificity of 56.8%., Conclusions: AM concentrations and MCA PI patterns change during CPB, mainly in infants with brain damage, and may be useful for early identification of infants at risk for brain damage.

Background: Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma that also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma., Materials and Methods: An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing HPLC for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity analysis using markers in and around NF1 was performed., Results: There were 37 eligible subjects (ages 14-70 yr). Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus vs. 0 of 12 sporadic tumors (P = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35% but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype., Conclusions: The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RAS-GAP domain, suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. Loss-of-heterozygosity of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1.

Background: It has been demonstrated that adrenomedullin, a newly discovered peptide, affects the release of insulin from pancreatic islets cells, suggesting a role in the insulin-regulating system., Objective: To investigate whether adrenomedullin secretion is modified in patients with insulin-secreting islet cell tumours., Design: The study was performed in nine patients with surgically treated insulinoma. Circulating adrenomedullin was assayed using a specific radioimmunoassay and its localization and distribution in the tumour were determined by means of immunohistochemistry., Results: Adrenomedullin concentrations were significantly greater in patients with insulinoma (6.6 +/- 3.2 fmol/ml) than in controls (2.1 +/- 1.1 fmol/ml). In six patients monitored before and after surgery, plasma adrenomedullin decreased from 6.3 +/- 2.9 fmol/ml to 3.0 +/- 1.6 fmol/ml. Immunoreactive adrenomedullin was localized exclusively in the tumours cells, whereas stroma, surrounding pancreas parenchyma and major ducts were negative for the peptide., Conclusions: Our findings indicate that circulating adrenomedullin is increased in insulinoma and that this increase is related to the neoplastic phenotype.

Objective: Adrenomedullin, a recently discovered vasoactive peptide originally identified in pheochromocytoma, has been found to be increased in the plasma of pregnant women at term. This study was designed to elucidate whether adrenomedullin secretion is dependent on gestational age and the possible source and function of this peptide in human pregnancy., Study Design: Adrenomedullin concentrations were determined by RIA in amniotic fluid and maternal plasma obtained from 110 pregnant women between 8 and 40 weeks of gestation. Subjects were stratified into five groups according to gestational age. In term patients (n = 15), adrenomedullin was also measured in the umbilical artery and vein separately., Results: High concentrations of adrenomedullin were present in plasma and amniotic fluid samples from patients in the first, second and third trimester. There was no significant difference in mean maternal plasma concentration of adrenomedullin between the five patient groupings. Amniotic fluid adrenomedullin concentrations decreased from 81.2 +/- 11.7 pg/ml at 8-12 weeks of gestation to 63.7 +/- 6.0 pg/ml at 13-20 weeks of gestation and then increased at 21-28 weeks of gestation to 99.1 +/- 10.4 pg/ml. A further increase was found in samples collected after 37 weeks of gestation (132.6 +/- 10.1 pg/ml). In the umbilical vein, adrenomedullin concentration was higher (P < 0.05) than in the artery (65.7 +/- 6.1 pg/ml and 48.5 +/- 5.2 pg/ml respectively), suggesting that adrenomedullin in the fetal circulation derives from the placenta., Conclusions: Our results demonstrate the presence of adrenomedullin in maternal plasma and amniotic fluid throughout gestation, and show that its production starts very early in gestation, suggesting that this hormone may have an important role in human reproduction, from implantation to delivery.

The aim of this study has been to investigate the plasma endothelin-1 (ET-1) levels in adult patients with proven Addison's disease (AD). Plasma ET-1 levels were measured in 29 subjects (17 males and 12 females, aged between 20 and 54 years): 15 of them were patients with AD and 14 were sex- and age-matched normal subjects, used as a control group. All patients with AD have been studied under basal conditions and nine of them also after 2 weeks on oral corticosteroid therapy (individual cortisol dosage ranging from 25 to 37.5 mg/day and 0.1 mg/day 9 alpha-fluorohydrocortisone). Extracted plasma ET-1 was determined by a specific radioimmunoassay using rabbit endothelin antisera. Mean ET-1 values in the patients with AD were three times higher than in normal subjects (21.09 +/- 4.38 pg/ml vs 6.72 +/- 1.74 pg/ml; p < 0.0001). Plasma ET-1 levels assayed in the patients with AD after 2 weeks of corticosteroid therapy were significantly decreased (14.47 +/- 3.7 pg/ml vs 22.8 +/- 5.2 pg/ml; -37%; p < 0.001) compared to values in untreated patients. However, the plasma ET-1 values obtained following corticosteroid therapy were still significantly higher (p < 0.001) than those detected in the control subjects. These results clearly indicate that patients with untreated AD have increased circulating ET-1 levels that may be reduced by short-term corticosteroid therapy.

The present study deals with the 24-h changes in circulating lymphocyte subpopulations in eight subjects with kidney grafts established for 2 to 5 years and treated with cyclosporin. The control group consisted of ten age-matched clinically healthy subjects. The chronobiological analysis of time series documented that the circadian rhythm of T-lymphocyte subsets is undetectable in transplanted subjects. Cortisol rhythmicity persists, however, suggesting that the abolition of T-cell rhythmicity is not attributable to a desynchronisation of the adrenal cycle. Even though the therapy was combined with prednisolone, the abrogation of rhythmicity for T-lymphocyte subpopulations seems to be related to the immunosuppressive action of cyclosporin, as the plasma concentrations of the drug show no periodic variations along the 24-h span. Antirejection therapy of kidney-transplanted subjects could be adjusted so that cyclosporin is given at a time that would promote suppression of T-lymphocytes without altering their rhythmic performance.