Cristiano Marinelli

Bone and Mineral Metabolism in Patients with Primary Aldosteronism

Primary aldosteronism represents major cause of secondary hypertension, strongly associated with high cardiovascular morbidity and mortality. Aldosterone excess may influence mineral homeostasis, through higher urinary calcium excretion inducing secondary increase of parathyroid hormone. Recently, in a cohort of PA patients a significant increase of primary hyperparathyroidism was found, suggesting a bidirectional functional link between the adrenal and parathyroid glands. The aim of this study was to evaluate the impact of aldosterone excess on mineral metabolism and bone mass density. In 73 PA patients we evaluated anthropometric and biochemical parameters, renin-angiotensin-aldosterone system, calcium-phosphorus metabolism, and bone mineral density; control groups were 73 essential hypertension (EH) subjects and 40 healthy subjects. Compared to HS and EH, PA subjects had significantly lower serum calcium levels and higher urinary calcium excretion. Moreover, PA patients showed higher plasma PTH, lower serum 25(OH)-vitamin D levels, higher prevalence of vitamin D deficiency (65% versus 25% and 25%; P < 0.001), and higher prevalence of osteopenia/osteoporosis (38.5 and 10.5%) than EH (28% and 4%) and NS (25% and 5%), respectively. This study supports the hypothesis that bone loss and fracture risk in PA patients are potentially the result of aldosterone mediated hypercalciuria and the consecutive secondary hyperparathyroidism.

Oxidative stress in patients affected by primary aldosteronism

Objective: Primary aldosteronism, an important form of secondary hypertension, is associated with significant increase of cardiovascular risk (ischaemic heart, cerebrovascular events, arrhythmias) (relative risk 4.6). The specific treatment of primary aldosteronism significantly reduces cardiovascular risk. In addition to high blood pressure values and direct action of aldosterone, new mechanisms such as increased oxidative stress are involved in the development of organ damage, metabolic, endothelial and coagulation complications. Methods: The aim of the study was to evaluate parameters of oxidative stress in 38 patients (21 men, 17 women, mean age 53.3 ± 4.7 years) with primary aldosteronism [11 aldosterone-producing adenoma (APA) (4 men, 7 women, mean age 50.2 ± 4.5 years) and 27 idiopathic adrenal hyperplasia (IHA) (17 men, 10 women, mean age 54.5 ± 5.3 years)] at diagnosis and after specific treatment (surgical or pharmacological), with respect to 50 patients with essential hypertension (26 men, 24 women, mean age 49 ± 7.4 years) and 50 healthy individuals (28 men, 22 women, mean age 48.7 ± 4.4 years). Results: Patients with primary aldosteronism showed significant increase of NADPH oxidase (Nox2-dp) plasma levels and urinary isoprostanes (34.9 ± 4.3 &mgr;g/dl and 216.3 ± 15.7 ng/mg, respectively; P < 0.05) than essential hypertensive patients (27.1 ± 3.7 &mgr;g/dl and 144.8 ± 9.4 ng/mg, respectively; P < 0.05). In APA patients undergoing adrenalectomy, we observed significant reduction of both circulating levels of Nox2-dp (29 ± 2.1  vs. 22,4 ± 1.7 &mgr;g/dl; P < 0.05) and urinary levels of isoprostanes (221.1 ± 10.5 vs. 132.6 ± 8.7 ng/mg; P < 0.05). Conclusions: This is the first study showing an increased oxidative stress in primary aldosteronism, characterized by increased serum levels of Nox2-dp and urinary excretion of isoprostanes. After APA removal with laparoscopic adrenalectomy, we found reduction of serum Nox2-dp and urinary isoprostanes.

Brown Fat Expresses Adiponectin in Humans

The presence of brown adipose tissue (BAT) in humans is unclear. Pheochromocytomas (PHEO) are rare tumors of neuroectodermal origin which occur in 0.1-0.2% of patients with hypertension. We sought to evaluate the presence and activity of BAT surrounding adrenal PHEO in a well-studied sample of 11 patients who were diagnosed with PHEO and then underwent adrenalectomy. Areas of white fat (WAT) and BAT surrounding PHEO were obtained by Laser Capture Microdissection for analysis of uncoupling protein (UCP)-1 and adiponectin mRNA expression. Adiponectin and UCP-1 mRNA levels were significantly higher in BAT than in WAT (0.62 versus 0.15 and 362.4 versus 22.1, resp., P < 0.01 for both). Adiponectin mRNA levels significantly correlated with urinary metanephrines (r = 0.76, P < 0.01), vanilly mandelic acid (VMA) (r = 0.95, P < 0.01), and serum adiponectin levels (r = 0.95, P < 0.01). Serum adiponectin levels significantly decreased (24.2 ± 2 μg/mL versus 18 ± 11 μg/mL, P < 0.01) after adrenalectomy in PHEO subjects. This study provides the following findings: (1) BAT surrounding PHEO expresses adiponectin and UCP-1 mRNA, (2) expression of adiponectin mRNA is significantly higher in BAT than in WAT surrounding PHEO, and (3) catecholamines and serum adiponectin levels significantly correlate with BAT UCP-1 and adiponectin mRNA.

Leptin and Adiponectin mRNA Expression From the Adipose Tissue Surrounding the Adrenal Neoplasia

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 Cushings 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.

Epicardial Fat Thickness and Primary Aldosteronism.

Primary aldosteronism (PA) is associated with increased cardiovascular risk and left ventricle (LV) changes. Given its peculiar biomolecular and anatomic properties, excessive epicardial fat, the heart-specific visceral fat depot, can affect LV morphology. Whether epicardial fat can be associated with aldosterone and LV mass (LVM) in patients with PA is unknown. We performed ultrasound measurement of the epicardial fat thickness (EAT) in 79 consecutive newly diagnosed patients with PA, 59 affected by bilateral adrenal hyperplasia (IHA), 20 aldosterone-producing adenoma (APA), and 30 patients with essential hypertension (low renin hypertension) (EH). The 3 groups did not differ by age, sex distribution, body mass index (BMI), waist circumference (WC), or blood pressure values. EAT showed a trend of increase in both APA and IHA groups when compared to patients with EH (8.3±1.8 vs. 7.9±1.3 vs. 7.8±2 mm, respectively). EAT was significantly correlated with indexed LVM in the IHA group (r=0.35, p<005), better than BMI or WC were. Interestingly, EAT was highly associated with plasma aldosterone concentrations (PAC) and PAC/plasma renin activity (PRA) (PAC/PRA) in the APA group (p=0.58, p=0.37, p<0.01, for both), whereas BMI and WC were not. EAT was also correlated with PRA in the IHA group (p=-0.28, p<0.05). Our study indicates a novel and interesting interaction of EAT with PA, independent of obesity, abdominal fat and blood pressure control. EAT can locally affect LVM, at least in patients with IHA. Further studies in larger population will be required to confirm these findings.

Ambulatory blood pressure monitoring-derived short-term blood pressure variability in primary hyperparathyroidism

IntroductionPrimary hyperparathyroidism is associated with a cluster of cardiovascular manifestations, including hypertension, leading to increased cardiovascular risk.PurposeThe aim of our study was to investigate the ambulatory blood pressure monitoring-derived short-term blood pressure variability in patients with primary hyperparathyroidism, in comparison with patients with essential hypertension and normotensive controls.MethodsTwenty-five patients with primary hyperparathyroidism (7 normotensive,18 hypertensive) underwent ambulatory blood pressure monitoring at diagnosis, and fifteen out of them were re-evaluated after parathyroidectomy. Short-term-blood pressure variability was derived from ambulatory blood pressure monitoring and calculated as the following: 1) Standard Deviation of 24-h, day-time and night-time-BP; 2) the average of day-time and night-time-Standard Deviation, weighted for the duration of the day and night periods (24-h “weighted” Standard Deviation of BP); 3) average real variability, i.e., the average of the absolute differences between all consecutive BP measurements.ResultsBaseline data of normotensive and essential hypertension patients were matched for age, sex, BMI and 24-h ambulatory blood pressure monitoring values with normotensive and hypertensive-primary hyperparathyroidism patients, respectively. Normotensive-primary hyperparathyroidism patients showed a 24-h weighted Standard Deviation (P < 0.01) and average real variability (P < 0.05) of systolic blood pressure higher than that of 12 normotensive controls. 24-h average real variability of systolic BP, as well as serum calcium and parathyroid hormone levels, were reduced in operated patients (P < 0.001). A positive correlation of serum calcium and parathyroid hormone with 24-h-average real variability of systolic BP was observed in the entire primary hyperparathyroidism patients group (P = 0.04, P  = 0.02; respectively).ConclusionSystolic blood pressure variability is increased in normotensive patients with primary hyperparathyroidism and is reduced by parathyroidectomy, and may potentially represent an additional cardiovascular risk factor in this disease.

Enhanced Soluble Serum CD40L and Serum P-Selectin Levels in Primary Aldosteronism

Primary aldosteronism (PA) is one of the most frequent forms of secondary hypertension, associated with atherosclerosis and higher risk of cardiovascular events. Platelets play a key role in the atherosclerotic process. The aim of the study was to evaluate the platelet activation by measuring serum levels of soluble CD40L (sCD40L) and P-selectin (sP-selectin) in consecutive PA patients [subgroup: aldosterone-secreting adrenal adenoma (APA) and bilateral adrenal hyperplasia (IHA)], matched with essential hypertensive (EH) patients. The subgroup of APA patients was revaluated 6-months after unilateral adrenalectomy. In all PA group, we measured higher serum levels of both sP-selectin (14.29±9.33 pg/ml) and sCD40L (9.53±4.2 ng/ml) compared to EH patients (9.39±5.3 pg/ml and 3.54±0.94 ng/ml, respectively; p<0.001). After removal of APA, PA patients showed significant reduction of blood pressure (BP) values, plasma aldosterone (PAC) levels and ARR-ratio, associated with a significant reduction of sP-selectin (16.74±8.9 pg/ml vs. 8.1±3.8 pg/ml; p<0.01) and sCD40L (8.6±1 ng/ml vs. 5.24±0.94 ng/ml; p<0.001). In PA patients, we found a significant correlation between sP-selectin and sCD40L with PAC (r=0.52, p<0.01; r=0.50, p<0.01, respectively); this correlation was stronger in APA patients (r=0.54; p<0.01 r=0.63; p<0.01, respectively). Our results showed that PA is related to platelet activation, expressed as higher plasma values of sCD40L and sP-selectin values. Surgical treatment and consequent normalization of aldosterone secretion was associated with significant reduction of sCD40L and sP-selectin values in APA patients.

Primary aldosteronism in a patient who exhibited heart failure.

Primary aldosteronism (PA) is a common cause of secondary hypertension due to unilateral adrenocortical adenoma (APA) or idiopathic hyperplasia. There is increased awareness of the possible cardiac sequelae of aldosterone excess, including cardiac hypertrophy, fibrosis, and vascular endothelium injury. A 54-year-old woman was referred for rest and nighttime worsening dyspnea and palpitations. One year earlier she was admitted to another hospital with the same symptoms and discharged with a diagnosis of idiopathic dilated cardiomiopathy. At admission, physical examination revealed a body mass index of 21 kg ⁄m and blood pressure (BP) of 210 ⁄105 mm Hg. Chest auscultation revealed mild expiratory wheezes and rales in both lower lobes. Electrocardiography showed signs of left ventricular (LV) overloading and hypertrophy. Laboratory analysis showed severe hypokalemia (1.8 mEq ⁄L; normal range 3.5–5 mEq ⁄L) and metabolic alkalosis (pH 7.51; partial pressure of carbon dioxide 41 mm Hg; partial pressure of oxygen 86 mm Hg; HCO 3 32.6 mmol ⁄L; excess bases 10 mmol ⁄L) (Table I). Chest radiography revealed an enlarged cardiac silhouette, congested pulmonary hilum, and bilateral pleural effusion (Figure 1A). Echocardiography showed an increase in LV end-diastolic diameter (58 mm) and left atrial volume (46 mm) and a signficant decrease in global LV performance (ejection fraction [EF] 30%) (Table II). The 24hour ambulatory BP monitoring (ABPM) revealed severe systo-diastolic hypertension without physiological nocturnal fall (nondipper pattern). Subsequent investigation showed suppressed plasma renin activity (PRA) (0.08 ng ⁄mL ⁄h; normal range 0.2–2.7 ng ⁄mL ⁄h), high plasma aldosterone (PAC 16.17 ng ⁄dL; normal range 7.5–15 ng ⁄dL), and PAC ⁄ PRA ratio (202.17 ng ⁄dL: ng ⁄ml ⁄h; normal value<30 ng ⁄dL: ng ⁄mL ⁄h). Because of suspicion of PA, we performed a captopril test. After 60 minutes of captopril 50 mg, the PAC ⁄PRA ratio was still elevated (529.93 ng ⁄dL: ng ⁄mL ⁄h). Magnetic resonance imaging of the superior abdomen demonstrated a 20-mm nodule in the left adrenal gland (Figure 2). The patient underwent laparoscopy adrenalectomy, and histopathology revealed an APA. Subsequently, her BP was normalized at 140 ⁄90 mm Hg with amlodipine, ramipril, and serum potassium. After 6 months of follow-up, BP was 110 ⁄80 mm Hg, with normal serum potassium. Chest radiography showed resolution of congestive heart pulmonary imaging with a decreased cardiac silhouette (Figure 1B). Repeat echocardiography demonstrated a significant improvement in LV hypertrophy and EF (50%). Recently, the Primary Aldosteronism Prevalence in Italy Study (PAPY) reported a PA prevalence of 11.2% in patients with new-onset hypertension. The potential comorbidity and prevention of excessive cardiovascular events and organ damage led to development of accurate strategies for diagnosis of PA. PA patients display an unfavorable cardiovascular profile, suggesting a role of aldosterone beyond its well-known hypertensive effects. TABLE I. Laboratory Data and Blood Gas Analysis

Primary aldosteronism due to adrenocortical adenoma with concurrent ileum carcinoid tumor: case report

Primary aldosteronism (PA) with synchronous carcinoid syndrome is extremely rare occurrence. In this article, we describe a case of PA due to adrenocortical adenoma (“aldosteronoma”) and concurrent malignant carcinoid tumor of ileum. The patient was treated with synchronous right adrenalectomy and resection of the ileum. This case is an example of concomitant presence of two types of tumors, effectively managed surgically. We report a case of a nonclassical form of multiple endocrine neoplasia type 1 (MEN 1) syndrome.

Plasma endothelin-1 levels in patients with resistant hypertension: effects of renal sympathetic denervation

Abstract Introduction: Resistant arterial hypertension (RHT) is defined as poor controlled blood pressure (BP) despite optimal doses of three or more antihypertensive agents, including a diuretic. In the development of RHT, hyperactivity of sympathetic (SNS) and renin–angiotensin–aldosterone (SRAA) systems are involved, and SNS is a potent stimulator of vasoactive endothelin-1 (ET-1) peptide. Renal sympathetic denervation (RSD) through disrupting renal afferent and efferent nerves attenuates SNS activity. Material and methods: We carried out pilot study investigating the effect of RSD on BP and plasma ET-1 levels in consecutive 9 RHT patients (7 male and 2 female, mean age of 56 ± 13.3). Results: After 12 months of the RSD, we observed a significant reduction of BP office, 24-h ambulatory BP monitoring (ABPM) (p < 0.05, respectively), and “non-dipping” pattern (from 55% to 35%) (p < 0.05). Moreover, RSD significantly decreased plasma ET-1 levels in both renal artery (at right from 21.8 ± 4.1 to 16.8 ± 2.9 pg/ml; p = 0.004; at left from 22.1 ± 3.7 to 18.9 ± 3.3 pg/ml; p = 0.02). We observed positive correlations between plasma renal arteries ET-1 levels and systolic BP values at ABPM [Global-SBP (r = 0.58; p < 0.01), Diurnal-SBP (r = 0.51; p < 0.03) and Nocturnal-SBP (r = 0.58; p < 0.01), respectively]. Discussion: Our data confirmed the positive effects of RSD on BP values in patients with RHT, and showed a possible physio-pathological role of ET-1. KEY MESSAGES RSD is associated to a significant reduction of plasma ET-1 levels, representing an useful tool into reduction of BP in RHT patients.