Subclinical atherosclerosis due to increase of plasma aldosterone concentrations in essential hypertensive individuals.

BACKGROUND AND AIMS: The adrenal mineralocorticoid system plays a key role in cardiovascular, metabolic and renal damage. This study aimed to assess the relationship between plasma aldosterone concentration (PAC) and some surrogate markers of subclinical atherosclerosis, such as carotid intima-media thickness (cIMT), ankle-brachial index (ABI) and biochemical parameters in patients with essential hypertension. METHODS AND RESULTS: From January 2014 to December 2017, we consecutively enrolled 804 essential hypertensive patients (407 men and 397 women, mean age 50 ±â€Š14 years) without cardiovascular complications, distinguishing patients in quartiles according to PAC. Compared with the first quartile, the highest PAC quartile was associated with the highest levels of serum uric acid (SUA) (5.3 ±â€Š1.3 vs. 5.0 ±â€Š1.0 mg/dl; P = 0.01), triglycerides (117.5 ±â€Š15.7 vs. 106.8 ±â€Š10.5 mg/dl; P < 0.05), 24-h urinary albumin excretion (UAE) (38.8 ±â€Š vs. 7.6 ±â€Šmg/24 h; P < 0.05), cIMT (0.87 ±â€Š0.22 vs. 0.80 ±â€Š0.21 mm; P = 0.001) and increased prevalence of carotid plaques (26 vs. 16%; P < 0.005). Moreover, we found that in patients with PAC more than 150 pg/ml, the ABI was significantly lower than those with PAC < 150 pg/ml (1.01 ±â€Š0.09 vs. 1.10 ±â€Š0.09; P < 0.022). PAC was also found to be an independent predictor of the presence of carotid plaques and pathological ABI (<0.9) in essential hypertensive individuals. CONCLUSION: Our results revealed that higher PAC values are strongly associated with some metabolic variables, as triglycerides, UAE, cIMT, worse ABI and major prevalence of carotid plaques that, together with elevated blood pressure values, are strictly correlated with higher risk of atherosclerosis and cardiovascular complications.

Analysis of Short-term Blood Pressure Variability in Pheochromocytoma/Paraganglioma Patients.

Data on short-term blood pressure variability (BPV), which is a well-established cardiovascular prognostic tool, in pheochromocytoma and paraganglioma (PPGL) patients is still lack and conflicting. We retrospectively evaluated 23 PPGL patients referred to our unit from 2010 to 2019 to analyze 24 h ambulatory blood pressure monitoring (24-h ABPM)-derived markers of short-term BPV, before and after surgical treatment. PPGL diagnosis was assessed according to guidelines and confirmed by histologic examination. The 24-h ABPM-derived markers of short-term BPV included: circadian pressure rhythm; standard deviation (SD) and weighted SD (wSD) of 24-h, daytime, and night-time systolic and diastolic blood pressure (BP); average real variability (ARV) of 24-h, daytime, and night-time systolic and diastolic BP. 7 males and 16 females of 53 ± 18 years old were evaluated. After surgical resection of PPGL we found a significant decrease in 24-h systolic BP ARV (8.8 ± 1.6 vs. 7.6 ± 1.3 mmHg, p < 0.001), in 24-h diastolic BP ARV (7.5 ± 1.6 vs. 6.9 ± 1.4 mmHg, p = 0.031), and in wSD of 24-h diastolic BP (9.7 ± 2.0 vs 8.8 ± 2.1 mmHg, p = 0.050) comparing to baseline measurements. Moreover, baseline 24-h urinary metanephrines significantly correlated with wSD of both 24-h systolic and diastolic BP. Our study highlights as PPGL patients, after proper treatment, show a significant decrease in some short-term BPV markers, which might represent a further cardiovascular risk factor.

Clinical Benefits of Unilateral Adrenalectomy in Patients with Subclinical Hypercortisolism Due to Adrenal Incidentaloma: Results from a Single Center.

INTRODUCTION: This study was designed to evaluate the results of unilateral laparoscopic adrenalectomy in patients with subclinical hypercortisolism (SH) due to adrenal incidentaloma (AI) concerning the main cardiometabolic disorders. METHODS: We have studied between January 2000 to December 2015, 645 patients with AI (283 males and 362 females; mean age 61.9 ± 10 years) and we found 70 patients with SH (27 males and 43 females; mean age 61.9 ± 8.4 years). Twenty-six (37%) SH patients (6 males and 20 females; mean age 58.7 ± 7.1 years) underwent unilateral laparoscopic adrenalectomy, whereas 44 SH patients (21 males and 23 females; mean age 63.9 ± 9.9 years) performed a conservative treatment. All SH patients were evaluated at diagnosis and after follow-up (mean 12 months; range 9-15 months). RESULTS: In only SH patients undergoing unilateral adrenalectomy we found a statistical significant reduction of the arterial hypertension and metabolic syndrome (p < 0.05, respectively). In particular we observed a reduction of 24-h systolic blood pressure and "non-dipper" pattern (p < 0.05, respectively) evaluated with ambulatory blood pressure monitoring (ABPM). CONCLUSIONS: Our study confirm the high prevalence of SH in AI, and the unilateral laparoscopic adrenalectomy seemed to have a beneficial effect on some cardiometabolic disorders.

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

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.

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 ±â€Š4.7 years) with primary aldosteronism [11 aldosterone-producing adenoma (APA) (4 men, 7 women, mean age 50.2 ±â€Š4.5 years) and 27 idiopathic adrenal hyperplasia (IHA) (17 men, 10 women, mean age 54.5 ±â€Š5.3 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 ±â€Š7.4 years) and 50 healthy individuals (28 men, 22 women, mean age 48.7 ±â€Š4.4 years). RESULTS: Patients with primary aldosteronism showed significant increase of NADPH oxidase (Nox2-dp) plasma levels and urinary isoprostanes (34.9 ±â€Š4.3 µg/dl and 216.3 ±â€Š15.7 ng/mg, respectively; P < 0.05) than essential hypertensive patients (27.1 ±â€Š3.7 µg/dl and 144.8 ±â€Š9.4 ng/mg, respectively; P < 0.05). In APA patients undergoing adrenalectomy, we observed significant reduction of both circulating levels of Nox2-dp (29 ±â€Š2.1  vs. 22,4 ±â€Š1.7 µg/dl; P < 0.05) and urinary levels of isoprostanes (221.1 ±â€Š10.5 vs. 132.6 ±â€Š8.7 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.

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.

Progressive loss in circulating volume during haemodialysis can be monitored by time voltage integral area of QRS complex: pilot study.

INTRODUCTION: Time voltage area of QRS is a parameter that showed a close association with modifications in endoventricular volume. The aim of the study was to investigate the efficacy of this parameter in identifying progressive reduction in circulating blood volume (BV) during haemodialytic treatment (HT). MATERIAL AND METHODS: Thirteen uraemic patients were studied. XYX like leads were monitored before, during and after HT. Summation of areas of each QRS complex was named QRS total area (TA). RESULTS: Increase in QRS TA and decrease in BV were found after vs. before HT. Progressive increase in QRS TA is strongly linked to a progressive reduction of BV during HT. CONCLUSIONS: THESE FINDINGS ENCOURAGE USE OF ECG MONITORING DURING HT WITH A DUAL PURPOSE: rhythm and haemodynamic control. In fact, excessive or insufficient subtractions of water, with consequent hypotensive or cardiorespiratory crisis, are the most frequent complications in these patients.

Dopamine receptor subtypes in the human coronary vessels of healthy subjects.

OBJECTIVE: Dopamine D(1)-D(5) receptors subtypes were studied in human coronary vessels of healthy subjects to assess their localization and their expression. METHODS: Samples of intraparenchymal and extraparenchymal branches of human coronary arteries and veins were harvested from four normal native hearts explanted from four young brain dead heart donors in case of orthoptic transplant, not carried out for technical reasons. In all the samples morphological, biochemical, immunochemical, and morphometrical studies were performed including quantitative analysis of images and evaluation of data. RESULTS: Microanatomical section showed healthy coronary vessels, which expressed all dopamine receptors (from D(1) to D(5)) with a different pattern of distribution between the different layers, in the intra and in the extraparenchymal branches.D(1) and D(5) (with a prevalence D(1) over D(5)) were distributed in the adventitia and to a lesser extent in the outer media but they were absent in arterioles, capillaries and venules. Endothelial and the middle layer showed D(2), D(3) and D(4) receptors, with a greater expression of D(2). Immunoblot analysis of dopamine monoclonal antibodies and dopamine receptors showed a different migration band for each receptor: D(1) (45 KDa); D(2) (43 KDa); D(3) (42 kDa); D(4) (40-42 KDa); D(5) (38-40 KDa) CONCLUSION: These findings demonstrate the presence of all dopamine receptor subtypes in the wall of human coronary vessels of healthy subjects. Dopamine D(1) and D(2) receptor subtypes are the most expressed, suggesting their prominent role in the coronary vasoactivity.

Age-related changes in the human thymus studied with scanning electron microscopy.

This investigation describes some morphological, age-related changes in different compartments and cells of the human thymus. Scanning electron microscopic observations were done on human thymus samples obtained from four young and eight elderly patients during thoracic surgery and/or diagnostic biopsy of the thymus, after receiving authorization from the Ethical Committee of our university. The morphological data were submitted to quantitative image analysis so as to obtain quantitative results. Subsequently, the related values were used for statistical analysis. Our findings demonstrate that (1) all thymus compartments (subcapsular spaces, cortical, medullar, thymus microenvironment) contain numerous thymocytes even after the thymus has aged. (2) In older humans, residual thymus lymphoid islets contain, in addition to fatty cells and/or fibrous cells, also the same types of resident and nonresident cells (permanent and moving cells) that are found in young and adult subjects. (3) Endothelial cells of thymus microvessels contain numerous gaps. These gaps are tight in young subjects and become loose with age. (4) Thymocytes, in older subjects, are always found near these loose endothelial gaps of thymus microvessels. (5) While thymus cortical microvessels are provided with pericytes and/or periarteriolar spaces, microvessels of the thymus medullar are free of such spaces. Our morphological and quantitative results lead us to consider the possibility that the thymus fraction of resident and permanent cells (including thymocytes and reticular epithelial cells) is larger in younger subjects compared with older ones. The endothelial loose gaps of thymus microvessels, in older subjects, can allow the bidirectional transit of thymocytes through the wall of the said microvessels.

Cholinergic staining of bronchus- associated lymphoid tissue.

The cholinergic staining of human bronchus-associated lymphoid tissue (BALT) was studied in humans. Morsels of the human lung (containing BALT) were harvested, after having obtained the appropriate approvals, during autopsies in 24 human subjects. The samples were stained by means of the enzymatic technique of acetylcholinesterase (AChE) and/or the monoclonal immunohistochemical method of choline acetyltransferase (ChAT). A morphometrical analysis was performed by means of quantitative analysis of images and statistical analyses of the data. AChE and proteins were also measured by biochemical assay. Our results demonstrate that both AChE and ChAT are localized in the BALT of young and old humans. These enzymes undergo age-related changes. The biochemical values of AChE are as follows: 22.3 +/- 2.5 international units in young subjects and 78.5 +/- 1.9 international units in old ones. The morphometrical values of AChE confirm the biochemical ones. The morphometrical data for ChAT are 31.6 +/- 1.4 conventional units in young subjects and 71.2 +/- 1.5 conventional units in old ones. Further results are needed to draw definite conclusions concerning the location and the distribution of these two enzymatic activities in BALT. In our opinion, the presence of AChE and ChAT in BALT can be both 'non-neuronal', with a role in general metabolism, and/or 'neuronal' with a role in neuroimmunomodulation.

Vitamin D status as the major factor determining the circulating levels of parathyroid hormone: a study in normal subjects.

We investigated the relative contribution of the major factors regulating calcium homeostasis in determining the circulating levels of PTH. We studied 137 males and 125 females who were healthy volunteers. Circulating PTH levels were determined by three different immunoradiometric assays (IRMA). The first one (PTH Sorin, PTH S) utilizes two affinity-purified polyclonal antibodies directed against the 1-34 and 39-84 sequence of the hormone. The two other IRMA share polyclonal anti-PTH (39-84) antibodies. The first assay (PTH Whole, PTH W) utilizes a second polyclonal antibody, directed against the 1-4 amino acid sequence. The second assay (PTH Total, PTH T) utilizes a second antibody specific for the 7-34 region. Concentrations of PTH fragments lacking the initial amino acid sequence (PTH N-truncated, PTH N-t) were determined by the difference of values between PTH T and PTH W. Vitamin D was the main explicative variable almost in every multiple linear regression model, both considering the group as a whole (PTH S: R2 = 0.238, P < 0.0001; PTH W: R2 = 0.08, P < 0.001; PTH T: R2 = 0.145, P < 0.0001; PTH N-t: R2 = 0.081, P < 0.009) and when considering men and women separately. In subjects with vitamin D insufficiency (n = 53) [25(OH)D < 30 nmol/l], mean serum levels of parathyroid hormone were significantly higher (P < 0.001) than those in subjects of similar age with normal vitamin status (n = 209) with all the assays employed. This study demonstrates the central role of 25(OH)D in regulating PTH secretion in physiological conditions.

Dopamine receptors in the human dura mater.

Dopamine receptors (Dar) were studied as a component of the nervous dopaminergic system in the human dura mater. Dar were stained in several dural zones (vascular, perivascular, intervascular) in different regions (basal, calvarial, tentorial, occipital, frontal, parietal, temporal) of the cranial meninges. Specimens of human dura mater were harvested from autopsies of 10 elderly male subjects (age range, 60-75 years). Dar were labeled with specific (H3) markers, studied with radiobinding techniques (including liquid scintillation), stained for light microscope autoradiography, and measured by means of quantitative analysis of images. All results were evaluated with statistical analysis to identify significant results. More dural Dar were found in the basal region than in the calvarial one. Moreover, Dar are more abundant in the vascular and perivascular dural zone than in the intervascular one. The vascular distribution of Dar seemed to indicate that Dar play a role in the control of meningeal blood vessels. The location and distribution of D1 and D2 receptors in the human cranial dura mater confirmed the presence of a dopaminergic system, which could play an important role in controlling blood flow and/or other functions of meningeal membranes.

Potential clinical utility of a new IRMA for parathyroid hormone in postmenopausal patients with primary hyperparathyroidism.

BACKGROUND: A new commercially available (so-called second-generation) IRMA for parathyroid hormone (PTH) separately detects intact PTH and its N-truncated fragments; however, no studies have compared the first- and second-generation IRMAs for PTH in patients with primary hyperparathyroidism (PHPT) to assess their respective diagnostic accuracies. METHODS: We concomitantly investigated 39 postmenopausal patients with PHPT and a control group of 70 healthy postmenopausal women matched for age, renal function, and vitamin D status. In all individuals, PTH was measured with a classic IRMA (PTH-S; DiaSorin Inc.), which uses antibodies directed against epitopes 1-34 and 39-84, and a new method (Scantibodies Laboratory. Inc.), which uses antibodies against epitopes 1-4 and 39-84 (PTH-W) and epitopes 7-34 and 39-84 (PTH-T). We also assayed serum PTH in 10 PHPT patients every 24 h for 5 days after successful surgery. RESULTS: The different assays gave serum PTH values that were >2 SD higher than values for the control population in 59% (PTH-S), 77% (PTH-W), and 82% (PTH-T) of patients with PHPT. However, ROC curve analysis showed no significant differences among the three PTH assays, demonstrating overlapping diagnostic sensitivities. In PHPT patients, the correlation among the assays was highly significant (r = 0.91-0.92; P <0.001). The ratio PTH-W:PTH-T x 100 showed a gaussian distribution in both PHPT patients and controls, whose mean (SD) values [63.4 (13.3)% vs 64.5 (9.5)%, respectively] did not differ significantly. After parathyroidectomy, the mean percentages of variation in PTH detected with all of the assays were quite similar. CONCLUSIONS: The distribution of the PTH-W:PTH-T ratio in patients and controls suggests that PHPT does not markedly influence the rate at which biologically inactive fragments are generated by central or peripheral cleavage of PTH. The similar postoperative curves seem to contradict the hypothesized effect of acute hypocalcemia in modulating the central secretion of hormonal fragments. Our results indicate that the three investigated assays have similar diagnostic sensitivities in PHPT.

Distribution of catecholaminergic neurotransmitters and related receptors in human bronchus-associated lymphoid tissue.

BACKGROUND: The functions of the bronchus-associated lymphoid tissue (BALT) are under the control of the autonomic nervous system (sympathetic and parasympathetic nerve fibers). OBJECTIVES: The relationships between the adrenergic nerve fibers and beta-adrenergic receptors were studied in the human BALT with the aim to demonstrate a probable neuromodulation. METHODS: Morphological observations (staining with hematoxylin-eosin and scanning electron microscopy images) were carried out on samples of human BALT harvested during autopsies. Moreover, histochemical staining for norepinephrine (adrenaline = adrenergic nerve fibers) as well as for other catecholamines was performed. Finally, beta-adrenergic receptors were stained by means of a beta-blocking, radiolabeled drug (pindolol 125I). All our data were submitted to morphometric analysis (quantitative analysis of images and statistical analysis of data). RESULTS: Our results provide direct evidence of the presence and distribution of catecholaminergic nerve fibers and related beta-adrenergic receptors in BALT. beta-Adrenergic receptors are present above all in the most richly innervated part of the BALT, and are, therefore, in close relationship with their related adrenergic nerve fibers. CONCLUSIONS: Studies on the distribution of adrenergic neurotransmitters and related beta-adrenergic receptors in the human BALT are the first step for the demonstration of a probable neuromodulation of BALT.

[Clinical aspects of osteoporosis]. / Gli aspetti clinici dell'osteoporosi.

The main clinical presentation of osteoporosis is fracture and its consequences. However a number of diseases and factors can induce bone loss and increase the risk of fracture. Therefore the clinical approach should be initially directed to exclude secondary osteoporosis. Vertebral fractures are the most common osteoporotic fractures; they are characterized by back pain, typical physical changes such as kyphosis and height loss, functional impairment and social decline. On the other hand, hip fracture is the most severe consequence of osteoporosis, because of its higher morbility and mortality. The main pathogenetic determinants of hip fracture are represented by both bone loss and several factors contributing to fall in the elderly. Moreover, a number of conditions are responsible for the high mortality rate following hip fracture. Colles' fracture is rarely hospitalized; however, most patients complain a complex algodystrophic syndrome which impairs the quality of life.