Skin-specific mechanisms of body fluid regulation in hypertension.

Increasing evidence suggests excess skin Na+ accumulation in hypertension; however, the role of skin-specific mechanisms of local Na+/water regulation remains unclear. We investigated the association between measures of sweat and trans-epidermal water loss (TEWL) with Na+ content in the skin ([Na+]skin) and clinical characteristics in consecutive hypertensive patients. We obtained an iontophoretic pilocarpine-induced sweat sample, a skin punch biopsy for chemical analysis, and measures of TEWL from the upper limbs. Serum vascular endothelial growth factor-c (VEGF-c) and a reflectance measure of haemoglobin skin content served as surrogates of skin microvasculature. In our cohort (n = 90; age 21-86 years; females = 49%), sweat composition was independent of sex and BMI. Sweat Na+ concentration ([Na+]sweat) inversely correlated with [K+]sweat and was higher in patients on ACEIs/ARBs (P < 0.05). A positive association was found between [Na+]sweat and [Na+]skin, independent of sex, BMI, estimated Na+ intake and use of ACEi/ARBs (Padjusted = 0.025); both closely correlated with age (P < 0.01). Office DBP, but not SBP, inversely correlated with [Na+]sweat independent of other confounders (Padjusted = 0.03). Total sweat volume and Na+ loss were lower in patients with uncontrolled office BP (Padjusted < 0.005 for both); sweat volume also positively correlated with serum VEGF-c and TEWL. Lower TEWL was paralleled by lower skin haemoglobin content, which increased less after vasodilatory pilocarpine stimulation when BMI was higher (P = 0.010). In conclusion, measures of Na+ and water handling/regulation in the skin were associated with relevant clinical characteristics, systemic Na+ status and blood pressure values, suggesting a potential role of the skin in body-fluid homeostasis and therapeutic targeting of hypertension.

Aldosterone Biosynthesis Is Potently Stimulated by Perfluoroalkyl Acids: A Link between Common Environmental Pollutants and Arterial Hypertension.

The large environmental contamination of drinking water by perfluoroalkyl substances (PFAS) markedly increased the plasma levels of pentadecafluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) in a Northern Italy population with a high prevalence of arterial hypertension and cardiovascular disease. As the link between PFAS and arterial hypertension is unknown, we investigated if they enhance the biosynthesis of the well-known pressor hormone aldosterone. We found that PFAS increased aldosterone synthase (CYP11B2) gene expression by three-fold and doubled aldosterone secretion and cell and mitochondria reactive oxygen species (ROS) production over controls (p < 0.01 for all) in human adrenocortical carcinoma cells HAC15. They also enhanced the effects of Ang II on CYP11B2 mRNA and aldosterone secretion (p < 0.01 for all). Moreover, when added 1 h before, the ROS scavenger tempol abolished the effect of PFAS on CYP11B2 gene expression. These results indicate that at concentrations mimicking those found in human plasma of exposed individuals, PFAS are potent disruptors of human adrenocortical cell function, and might act as causative factors of human arterial hypertension via increased aldosterone production.

Angiotensin II Promotes SARS-CoV-2 Infection via Upregulation of ACE2 in Human Bronchial Cells.

Blockers of the renin-angiotensin system (RAS) have been reported to increase the angiotensin converting enzyme (ACE)2, the cellular receptor of SARS-CoV-2, and thus the risk and course of COVID-19. Therefore, we investigated if angiotensin (Ang) II and RAS blockers affected ACE2 expression and SARS-CoV-2 infectivity in human epithelial bronchial Calu-3 cells. By infectivity and spike-mediated cell-cell fusion assays, we showed that Ang II acting on the angiotensin type 1 receptor markedly increased ACE2 at mRNA and protein levels, resulting in enhanced SARS-CoV-2 cell entry. These effects were abolished by irbesartan and not affected by the blockade of ACE-1-mediated Ang II formation with ramipril, and of ACE2- mediated Ang II conversion into Ang 1-7 with MLN-4760. Thus, enhanced Ang II production in patients with an activated RAS might expose to a greater spread of COVID-19 infection in lung cells. The protective action of Angiotensin type 1 receptor antagonists (ARBs) documented in these studies provides a mechanistic explanation for the lack of worse outcomes in high-risk COVID-19 patients on RAS blockers.

Aldosterone synthase inhibitors for cardiovascular diseases: A comprehensive review of preclinical, clinical and in silico data.

Aldosterone, the main mineralocorticoid hormone, plays a fundamental role in maintaining blood pressure (BP)and volume under hypovolemic conditions. However, in numerous diseases, where it is produced in excess, it plays a detrimental role and contributes to cardiovascular events and ultimately to death in a multitude of patients. The seminal observation that the fungicide-derivative fadrozole blunted steroidogenesis has led to develop several agents to inhibit aldosterone synthase (AS, CYP11B2), the mitochondrial NADH-dependent enzyme that is necessary for aldosterone biosynthesis. Aldosterone synthase inhibitors (ASI) have, thereafter, been conceived and investigated in phase I and phase II studies. We herein reviewed the ASIs available so far considering their chemical structure, the related aldosterone synthase binding and pharmacodynamic properties. We also examined the promising results obtained with ASIs that have already been tested in phase II human studies.

Familial hyperaldosteronism type 1 and pregnancy: successful treatment with low dose dexamethasone.

PURPOSE: Familial hyperaldosteronism type 1 (FH-1) is an autosomal dominant form of primary aldosteronism (PA), featuring a marked phenotypic heterogeneity, ranging from mild forms of PA and arterial hypertension (HT) to severe forms complicated by stroke at a young age. Affected patients usually reach the fertile age; hence, transmission of the disease to offspring is common. Notwithstanding this, only anecdotal reports of FH-1 in pregnancy exist and recommendations for treatment remain vague. MATERIALS AND METHODS AND RESULTS: We herein report on a novel FH-1 pedigree featuring very severe HT, fatal aortic dissection, and high rate of early stroke, where a young FH-1 woman was successfully managed throughout pregnancy with low-dose dexamethasone. CONCLUSIONS: Based on this experience and on available information on pathophysiology of FH-1 in pregnancy, the pros and cons of dexamethasone administration in the treatment of FH-1 in pregnancy are also discussed.

Management of hypertensive emergencies: a practical approach.

Background: Acute increases of high blood pressure values, usually described as 'hypertensive crises', 'hypertensive urgencies' or 'hypertensive emergencies', are common causes of patients' presentation to emergency departments. Owing to the lack of ad hoc randomized clinical trials, current recommendations/suggestions for treatment of these patients are not evidenced-based and, therefore, the management of acute increases of blood pressure values represent a clinical challenge. However, an improved understanding of the underlying pathophysiology has changed radically the approach to management of the patients presenting with these conditions in recent years. Accordingly, it has been proposed to abandon the terms 'hypertensive crises' and 'hypertensive urgencies', and restrict the focus to 'hypertensive emergencies'. Aims and Methods: Starting from these premises, we aimed at systematically review all available studies (years 2010-2020) to garner information on the current management of hypertensive emergencies, in order to develop a novel symptoms- and evidence-based streamlined algorithm for the assessment and treatment of these patients.Results and Conclusions: In this educational review we proposed the BARKH-based algorithm for a quick identification of hypertensive emergencies and associated acute organ damage, to allow the patients with hypertensive emergencies to receive immediate treatment in a proper setting.

Resolution of drug-resistant hypertension by adrenal vein sampling-guided adrenalectomy: a proof-of-concept study.

Drug-resistant hypertension (RH) is a very high-risk condition involving many hypertensive patients, in whom primary aldosteronism (PA) is commonly overlooked. Hence, we aimed at determining if (1) adrenal vein sampling (AVS) can identify PA in RH patients, who are challenging because of receiving multiple interfering drugs; (2) AVS-guided adrenalectomy can resolve high blood pressure (BP) resistance to treatment in these patients. Based on a pilot study we selected from 1016 consecutive patients referred to our Centre for 'difficult-to-treat' hypertension those with RH, for an observational prospective cohort study. We excluded those non-adherent to treatment (by therapeutic drug monitoring) and those with pseudo-RH (by 24-h BP monitoring), which left 110 patients who met the European Society of Cardiology/European Society of Hypertension (ESC/ESH) 2013 definition for RH. Of these patients, 77 were submitted to AVS, who showed unilateral PA in 27 (mean age 55 years; male/female 19/8). Therefore, these patients underwent AVS-guided laparoscopic unilateral adrenalectomy, which resolved RH in all: 20% were clinically cured in that they no longer needed any antihypertensive treatment; 96% were biochemically cured. Systolic and diastolic BP fell from 165/100 ± 26/14 mmHg at baseline, to 132/84 ± 14/9 mmHg at 6 months after surgery (P<10-4 for both) notwithstanding the fall of number and defined daily dose (DDD) of antihypertensive drugs required to achieve BP control (P<10-4 for both). A prominent regression of cardiac and renal damage was also observed. Thus, the present study shows the feasibility of identifying PA by AVS in RH patients, and of resolving high BP resistance to treatment in these patients by AVS-guided adrenalectomy.

Simultaneous bilateral adrenal vein sampling for primary aldosteronism: useful tips to make it simple and safe.

Adrenal vein sampling (AVS) is the key test for subtyping patients with primary aldosteronism (PA) before referring those with unilateral disease for laparoscopic unilateral adrenalectomy. However, it is still not systematically used, despite guidelines recommendations, because it is still considered as an invasive, risky, and challenging procedure. Simultaneous bilateral catheterization is believed to add technical difficulties inherent with attempting to catheterize both adrenal veins at the same time, but can be useful to minimize differences between the sides due to timing. We herein report on the protocol for routine clinical use. Tips for preparation of the patient as well as optimal catheterization of adrenal veins and sampling are provided to propose a protocol that is easy, safe, and reliable. Key Points • Adrenal vein sampling is the reference standard in the case of primary aldosteronism to detect the hyper-functioning side and allow subsequent treatment. • Simultaneous bilateral adrenal vein sampling avoids bias related to sampling timing. • Some technical suggestions concerning patient preparation and catheterization are proposed to make simultaneous adrenal vein sampling easier and safer.

Arterial Hypertension, Aldosterone, and Atrial Fibrillation.

PURPOSE: Atrial fibrillation is the most common sustained arrhythmia, with a prevalence of 1-2% in the general population and over 15% in people older than 80 years. Due to aging of the population it imposes an increasing burden on the healthcare system because of the need for life-long pharmacological treatment and the associated increased risk of heart failure and hospitalization. Hence, identification of the factors that predispose to atrial fibrillation it is of utmost relevance. RECENT FINDINGS: Several conditions exist that are characterized by inappropriately high levels of aldosterone, mostly primary aldosteronism and the severe or drug-resistant forms of arterial hypertension. In these forms, aldosterone can cause prominent target organ damage, mostly in the heart, vasculature, and kidney. This review examines the experimental data and clinical evidences that support a link between hyperaldosteronism and atrial fibrillation, and how this knowledge should lead to a change in our management of the hypertensive patients presenting with atrial fibrillation.

Design of a study to investigate the mechanisms of obstructive sleep apnoea by means of drug-induced sleep endoscopy.

Background Obstructive sleep apnoea (OSA) is an independent risk factor of hypertension and cardiovascular diseases. Recurrent episodes of upper airways collapse during sleep causing blood oxygen desaturation, hypercapnia, and micro-arousals, are known to activate the sympathetic nervous system (SNS). However, whether changes in the renin-angiotensin-aldosterone system and endothelial activation also occur remains contentious. Methods Based on routine use of drug-induced sleep endoscopy (DISE) for the work-up of OSA patients in our centre, we designed a prospective study to investigate the haemodynamic and humoral changes occurring during the apnoeic episodes reproduced in vivo in the course of DISE. Specifically, plasma aldosterone concentration and renin activity, C-terminal fragment of proendothelin-1, as a marker of endothelial damage, and free plasma catecholamines, will be measured at fixed times during DISE. The activity of catechol-O-methyltransferase (COMT), a key catecholamine-inactivating enzyme that has been scantly investigated thus far owing to the lack of commercially available kits, will be also determined by a newly developed high performance liquid chromatography method, which is herein described. Results and conclusions The aim of this study is to provide novel information on the haemodynamic, hormonal, and SNS changes, and also on COMT activity modification concomitantly occurring during apnoea, thus contributing substantively to the understanding of the pathophysiology of OSA.

A sleep apnoea questionnaire predicts organ damage in hypertensive patients.

BACKGROUND: Arterial hypertension is associated with obstructive sleep apnoea, poor quality and duration of sleep, which might contribute to hypertension-mediated organ damage. METHODS: We investigated the presence of insomnia, restless legs syndrome, and obstructive sleep apnoea using validated questionnaires (Insomnia Severity Index, Restless Legs Syndrome Rating Scale, and STOP-Bang), and their relationship with hypertension-mediated organ damage, in hypertensive patients. RESULTS: In 159 consecutive consenting hypertensive patients [age 47(11) years, median and (interquartile range), body mass index 25.5(5.9) kg/m2, office systolic and diastolic blood pressure 144(23)/92(12) mmHg], the STOP-Bang, but not the other scores, predicted cardiac remodelling: compared to patients with a STOP-Bang score < 3, those at high risk of obstructive sleep apnoea showed higher left ventricular mass index [49.8(11.9) vs. 43.3(11.9) g/m2.7, p < 0.0001], left atrium volume [25.7(2.5) vs. 25.0(2.8) ml/m2, p = 0.003], and aortic root diameter [33.6(3.0) vs. 33.0(3.7) mm, p < 0.0001]. They did not differ for microalbuminuria and estimated glomerular filtration rate. At multivariate analysis, after adjustment for office systolic blood pressure values, the STOP-Bang score remained a predictor of left ventricular mass index; while the Insomnia Severity Index and restless legs syndrome risk score had no predictive value. However, a significant interaction between STOP-Bang and Restless Legs Syndrome Rating Scale scores in determining left ventricular remodelling was found. CONCLUSIONS: In consecutive hypertensive stage I patients the STOP-Bang questionnaire allowed identification of a high-risk cohort featuring a more prominent cardiac damage. Hence, this inexpensive tool can be useful for risk stratification purposes in municipalities with limited access to health care resources.

Effect of unilateral adrenalectomy on the quality of life of patients with lateralized primary aldosteronism.

BACKGROUND: Primary aldosteronism (PA) is associated with an increased prevalence of anxiety and depression. Subnormal quality of life (QoL) scores in PA patients may be improved after surgical treatment. The aim of the study was to assess the impact of surgery on health-related QoL and depression status of patients suffering from PA, comparing the results with a control group of patients undergoing surgery for non-secreting adrenal tumors. METHODS: Data on QoL and depression status were prospectively collected, from January 2014 to January 2017, before, early after surgery (at 1 month) and at late follow up (at least 6 months) in patients with unilateral PA and in a control group with non-secreting adrenal tumors submitted to unilateral laparoscopic adrenalectomy. QoL was assessed using the Short Form 36 (SF-36) Health Survey for Physical (PCS) and Mental Component (MCS); the depression status by a 20-item depression scale (DS) questionnaire. RESULTS: Twenty-six PA patients and 15 controls were recruited. Biochemical cure of the disease was achieved following surgery in all PA patients; hypertension was cured in 31% of cases and improved in the remaining 69% of cases. No morbidity occurred in both groups. There were no significant differences between PA patients and controls concerning demographics, preoperative PCS, MCS and DS values. In patients with PA, MCS values improved at early (42.72 ± 13.68 vs 51.56 ± 9.03, p = 0.0005) and late follow up (42.72 ± 13.68 vs 51.81 ± 7.04, p < 0.0001); also DS values improved at early (15.92 ± 11.98 vs 8.3 ± 8.8, p = 0.0002) and late follow up (15.92 ± 11.98 vs 4.57 ± 6.11, p < 0.0001). In PA patients PCS values significantly improved at late follow up (51.02 ± 8.04 vs 55.85 ± 5.1, p = 0.013). Also in controls an improvement of MCS and DS scores was found at early and late follow up compared to preoperative values, while no significant differences in PCS were found. CONCLUSIONS: Both PA and non-secreting adrenal tumors affect health-related QoL, worsening MCS and DS scores. Adrenalectomy is effective in curing PA, and improving MCS and DS scores at early and late follow-up, in patients with PA and non-secreting adrenal tumors. In PA patient surgery also significantly improves PCS at late follow up.

The Key Role of Epithelial to Mesenchymal Transition (EMT) in Hypertensive Kidney Disease.

Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT), originally described as a key process for organ development and metastasis budding in cancer, plays a key role in the development of renal fibrosis in several diseases, including hypertensive nephroangiosclerosis. We herein reviewed the concept of EMT and its role in renal diseases, with particular focus on hypertensive kidney disease, the second leading cause of end-stage renal disease after diabetes mellitus. After discussing the pathophysiology of hypertensive nephropathy, the 'classic' view of hypertensive nephrosclerosis entailing hyalinization, and sclerosis of interlobular and afferent arterioles, we examined the changes occurring in the glomerulus and tubulo-interstitium and the studies that investigated the role of EMT and its molecular mechanisms in hypertensive kidney disease. Finally, we examined the reasons why some studies failed to provide solid evidence for renal EMT in hypertension.

The angiotensin type 2 receptor in the human adrenocortical zona glomerulosa and in aldosterone-producing adenoma: low expression and no functional role.

The angiotensin II (Ang II) type 2 receptor (AT2R) and the angiotensin-(1-7) (Ang-(1-7)) receptor (MasR) play a cardiovascular protective role by counter-regulating Ang II type 1 receptor (AT1R)-mediated effects, but whether this involves blunting of adrenocortical hormone secretion is unknown. We investigated the presence of AT1R, AT2R, and MasR in aldosterone-producing adenoma (APA), a condition featuring hyperaldosteronism, and in APA-adjacent tissue. The effect of Compound 21 (C21), an AT2R agonist, on CYP11B1 (cortisol synthase) and CYP11B2 (aldosterone synthase) gene expression in NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, was also assessed using the AT1R antagonist irbesartan to ascertain the specificity of C21 effect. We found that the AT1R, AT2R, and MasR were expressed in APA and APA-adjacent tissue, albeit heterogeneously. The gene expression of AT1R and AT2R was lower, and that of the MasR higher in APAs than in APA-adjacent tissue. In steroid-producing NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, C21 was ineffective at nanomolar concentrations, but increased CYP11B1 and CYP11B2 gene expression at micromolar concentrations through AT1R, as this effect was blunted by irbesartan. The scant expression of the AT2R, along with the lack of any effect of C21 at low concentrations on CYP11B2, do not support the contention that the protective arm of renin-angiotensin system (RAS) blunts aldosterone synthase in the normal adrenal cortex and primary aldosteronism.

The acute effect of continuous positive airway pressure titration on blood pressure in awake overweight/obese patients with obstructive sleep apnoea.

OBJECTIVES: Continuous positive airway pressure (CPAP) improves upper airway obstruction in patients with obstructive sleep apnoea (OSA), who often are overweight-obese. Although it is thought that CPAP improves long-term blood pressure control (BP), the impact of acute and short-term CPAP use on the cardiovascular system in obese patients has not been described in detail. METHODS: Obese patients (body mass index, BMI > 25 kg/m2) with OSA were studied awake, supine during incremental CPAP titration (4-20 cmH2O, +2 cmH2O/3 mins). BP was measured continuously with a beat-to-beat BP monitor (Ohmeda 2300, Finapres Medical Systems, Amsterdam/NL), BP variability (BPV) was calculated as the standard deviation of BP at each CPAP level, the 95% confidence interval (95%CI) was calculated and changes in BP and BPV were reported. RESULTS: 15 patients (12 male, 48 ± 10) years, BMI 38.9 ± 5.8 kg/m2) were studied; the baseline BP was 131.0 ± 10.2/85.1 ± 9.1 mmHg. BP and BPV increased linearly with CPAP titration (systolic BP r = 0.960, p < .001; diastolic BP r = 0.961, p < .001; systolic BPV r = 0.662, p = .026; diastolic BPV r = 0.886, p < .001). The systolic BP increased by +17% (+23.15 (7.9, 38.4) mmHg; p = .011) and the diastolic BP by +23% (+18.27 (2.33, 34.21) mmHg; p = .009), when titrating CPAP to 20 cmH2O. Systolic BPV increased by +96% (+5.10 (0.67, 9.53) mmHg; p < .001) and was maximal at 14 cmH2O, and diastolic BPV by +97% (+3.02 (0.26, 5.78) mmHg; p < .001) at 16 cmH2O. CONCLUSION: Short-term incremental CPAP leads to significant increases in BP and BPV in obese patients with OSA while awake. Careful titration of pressures is required to minimise the risk of nocturnal awakenings while improving BP control.

Macrolides for KCNJ5-mutated aldosterone-producing adenoma (MAPA): design of a study for personalized diagnosis of primary aldosteronism.

PURPOSE: Aldosterone-producing adenoma (APA) is the main curable cause of endocrine hypertension cause of primary aldosteronism (PA) and it is in up to 66% of all cases investigated with adrenal vein sampling (AVS). Mutations in the KCNJ5 potassium channel involve up to 70% of APA and cause the most florid PA phenotypes. The recent finding that macrolide antibiotics specifically inhibit in vitro the altered function of mutated KCNJ5 channels has opened new horizons for the diagnosis and treatment of APA with KCNJ5 mutations in that it can allow identification and target treatment of PA patients harbouring a mutated APA. Thus, we aimed at investigating if clarithromycin and roxithromycin, two macrolides that potently blunt mutated Kir3.4 channel function in vitro, affect plasma aldosterone concentration in adrenal vein blood during AVS and in peripheral blood, respectively, in PA patients with a mutated APA. METHODS AND DESIGN: We designed two proof of concept studies. In study A: consecutive patients with an unambiguous biochemical evidence of PA will be exposed to a single dose of 250 mg clarithromycin during AVS, to assess its effect on the relative aldosterone secretion index in adrenal vein blood from the gland with and without APA. In study B: consecutive hypertensive patients submitted to the work-up for hypertension will receive a single oral dose of 150 mg roxithromycin. The experimental endpoints will be the change induced by roxithromycin of plasma aldosterone concentration and other steroids, direct active renin concentration, serum K+, systolic and diastolic blood pressure. DISCUSSION: We expect to prove that: (i) clarithromycin allows identification of mutated APA before adrenalectomy and sequencing of tumour DNA; (ii) the acute changes of plasma aldosterone concentration, direct active renin concentration, and blood pressure in peripheral venous blood after roxithromycin can be a proxy for the presence of an APA with somatic mutations.

Randomised sham-controlled trial of transcutaneous electrical stimulation in obstructive sleep apnoea.

INTRODUCTION: Obstructive sleep apnoea (OSA) is characterised by a loss of neuromuscular tone of the upper airway dilator muscles while asleep. This study investigated the effectiveness of transcutaneous electrical stimulation in patients with OSA. PATIENTS AND METHODS: This was a randomised, sham-controlled crossover trial using transcutaneous electrical stimulation of the upper airway dilator muscles in patients with confirmed OSA. Patients were randomly assigned to one night of sham stimulation and one night of active treatment. The primary outcome was the 4% oxygen desaturation index, responders were defined as patients with a reduction >25% in the oxygen desaturation index when compared with sham stimulation and/or with an index <5/hour in the active treatment night. RESULTS: In 36 patients (age mean 50.8 (SD 11.2) years, male/female 30/6, body mass index median 29.6 (IQR 26.9-34.9) kg/m(2), Epworth Sleepiness Scale 10.5 (4.6) points, oxygen desaturation index median 25.7 (16.0-49.1)/hour, apnoea-hypopnoea index median 28.1 (19.0-57.0)/hour) the primary outcome measure improved when comparing sham stimulation (median 26.9 (17.5-39.5)/hour) with active treatment (median 19.5 (11.6-40.0)/hour; p=0.026), a modest reduction of the mean by 4.1 (95% CI -0.6 to 8.9)/hour. Secondary outcome parameters of patients' perception indicated that stimulation was well tolerated. Responders (47.2%) were predominantly from the mild-to-moderate OSA category. In this subgroup, the oxygen desaturation index was reduced by 10.0 (95% CI 3.9 to 16.0)/hour (p<0.001) and the apnoea-hypopnoea index was reduced by 9.1 (95% CI 2.0 to 16.2)/hour (p=0.004). CONCLUSION: Transcutaneous electrical stimulation of the pharyngeal dilators during a single night in patients with OSA improves upper airway obstruction and is well tolerated. TRIAL REGISTRATION NUMBER: NCT01661712.

Galectin-3 predicts long-term cardiovascular death in high-risk patients with coronary artery disease.

OBJECTIVE: Galectin-3 (Gal-3) can affect atherogenesis by multiple mechanisms, but it remains scarcely known whether plasma Gal-3 levels predict cardiovascular events in patients with coronary artery disease. Therefore, we investigated if Gal-3 predicts cardiovascular death in patients with coronary artery disease of the Genetic and ENvironmental factors In Coronary Artery disease study. APPROACH AND RESULTS: In a prospective cohort study, we measured the plasma levels of Gal-3 in 1013 randomly selected patients who underwent coronary angiography and long-term follow-up to assess incident cardiovascular events. The primary end points were (1) cardiovascular death and (2) a composite of cardiovascular death, acute coronary syndrome, and stroke. Secondary end points entailed (1) acute myocardial infarction, (2) stroke, and (3) a composite fatal ischemic event including fatal myocardial infarction and stroke. The effect of Gal-3 on prognosis was assessed using Kaplan-Meier analysis and multivariate Cox's regression. During long-term follow-up (median, 7.2 years), 115 cardiovascular deaths occurred (15.2%), more commonly in the high Gal-3 tertile (25.2%) than in the intermediate and the low tertiles (13.6% versus 7.5%, respectively; P<0.001). The adverse prognostic effect of high Gal-3 was confirmed in subgroup analysis of the patients with angiographically documented coronary artery disease and also of those with a normal left ventricular ejection fraction. At multivariate analysis, Gal-3 was a predictor of cardiovascular mortality (hazard ratio, 1.79; 95% confidence interval, 1.10-2.93; P=0.020) along with age, left ventricular ejection fraction, and coronary atherosclerotic burden. CONCLUSIONS: In high cardiovascular risk patients referred for coronary angiography Gal-3 is a strong independent predictor of cardiovascular death.

Prospective validation of an automated chemiluminescence-based assay of renin and aldosterone for the work-up of arterial hypertension.

BACKGROUND: The availability of simple and accurate assays of plasma active renin (DRC) and aldosterone concentration (PAC) can improve the detection of secondary forms of arterial hypertension. Thus, we investigated the performance of an automated chemiluminescent assay for DRC and PAC in referred hypertensive patients. METHODS: We prospectively recruited 260 consecutive hypertensive patients referred to an ESH Center for Hypertension. After exclusion of six protocol violations, 254 patients were analyzed: 67.3% had primary hypertension, 17.3% an aldosterone producing adenoma (APA), 11.4% idiopathic hyperaldosteronism (IHA), 2.4% renovascular hypertension (RVH), 0.8% familial hyperaldosteronism type 1 (FH-1), 0.4% apparent mineralocorticoid excess (AME), 0.4% a renin-producing tumor, and 3.9% were adrenalectomized APA patients. Bland-Altman plots and Deming regression were used to analyze results. The diagnostic accuracy (area under the curve, AUC of the ROC) of the DRC-based aldosterone-renin ratio (ARRCL) was compared with that of the PRA-based ARR (ARRRIA) using as reference the conclusive diagnosis of APA. RESULTS: At Bland-Altman plot, the DRC and PAC assay showed no bias as compared to the PRA and PAC assay. A tight relation was found between the DRC and the PRA values (concordance correlation coefficient=0.92, p<0.0001) and the PAC values measured with radioimmunoassay and chemiluminescence (concordance correlation coefficient=0.93, p<0.001). For APA identification the AUC of the ARRCL was higher than that of the ARRRIA [0.974 (95% CI 0.940-0.991) vs. 0.894 (95% CI 0.841-0.933), p=0.02]. CONCLUSIONS: This rapid automated chemiluminescent DRC/PAC assay performed better than validated PRA/PAC radioimmunoassays for the identification of APA in referred hypertensive patients.

Treatment of atherosclerotic renovascular hypertension: review of observational studies and a meta-analysis of randomized clinical trials.

Atherosclerotic renal artery stenosis can cause ischaemic nephropathy and arterial hypertension. We herein review the observational and randomized clinical trials (RCTs) comparing medical and endovascular treatment for control of hypertension and renal function preservation. Using the Population Intervention Comparison Outcome (PICO) strategy, we identified the relevant studies and performed a novel meta-analysis of all RCTs to determine the efficacy and safety of endovascular treatment when compared with medical therapy. The following outcomes were examined: baseline follow-up difference in mean systolic and diastolic blood pressure (BP), serum creatinine, number of drugs at follow-up, incident events (heart failure, stroke, and worsening renal function), mortality, cumulative relative risk of heart failure, stroke, and worsening renal function. Seven studies comprising a total of 2155 patients (1741 available at follow-up) were considered, including the recently reported CORAL Study. Compared with baseline, diastolic BP fell more at follow-up in patients in the endovascular than in the medical treatment arm (standard difference in means -0.21, 95% confidence interval (CI): -0.342 to -0.078, P = 0.002) despite a greater reduction in the mean number of antihypertensive drugs (standard difference in means -0.201, 95% CI: -0.302 to -0.1, P < 0.001). At variance, follow-up changes (from baseline) of systolic BP, serum creatinine, and incident cardiovascular event rates did not differ between treatment arms. Thus, patients with atherosclerotic renal artery stenosis receiving endovascular treatment required less anti-antihypertensive drugs at follow-up than those medically treated. Notwithstanding this, they evidenced a better control of diastolic BP.