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Background: Endothelin-1 (ET-1) and Nitric Oxide (NO) are crucial mediators for establishing pulmonary artery hypertension (PAH). We tested the hypothesis that their imbalance might also occur in COPD patients with PAH. Methods: The aims of the study were to measure exhaled breath condensate (EBC) and circulating levels of ET-1, as well as exhaled NO (FENO) levels by, respectively, a specific enzyme immunoassay kit, and by chemiluminescence analysis in 3 groups of subjects: COPD with PAH (12), COPD only (36), and healthy individuals (15). In order to evaluate pulmonary-artery systolic pressure (PaPs), all COPD patients underwent Echo-Doppler assessment. Results: Significantly increased exhaled and circulating levels of ET-1 were found in COPD with PAH compared to both COPD (p < 0.0001) only, and healthy controls (p < 0.0001). In COPD with PAH, linear regression analysis showed good correlation between ET-1 in EBC and PaPs (r = 0.621; p = 0.031), and between arterial levels of ET-1 and PaPs (r = 0.648; p = 0.022), while arterial levels of ET-1 inversely correlated with FEV1%, (r = -0.59, p = 0.043), and PaPs negatively correlated to PaO2 (r = -0.618; p = 0.032). Significantly reduced levels of FENO were found in COPD associated with PAH, compared to COPD only (22.92 ± 11.38 vs.35.07 ± 17.53 ppb; p = 0.03). Thus, we observed an imbalanced output in the breath between ET-1 and NO, as expression of pulmonary endothelium and epithelium impairment, in COPD with PAH compared to COPD only. Whether this imbalance is an early cause or result of PAH due to COPD is still unknown and deserves further investigations. [ABSTRACT FROM AUTHOR]

Background: Primary aldosteronism (PA), the most common curable salt-dependent form of arterial hypertension, features renal K + loss and enhanced Na + reabsorption. We investigated whether the electrolyte, water, and TonEBP (tonicity-responsive enhancer binding protein)/NFAT5 (nuclear factor of activated T cells 5) content is altered in the skin of patients with PA and corrected by surgical cure., Methods: We obtained skin biopsies from 80 subjects: 49 consecutive patients with PA, optimally treated with a mineralocorticoid receptor antagonist; 6 essential hypertensives; and 25 normotensive controls. We measured Na + , K + , water content with atomic absorption spectroscopy after ashing, and NFAT5 mRNA with digital droplet polymerase chain reaction. The patients with PA were retested after adrenalectomy., Results: We discovered a higher dry weight of the skin biopsy specimen at surgery than at follow-up ( P <0.001) and a direct correlation with electrolyte and water content (all P <0.01), indicating the need for dry weight adjustment of electrolyte and water data. Surgical cure of PA markedly increased skin dry weight-adjusted K + (from 1.14±0.1 to 2.81±0.27 µg/mg; P <0.001) and water content (from 2.92±1.4 to 3.85±0.23 mg/mg; P <0.001), but left dry weight-adjusted skin Na + content unaffected. In patients with PA, NFAT5 mRNA was higher ( P =0.031) than in normotensive controls and decreased after surgery ( P =0.035)., Conclusions: Despite mineralocorticoid receptor antagonist treatment ensuring normokalemia, the patients with PA had a skin cell K + depletion that was corrected by adrenalectomy. The activated NFAT5/TonEBP pathway during mineralocorticoid receptor antagonist administration suggests enhanced skin Na + lymphatic drainage and can explain the lack of overt skin Na + accumulation in patients with PA. Its deactivation after surgical cure can account for the lack of skin Na + decrease postadrenalectomy., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06090617.

Context: The search for somatic mutations in adrenals resected from patients with primary aldosteronism (PA) is performed by Sanger sequencing, often implemented with immunohistochemistry (IHC)-guidance focused on aldosterone-producing (CYP11B2-positive) areas., Objective: To investigate the impact of double IHC for CYP11B1 and CYP11B2 on Sanger and next-generation sequencing (NGS)., Methods: We investigated 127 consecutive adrenal aldosterone-producing adenomas from consenting surgically cured PA patients using double IHC for CYP11B1 and CYP11B2, by Sanger sequencing and NGS., Results: Double IHC for CYP11B2 and CYP11B1 revealed 3 distinct patterns: CYP11B2-positive adenoma (pattern 1), mixed CYP11B1/CYP11B2-positive adenoma (pattern 2), and adrenals with multiple small CYP11B2-positive nodules (pattern 3). Sanger sequencing allowed detection of KCNJ5 mutations in 44% of the adrenals; NGS revealed such mutations in 10% of those negative at Sanger and additional mutations in 61% of the cases. Importantly the rate of KCNJ5 mutations differed across patterns: 17.8% in pattern 1, 71.4% in pattern 2, and 10.7% in pattern 3 (χ2 = 22.492, P < .001)., Conclusion: NGS allowed detection of mutations in many adrenals that tested negative at Sanger sequencing. Moreover, the different distribution of KCNJ5 mutations across IHC patterns indicates that IHC-guided sequencing protocols selecting CYP11B2-positive areas could furnish results that might not be representative of the entire mutational status of the excised adrenal, which is important at a time when KCNJ5 mutations are suggested to drive management of patients with aldosterone-producing adenomas., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Despite carrying an excess risk of cardiovascular events, primary aldosteronism (PA) is a commonly overlooked secondary form of arterial hypertension. An increased awareness of its high prevalence and broader screening strategies are urgently needed to improve its detection rate and allow early diagnosis and targeted treatment. For patients with unilateral PA, these measures can correct hyperaldosteronism and ensure cure of hypertension, even when resistant to drug treatment, thus preventing adverse cardiovascular events. Among these, atrial fibrillation is the most common, but left ventricular hypertrophy, stroke, chronic kidney disease, and myocardial infarction also occur more often than in patients with hypertension and no PA. Young patients, who have higher chances of being cured long term, and high-risk patients, such as those with stage III or resistant hypertension, are those who will benefit most from an early diagnosis of PA. Therefore, the implementation of strategies to detect PA by a simplified diagnostic algorithm is necessary. In the patients who seek for surgical cure, adrenal vein sampling is key for the identification of unilateral PA and the achievement of optimal outcomes. Unfortunately, being technically demanding and poorly available, adrenal vein sampling represents the bottleneck in the workup of PA. Considering the novel knowledge generated in the past 5 years in many studies, particularly in the AVIS-2 study (Adrenal Vein Sampling International Study-2), based on 4 decades of experience at our center and on the last guidelines, we herein provide an update on the management of PA with recommendations for drug treatment and strategies to avoid adrenal vein sampling wherever it is poorly, or not, available., Competing Interests: None.

The exclusion of causes of hypertension is not systematically exploited in clinical practice. Therefore, essential hypertension is consistently presented as the most prevalent 'cause'. The paradox of a condition with unknown causes being described as a common cause of hypertension translates into a diagnosis of essential hypertension in most patients, which precludes the detection of a curable cause of hypertension. The aim of this review is to investigate how the notion of essential hypertension has developed and whether scientific evidence still support the notion of its high prevalence by examining the most recent studies. These studies provided solid scientific evidence that, when systematically sought for, secondary hypertension is quite common and that secondary hypertension is highly prevalent. The increased awareness should lead to a systematic search for, with the goal of curing or achieving a better control of high blood pressure, and ultimately improving patients' quality of life., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Current guidelines and consensus documents recommend withdrawal of mineralocorticoid receptor antagonists (MRAs) before primary aldosteronism (PA) subtyping by adrenal vein sampling (AVS), but this practice can cause severe hypokalemia and uncontrolled high blood pressure. Our aim was to investigate if unilateral PA can be identified by AVS during MRA treatment., Methods: We compared the rate of unilateral PA identification between patients with and without MRA treatment in large data sets of patients submitted to AVS while off renin-angiotensin system blockers and β-blockers. In sensitivity analyses, the between-group differences of lateralization index values after propensity score matching and the rate of unilateral PA identification in subgroups with undetectable (≤2 mUI/L), suppressed (<8.2 mUI/L), and unsuppressed (≥8.2 mUI/L) direct renin concentration levels were also evaluated., Results: Plasma aldosterone concentration, direct renin concentration, and blood pressure values were similar in non-MRA-treated (n=779) and MRA-treated (n=61) patients with PA, but the latter required more antihypertensive agents ( P =0.001) and showed a higher rate of adrenal nodules (82% versus 67%; P =0.022) and adrenalectomy (72% versus 54%; P =0.01). However, they exhibited no significant differences in commonly used AVS indices and the area under the receiving operating characteristic curve of lateralization index, both under unstimulated conditions and postcosyntropin. Several sensitivity analyses confirmed these results in propensity score matching adjusted models and in patients with undetectable, or suppressed or unsuppressed renin levels., Conclusions: At doses that controlled blood pressure and potassium levels, MRAs did not preclude the identification of unilateral PA at AVS., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01234220., Competing Interests: Disclosures None.

Competing Interests: Disclosures None.

Background: Congestion predicts a poor prognosis, but its assessment is challenging in clinical practice and requires a multiparametric approach. We investigated if the coronary sinus (CS) diameter can predict mortality in a human model of rapid fluid unloading., Methods: We measured by echocardiography the CS, and the inferior vena cava (IVC) for comparison, in 60 patients with end-stage chronic kidney disease (ESKD) immediately before and after hemodialysis (HD; age 76 [57-81] years, 40% female, left ventricular ejection fraction 57 [53-56]%). Patients were prospectively followed up for all-cause mortality., Results: HD-induced decongestion decreased the maximum diameters of both CS and IVC (p ≤ 0.001 for all). The maximum diameter of the CS (CS max ) was as accurate as the IVC maximum diameter and collapsibility for the identification of congestion, defined as pre-hemodialysis status (AUROC CS max  = 0.902 vs IVC = 0.895, p = n.s.). A CS max diameter after hemodialysis > 9 mm predicted all-cause mortality at 12 months (Log-rank Chi square = 11.49, p < 0.001)., Conclusions: A persistently dilated CS after hemodialysis is a marker of residual congestion and predicts death at one year in high-risk ESKD patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Even though SARS-CoV-2 was declared by WHO as constituting no longer a public health emergency, the development of effective treatments against SARS-CoV-2 infection remains a critical issue to prevent complications, particularly in fragile patients. The protease inhibitor nafamostat, currently used in Japan and Korea for pancreatitis, owing to its anticoagulant properties for disseminated intravascular coagulation (DIC), is appealing for the treatment of COVID-19 infection, because it potently inhibits the transmembrane protease serine 2 (TMPRSS2) that, after virus binding to ACE-2, allows virus entry into the cells and replication. Moreover, it could prevent the DIC and pulmonary embolism frequently associated with COVID-19 infection. The goal of the RAndomized Clinical Trial Of NAfamostat (RACONA) study, designed as a prospective randomized, double-blind placebo-controlled clinical trial, was to investigate the efficacy and safety of nafamostat mesylate (0.10 mg/kg/h iv for 7 days), on top of the optimal treatment, in COVID-19 hospitalized patients. We could screen 131 patients, but due to the predefined strict inclusion and exclusion criteria, only 15 could be randomized to group 1 (n = 7) or group 2 (n = 8). The results of an ad interim safety analysis showed similar overall trends for variables evaluating renal function, coagulation, and inflammation. No adverse events, including hyperkalemia, were found to be associated with nafamostat. Thus, the RACONA study showed a good safety profile of nafamostat, suggesting that it could be usefully used in COVID-19 hospitalized patients.

ABSTRACTRecurring and rapidly developing (flash) pulmonary edema is the hallmark of Pickering syndrome, affecting patients with hypertension and atherosclerotic renal artery stenosis (either bilateral or unilateral) in a solitary functioning kidney, and impaired renal function. We herein report on a series of consecutive patients with recurrent hospital admissions for pulmonary edema, impaired renal function (chronic kidney disease class 4-5), and atherosclerotic bilateral renal artery stenosis, in whom Pickering syndrome had been long neglected. We also describe a streamlined diagnostic strategy entailing little or no need for contrast medium, thus carrying no risks of further worsening of renal function. This allowed us to make the correct diagnosis and opened the way to revascularization by percutaneous transluminal renal angioplasty with stent, which provided swift recovery of kidney function with resolution of pulmonary congestion and long-term pulmonary edema- and dialysis-free survival in all cases. In summary, these findings support the following key messages: (1) considering the diagnosis of Pickering syndrome, followed by searching atherosclerotic renal artery stenosis, is an essential step toward a life-saving revascularization that avoids dialysis and an otherwise poor outcome; and (2) a simplified strategy entailing little or no need for contrast medium, carrying no associated risks of deteriorating renal function, permits the diagnosis of Pickering syndrome.

Background: Adrenal venous sampling is recommended for the identification of unilateral surgically curable primary aldosteronism but is often clinically useless, owing to failed bilateral adrenal vein cannulation., Objectives: To investigate if only unilaterally selective adrenal vein sampling studies can allow the identification of the responsible adrenal., Methods: Among 1625 patients consecutively submitted to adrenal vein sampling in tertiary referral centers, we selected those with selective adrenal vein sampling results in at least one side; we used surgically cured unilateral primary aldosteronism as gold reference. The accuracy of different values of the relative aldosterone secretion index (RASI), which estimates the amount of aldosterone produced in each adrenal gland corrected for catheterization selectivity, was examined., Results: We found prominent differences in RASI values distribution between patients with and without unilateral primary aldosteronism. The diagnostic accuracy of RASI values estimated by the area under receiver operating characteristic curves was 0.714 and 0.855, respectively, in the responsible and the contralateral side; RASI values >2.55 and ≤0.96 on the former and the latter side furnished the highest accuracy for detection of surgically cured unilateral primary aldosteronism. Moreover, in the patients without unilateral primary aldosteronism, only 20% and 16% had RASI values ≤0.96 and >2.55., Conclusions: With the strength of a large real-life data set and use of the gold reference entailing an unambiguous diagnosis of unilateral primary aldosteronism, these results indicate the feasibility of identifying unilateral primary aldosteronism using unilaterally selective adrenal vein sampling results., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01234220., Competing Interests: Disclosures None.

Patients with an aldosterone-producing adenoma (APA) carry a higher risk of cardiovascular disease and commonly have high levels of autoantibodies (AT1AA) that may activate the angiotensin II type 1 receptor (AT1R). AT1R activation is linked to an increase of the glucose metabolite methylglyoxal (MGO), a potential precursor of advanced glycation endproducts (AGEs) and driver of vascular inflammation. We investigated whether serum AT1AA levels are associated with serum MGO and AGE levels in APA patients. In a case series of 26 patients with APA we measured levels of dicarbonyls MGO, glyoxal (GO) and 3-deoxyglucosone (3-DG), and dicarbonyl-derived AGEs 5-hydro-5-methylimidazolone (MG-H1), N ε -(carboxyethyl)lysine (CEL) and N ε -(carboxymethyl)lysine (CML) with UPLC-MS/MS. We also measured AT1AA by ELISA. These measurements were repeated 1-month after adrenalectomy in a subset of 14 patients. Panels of inflammation and endothelial function were also measured by immunoassays. Although baseline higher AT1AA levels tended to be correlated with higher baseline serum MGO, GO and 3-DG levels (r = 0.18, p = 0.38; r = 0.20, p = 0.33; r = 0.23, p = 0.26; respectively), these correlations were not statistically significant. We observed no obvious correlations between higher AT1AA levels and protein-bound and free MG-H1, CEL and CML levels, and markers of inflammation and endothelial function. No decrease was observed in any of the dicarbonyls, protein-bound AGE levels and markers of inflammation and endothelial function after adrenalectomy. In patients with APA the serum levels of AT1AA were not significantly correlated with serum dicarbonyls, protein-bound and free AGE levels. Increased signalling of the AT1AA receptor may therefore be unlikely to overtly increase systemic dicarbonyl levels., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Drug-resistant arterial hypertension (RH) is a major risk factor for cardiovascular disease, often due to overlooked underlying causes. Identification of such causes poses significant clinical challenges. In this setting, primary aldosteronism (PA) is a frequent cause of RH and its prevalence in RH patients is likely higher than 20%.The pathophysiological link between PA and the development and maintenance of RH involves target organ damage and the cellular and extracellular effects of aldosterone excess that promote pro-inflammatory and pro-fibrotic changes in the kidney and vasculature.The feasibility of adrenal vein sampling in PA patients with RH, and the clinical benefit achieved by adrenalectomy, further emphasize the need to implement systematic screening for this common form of secondary hypertension in the management of a high-risk population as RH patients.: We herein review the current knowledge of the factors that contribute to the RH phenotype with a focus on PA and discuss the issues regarding the screening for PA in this setting and the therapeutic approaches (surgical and medical) aimed at resolving RH caused by PA., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

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.

Endothelial cell function is mediated by different mechanisms in different vascular beds. Moreover, in humans, endothelial cell dysfunction triggers and accelerates the progression of cardiovascular and chronic kidney diseases. Progression of such diseases can be in part mitigated by the control of cardiovascular risk factors and drugs targeting different systems, including endothelin receptor antagonists (ERAs), renin-angiotensin aldosterone antagonists and agents affecting glucose metabolism, all of which were shown to improve endothelial cell function. In recent years, the microRNAs, which are endogenous regulators of gene expression, have been identified as transmitters of information from endothelial cells to vascular smooth muscle cells, suggesting that they can entail tools to assess the endothelial cell dysfunction in arterial hypertension and target for pharmacologic intervention. This article critically reviews current challenges and limitations of available techniques for the invasive and noninvasive assessment of endothelial cell function, and also discusses therapeutic aspects as well as directions for future research in the areas of endothelial cell biology and pathophysiology in humans., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Context: Determining the diagnostic accuracy of "exclusion" tests for primary aldosteronism (PA) compared to the aldosterone to renin ratio (ARR) is fundamental to avoid invasive subtyping in false-positive patients at screening., Objective: To assess the accuracy of exclusion tests for PA using the diagnosis of unilateral PA as reference., Methods: PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched for studies published from January 1, 1970, to December 31, 2021, meeting tight quality criteria. Data were extracted following the PRISMA methodology. We performed a two-stage meta-analysis that entailed an exploratory and a validation phase based on a "golden" or "gold" diagnostic standard, respectively. Pooled specificity, negative likelihood ratio, diagnostic odds ratio, and summary area under the ROC curve (sAUROC) were calculated to analyze the accuracy of exclusion tests., Results: A meta-analysis of 31 datasets comprising a total of 4242 patients fulfilling the predefined inclusion criteria found that pooled accuracy estimates (sAUROC) did not differ between the ARR (0.95; 95% CI, 0.92-0.98), the captopril challenge test (CCT) (0.92; 95% CI, 0.88-0.97), and the saline infusion test (SIT) (0.96; 95% CI, 0.94-0.99). Solid information could not be obtained for the fludrocortisone suppression test and the furosemide upright test, which were assessed in only 1 study each., Conclusion: The apparently high diagnostic accuracy of the CCT and the SIT was due to the selection of patients with an elevated ARR and thus a high pretest probability of unilateral PA; however, neither test furnished a diagnostic gain over the ARR. Therefore, the systematic use of these exclusion tests in clinical practice is not justified by available evidence., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

An altered secretion of adrenocortical and adrenomedullary hormones plays a role in the clinical syndromes of primary aldosteronism (PA), Cushing, and pheochromocytoma. Moreover, an altered production of adrenocortical hormones and/or an abnormal release of factors by the adrenal medulla are involved in several other diseases, including high blood pressure, congestive heart failure, liver cirrhosis, nephrotic syndrome, primary reninism, renovascular hypertension, Addison disease, Bartter, Gitelman, and virilization syndromes. Understanding the regulation of adrenal function and the interactions between adrenal cortex and medulla is, therefore, the prerequisite for mechanistic understanding of these disorders. Accumulating evidence indicates that the modulation of adrenal hormone biosynthesis is a process far more complex than originally thought, as it involves several factors, each cooperating with the other. Moreover, the tight vascular and neural interconnections between the adrenal cortex and medulla underlie physiologically relevant autocrine/paracrine interactions involving several peptides. Besides playing a pathophysiological role in common adrenal diseases, these complex mechanisms could intervene also in rare diseases, such as pheochromocytoma concomitant with adrenal Cushing or with PA, and PA co-occurring with Cushing, through mechanisms that remain to be fully understood at the molecular levels. Heterodimerization of G protein-coupled receptors (GPCRs) induced by peptide signaling is a further emerging new modulatory mechanism capable of finely tuning adrenal hormones synthesis and release. In this review we will examine current knowledge on the role of peptides that act via GPCRs in the regulation of adrenal hormone secretion with a particular focus on autocrine-paracrine signals., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Primary aldosteronism (PA) in pregnancy (PAP) can be a serious condition and is challenging to diagnose. This study was conceived to help in the diagnosis of PAP and provide suggestions on management of PAP based on evidence retrieved using a Population, Intervention, Comparison, and Outcome search strategy. Based on the changes of aldosterone and renin occurring in normal pregnancies, we developed a nomogram that will allow to identify PAP cases. Moreover, we found that published PAP cases fell into 4 main groups differing for management and outcomes: (1) unilateral medically treated, (2) unilateral surgically treated, (3) bilateral medically treated and (4) familial forms. Results showed that complications involved 62.2% of pregnant women with nonfamilial PA and 18.5% of those with familial hyperaldosteronism type I. Adrenalectomy during pregnancy in women with PAP did not improve maternal and fetal outcomes, over medical treatment alone. Moreover, cure of maternal hypertension and mother and baby outcome were better when unilateral PA was discovered and surgically treated before or after pregnancy. Therefore, fertile women with arterial hypertension should be screened for PA before pregnancy and, if necessary, subtyped to identify unilateral forms of PA. This will allow to furnish adequate counseling, a chance for surgical cure and, therefore, for a pregnancy not complicated by aldosterone excess.

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.

Vasoactive molecules, such as vascular endothelial growth factor (VEGF) and endothelins, share cytokine-like activities and regulate endothelial cell (EC) growth, migration, and inflammation. Some endothelial mediators and their receptors are targets for currently approved angiogenesis inhibitors, drugs that are either monoclonal antibodies raised towards VEGF, or inhibitors of vascular receptor protein kinases and signalling pathways. Pharmacological interference with the protective functions of ECs results in a similar spectrum of adverse effects. Clinically, the most common side effects of VEGF signalling pathway inhibition include an increase in arterial pressure, left ventricular dysfunction facilitating the development of heart failure, thromboembolic events including pulmonary embolism and stroke, and myocardial infarction. Sex steroids, such as androgens, progestins, and oestrogens and their receptors (ERα, ERβ, GPER; PR-A, PR-B; AR) have been identified as important modifiers of angiogenesis, and sex differences have been reported for anti-angiogenic drugs. This review article discusses the current challenges clinicians are facing with regard to angiogenesis inhibitor therapy, including the need to consider sex differences affecting clinical efficacy and safety. We also propose areas for future research taking into account the role of sex hormone receptors and sex chromosomes. Development of new sex-specific drugs with improved target- and cell-type selectivity likely will open the way to personalized medicine in men and women requiring anti-angiogenic therapy to reduce adverse effects and to improve therapeutic efficacy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: We aimed at determining the rate of drug-resistant arterial hypertension in patients with an unambiguous diagnosis of primary aldosteronism (PA). Moreover, we sought for investigating the diagnostic performance of adrenal vein sampling (AVS), and the effect of adrenalectomy on blood pressure (BP) and prior treatment resistance in PA patients subtyped by AVS in major referral centres., Methods and Results: The Adrenal Vein Sampling International Study-2 (AVIS-2) was a multicentre international study that recruited consecutive PA patients submitted to AVS, according to current guidelines, during 15 years. The patients were over 18 years old with arterial hypertension and had an unambiguous diagnosis of PA. The rate of resistant hypertension was assessed at baseline and after adrenalectomy using the American Heart Association (AHA) 2018 definition. Information on presence or absence of resistant hypertension was available in 89% of the 1625 enrolled PA patients. Based on the AHA 2018 criteria, resistant hypertension was found in 20% of patients, of which about two-thirds (14%) were men and one-third (6%) women (χ2 = 17.1, P < 1*10-4) with a higher rate of RH in men than in women (23% vs. 15% P < 1*10-4). Of the 292 patients with resistant hypertension, 98 (34%) underwent unilateral AVS-guided adrenalectomy, which resolved BP resistance to antihypertensive treatment in all., Conclusions: (i) Resistant hypertension is a common presentation in patients seeking surgical cure of PA; (ii) AVS is key for the optimal management of patients with PA due to resistant hypertension; and (iii) AVS-guided adrenalectomy allowed resolution of treatment-resistant hypertension., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Acute increases of blood pressure values are common causes of patients' presentation to emergency departments, and their management represents a clinical challenge. They are usually described as 'hypertensive crises', 'hypertensive urgencies', terms that should be abandoned because they are misleading and inappropriate according to a recent task force of the European Society of Cardiology, which recommended to focus only on 'hypertensive emergencies'. The latter can be esasily identified by using the Brain, Arteries, Retina, Kidney, and/or Heart (BARKH) strategy as herein described. Although current guidelines recommendations/suggestions for treatment of these patients are not evidence-based, owing to the lack of randomized clinical trials, improved understanding of the underlying pathophysiology has changed the approach to management of the patients presenting with hypertensive emergencies in recent years. Starting from these premises and a systematic review of the available studies graded by their quality, using the AHA class of recommendation/level of evidence grading, whenever possible, we herein present a novel a streamlined symptoms- and evidence-based algorithm for the assessment and management of patients with hypertensive emergencies., (© 2021. Italian Society of Hypertension.)

Many of the patients with primary aldosteronism (PA) are denied curative adrenalectomy because of limited availability or failure of adrenal vein sampling. It has been suggested that adrenal vein sampling can be omitted in young patients with a unilateral adrenal nodule, who show a florid biochemical PA phenotype. As this suggestion was based on a very low quality of evidence, we tested the applicability and accuracy of imaging, performed by computed tomography and/or magnetic resonance, for identification of unilateral PA, as determined by biochemical and/or clinical cure after unilateral adrenalectomy. Among 1625 patients with PA submitted to adrenal vein sampling in a multicenter multiethnic international study, 473 were ≤45 years of age; 231 of them had exhaustive imaging and follow-up data. Fifty-three percentage had a unilateral adrenal nodule, 43% had no nodules, and 4% bilateral nodules. Fifty-six percentage (n=131) received adrenalectomy and 128 were unambiguously diagnosed as unilateral PA. A unilateral adrenal nodule on imaging and hypokalemia were the strongest predictors of unilateral PA at regression analysis. Accordingly, imaging allowed correct identification of the responsible adrenal in 95% of the adrenalectomized patients with a unilateral nodule. The rate raised to 100% in the patients with hypokalemia, who comprised 29% of the total, but fell to 88% in those without hypokalemia. Therefore, a unilateral nodule and hypokalemia could be used to identify unilateral PA in patients ≤45 years of age if adrenal vein sampling is not easily available. However, adrenal vein sampling remains indispensable in 71% of the young patients, who showed no nodules/bilateral nodules at imaging and/or no hypokalemia. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01234220.

Context: Adrenal gland imaging is recommended by the current guidelines for the workup of primary aldosteronism (PA). However, its diagnostic performance has not been established in large, multiethnic cohorts of patients who undergo adrenal vein sampling (AVS) and adrenalectomy., Objective: This work aims to assess the diagnostic accuracy of cross-sectional adrenal imaging., Methods: This international multicenter study took place in tertiary referral centers. A total of 1625 PA patients seeking surgical cure were enrolled in an international study involving 19 centers in North America, Europe, Asia, and Australia. Of these, 1311 (81%) had imaging data available and 369 (23%), who received a final diagnosis of surgically cured unilateral PA, were examined. Patients underwent AVS and imaging by computed tomography and/or magnetic resonance imaging. The accuracy of detection of unilateral PA at imaging was estimated by the area under the receiver operator characteristics curve using cure (biochemical and/or full clinical success) as the reference at follow-up after unilateral adrenalectomy., Results: In the cohort of 1311 patients with imaging data available, 34% and 7% of cases showed no detectable or bilateral nodules, respectively. Imaging did not detect the culprit adrenal in 28% of the surgically cured unilateral PA patients. Moreover, the clinical outcome did not differ significantly between the imaging-positive and imaging-negative patients., Conclusion: Cross-sectional imaging did not identify a lateralized cause of disease in around 40% of PA patients and failed to identify the culprit adrenal in more than one-fourth of patients with unilateral PA., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Familial hyperaldosteronism type 1 (FH-1) is a rare autosomal dominant form of primary aldosteronism, which features a marked phenotypic heterogeneity, ranging from mild to severe forms of arterial hypertension that can be complicated by stroke and cardiovascular events at a young age. As affected patients usually reach the fertile age, transmission of the disease to offspring is common. Notwithstanding this, reports of FH-1 in pregnancy are limited and there is a lack of treatment guidelines., Methods and Results: We searched the PubMed and EuropePMC databases with a PICO strategy to retrieve available information on management of FH-1 patients during pregnancy. We could identify seven relevant articles, which are herein reviewed., Conclusion: Based on available information on pathophysiology and treatment of FH-1 in pregnancy, recommendations for the rational management of FH-1 in pregnancy are provided., (© 2021. The Author(s).)

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.

Objective: The branch of the renin--angiotensin system constituting angiotensin-(1-7) [Ang-(1-7)], the Ang II type 2 receptor, the Mas receptors and the Ang-(1-7)-forming enzyme ACE-2, by counteracting the Ang II type 1 receptor (AT1R)-mediated effects, are held to be cardiovascular protective in several conditions. However, whether Ang-(1-7) and ACE-2 are detectable in human adrenocortical tissues and whether they affect aldosterone and cortisol biosynthesis was unknown., Methods: We measured angiotensin peptides with liquid chromatography tandem-mass spectrometry and ACE-2 mRNA with digital droplet (dd)PCR in human aldosterone-producing adenoma (APA) and APA-adjacent tissue obtained from patients with primary aldosteronism. We also investigated the effects of Ang-(1-7) and the ACE-2 activator diminazene aceturate (DIZE) on aldosterone synthase (CYP11B2) and 11β-hydroxylase (CYP11B1) gene expression, in the absence or presence of the AT1R antagonist irbesartan, or of the MasR antagonist A779., Results: APA and APA-adjacent adrenocortical tissues express ACE-2 mRNA and contain detectable amounts of Ang II and Ang-(2-8), but not of Ang I, Ang-(1-5), Ang (3-8) and Ang-(1-7). Under unstimulated and Ang II- stimulated conditions Ang-(1-7) did not blunt CYP11B1 and CYP11B2 mRNA. At supraphysiological concentrations (10-4 mol/l), Ang-(1-7) stimulated both CYP11B1 and CYP11B2 mRNA via the AT1R. The ACE-2 activator DIZE increased by 1.5-fold ACE-2 mRNA but did not blunt Ang II- upregulated CYP11B1 and CYP11B2 expression., Conclusion: These results do not support the hypothesis that the ACE-2/Ang-(1-7)/MasR axis play a protective role by counteracting enhanced aldosterone secretion in humans., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Primary aldosteronism (PA), the most common form of secondary hypertension, has been considered for decades as a "benign" form of hypertension, but evidences progressively built up to show that patients with PA had an excess rate of cardiovascular damage as compared to blood pressure-matched essential hypertensive patients. This review provides an updated view of structural and electrical cardiac remodeling and of vascular changes in hyperaldosteronism, and how they can favor development of cardiovascular events. The link between hyperaldosteronism and resistant hypertension is also examined, and the impact of targeted treatment of hyperaldosteronism on cardiovascular changes is finally discussed., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Aims: A blood pressure (BP)-independent metabolic shift towards a catabolic state upon high sodium (Na+) diet, ultimately favouring body fluid preservation, has recently been described in pre-clinical controlled settings. We sought to investigate the real-life impact of high Na+ intake on measures of renal Na+/water handling and metabolic signatures, as surrogates for cardiovascular risk, in hypertensive patients., Methods and Results: We analysed clinical and biochemical data from 766 consecutive patients with essential hypertension, collected at the time of screening for secondary causes. The systematic screening protocol included 24 h urine (24 h-u-) collection on usual diet and avoidance of renin-angiotensin-aldosterone system-confounding medications. Urinary 24 h-Na+ excretion, used to define classes of Na+ intake (low ≤2.3 g/day; medium 2.3-5 g/day; high >5 g/day), was an independent predictor of glomerular filtration rate after correction for age, sex, BP, BMI, aldosterone, and potassium excretion [P = 0.001; low: 94.1 (69.9-118.8) vs. high: 127.5 (108.3-147.8) mL/min/1.73 m2]. Renal Na+ and water handling diverged, with higher fractional excretion of Na+ and lower fractional excretion of water in those with evidence of high Na+ intake [FENa: low 0.39% (0.30-0.47) vs. high 0.81% (0.73-0.98), P < 0.001; FEwater: low 1.13% (0.73-1.72) vs. high 0.89% (0.69-1.12), P = 0.015]. Despite higher FENa, these patients showed higher absolute 24 h Na+ reabsorption and higher associated tubular energy expenditure, estimated by tubular Na+/ATP stoichiometry, accordingly [Δhigh-low = 18 (12-24) kcal/day, P < 0.001]. At non-targeted liquid chromatography/mass spectrometry plasma metabolomics in an unselected subcohort (n = 67), metabolites which were more abundant in high versus low Na+ intake (P < 0.05) mostly entailed intermediates or end products of protein catabolism/urea cycle., Conclusion: When exposed to high Na+ intake, kidneys dissociate Na+ and water handling. In hypertensive patients, this comes at the cost of higher glomerular filtration rate, increased tubular energy expenditure, and protein catabolism from endogenous (muscle) or excess exogenous (dietary) sources. Glomerular hyperfiltration and the metabolic shift may have broad implications on global cardiovascular risk independent of BP., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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.

The vast majority of hypertensive patients are never sought for a cause of their high blood pressure, i.e. for a 'secondary' form of arterial hypertension. This under detection explains why only a tiny percentage of hypertensive patients are ultimately diagnosed with a secondary form of arterial hypertension. The prevalence of these forms is, therefore, markedly underestimated, although, they can involve as many as one-third of the cases among referred patients and up to half of those with difficult to treat hypertension. The early detection of a secondary form is crucial, because if diagnosed in a timely manner, these forms can be cured at long-term, and even when cure cannot be achieved, their diagnosis provides a better control of high blood pressure, and allows prevention of hypertension-mediated organ damage, and related cardiovascular complications. Enormous progress has been made in the understanding, diagnostic work-up, and management of secondary hypertension in the last decades. The aim of this minireview is, therefore, to provide updated concise information on the screening, diagnosis, and management of the most common forms, including primary aldosteronism, renovascular hypertension, pheochromocytoma and paraganglioma, Cushing's syndrome, and obstructive sleep apnea.