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.

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.

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.

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.

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.

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.

Systolic and diastolic short-term blood pressure variability and its determinants in patients with controlled and uncontrolled hypertension: a retrospective cohort study.

Absolute blood pressure (BP) values are not the only causes of adverse cardiovascular consequences. BP variability (BPV) has also been demonstrated to be a predictor of mortality for cardiovascular events; however, its determinants are still unknown. This study considers 426 subjects with ambulatory BP monitoring (ABPM) measuring 24-h, diurnal and nocturnal absolute BP values and their standard deviations of the mean, along with nocturnal fall, age, sex and current treatment. Patients were divided in two subgroups, controlled and uncontrolled BP, and BPV of patients with "true" and "false" resistant hypertension was also analyzed. Nocturnal and 24-h BPV were higher in the group with uncontrolled hypertension. Multiple regression analysis showed that absolute BP, age, nocturnal fall, but not sex predicted BPV. Patients with "true" resistant hypertension had greater BPV than "false" resistant hypertension patients. Absolute BP resulted as the main determinant of 24-h and nocturnal BPV but not daytime BPV. Also nocturnal BP fall and age resulted as predictors of BPV in treated and untreated patients. Patients with "true" resistant hypertension have a higher BPV, suggesting a higher sympathetic activation. Evidence is still limited regarding the importance of short-term BPV as a prognostic factor and assessment of BPV cannot yet represent a parameter for routine use in clinical practice. Future prospective trials are necessary to define which targets of BPV can be achieved with antihypertensive drugs and whether treatment-induced reduction in BPV is accompanied by a corresponding reduction in cardiovascular events.

Double CYP11B1/CYP11B2 Immunohistochemistry and Detection of KCNJ5 Mutations in Primary Aldosteronism.

CONTEXT: The search for somatic mutations in adrenals resected from primary aldosteronism (PA) patients is being 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 adenoma from consenting surgically cured PA patients using double IHC for CYP11B1 and CYP11B2, 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<0.001). CONCLUSIONS: 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 APA patient.

Subtype Identification of Surgically Curable Primary Aldosteronism During Treatment With Mineralocorticoid Receptor Blockade.

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 ß-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.

Exclusion Tests in Unilateral Primary Aldosteronism (ExcluPA) Study.

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.

Pickering Syndrome: An Overlooked Renovascular Cause of Recurrent Heart Failure.

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.

RAndomized Clinical Trial Of NAfamostat Mesylate, A Potent Transmembrane Protease Serine 2 (TMPRSS2) Inhibitor, in Patients with COVID-19 Pneumonia.

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.

Coronary sinus diameter to estimate congestion and predict survival.

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 (CSmax) was as accurate as the IVC maximum diameter and collapsibility for the identification of congestion, defined as pre-hemodialysis status (AUROC CSmax = 0.902 vs IVC = 0.895, p = n.s.). A CSmax 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.

Unilaterally Selective Adrenal Vein Sampling for Identification of Surgically Curable Primary Aldosteronism.

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.

Peptidergic G Protein-Coupled Receptor Regulation of Adrenal Function: Bench to Bedside and Back.

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.

Management and Outcomes of Primary Aldosteronism in Pregnancy: A Systematic Review.

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.

Clinical efficacy and safety of angiogenesis inhibitors: sex differences and current challenges.

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, ERß, 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.

Feasibility of Imaging-Guided Adrenalectomy in Young Patients With Primary Aldosteronism.

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.

Exon 11 deletion in the myocyte enhancer factor (MEF)2A and early onset coronary artery disease gene in a Sicilian family.

AIMS: We investigated the prevalence of the myocyte enhancer factor (MEF)2A exon 11 deletion, a putative coronary artery disease (CAD) susceptibility gene, in patients referred for coronary angiography. METHODS AND RESULTS: In total, 1079 consecutive patients referred for coronary angiography in the GENICA Study were genotyped and 301 low-risk subjects were used as controls. One patient with early onset three vessels CAD, carrying the MEF2A deletion was found in the GENICA Study cohort and none in the control group. CONCLUSION: In a cohort of patients undergoing coronary angiography for suspected CAD the MEF2A exon 11 deletion occurred in 0.09%.