Abstract-Adrenal venous sampling is recommended by current guidelines to identify surgically curable causes of hyperaldosteronism but remains markedly underused. Key factors contributing to the poor use of adrenal venous sampling include the prevailing perceptions that it is a technically challenging procedure, difficult to interpret, and can be complicated by adrenal vein rupture. In addition, the lack of uniformly accepted standards for the performance of adrenal venous sampling contributes to its limited use. Hence, an international panel of experts working at major referral centers was assembled to provide updated advice on how to perform and interpret adrenal venous sampling. To this end, they were asked to use the PICO (Patient or Problem, Intervention, Control or comparison, Outcome) strategy to gather relevant information from the literature and to rely on their own experience. The level of evidence/recommendation was provided according to American Heart Association gradings whenever possible. A consensus was reached on several key issues, including the selection and preparation of the patients for adrenal venous sampling, the procedure for its optimal performance, and the interpretation of its results for diagnostic purposes even in the most challenging

Abstract-Primary aldosteronism is the most common form of secondary hypertension. Mutations in the KCNJ5 gene have been described recently in aldosterone-producing adenomas (APAs). The aim of this study was to investigate the prevalence of KCNJ5 mutations in unselected patients with primary aldosteronism and their clinical, biological and molecular correlates. KCNJ5 sequencing was performed on somatic (APA, nϭ380) and peripheral (APA, nϭ344; bilateral adrenal hyperplasia, nϭ174) DNA of patients with primary aldosteronism, collected through the European Network for the Study of Adrenal Tumors. Transcriptome analysis was performed in 102 tumors. Somatic KCNJ5 mutations (p.Gly151Arg or p.Leu168Arg) were found in 34% (129 of 380) of APA. They were significantly more prevalent in females (49%) than males (19%; PϽ10 Ϫ3) and in younger patients (42.1Ϯ1.0 versus 47.6Ϯ0.7 years; PϽ10 Ϫ3 ) and were associated with higher preoperative aldosterone levels (455Ϯ26 versus 376Ϯ17 ng/L; Pϭ0.012) but not with therapeutic outcome after surgery. Germline KCNJ5 mutations were found neither in patients with APA nor those with bilateral adrenal hyperplasia. Somatic KCNJ5 mutations were specific for APA, because they were not identified in 25 peritumoral adrenal tissues or 16 cortisol-producing adenomas. Hierarchical clustering of transcriptome profiles showed that APAs with p.Gly151Arg or p.Leu168Arg mutations were indistinguishable from tumors without KCNJ5 mutations. In conclusion, although a large proportion of sporadic APAs harbors somatic KCNJ5 mutations, germline mutations are not similarly causative for bilateral adrenal hyperplasia. KCNJ5 mutation carriers are more likely to be females; younger age and higher aldosterone levels at diagnosis suggest that KCNJ5 mutations may be associated with a more florid phenotype of primary aldosteronism. H ypertension is a major cardiovascular risk factor that affects between 10% and 40% of the population in industrialized countries. Detection of secondary forms of hypertension is particularly important because it allows for the targeted management of the underlying disease. Primary aldosteronism (PA) is the most common form of secondary hypertension, with an estimated prevalence between 6% and 12% of hypertensives and as high as 20% in patients with resistant hypertension. 1-5 PA occurs as the result of a dysregulation of the mechanisms controlling adrenal aldosterone production, ultimately leading to hypertension with low plasma renin and elevated aldosterone sometimes associated with hypokalemia. Among subtypes of PA, aldosteroneproducing adenoma (APA) and bilateral adrenal hyperplasia (BAH; also known as idiopathic hyperaldosteronism) together account for Ϸ95% of cases. [1][2][3] Aldosterone production from the adrenal zona glomerulosa is tightly controlled to maintain electrolyte and fluid homeostasis by the kidney. Thus, the two most important physiological stimuli of aldosterone secretion are angiotensin II and serum potassium. Glomerulosa cell membrane depolarization leads to openi...

P rimary aldosteronism (PA) is a common curable cause of high blood pressure (BP).1 PA is of peculiar interest because the excess aldosterone secretion is held to be autonomous from angiotensin II, which allows elucidating the cardiovascular effects of excess aldosterone without the confounding effects of excess angiotensin II. Moreover, as the excess of aldosterone is cured with adrenalectomy in practically all patients, 2 causation between aldosterone excess and the cardiovascular changes could be inferred. However, whether surgery or pharmacological blockade of the mineralocorticoid receptor (MR) warrant cure of high BP and regression of cardiovascular damage, and of cardiac remodeling, at long term remains unclear because limited data exist. 3,4 The adaption of the left ventricle (LV) to the increased afterload of patients with high BP involves development of hypertrophy (LVH), which predicts cardiovascular events and death, 5 and when regressed improved prognosis. 6 In the complex interplay of hemodynamic, genetic, and endocrine-paracrine factors that underlie development of LVH aldosterone plays a pivotal role. [7][8][9] In the setting of a high sodium intake, this major effector of the system causes LVH, transcription of collagen type I and III genes, 10 and promotes fibroblasts proliferation, oxidative stress, and inflammation, 11 in part, by potentiating the effects of angiotensin II on AT-1 receptors.12-15 These actions, alongside the effects of the steroid on pre-and after-load, are held to cause inflammation and fibrosis, which contribute to worsening prognosis of patients with hyperaldosteronism, 8,16 and can explain the survival benefit conferred by MR antagonists to optimally treated patients with LV systolic dysfunction. 17,18 Compared with BP-matched primary (essential) hypertensive patients, those with PA have an excess LVH and a LV mass inappropriately high for the degree of LV workload and BP elevation. [2][3][4]9,[19][20][21][22][23][24][25][26][27][28] Cardiac fibrosis with ensuing altered LV diastolic dysfunction can lead to left atrium dilatation and increased risk of atrial fibrillation (AF) 7,8,29 ; whether these changes regress with specific treatment for PA remains uncertain. 3,4,19,20,26 We, therefore, set out to prospectively investigate the long-term effects of correction of hyperaldosteronism on BP, LV mass, and cardiovascular events in a large cohort of patients with PA.Abstract-Primary aldosteronism (PA), a common cause of high blood pressure (BP), induces left ventricular (LV) hypertrophy and an excess rate of cardiovascular events. Whether its treatment provides long-term cure of hypertension and regression of cardiovascular damage remains uncertain. To the aim of assessing the effect of treatment of PA on BP and LV changes, we prospectively recruited 323 patients in a long-term follow-up study entailing serial echocardiography evaluations. Of them, 180 had PA and were assigned to either adrenalectomy (n=110) or medical therapy (n=70)

HEOCHROMOCYTOMAS AND paragangliomas are chromaffin cell tumors of neural crest origin that arise from the adrenal medulla or extra-adrenal sympathetic paraganglia, respectively, and are frequently catecholamine secreting. 1 These tumors are usually benign and can occur as a single entity or as part of various hereditary tumor syndromes. Genetically, pheochromocytomas and paragangliomas are heterogeneous , with at least one-third of cases resulting from germline but not somatic mutations in 1 of several independent genes: RET, VHL, NF1, and succinate dehydrogenase (SDH) subunit B, C, and D genes. 2-5 More recently, other candidate susceptibil-Author Affiliations are listed at the end of this article.

Abstract-Adrenocorticotropic hormone administration was proposed to overcome the biases associated with pulsatile aldosterone secretion during adrenal venous sampling, but the usefulness of different protocols of stimulation was never systematically assessed. We, therefore, compared the effects of a high dose (HD; 250 g IV as a bolus), a very low dose (VLD; 250 pg IV), and an intermediate dose (ID; 50 g/h) of adrenocorticotropic hormone on the selectivity index (SI) and the lateralization index in primary aldosteronism patients, using the diagnosis of aldosterone-producing adenoma, based on pathology and follow-up data, as a reference. The HD (nϭ47) significantly increased plasma cortisol concentration in infrarenal inferior vena cava (ϩ79%) blood and the SI on both sides (SI RIGHT ϩ113% and SI LEFT ϩ131%), as compared with baseline values. The ID (nϭ14) also markedly increased both plasma cortisol concentration inferior vena cava (ϩ93%) and the SI (SI RIGHT ϩ690% and SI LEFT ϩ410%); the very low dose (nϭ6) had no effect on either the plasma cortisol concentration or SI. In the patients with unilateral aldosterone-producing adenoma, the increase of selectivity with the HD and ID was counterbalanced by a confounding effect on the correct identification of the aldosterone-producing adenoma side, which was attributed to the wrong side in 3.0% and 12.5% with HD and ID, respectively. In conclusion, the HD and the ID, but not the very low dose, adrenocorticotropic hormone stimulation protocol facilitated the ascertainment of selectivity of adrenal vein catheterization. However, this favorable effect was overridden by a confounding effect on the identification of lateralized aldosterone excess to the aldosterone-producing adenoma side. Hence, we do not recommend adrenocorticotropic hormone stimulation.

The discovery that SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) binds to the angiotensin converting enzyme (ACE)-2, which is highly expressed in the lower airways, explained why SARS-CoV-2 causes acute respiratory distress syndrome (ARDS) and respiratory failure. After this, the news spread that ACEis and ARBs would be harmful in SARS-CoV-2-infected subjects.To the contrary compelling evidence exists that the ACE-1/angiotensin (Ang) II/ATR-1 pathway is involved in SARS-CoV-2-induced ARDS, while the ACE-2/Ang (1-7)/ATR2/MasR pathway counteracts the harmful actions of AngII in the lung. A reduced ACE-1/ACE-2 ratio is, in fact, a feature of ARDS that can be rescued by human recombinant ACE-2 and Ang (1-7) administration, thus preventing SARS-CoV-2-induced damages to the lung. Based on the current clinical evidence treatment with ACE-inhibitors I (ACEis) or angiotensin receptor blockers (ARBs) continues to provide cardiovascular and renal protection in patients diagnosed with COVID-19. Discontinuing these medications may therefore potentially be harmful in this patients population. COVID19 PandemicsThe pandemic proportions of Covid-19 (Coronavirus Disease 2019) from the SARS (Severe Acute Respiratory Syndrome) Coronavirus 2 (CoV-2) infecting a million and killing 47,266 people worldwide as of April 2, has fueled enormous interest in the mechanisms whereby this new coronavirus causes acute respiratory distress syndrome (ARDS) and multiorgan failure. The estimated 79% infection rate from undocumented cases in Covid-19 patients (Li et al., 2020), and the high lethality of the infections, along with its enormous socio-economic impact, emphasise the importance of fully understanding these mechanisms for developing effective treatment strategies.Early in 2020 reports of the full RNA sequence of the SARS-CoV-2 virus highlighted remarkable similarities with the SARS-CoV virus, which was responsible of an outbreak that killed 774 people in 2003(Xu et al., 2020. As the processes whereby the SARS-CoV virus infects the lung cells were already dissected (Kuba et al., 2005), and it was held that SARS-CoV-2 uses identical mechanisms, these discoveries allowed an unprecedented acceleration of knowledge.

Primary aldosteronism is much more common than previously thought. The high prevalence of primary aldosteronism, the damage this condition does to the heart, blood vessels and kidneys (which causes a high rate of cardiovascular events), along with the notion that a timely diagnosis followed by an appropriate therapy can correct the arterial hypertension and hypokalemia, justify efforts to search for primary aldosteronism in many patients with hypertension. Most centers can use a cost-effective strategy to screen for patients with primary aldosteronism. By contrast, the identification of primary aldosteronism subtypes, which involves adrenal-vein sampling, should only be undertaken at tertiary referral centers that have experience in performing and interpreting this test. The identification of a curable form of primary aldosteronism can be beneficial for the patient. In some subgroups of patients with hypertension who are at high risk of primary aldosteronism or can benefit most from an accurate diagnosis, an aggressive diagnostic approach is necessary.

Objective: Abnormalities of glucose metabolism are common findings of acromegaly. However, robust evidence on whether therapy with somatostatin analogs (SSAs) or pegvisomant (PEG) differently affects glucose metabolism is lacking. The purpose of this study was to evaluate the effects of therapy with SSAs, PEG, or their combination on glucose metabolism in a large series of acromegalic patients. Design: This was a historical-prospective study. Among 50 consecutive acromegalic patients under SSA therapy, acromegaly in 19 patients was controlled. PEG used in combination with SSA therapy allowed the control of acromegaly in the remaining 31 patients and was then continued as monotherapy in 18 patients. Methods: The following parameters were evaluated at the diagnosis of acromegaly and during different treatments: fasting plasma glucose (FPG) and insulin concentrations, insulin sensitivity (QUICK-I), homeostasis model assessment of insulin resistance (HOMA2-IR), and plasma glucose and insulin concentrations during the oral glucose tolerance test (OGTT). Comparison was made using analysis for paired data. Results: Insulin resistance improved when acromegaly was controlled with therapy with SSAs, PEG, or SSACPEG. However, FPG concentrations were higher during SSA therapy (alone or combined with PEG) than at the diagnosis of acromegaly, even when corrected for disease activity, whereas they were reduced during PEG therapy. Mean glucose concentrations during the OGTT were higher in patients receiving SSA therapy than in those receiving PEG therapy. In addition, the prevalence of diabetes or impaired glucose tolerance was higher during SSA therapy than at diagnosis or during PEG therapy and was not influenced by disease control. Conclusions: Medical therapies for acromegaly reduce insulin resistance and increase insulin sensitivity; on the contrary, glucose indexes may be differently affected by SSA or PEG therapy.