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Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease that may involve medium-sized muscular arteries throughout the body. The majority of FMD patients are women. Although a variety of genetic, mechanical, and hormonal factors play a role in the pathogenesis of FMD, overall, its cause remains poorly understood. It is probable that the pathogenesis of FMD is linked to a combination of genetic and environmental factors. Extensive studies have correlated the arterial lesions of FMD to histopathological findings of arterial fibrosis, cellular hyperplasia, and distortion of the abnormal architecture of the arterial wall. More recently, the vascular phenotype of lesions associated with FMD has been expanded to include arterial aneurysms, dissections, and tortuosity. However, in the absence of a string-of-beads or focal stenosis, these lesions do not suffice to establish the diagnosis. While FMD most commonly involves renal and cerebrovascular arteries, involvement of most arteries throughout the body has been reported. Increasing evidence highlights that FMD is a systemic arterial disease and that subclinical alterations can be found in non-affected arterial segments. Recent significant progress in FMD-related research has led to improve our understanding of the disease’s clinical manifestations, natural history, epidemiology, and genetics. Ongoing work continues to focus on FMD genetics and proteomics, physiological effects of FMD on cardiovascular structure and function, and novel imaging modalities and blood-based biomarkers that can be used to identify subclinical FMD. It is also hoped that the next decade will bring the development of multi-centred and potentially international clinical trials to provide comparative effectiveness data to inform the optimal management of patients with FMD.

Context Most patients with adrenal incidentaloma have nonfunctional lesions that do not require treatment, while others have functional or malignant tumors that require intervention. The plasma steroid metabolome may be useful to assess therapeutic need. Objective This work aimed to establish the utility of plasma steroid profiling combined with metanephrines and adrenal tumor size for the differential diagnosis of patients with adrenal incidentaloma. Methods This retrospective cross-sectional study, which took place at 7 European tertiary-care centers, comprised 577 patients with adrenal incidentaloma, including 19, 77, 65, 104 and 312 respective patients with adrenocortical carcinoma (ACC), pheochromocytoma (PHEO), primary aldosteronism (PA), autonomous cortisol secretion (ACS), and nonfunctional adrenal incidentaloma (NFAI). Mesaures of diagnostic performance were assessed (with [95% CIs]) for discriminating different subgroups of patients with adrenal incidentaloma. Results Patients with ACC were characterized by elevated plasma concentrations of 11-deoxycortisol, 11-deoxycorticosterone, 17-hydroxyprogesterone, androstenedione, and dehydroepiandrosterone-sulfate, whereas patients with PA had elevations of aldosterone, 18-oxocortisol, and 18-hydroxycortisol. A selection of those 8 steroids, combined with 3 others (cortisol, corticosterone, and dehydroepiandrosterone) and plasma metanephrines, proved optimal for identifying patients with ACC, PA, and PHEO at respective sensitivities of 83.3% (66.1%-100%), 90.8% (83.7%-97.8%), and 94.8% (89.8%-99.8%); and specificities of 98.0% (96.9%-99.2%), 92.0% (89.6%-94.3%), and 98.6% (97.6%-99.6%). With the addition of tumor size, discrimination improved further, particularly for ACC (100% [100%-100%] sensitivity, 99.5% [98.9%-100%] specificity). In contrast, discrimination of ACS and NFAI remained suboptimal (70%-71% sensitivity, 89%-90% specificity). Conclusion Among patients with adrenal incidentaloma, the combination of plasma steroid metabolomics with routinely available plasma free metanephrines and data from imaging studies may facilitate the identification of almost all clinically relevant adrenal tumors.

Background: Pregnant women with cardiovascular diseases (CVD) and their offspring are at higher risk of morbidity and mortality. Aims: To provide data on pregnancy outcomes among women with different types of CVD requiring non-elective cardiac hospitalization in a tertiary referral cardiac center. Methods: We identified all records of non-elective hospitalizations of pregnant women hospitalized between January 2009 through March 2018, at our institution — a tertiary referral cardiac center. The incidence and types of cardiac complications during pregnancy, as well as the pregnancy and offspring outcomes, were determined. Results: One hundred and sixty-one out of 328 pregnancy-related hospitalizations in 140 pregnancies were non-elective. Cardiac complications occurred in 62 (44%) pregnancies, with the most frequent being episodes of arrhythmia (22.1% pregnancies), followed by heart failure exacerbations (6.4% pregnancies). Maternal mortality reached 2.1% and affected only women with primary cardiomyopathies (CMP). Offspring mortality was 2.8%. Newborns of mothers with cardiac complications had significantly lower Apgar scores and gestational age at delivery, compared to mothers without cardiac complications. Conclusions: In our series mortality and morbidity among pregnant women with CVD hospitalizations were high. An unfavorable maternal outcome mainly affected women with CMP. Offspring of mothers with cardiovascular complications are prone to have a lower gestational age and Apgar score.

Purpose Little is known on the beliefs, perceptions and practices of hypertension specialists in addressing non-adherence to therapy. Therefore, a survey was undertaken amongst healthcare professionals (HCPs) managing hypertension in the European Society of Hypertension (ESH) Centres of Excellence. Materials and methods Cross-sectional data were obtained between December 2020 and April 2021 using an online anonymous structured questionnaire including 26 questions/136 items, that was sent to all ESH Excellence centres. Results Overall 67 from 187 centres (37.3%) responded and 200 HCPs from 30 countries answered the questionnaire. Participants (60% men) were mainly physicians (91%) and nurses (8%) from University hospitals (77%). Among physicians, 83% had >10 years professional experience. Average time dedicated to discuss medications was 1-5 min in 48% and 6-10 min in 29% of cases. Interviews with patients about adherence were the most frequently used assessment method. Chemical detection of medications in urine was available in 36% of centres. One third of physicians involved their patients regularly in treatment decisions. The most frequent methods to improve adherence included simplification of medication therapy, more frequent visits, and home blood pressure monitoring. Conclusions: The level of implementation of tools to detect and improve adherence in hypertension management in ESH excellence centres is low. Structured educational activities and access to the newest objective measures to detect non-adherence might improve these deficits. Conclusions The level of implementation of tools to detect and improve adherence in hypertension management by HCPs in ESH excellence centres is low. Structured educational activities focussing on adherence management and access to the newest objective measures to detect non-adherence might improve these deficits.

There is a bidirectional, causal relationship between obstructive sleep apnea (OSA) and hypertension. OSA-related hypertension is characterized by high rates of masked hypertension, elevated nighttime blood pressure, a nondipper pattern of nocturnal hypertension, and abnormal blood pressure variability. Hypoxia/hypercapnia-related sympathetic activation is a key pathophysiological mechanism linking the 2 conditions. Intermittent hypoxia also stimulates the renin-angiotensin-aldosterone system to promote hypertension development. The negative and additive cardiovascular effects of OSA and hypertension highlight the importance of effectively managing these conditions, especially when they coexist in the same patient. Continuous positive airway pressure is the gold standard therapy for OSA but its effects on blood pressure are relatively modest. Furthermore, this treatment did not reduce the cardiovascular event rate in nonsleepy patients with OSA in randomized controlled trials. Antihypertensive agents targeting sympathetic pathways or the renin-angiotensin-aldosterone system have theoretical potential in comorbid hypertension and OSA, but current evidence is limited and combination strategies are often required in drug resistant or refractory patients. The key role of sympathetic nervous system activation in the development of hypertension in OSA suggests potential for catheter-based renal sympathetic denervation. Although long-term, randomized controlled trials are needed, available data indicate sustained and relevant reductions in blood pressure in patients with hypertension and OSA after renal denervation, with the potential to also improve respiratory parameters. The combination of lifestyle interventions, optimal pharmacological therapy, continuous positive airway pressure therapy, and perhaps also renal denervation might improve cardiovascular risk in patients with OSA.

Nowadays there is a worldwide trend to postpone the moment of the first pregnancy to a later period of life. This is due to social and economic changes and has a huge impact on the economics of health care for pregnant women. The more advanced the age of a pregnant woman, the greater risk of comorbidities, including hypertension. Hypertension is one of the most common complications of pregnancy and it is associated with serious consequences for mothers and their children such as preterm birth and prematurity, which for many years has been the main cause of illness and mortality in pregnant, fetuses and newborns in industrialized and developing countries, including Poland. Medical care for women with chronic hypertension who are planning pregnancy and pregnant women with chronic hypertension is associated with many additional medical activities and the main aim is to reduce the risk of complications for the mother and her newborn baby. This document presents practical knowledge on pregnancy planning in women with chronic hypertension based on current literature.

Current literature suggests a higher risk of pregnancy-related complications in patients with renal fibromuscular dysplasia (FMD). The aim of our study was to assess the nature and prevalence of pregnancy-related complications in patients subsequently diagnosed with FMD. A call for participation was sent to centers contributing to the European/International FMD Registry. Patients with at least 1 pregnancy were included. Data on pregnancy were collected through medical files and FMD characteristics through the European/International FMD Registry. Data from 534 pregnancies were obtained in 237 patients. Despite the fact that, in 96% of cases, FMD was not diagnosed before pregnancy, 40% of women (n=93) experienced pregnancy-related complications, mostly gestational hypertension (25%) and preterm birth (20%), while preeclampsia was reported in only 7.5%. Only 1 patient experienced arterial dissection and another patient an aneurysm rupture. When compared with patients without pregnancy-related complications, patients with complicated pregnancies were younger at FMD diagnosis (43 versus 51 years old; P P =0.003) but underwent more often renal revascularization (63% versus 40%, P

Pomimo 30 lat (simwastatyna została dopuszczona w 1991 przez FDA do stosowania klinicznego [1]) starań ekspertów, towarzystw i organizacji pacjenckich zaburzenia lipidowe wciąż stanowią wyzwanie diagnostyczne, ale przede wszystkim terapeutyczne. Dotyczy to zarówno właściwej oceny ryzyka pacjentów, włączenia odpowiedniego leczenia, problemów z jego adherencją, ale także problemów z tak ważnym leczeniem niefarmakologicznym – dietą, redukcją masy ciała czy regularnym wysiłkiem fizycznym [2]. Nie można także umniejszać znaczenia inercji terapeutycznej, czy to polegającej na niewłaściwie dobranej terapii (najczęściej brakiem intensywnego leczenia statynami czy jeszcze rzadziej leczenia skojarzonego), czy wręcz na błędach polegających na zmniejszeniu dawki czy odstawieniu terapii po uzyskaniu celu terapeutycznego. Właśnie dlatego w Polsce mamy wciąż prawie 20 milionów osób z hipercholesterolemią, z czego większość osób nie zdaje sobie z tego sprawy [3], to właśnie dlatego dotychczas rozpoznaliśmy tylko około 5% pacjentów z rodzinną hipercholesterolemią z prognozowanych nawet 140,000.

ContextIdentification of patients with endocrine forms of hypertension (EHT) (primary hyperaldosteronism [PA], pheochromocytoma/paraganglioma [PPGL], and Cushing syndrome [CS]) provides the basis to implement individualized therapeutic strategies. Targeted metabolomics (TM) have revealed promising results in profiling cardiovascular diseases and endocrine conditions associated with hypertension.ObjectiveUse TM to identify distinct metabolic patterns between primary hypertension (PHT) and EHT and test its discriminating ability.MethodsRetrospective analyses of PHT and EHT patients from a European multicenter study (ENSAT-HT). TM was performed on stored blood samples using liquid chromatography mass spectrometry. To identify discriminating metabolites a “classical approach” (CA) (performing a series of univariate and multivariate analyses) and a “machine learning approach” (MLA) (using random forest) were used.The study included 282 adult patients (52% female; mean age 49 years) with proven PHT (n = 59) and EHT (n = 223 with 40 CS, 107 PA, and 76 PPGL), respectively.ResultsFrom 155 metabolites eligible for statistical analyses, 31 were identified discriminating between PHT and EHT using the CA and 27 using the MLA, of which 16 metabolites (C9, C16, C16:1, C18:1, C18:2, arginine, aspartate, glutamate, ornithine, spermidine, lysoPCaC16:0, lysoPCaC20:4, lysoPCaC24:0, PCaeC42:0, SM C18:1, SM C20:2) were found by both approaches. The receiver operating characteristic curve built on the top 15 metabolites from the CA provided an area under the curve (AUC) of 0.86, which was similar to the performance of the 15 metabolites from MLA (AUC 0.83).ConclusionTM identifies distinct metabolic pattern between PHT and EHT providing promising discriminating performance.

Mosaic or somatic EPAS1 mutations are associated with a range of phenotypes including pheochromocytoma and/or paraganglioma (PPGL), polycythemia and somatostatinoma. The pathogenic potential of germline EPAS1 variants however is not well understood. We report a number of germline EPAS1 variants occurring in patients with PPGL, including a novel variant c.739C>A (p.Arg247Ser); a previously described variant c.1121T>A (p.Phe374Tyr); several rare variants, c.581A>G (p.His194Arg), c.2353C>A (p.Pro785Thr) and c.2365A>G (p.Ile789Val); a common variant c.2296A>C (p.Thr766Pro). We performed detailed functional studies to understand their pathogenic role in PPGL. In transient transfection studies, EPAS1/HIF-2α p.Arg247Ser, p.Phe374Tyr and p.Pro785Thr were all stable in normoxia. In co-immunoprecipitation assays, only the novel variant p.Arg247Ser showed diminished interaction with pVHL. A direct interaction between HIF-2α Arg247 and pVHL was confirmed in structural models. Transactivation was assessed by means of a HRE-containing reporter gene in transiently transfected cells, and significantly higher reporter activity was only observed with EPAS1/HIF-2α p.Phe374Tyr and p.Pro785Thr. In conclusion, three germline EPAS1 variants (c.739C>A (p.Arg247Ser), c.1121T>A (p.Phe374Tyr) and c.2353C>A (p.Pro785Thr)) all have some functional features in common with somatic activating mutations. Our findings suggest that these three germline variants are hypermorphic alleles that may act as modifiers to the expression of PPGLs.

The clinical case of a middle-aged woman with long-standing history of dyslipidemia and coronary heart disease, as well as a strong family history of cardiovascular diseases, was presented. The diagnostic criteria, management, and target cholesterol LDL level concentrations were discussed in the group of patients with familial hypercholesterolemia (FH). The detailed clinical presentation of a patient with a high risk of FH and The Dutch Lipid Network Criteria were presented. The treatment and diagnostic strategies were also discussed.

In December 2018, an article summarizing available results of randomized studies on renal denervation (RDN), entitled “Renal denervation: can we press the ON button again?” was published in the Advances in Interventional Cardiology. Since then, several positive reports, including SPYRAL HTN OFF-MED Pivotal trial have been presented. In the current review the authors discuss the latest data on RDN in arterial hypertension treatment and try to answer the burning question: can we press the ON button again in 2020? The results of recently published studies potentially justify new recommendations for the use of RDN in clinical practice in appropriately selected patients in the new hypertension guidelines. The current review also summarizes the results of trials on RDN applied in another potential indication – atrial fibrillation. Six most important, prospective, randomized trials assessing RDN as adjunct therapy to pulmonary vein isolation for treatment of atrial fibrillation were discussed. In 5 studies, patients had uncontrolled BP despite treatment with three antihypertensive agents. The ratio for recurrence of atrial fibrillation for pulmonary vein isolation with RDN procedure was reduced by 57% as compared to pulmonary vein isolation (PVI) alone. BP was also reduced significantly after RDN in this subset of patients. Further multicenter studies involving standardized PVI and RDN procedures are needed.

Fibromuscular dysplasia (FMD), regarded as a generalized vascular disease, may affect all vascular beds and may result in arterial stenosis, occlusion, aneurysm, or dissection. It has been proposed to systematically evaluate all vascular beds in patients with FMD, regardless of initial FMD involvement. However, the impact of this approach on clinical decisions and on management is unknown. Within the prospective ARCADIA-POL study (Assessment of Renal and Cervical Artery Dysplasia–Poland), we evaluated 232 patients with FMD lesions confirmed in at least one vascular bed, out of 343 patients included in the registry. All patients underwent a detailed clinical evaluation including computed tomography angiography of intracranial and cervical arteries, as well as computed tomography angiography of the abdominal aorta, its branches, and upper and lower extremity arteries. In the study group, FMD lesions were most frequently found in renal arteries (87.5%). FMD was also found in cerebrovascular (24.6%), mesenteric (13.8%), and upper (3.0%) and lower extremity (9.9 %) arteries. Newly diagnosed FMD lesions were found in 34.1% of the patients, and previously undetected vascular complications were found in 25% of the patients. Among all FMD patients included in the study, one out of every 4 evaluated patients qualified for interventional treatment due to newly diagnosed FMD lesions or vascular complications. The ARCADIA-POL study shows for the first time that the systematic and multidisciplinary evaluation of patients with FMD based on a whole-body computed tomography angiography scan has an impact on their clinical management. This proved the necessity of the systematic evaluation of all vascular beds in patients with FMD, regardless of initial FMD involvement.

AIMS: Since December 2015, the European/International Fibromuscular Dysplasia (FMD) Registry enrolled 1022 patients from 22 countries. We present their characteristics according to disease subtype, age and gender, as well as predictors of widespread disease, aneurysms and dissections. METHODS AND RESULTS: All patients diagnosed with FMD (string-of-beads or focal stenosis in at least one vascular bed) based on CTA, MRA and/or catheter-based angiography were eligible.Patients were predominantly women (82%) and Caucasians (88%). Age at diagnosis was 46±16 years (12% ≥65yo), 86% were hypertensive, 72% had multifocal and 57% multivessel FMD. Compared to patients with multifocal FMD, patients with focal FMD were younger, more often men, had less often multivessel FMD but more revascularizations. Compared to women with FMD, men were younger, had more often focal FMD and arterial dissections. Compared to younger patients with FMD, patients ≥65yo had more often multifocal FMD, lower eGFR and more atherosclerotic lesions. Independent predictors of multivessel FMD were age at FMD diagnosis, stroke, multifocal subtype, presence of aneurysm or dissection and family history of FMD. Predictors of aneurysms were multivessel and multifocal FMD. Predictors of dissections were age at FMD diagnosis, male gender, stroke and multivessel FMD. CONCLUSIONS: The European/International FMD Registry allowed large-scale characterization of distinct profiles of patients with FMD and, more importantly, identification of a unique set of independent predictors of widespread disease, aneurysms and dissections, paving the way for targeted screening, management and follow-up of FMD. TRANSLATIONAL PERSPECTIVE: Fibromuscular dysplasia (FMD) is nowadays considered as a systemic arterial disease, warranting brain-to-pelvis vascular imaging in all patients. However, most current evidence is derived from a limited number of expert centres. Furthermore, one size may not fit all. Based on analysis of the first thousand patients enrolled in the European/International FMD registry (46 centres; 22 countries) we characterized distinct patient profiles according to FMD subtype, age and gender and identified predictors of widespread disease, aneurysms and dissections, paving the way for individualized management and follow-up. Further studies will allow refining patient characterization according to ethnicity, genetic profile and imaging biomarkers.

SUMMARY: The coronavirus disease 2019 (COVID-19) pandemic considerably affects health, wellbeing, social, economic and other aspects of daily life. The impact of COVID-19 on blood pressure (BP) control and hypertension remains insufficiently explored. We therefore provide a comprehensive review of the potential changes in lifestyle factors and behaviours as well as environmental changes likely to influence BP control and cardiovascular risk during the pandemic. This includes the impact on physical activity, dietary patterns, alcohol consumption and the resulting consequences, for example increases in body weight. Other risk factors for increases in BP and cardiovascular risk such as smoking, emotional/psychologic stress, changes in sleep patterns and diurnal rhythms may also exhibit significant changes in addition to novel factors such as air pollution and environmental noise. We also highlight potential preventive measures to improve BP control because hypertension is the leading preventable risk factor for worldwide health during and beyond the COVID-19 pandemic.

OBJECTIVE The aim of the study was to investigate a new possible background of increased risk of cardiovascular events in two forms of endocrine hypertension: in primary aldosteronism (PA) and pheochromocytoma/paraganglioma (PPGL) in comparison to essential hypertension (EHT). CONTEXT Prothrombotic properties of the fibrin clot structure, impaired fibrinolysis and enhanced thrombin generation have been reported to be associated with increased cardiovascular risk. DESIGN Patients with PA and PPGL were evaluated at baseline and re-evaluated 3 months after causative treatment. At baseline PA and PPGL patients were compared to matched EHT patients and to healthy controls. PATIENTS The study included 35 patients with PA, 16 patients with PPGL and two reference groups of patients with EHT (32 and 22 patients) and healthy controls (35 and 23 subjects). MEASUREMENTS All subjects underwent evaluation according to the study protocol that included plasma fibrin clot permeability (Ks), clot lysis time, endogenous thrombin potential. RESULTS There were no differences in clot structure and fibrinolytic activity in PA and PPGL patients as compared to matched patients with EHT, whereas all hypertensive groups were characterized by more compact fibrin clot structure, faster clot formation and enhanced thrombin generation in comparison to healthy controls. Both in PA and PPGL patients, fibrin clot properties and fibrinolytic parameters remained stable after the causative treatment. CONCLUSIONS Patients with PA and PPGL are at a prothrombic state comparable to patients with EHT. The results suggest the higher risk of cardiovascular events observed in hypertensive PA and PPGL as compared to EHT is not mediated through investigated prothrombic mechanisms.

Systemic arterial hypertension (referred to as hypertension herein) is a major risk factor of mortality worldwide, and its importance is further emphasized in the context of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection referred to as COVID-19. Patients with severe COVID-19 infections commonly are older and have a history of hypertension. Almost 75% of patients who have died in the pandemic in Italy had hypertension. This raised multiple questions regarding a more severe course of COVID-19 in relation to hypertension itself as well as its treatment with renin-angiotensin system (RAS) blockers, e.g. angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). We provide a critical review on the relationship of hypertension, RAS, and risk of lung injury. We demonstrate lack of sound evidence that hypertension per se is an independent risk factor for COVID-19. Interestingly, ACEIs and ARBs may be associated with lower incidence and/or improved outcome in patients with lower respiratory tract infections. We also review in detail the molecular mechanisms linking the RAS to lung damage and the potential clinical impact of treatment with RAS blockers in patients with COVID-19 and a high cardiovascular and renal risk. This is related to the role of angiotensin-converting enzyme 2 (ACE2) for SARS-CoV-2 entry into cells, and expression of ACE2 in the lung, cardiovascular system, kidney, and other tissues. In summary, a critical review of available evidence does not support a deleterious effect of RAS blockers in COVID-19 infections. Therefore, there is currently no reason to discontinue RAS blockers in stable patients facing the COVID-19 pandemic.

International audience; Renovascular hypertension is one of the most common forms of secondary hypertension. Over 95% of cases of renovascular hypertension are due either to atherosclerosis of the main renal artery trunks or to fibromuscular dysplasia. These two causes of renal artery stenosis have been extensively discussed in recent reviews and consensus. The aim of the current article is to provide comprehensive and up-to-date information on the remaining causes. While these causes are rare or extremely rare, etiologic and differential diagnosis matters both for prognosis and management. Therefore, the clinician cannot ignore them. For didactic reasons, we have grouped these different entities into stenotic lesions (neurofibromatosis type 1 and other rare syndromes, dissection, arteritis, and segmental arterial mediolysis) often associated with aortic coarctation and other arterial abnormalities, and nonstenotic lesions, where hypertension is secondary to compression of adjacent arteries and changes in arterial pulsatility (aneurysm) or to the formation of a shunt, leading to kidney ischemia (arteriovenous fistula). Finally, thrombotic disorders of the renal artery may also be responsible for renovascular hypertension. Although thrombotic/embolic lesions do not represent primary vessel wall disease, they are characterized by frequent macrovascular involvement. In this review, we illustrate the most characteristic aspects of these different entities responsible for renovascular hypertension and discuss their prevalence, pathophysiology, clinical presentation, management, and prognosis.

Diagnosis of pheochromocytomas and paragangliomas in patients receiving hemodialysis is troublesome. The aim of the study was to establish optimal conditions for blood sampling for mass spectrometric measurements of normetanephrine, metanephrine and 3-methoxytyramine in patients on hemodialysis and specific reference intervals for plasma metanephrines under the most optimal sampling conditions. Blood was sampled before and near the end of dialysis, including different sampling sites in 170 patients on hemodialysis. Plasma normetanephrine concentrations were lower (P

Item does not contain fulltext PURPOSE: Current evidence regarding renal involvement in pheochromocytoma and paraganglioma (PPGL) is scant. More accurate diagnostic methods, such as renal Doppler ultrasound for intrarenal hemodynamic studies, may provide more detailed information on renal function. It might be postulated that renal function in PPGL patients might be altered by high blood pressure and excess secretion of catecholamines. The aim of this prospective study was to assess intrarenal blood flow parameters in PPGL patients included in the prospective monoamine-producing tumour (PMT) study and to evaluate the effects of normalisation of catecholamine production after surgical treatment on long-term renal function. MATERIALS AND METHODS: Seventy consecutive patients (aged 46.5 ± 14.0 years) with PPGL were included. Forty-eight patients from the PMT study cohort, matched for age, gender, blood pressure level and presence of hypertension, served as a control group. Renal artery doppler ultrasound spectral analysis included mean resistance index (RRI) and pulsatility index (PI). Forty-seven patients completed 12 months follow-up. RESULTS: There were no differences in renal parameters such as RRI, PI and kidney function between PPGL and non-PPGL patients as assessed by renal ultrasound, serum creatinine, eGFR and albumin excretion rate. No correlations between kidney function parameters, intrarenal doppler flow parameters and plasma catecholamines were observed in PPGL patients. At 12 months after surgery, no differences in creatinine level, eGFR, albumin excretion rate, RI and PI were found as compared to baseline results. CONCLUSIONS: In contrast to patients with other forms of secondary hypertension, our study did not show differences in intrarenal blood flow parameters and renal function between PPGL and non-PPGL subjects. Intrarenal hemodynamics and renal function did not change after normalisation of catecholamine levels by surgical treatment.

Purpose Pheochromocytomas and Paragangliomas (PPGL) result in chronic catecholamine excess and serious health complications. A recent study obtained a metabolic signature in plasma from PPGL patients; however, its targeted nature may have generated an incomplete picture and a broader approach could provide additional insights. We aimed to characterize the plasma metabolome of PPGL patients before and after surgery, using an untargeted approach, and to broaden the scope of the investigated metabolic impact of these tumors. Design A cohort of 36 PPGL patients was investigated. Blood plasma samples were collected before and after surgical tumor removal, in association with clinical and tumor characteristics. Methods Plasma samples were analyzed using untargeted nuclear magnetic resonance (NMR) spectroscopy metabolomics. The data were evaluated using a combination of uni- and multi-variate statistical methods. Results Before surgery, patients with a nonadrenergic tumor could be distinguished from those with an adrenergic tumor based on their metabolic profiles. Tyrosine levels were significantly higher in patients with high compared to those with low BMI. Comparing subgroups of pre-operative samples with their post-operative counterparts, we found a metabolic signature that included ketone bodies, glucose, organic acids, methanol, dimethyl sulfone and amino acids. Three signals with unclear identities were found to be affected. Conclusions Our study suggests that the pathways of glucose and ketone body homeostasis are affected in PPGL patients. BMI-related metabolite levels were also found to be altered, potentially linking muscle atrophy to PPGL. At baseline, patient metabolomes could be discriminated based on their catecholamine phenotype.

STUDY OBJECTIVES: It has been suggested that there might be a pathophysiological link and overlap between primary aldosteronism (PA) and obstructive sleep apnea (OSA). Therefore, in a prospective study, we evaluated the frequency of PA in hypertensive patients suspected of having OSA. METHODS: We included 207 consecutive hypertensive patients (mean age 53.2 ± 12.1 years, 133 M, 74 F) referred for polysomnography on the basis of one or more of the following clinical features: typical OSA symptoms, resistant or difficult-to-treat hypertension, diabetes, or cardiovascular disease. PA was diagnosed based on thew saline infusion test. RESULTS: Moderate-to-severe OSA was diagnosed in 94 patients (45.4% of the whole group). PA was diagnosed in 20 patients with OSA (21.3%) compared with 9 patients in the group without OSA (8.0%; P = .006). PA was also frequent in patients in whom symptoms of OSA were a sole indication for PA screening (15.4%) and in patients with and without resistant hypertension (24.5% and 17.8%, respectively). Most patients with PA and OSA were diagnosed with bilateral adrenal hyperplasia (18 patients, 90%). There were no major differences in clinical characteristics between patients with OSA with PA and those without PA. In multivariate models, moderate-to-severe OSA predicted the presence of PA (odds ratio 2.89, P = .018). CONCLUSIONS: Patients with clinically important moderate-to-severe OSA are characterized by a relatively high frequency of PA. Our results support the recommendations to screen patients with moderate-to-severe OSA for PA, regardless of the presence of other indications for PA screening. CITATION: Dobrowolski P, Kołodziejczyk-Kruk S, Warchoł-Celińska E, et al. Primary aldosteronism is highly prevalent in patients with hypertension and moderate to severe obstructive sleep apnea. J Clin Sleep Med. 2021;17(4):629–637.

Objectives Plasma free metanephrines are commonly used for diagnosis of pheochromocytoma and paraganglioma (PPGLs), but can also provide other information. This multicenter study prospectively examined whether tumor size, location, and mutations could be predicted by these metabolites. Methods Predictions of tumor location, size, and mutation type, based on measurements of plasma normetanephrine, metanephrine, and methoxytyramine were made without knowledge of disease in 267 patients subsequently determined to have PPGLs. Results Predictions of adrenal vs. extra-adrenal locations according to increased plasma concentrations of metanephrine and methoxytyramine were correct in 93 and 97% of the respective 136 and 33 patients in who these predictions were possible. Predicted mean tumor diameters correlated positively (pNF1 or RET mutations were correctly predicted with those mutations according to increased plasma metanephrine, whereas no or minimal increase in metanephrine correctly predicted all 71 patients with either VHL or SDHx mutations; furthermore, among the latter group increases in methoxytyramine correctly predicted SDHx mutations in 93% of the 29 cases for this specific prediction. Conclusions Extents and patterns of increased plasma O-methylated catecholamine metabolites among patients with PPGLs allow predictions of tumor size, adrenal vs. extra-adrenal locations and general types of mutations. Predictions of tumor location are, however, only possible for patients with clearly increased plasma methoxytyramine or metanephrine. Where possible or clinically relevant the predictions are potentially useful for subsequent clinical decision-making.

Background Fibromuscular dysplasia (FMD) is a non-atherosclerotic arterial disease that manifests as the presence of beaded or focal lesions in medium or small-sized arteries and may also include arterial dissection, aneurysm, and tortuosity. FMD could be revealed in various manifestations, however limited data on the involvement of the thoracic aorta is reported. Purpose To measure and evaluate involvement of thoracic aorta in patients with FMD. Methods We analysed aortas of 144 consecutive patients (mean age 50.2±14.0, 116 women) with confirmed FMD in at least one vascular bed. The control group consisted of 144 (mean age 50.5±14.0, 116 women) age and sex matched individuals. All patients underwent detailed clinical evaluation including angio-CT scan including aortic valve, thoracic aorta and coronary arteries. We measured the aortic valve annulus, sinus of valsalva, sinotubular junction, the diameters of ascending and descending aorta, aortic unfolding, the height of ostium of RCA and LCA and diameter of right and left coronary artery ostia in patients with fibromuscular dysplasia and compared them to matched controls. Results The FMD group had significantly smaller dimensions of aortic valve annulus and sinus of Valsalva than control group (2.3 [2.1–2.6] vs 2.9 [2.7–3.1] p Conclusions Patients with fibromuscular dysplasia display smaller dimensions of aortic valve and larger diameter of ascending and descending aorta as compared to control subjects. Despite the predominant clinical significance of focal pathologies in FMD patients, the disease may display a specific, pan-vascular phenotype. Funding Acknowledgement Type of funding source: None

Background Fibromuscular dysplasia (FMD) is a non-atherosclerotic arterial disease characterized by the presence of string-of-beads or focal stenosis. Other FMD-related lesions include arterial dissections, aneurysms, and tortuosity. However, limited data are available on the involvement of coronary arteries in pts diagnosed with “extra-coronary” FMD. Purpose To examine FMD-related coronary artery involvement, coronary artery lesions and coronary tortuosity in patients with a diagnosis of “extra-coronary” FMD. Methods In a case control study we enrolled 103 (age 45.7±13.2, 82 women) consecutive patients with a diagnosis of FMD, in whom atherosclerotic coronary artery disease was excluded on the basis of coronary CTA, and 96 (age 47.3±12.2, 75 women) sex- and age-matched controls without coronary atherosclerosis based on CTA imaging (Siemens Force 2x192 scanner). Detailed analysis of coronary arteries was assessed, with detailed analysis of arterial tortuosity, defined as curves >30 OR >45 OR >90 degrees. Tortuosity Index (TI) was defined as number of curves x artery length (centerline) / vector artery start-end. Each arterial tortuosity evaluation was performed per coronary segment AND per artery. Size (area, length) of coronary arteries was also measured. Results Intravessel symmetry sign and cork-screw sign were more common in arteries of FMD patients than in controls (5.4% vs 1.3%, p30 degrees) (0.777; 95% CI:0.713 to 0.833) or TI (0.794; 95% CI: 0.731 to 0.848), both in distal LAD. For the distal LAD indices, the best sensitivity and specificity values were for ≥4 curves (sens. 74%, spec. 72%) or for a TI >5.6 (sens. 55%, spec. 94%), respectively. These predictive values were confirmed after correction for potential confounders. Interestingly, neither proximal LAD or proximal LCx number of curves or TI were related to FMD. No difference was found in terms of areas of coronary arteries between FMD patients and controls, with the only exception of LM (20.8±6.6 vs 17.9±5.8, p=0.002). Mean coronary artery lenght was significantly different between controls and patients with FMD (respectively LM 8.4±4.2 vs 9.8±4.5, p=0.022; LAD 117.8±28.6 vs 109.1±30.2, p=0.042; LCx 85.2±43.9 vs 62.9±31.4, p Conclusions Distal and not proximal coronary arterial tortuosity is related to FMD. Coronary tortuosity defined as 4 distal LAD curves or a TI >5.6 are highly specific for FMD. Funding Acknowledgement Type of funding source: None

Fibromuscular dysplasia (FMD) is an arteriopathy that presents clinically by hypertension and stroke, mostly in early middle-aged women. We report results from the first genome-wide association meta-analysis of FMD including 1962 FMD cases and 7100 controls. We confirmedPHACTR1and identified three new loci (LRP1, ATP2B1, andLIMA1)associated with FMD. Transcriptome-wide association analysis in arteries identified one additional locus (SLC24A3). FMD associated variants were located in arterial-specific enhancers active in vascular smooth muscle cells and fibroblasts. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. Cross-trait linkage disequilibrium analyses identified positive genetic correlations with blood pressure, migraine and intracranial aneurysm, and an inverse correlation with coronary artery disease, independent from the genetics of blood pressure.

Mutations that drive the stabilization of hypoxia inducible factor 2α (HIF2α) and downstream pseudohypoxic signaling are known to predispose to the development of pheochromocytomas and paragangliomas (PPGLs). However, any role of HIF2α in predisposition to metastatic disease remains unclear. To assess such a role we combined gene-manipulations in pheochromocytoma cell lines with retrospective analyses of patient data and gene expression profiling in tumor specimens. Among 425 patients with PPGLs identified with mutations in tumor-susceptibility genes, those with tumors due to activation of pseudohypoxic pathways had a higher frequency of metastatic disease than those with tumors due to activation of kinase-signaling pathways, even without inclusion of patients with mutations in SDHB (18.6% vs 4.3% in, P < 0.0001). Three out of nine (33%) patients with gain-of-function mutations in HIF2α had metastatic disease. In cell line studies, elevated expression of HIF2α enhanced cell proliferation and led to increased migration and invasion capacity. Moreover, HIF2α expression in HIF2α-deficient cells resulted in increased cell motility, diffuse cluster formation and emergence of pseudopodia indicating changes in cell adhesion and cytoskeletal remodeling. In a mouse liver metastasis model, Hif2a enhanced the metastatic load. Transcriptomics data revealed alterations in focal adhesion and extracellular matrix–receptor interactions in HIF2α-mutated PPGLs. Our translational findings demonstrate that HIF2α supports pro-metastatic behavior in PPGLs, though other factors remain critical for subsequent transition to metastasis. We identified LAMB1 and COL4A2 as new potential therapeutic targets for HIF2α-driven PPGLs. Identified HIF2α downstream targets might open a new therapeutic window for aggressive HIF2α-expressing tumors.

Phaeochromocytoma and paraganglioma (PPGL) are chromaffin cell tumours that require timely diagnosis because of their potentially serious cardiovascular and sometimes life- threatening sequelae. Tremendous progress in biochemical testing, imaging, genetics and pathophysiological understanding of the tumours has far-reaching implications for physicians dealing with hypertension and more importantly affected patients. Because hypertension is a classical clinical clue for PPGL, physicians involved in hypertension care are those who are often the first to consider this diagnosis. However, there have been profound changes in how PPGLs are discovered; this is often now based on incidental findings of adrenal or other masses during imaging and increasingly during surveillance based on rapidly emerging new hereditary causes of PPGL. We therefore address the relevant genetic causes of PPGLs and outline how genetic testing can be incorporated within clinical care. In addition to conventional imaging (CT, MRI), new functional imaging approaches are evaluated. The novel knowledge of genotype-phenotype relationships, linking distinct genetic causes of disease to clinical behaviour and biochemical phenotype, provides the rationale for patient-tailored strategies for diagnosis, follow-up and surveillance. Most appropriate preoperative evaluation and preparation of patients are reviewed, as is minimally invasive surgery. Finally we discuss risk factors for developing metastatic disease and how they may facilitate personalised follow-up. Experts from the European Society of Hypertension have prepared this position document which summarises the current knowledge in epidemiology, genetics, diagnosis, treatment and surveillance of PPGL. CONDENSED ABSTRACT: Phaeochromocytomas and paragangliomas (PPGL) are rare causes of secondary hypertension. The unpredictable serious effects of tumoural surges of catecholamines into the circulation result in significant cardiovascular mortality and morbidity when the diagnosis is delayed or missed. After publication of the Endocrine Society Clinical Practice Guideline on PPGL in 2014, relevant new data have been published reflecting further scientific advances impacting on patient care. This position statement, written by the working group on Endocrine Hypertension of the European Society of Hypertension, provides an update in epidemiology, genetics, diagnosis and therapeutic and surveillance strategies for patients with PPGLs.

Introduction Polycythemia vera (PV) is a rare myeloproliferative disease associated with an increased prevalence of hypertension and increased risk of cardiovascular complications. However, the precise mechanisms leading to the elevation of blood pressure (BP) and secondary target organ damage remain poorly understood. Objectives The study aimed to evaluate BP profile, assess the activity of the sympathetic nervous system and the renin‑angiotensin system, and provide a comprehensive assessment of subclinical target organ damage in patients with PV. Patients and methods Twenty consecutive patients with newly diagnosed PV and 20 control subjects were included. The following were assessed: BP, levels of catecholamines, urinary and plasma O‑methylated catecholamine metabolites, concentrations of aldosterone and renin. We also assessed microneurography sympathetic nervous system activity (MSNA) and baroreflex control of heart rate as well as subclinical target organ damage. Results At similar levels of BP, BP variability was decreased in the PV group (mean [SD] 24‑hour systolic BP, 9 [3] vs 12 [3] mm Hg; P = 0.003). Patients with PV had lower norepinephrine excretion (mean [SD], 16.54 [6.32] vs 25.46 [12.88] μg/d; P = 0.03) as well as decreased MSNA as assessed by microneurography compared with controls (mean [SD] MSNA, 30.7 [8.7] bursts/min vs 38.7 [5.4] bursts/min; P = 0.007 and MSNA 51.8 [11] bursts/100 beats vs 61.1 [11.3] bursts/100 heart beats; P = 0.04). Baroreflex control of HR was unaltered in the PV group. Increased hemoglobin levels and red blood cell count correlated with decreased retinal capillary flow in patients with PV. Conclusions Patients with PV, characterized by high hemoglobin concentrations and hematocrit levels had lower sympathetic nervous activity and decreased BP variability as compared with controls. There was no relationship between hemoglobin plasma concentration, hematocrit level, and target organ damage.

Arterial hypertension [HT] is a global epidemic that requires adequate treatment to reduce cardiovascular morbidity and mortality. Secondary causes of HT and specifically endocrine hypertension [EHT] (primary hyperaldosteronism [PA], pheochromocytoma/paraganglioma [PPGL] and Cushing syndrome [CS]) can potentially be cured by surgery or treated by targeted medication. However, diagnosis of EHT requires expertise in test selection and interpretation of test results. The availability of experts outnumbers its demand. Thus, preselecting tools are necessary to identify patients who require further referral to an expert. Since targeted metabolomics [TM] is a new method showing promising results in profiling cardiovascular diseases and endocrine conditions associated with HT, we tested the ability of TM in discriminating primary hypertension [PHT] from EHT cases. The study included 282 adult patients (52% female; mean age 49 years) from the European multicentre consortium ENSAT-HT (www.ensat-ht.eu). Of these, 59 were diagnosed with PHT and 223 with EHT (40 CS, 107 PA and 76 PPGL). TM was performed on stored blood samples with a mass spectrometry based approach using the AbsoluteIDQTM p180 Kit (BIOCRATES Life Sciences, Austria). In total, 188 metabolites were determined, of which 155 were eligible for statistical analyses according to established selection criteria. To identify relevant discriminating metabolites, a series of univariate and multivariate analyses were applied. Since the distribution of the patients between the clinical entities was different according to sex (p

OBJECTIVE: Visceral artery fibromuscular dysplasia (VA FMD) manifestations range from asymptomatic to life-threatening. The aim of the study is to evaluate the prevalence and clinical characteristics of VA FMD. METHODS: A total of 232 FMD patients enrolled into ongoing ARCADIA-POL study were included in this analysis. All patients underwent detailed clinical evaluation including ambulatory blood pressure monitoring, biobanking, duplex Doppler of carotid and abdominal arteries and whole body angio-computed tomography. Three control groups (patients with renal FMD without visceral involvement, healthy normotensive patients and resistant hypertensive patients) matched for age and sex were included. RESULTS: VA FMD was present in 32 patients (13.8%). Among these patients (women: 84.4%), FMD lesions were more frequent in celiac trunk (83.1%), 62.5% of patients showed at least one visceral aneurysm, and five patients presented with severe complications related to VA FMD. No demographic differences were found between patients with VA FMD and individuals from the three control groups, with the exception of lower weight (P < 0.001) and BMI (P < 0.001) in VA FMD patients. Patients with FMD (with or without visceral artery involvement) showed significantly smaller visceral arterial diameters compared with controls without FMD. CONCLUSION: Patients with FMD showed smaller visceral arterial diameters when compared with patients without FMD. This may reflect a new phenotype of FMD, as a generalized arteriopathy, what needs further investigation. Lower BMI in patients with VA FMD might be explained by chronic mesenteric ischemia resulting from FMD lesions. FMD visceral involvement and visceral arterial aneurysms in patients with renal FMD are far to be rare. This strengthens the need for a systematic evaluation of all vascular beds, including visceral arteries, regardless of initial FMD involvement.

OBJECTIVE Structural abnormalities in resistance arteries are a hallmark of patients with hypertension. In hypertensive patients with pheochromocytoma or paraganglioma (PPGL), it is still a matter of debate whether structural vascular changes are because of elevated blood pressure (BP) or to toxic effects of elevated circulating catecholamines. Hence, the aim of our study was to assess whether catecholamine excess and/or elevated BP affect the structure of small retinal arteries in patients with catecholamine-producing tumors. METHODS The study included 27 patients with PPGL and 27 hypertensive patients. All patients underwent biochemical tests for catecholamine excess, echocardiography and analyses of scanning-laser-Doppler-flowmetry (SLDF) both at baseline and 12 months following surgical resection of PPGL. RESULTS Baseline retinal arterial diameter, arterial wall thickness and wall cross sectional area (WCSA) were higher in patients with PPGL as compared with subjects without PPGL (arterial diameter: 110 ± 16.5 vs. 99.5 ± 10.8 μm, wall thickness: 16.3 ± 6.0 vs. 13.5 ± 4.0 μm, WCSA: 4953.9 ± 2472.8 vs. 3784.1 ± 1446.3 μm, P

Smoking was identified as a potential factor contributing to fibromuscular dysplasia (FMD). To evaluate the prevalence of smoking and clinical characteristics in FMD subjects.We analysed 190 patients with confirmed FMD in at least one vascular bed. The rate of smokers in FMD patients was compared to that in two control groups selected from a nationwide survey.The rate of smokers in FMD patients was 42.6%. There were no differences in frequency of smokers between FMD patients and: a group of 994 matched control subjects from general population and a group of matched hypertensive subjects. There were no differences in the characteristics of FMD (including rates of multisite FMD and significant renal artery stenosis) and its complications (including rates of dissections and aneurysms) between smokers and non-smokers. Smokers as compared with non-smokers were characterized by higher left ventricle mass index.There is no difference in the rate of smokers between FMD patients and subjects from the general population. Moreover, we did not find any association between smoking and clinical characteristics of FMD patients nor its extent and vascular complications. Our results do not support the hypothesis that smoking is involved in the pathophysiology of FMD.

Objective To provide a comprehensive assessment of left ventricle (LV) structure, and function and to detect alterations in cardiac properties in relationship to presence, subtypes and extent of fibromuscular dysplasia (FMD). Methods We studied 144 patients with FMD. The control group consisted of 50 matched individuals. Office and ambulatory blood pressure levels were evaluated. Echocardiography was employed to assess: left ventricular mass index (LVMI), systolic function including speckle tracking echocardiography and diastolic function assessed by mitral flow and tissue Doppler imaging. Results There were no differences in LV morphology and function between patients with FMD and the control group. Among 128 patients with renal FMD, there were no differences in LVMI and LV systolic function between patients with unifocal and multifocal FMD. The patients with multifocal FMD were characterized by lower early diastolic velocity (e') as compared with unifocal FMD and control groups. However, in a multivariate regression model, e' was not independently correlated with FMD. There were no associations between echocardiographic indexes and vascular involvement of FMD. Also, there were no differences in LV morphology and function in patients with significant renal artery stenosis (RAS) compared with patients with history of significant RAS and patients with nonsignificant RAS. Conclusion Our study in contrast to those with atherosclerotic RAS, did not show differences in LV morphology and function between FMD patients and matched controls. Although FMD can result in hypertension and serious vascular complications, there is no proof that it can alter LV regardless of FMD type and its extent.

Objective Our objective was to improve molecular diagnostics in patients with hereditary pheochromocytoma and paraganglioma (PPGL) by using next-generation sequencing (NGS) multi-gene panel analysis. Derived from this study, we here present three cases that were diagnosed with NF1 germline mutations but did not have a prior clinical diagnosis of neurofibromatosis type 1 (NF1). Design We performed genetic analysis of known tumor predisposition genes, including NF1, using a multi-gene NGS enrichment-based panel applied to a total of 1029 PPGL patients. We did not exclude genes known to cause clinically defined syndromes such as NF1 based on missing phenotypic expression as is commonly practiced. Methods Genetic analysis was performed using NGS (TruSight Cancer Panel/customized panel by Illumina) for analyzing patients’ blood and tumor samples. Validation was carried out by Sanger sequencing. Results Within our cohort, three patients, who were identified to carry pathogenic NF1 germline mutations, attracted attention, since none of the patients had a clinical suspicion of NF1 and one of them was initially suspected to have MEN2A syndrome due to co-occurrence of a medullary thyroid carcinoma. In these cases, one splice site, one stop and one frameshift mutation in NF1 were identified. Conclusions Since phenotypical presentation of NF1 is highly variable, we suggest analysis of the NF1 gene also in PPGL patients who do not meet diagnostic NF1 criteria. Co-occurrence of medullary thyroid carcinoma and PPGL was found to be a clinical decoy in NF1 diagnostics. These observations underline the value of multi-gene panel NGS for PPGL patients.

Item does not contain fulltext BACKGROUND: Although unilateral primary aldosteronism is the most common surgically correctable cause of hypertension, no standard criteria exist to classify surgical outcomes. We aimed to create consensus criteria for clinical and biochemical outcomes and follow-up of adrenalectomy for unilateral primary aldosteronism and apply these criteria to an international cohort to analyse the frequency of remission and identify preoperative determinants of successful outcome. METHODS: The Primary Aldosteronism Surgical Outcome (PASO) study was an international project to develop consensus criteria for outcomes and follow-up of adrenalectomy for unilateral primary aldosteronism. An international panel of 31 experts from 28 centres, including six endocrine surgeons, used the Delphi method to reach consensus. We then retrospectively analysed follow-up data from prospective cohorts for outcome assessment of patients diagnosed with unilateral primary aldosteronism by adrenal venous sampling who had undergone a total adrenalectomy, consecutively included from 12 referral centres in nine countries. On the basis of standardised criteria, we determined the proportions of patients achieving complete, partial, or absent clinical and biochemical success in accordance with the consensus. We then used logistic regression analyses to identify preoperative factors associated with clinical and biochemical outcomes. FINDINGS: Consensus was reached for criteria for six outcomes (complete, partial, and absent success of clinical and biochemical outcomes) based on blood pressure, use of antihypertensive drugs, plasma potassium and aldosterone concentrations, and plasma renin concentrations or activities. Consensus was also reached for two recommendations for the timing of follow-up assessment. For the international cohort analysis, we analysed clinical data from 705 patients recruited between 1994 and 2015, of whom 699 also had biochemical data. Complete clinical success was achieved in 259 (37%) of 705 patients, with a wide variance (range 17-62), and partial clinical success in an additional 334 (47%, range 35-66); complete biochemical success was seen in 656 (94%, 83-100) of 699 patients. Female patients had a higher likelihood of complete clinical success (odds ratio [OR] 2.25, 95% CI 1.40-3.62; p=0.001) and clinical benefit (complete plus partial clinical success; OR 2.89, 1.49-5.59; p=0.002) than male patients. Younger patients had a higher likelihood of complete clinical success (OR 0.95 per extra year, 0.93-0.98; p