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Background: The prevalence of secondary causes of hypertension in young adults is unknown, and therefore, there is no consensus about the indication of screening of secondary hypertension (2HTN) in this population. The objective was to report the prevalence and the causes of 2HTN in young subjects., Methods: In this cross-sectional study, 2090 patients with confirmed hypertension aged 18 to 40 years with full workup for 2HTN screening were included. We assessed the prevalence of 2HTN and analyzed the factors associated., Results: Among 2090 patients, 619 (29.6%) had a 2HTN. The most frequent diagnoses of 2HTN in descending order were primary aldosteronism (n=339; 54.8%), renovascular hypertension (n=114; 18.4%), primary kidney disease (n=80; 12.9%), pheochromocytoma/functional paraganglioma (n=37; 5.9%), hypertension caused by drugs or substances (n=32; 6.0%), and other diagnoses (n=17; 2.7%). Patients with blood pressure <160/100 mm Hg did not have a lower prevalence of 2HTN regardless of the number of treatments. The prevalence of 2HTN was higher in the decade between 30 and 40 years of age than between 18 and 30 years of age ( P =0.024). Female sex, hypokalemia, treatment with at least 2 medications, no familial history of hypertension, body mass index <25 kg/m², and diabetes were associated with a higher prevalence of 2HTN., Conclusions: The prevalence of 2HTN is high among young patients with hypertension (29.6% in our cohort), regardless of age and blood pressure level. All patients with hypertension under 40 years of age should be screened for secondary causes., Competing Interests: None.

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

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

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.

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.

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Aldosterone-producing adenoma (APA) cause primary aldosteronism-the most frequent form of secondary hypertension. Somatic mutations in genes coding for ion channels and ATPases are found in APA and in aldosterone-producing cell clusters. We investigated the genetic, cellular, and molecular heterogeneity of different aldosterone-producing structures in adrenals with APA, to get insight into the mechanisms driving their development and to investigate their clinical and biochemical correlates. Genetic analysis of APA, aldosterone-producing cell clusters, and secondary nodules was performed in adrenal tissues from 49 patients by next-generation sequencing following CYP11B2 immunohistochemistry. Results were correlated with clinical and biochemical characteristics of patients, steroid profiles, and histological features of the tumor and adjacent adrenal cortex. Somatic mutations were identified in 93.75% of APAs. Adenoma carrying KCNJ5 mutations had more clear cells and cells expressing CYP11B1, and fewer cells expressing CYP11B2 or activated β-catenin, compared with other mutational groups. 18-hydroxycortisol and 18-oxocortisol were higher in patients carrying KCNJ5 mutations and correlated with histological features of adenoma; however, mutational status could not be predicted using steroid profiling. Heterogeneous CYP11B2 expression in KCNJ5 -mutated adenoma was not associated with genetic heterogeneity. Different mutations were identified in secondary nodules expressing aldosterone synthase and in independent aldosterone-producing cell clusters from adrenals with adenoma; known KCNJ5 mutations were identified in 5 aldosterone-producing cell clusters. Genetic heterogeneity in different aldosterone-producing structures in the same adrenal suggests complex mechanisms underlying APA development.

The effect of renal artery angioplasty on blood pressure in patients with true resistant hypertension and atherosclerotic renal artery stenosis has not been fully investigated due to the exclusion of these patients from most trials. In this study, we assessed the benefits of renal angioplasty on daytime ambulatory blood pressure (dABP) in this subgroup of patients. Medical records of our hypertension department were retrospectively analyzed from 2000 to 2016. Seventy-two patients were identified with resistant hypertension (dABP >135 or 85 mm Hg despite at least 3 antihypertensive drugs, including a diuretic) and atherosclerotic renal artery stenosis treated by angioplasty. Atherosclerotic renal artery stenosis was unilateral in 57 patients and bilateral in 15 patients. The mean age of the patients was 67.8±11.2 years; dABP was 157±16/82±10 mm Hg despite 4.0±1.0 antihypertensive treatments; estimated glomerular filtration rate was 52 (41-63) mL/min. After renal angioplasty, dABPM decreased by 14.0±17.3/6.4±8.7 mm Hg ( P <0.001 for both), and the number of antihypertensive treatments decreased to 3.6±1.4 ( P =0.002) with no significant change in estimated glomerular filtration rate. A high baseline systolic dABP and a low body mass index were independent predictors of systolic dABP changes. The decrease in dABP was confirmed in a subgroup of patients at one and 3 years of follow-up (N=31 and N=18 respectively, P ≤0.001 for systolic and diastolic blood pressure at both visits). In this retrospective uncontrolled single-center study, angioplasty in patients with atherosclerotic renal artery stenosis and with true resistant hypertension significantly decreased dABP, reducing the need for antihypertensive treatment with no change in estimated glomerular filtration rate.

We sought to measure the clinical benefits of adrenal venous sampling (AVS), a test recommended by guidelines for primary aldosteronism (PA) patients seeking surgical cure, in a large registry of PA patients submitted to AVS. Data of 1625 consecutive patients submitted to AVS in 19 tertiary referral centers located in Asia, Australia, Europe, and North America were collected in a large multicenter international registry. The primary end points were the rate of bilateral success, ascertained lateralization of PA, adrenalectomy, and of cured arterial hypertension among AVS-guided and non AVS-guided adrenalectomy patients. AVS was successful in 80.1% of all cases but allowed identification of unilateral PA in only 45.5% by the criteria in use at each center. Adrenalectomy was performed in 41.8% of all patients and cured arterial hypertension in 19.6% of the patients, 2-fold more frequently in women than men ( P <0.001). When AVS-guided, surgery provided a higher rate of cure of hypertension than when non-AVS-guided (40.0% versus 30.5%; P =0.027). Compared with surgical cases, patients treated medically needed more antihypertensive medications ( P <0.001) and exhibited a higher rate of persistent hypokalemia requiring potassium supplementation (4.9% versus 2.3%; P <0.01). The low rate of adrenalectomy and cure of hypertension in PA patients seeking surgical cure indicates suboptimal AVS use, possibly related to issues in patient selection, technical success, and AVS data interpretation. Given the better outcomes of AVS-guided adrenalectomy, these results call for actions to improve the diagnostic use of this test that is necessary for detection of surgical PA candidates. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01234220.

Fibromuscular dysplasia (FMD) commonly affects the renal and cervical arteries but has been described to affect other vascular beds as well. The prevalence of and clinical characteristics associated with multisite FMD (string-of-beds or focal stenoses affecting at least 2 vascular beds) are not known. In the prospective ARCADIA registry (Assessment of Renal and Cervical Artery Dysplasia), symptomatic patients with renal artery (RA) FMD underwent tomographic- or magnetic resonance-angiography from the aortic arch to the intracranial arteries and those with cervical FMD from the diaphragm to the pelvis. Of 469 patients (84.0% women), 225 (48.0%) had multisite FMD. In addition, 86 of 244 patients with single-site disease had dissections or aneurisms affecting other vascular beds, totaling 311 patients (66.3%) with lesions in >1 vascular bed. Among patients with a cerebrovascular presentation, the prevalence of RA lesions was higher in patients with than in those without hypertension (odds ratio, 3.4; 95% confidence interval, 1.99-6.15). Among patients with a renal presentation, the prevalence of cervical lesions was higher in patients with bilateral than in those with unilateral RA lesions (odds ratio, 1.9; 95% confidence interval, 0.99-3.57). In conclusion, FMD is a systemic arterial disease. At least 2 vascular beds were affected by dysplastic stenoses in 48.0% of cases and by dysplastic stenoses, aneurysms, and dissections in 66.1% of cases. RA imaging should be proposed to hypertensive patients with a cerebrovascular presentation. Cervical artery imaging should be considered in patients with a renal presentation and bilateral RA lesions., Clinical Trial Registration: URL: www.Clinicaltrials.gov. Unique identifier: NCT02884141., (© 2017 American Heart Association, Inc.)

Guidelines recommend suppression tests such as the saline infusion test (SIT) to ascertain the diagnosis of primary aldosteronism (PA) in patients with a high aldosterone:renin ratio. However, suppression tests have only been evaluated in small retrospective series, and some experts consider that they are not helpful for the diagnosis of PA. In this study, we evaluated whether low post-SIT aldosterone concentrations do exclude lateralized PA. Between February 2009 and December 2013, 199 patients diagnosed with PA on the basis of 2 elevated aldosterone:renin ratio results and a high basal plasma or urinary aldosterone level or high post-SIT aldosterone level had a selective adrenal venous sampling. We used a selectivity index of 2 and a lateralization index of 4 to interpret the adrenal venous sampling results. Baseline characteristics of the patients were the following (percent or median): men 63%, 48 years old, office blood pressure 142/88 mm Hg, serum potassium 3.4 mmol/L, aldosterone:renin ratio 113 pmol/mU, plasma aldosterone concentration 588 pmol/L. The proportion of patients with lateralized adrenal venous sampling was 12 of 41 (29%) among those with post-SIT aldosterone <139 pmol/L (5 ng/dL) and 38 of 104 (37%) among those with post-SIT aldosterone <277 pmol/L (10 ng/dL). Post-SIT aldosterone levels were not associated with the blood pressure outcome of adrenalectomy. A low post-SIT aldosterone level cannot rule out lateralized PA, even with a low threshold (139 pmol/L). Adrenal venous sampling should be considered for patients who are eligible for surgery with elevated basal aldosterone levels even if they have low aldosterone concentrations after recumbent saline suppression testing., (© 2016 American Heart Association, Inc.)

Primary aldosteronism is the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D are found in aldosterone-producing adenoma. In addition, adrenals with aldosterone-producing adenomas show cortical remodeling and frequently multiple secondary nodules. Our aim was to investigate whether different aldosterone-producing nodules from the same adrenal share the same mutational status. Aldosterone synthase expression was assessed in multinodular adrenals from 27 patients. DNA of 37 aldosterone-producing secondary nodules was extracted from formalin-fixed paraffin-embedded tissues and genotyped for KCNJ5, ATP1A1, ATP2B3, and CACNA1D mutations. Among 17 adrenals with a somatic mutation in the principal nodule, 4 showed the same mutation in a secondary nodule, whereas 10 had no mutation in any of the known genes. In 1 adrenal harboring the KCNJ5 p.Gly151Arg mutation in the principal nodule, the same mutation was present in 2 secondary nodules, but no mutation was found in a third nodule. Finally, in 2 adrenals with a CACNA1D mutation in the principal nodule, a KCNJ5 mutation was identified in the secondary nodule. Among 10 adrenals without mutations in the principal nodule, 1 carried a KCNJ5 mutation in the secondary nodule. No mutations were detected in 7 aldosterone-producing cell clusters from 6 adrenals. No association was observed between the presence of mutations in secondary nodules and clinical parameters. In conclusion, different mutations are found in different aldosterone-producing nodules from the same adrenal, suggesting that somatic mutations are independent events triggered by mechanisms that remain to be identified., (© 2015 American Heart Association, Inc.)

Guidelines promote the use of adrenal vein sampling (AVS) to document lateralized aldosterone hypersecretion in primary aldosteronism. However, there are large discrepancies between institutions in the criteria used to interpret its results. This study evaluates the consequences of these differences on the classification and management of patients. The results of all 537 AVS procedures performed between January 2001 and July 2010 in our institution were interpreted with 4 diagnostic criteria used in experienced institutions where AVS is performed without cosyntropin (Brisbane, Padua, Paris, and Turin) and with criteria proposed by a recent consensus statement. AVS procedures were classified as unsuccessful, lateralized, or not lateralized according to each set of criteria. Almost 5× more AVS procedures were classified as unsuccessful with the strictest criteria than with the least strict criteria (18% versus 4%, respectively). Similarly, over 2× more AVS procedures were classified as lateralized with the least stringent criteria than with the most stringent criteria (60% versus 26%, respectively). Multiple samples were available from ≥1 side for 155 AVS procedures. These procedures were classified differently by ≥2 right-left sample pairs in 12% to 20% of cases. Thus, different sets of criteria used to interpret AVS in experienced institutions translate into heterogeneous classifications and hence management decisions, for patients with primary aldosteronism. Defining the most appropriate procedures and diagnostic criteria is needed for AVS to achieve optimal performance and fully justify its status as a gold standard., (© 2015 American Heart Association, Inc.)

Primary aldosteronism is the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D have been described in aldosterone-producing adenomas (APAs). Our aim was to investigate the prevalence of somatic mutations in these genes in unselected patients with APA (n=474), collected through the European Network for the Study of Adrenal Tumors. Correlations with clinical and biochemical parameters were first analyzed in a subset of 199 patients from a single center and then replicated in 2 additional centers. Somatic heterozygous KCNJ5 mutations were present in 38% (180/474) of APAs, whereas ATP1A1 mutations were found in 5.3% (25/474) and ATP2B3 mutations in 1.7% (8/474) of APAs. Previously reported somatic CACNA1D mutations as well as 10 novel CACNA1D mutations were identified in 44 of 474 (9.3%) APAs. There was no difference in the cellular composition of APAs or in CYP11B2, CYP11B1, KCNJ5, CACNA1D, or ATP1A1 gene expression in APAs across genotypes. Patients with KCNJ5 mutations were more frequently female, diagnosed younger, and with higher minimal plasma potassium concentrations compared with CACNA1D mutation carriers or noncarriers. CACNA1D mutations were associated with smaller adenomas. These associations were largely dependent on the population structure of the different centers. In conclusion, recurrent somatic mutations were identified in 54% of APAs. Young women with APAs are more likely to be KCNJ5 mutation carriers; identification of specific characteristics or surrogate biomarkers of mutation status may lead to targeted treatment options., (© 2014 American Heart Association, Inc.)

A higher risk of cardiovascular events has been reported in patients with primary aldosteronism (PA) than in otherwise similar patients with essential hypertension (EH). However, the evidence is limited by small sample size and potential confounding factors. We, therefore, compared the prevalence of cardiovascular events in 459 patients with PA diagnosed in our hypertension unit from 2001 to 2006 and 1290 controls with EH. PA cases and EH controls were individually matched for sex, age (± 2 years), and office systolic blood pressure (± 10 mm Hg). Patients with PA and EH differed significantly in duration of hypertension, serum potassium, plasma aldosterone and plasma renin concentrations, aldosterone-to-renin ratio, and urinary aldosterone concentration (P<0.001 for all comparisons). The prevalence of electrocardiographic and echocardiographic left ventricular hypertrophy was about twice higher in patients with PA even after adjustment for hypertension duration. PA patients also had a significantly higher prevalence of coronary artery disease (adjusted odds ratio, 1.9), nonfatal myocardial infarction (adjusted odds ratio, 2.6), heart failure (adjusted odds ratio, 2.9), and atrial fibrillation (adjusted odds ratio, 5.0). The risks associated with PA were similar across levels of serum potassium and plasma aldosterone. To conclude, patients with PA are more likely to have had a cardiovascular complication at diagnosis than otherwise similar patients with EH. Target organ damage and complications disproportionate to blood pressure should be considered as an additional argument for suspecting PA in a given individual and possibly for broadening the scope of screening at the population level.

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, n=380) and peripheral (APA, n=344; bilateral adrenal hyperplasia, n=174) 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%; P<10(-3)) and in younger patients (42.1±1.0 versus 47.6±0.7 years; P<10(-3)) and were associated with higher preoperative aldosterone levels (455±26 versus 376±17 ng/L; P=0.012) 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.

Primary aldosteronism is the most frequent cause of endocrine hypertension. Three forms of familial hyperaldosteronism (FH) have been described, named FH-I to -III. Recently, a mutation of KCNJ5 has been shown to be associated with FH-III, whereas the cause of FH-II is still unknown. In this study we searched for mutations in KCNJ5 in 46 patients from 21 families with FH, in which FH-I was excluded. We identified a new germline G151E mutation in 2 primary aldosteronism-affected subjects from an Italian family and 3 somatic mutations in aldosterone-producing adenomas, T158A described previously as a germline mutation associated with FH-III, and G151R and L168R both described as somatic mutations in aldosterone-producing adenoma. The phenotype of the family with the G151E mutation was remarkably milder compared with the previously described American family, in terms of both clinical and biochemical parameters. Furthermore, patients with somatic KCNJ5 mutations displayed a phenotype indistinguishable from that of sporadic primary aldosteronism. The functional characterization of the effects of the G151E mutation in vitro showed a profound alteration of the channel function, with loss of K(+) selectivity, Na(+) influx, and membrane depolarization. These alterations have been postulated to be responsible for voltage gate Ca(2+) channel activation, increase in cytosolic calcium, and stimulation of aldosterone production and adrenal cell proliferation. In conclusion, we describe herein a new mutation in the KCNJ5 potassium channel associated with FH-III, responsible for marked alterations of channel function but associated with a mild clinical and hormonal phenotype.

Primary aldosteronism is the most common form of secondary hypertension with hypokalemia and suppressed renin-angiotensin system caused by autonomous aldosterone production. Our aim was to compare zona glomerulosa (ZG) structure and function between control adrenals and the peritumoral tissue from patients operated on for aldosterone-producing adenoma. ZG morphology and CYP11B1, CYP11B2, and disabled 2 expression were studied in 15 control adrenals and 25 adrenals with aldosterone-producing adenoma. A transcriptome analysis was done using publicly available data sets. In control adrenals, ZG was discontinuous, and CYP11B2 expression was focal or partly continuous and localized to 3 structures, foci, megafoci, and aldosterone-producing cell clusters. CYP11B2 expression was restricted to a limited number of ZG cells expressing Dab2 but not CYP11B1; aldosterone-producing cell clusters were composed of cells with an intermediate phenotype expressing CYP11B2 but not disabled 2 or CYP11B1. In peritumoral tissue, large remodeling of the adrenal cortex was observed with increased nodulation and decreased vascularization that were not correlated with CYP11B2 expression. In 17 out of 25 adrenals, hyperplasia of adjacent ZG was observed with persistent expression of CYP11B2 that was extended to the entire ZG. In all of the adrenals from patients with aldosterone-producing adenoma, CYP11B2 expression was present in foci, megafoci, and aldosterone-producing cell clusters. Transcriptome profiling indicates a close relationship between peritumoral and control adrenal cortex. In conclusion, adrenal cortex remodeling, reduced vascularization, and ZG hyperplasia are major features of adrenals with aldosterone-producing adenoma. Transcriptional phenotyping is not in favor of this being an intermediate step toward the formation of aldosterone-producing adenoma.

We report the first administration of an orally active aldosterone synthase inhibitor, LCI699, to 14 patients with primary aldosteronism. After a 2-week placebo run-in, patients received oral LCI699 (0.5 mg BID) for 2 weeks, LCI699 (1.0 mg BID) for 2 weeks, and placebo for 1 week. We assessed changes in hormone concentrations, plasma potassium levels, and 24-hour ambulatory systolic blood pressure and safety. The supine plasma aldosterone concentration decreased from 540 pmol/L (95% CI: 394 to 739 pmol/L) to 171 pmol/L (95% CI: 128 to 230 pmol/L) after 0.5 mg of LCI699 (-68%; P<0.0001) and to 133 pmol/L (95% CI: 100 to 177 pmol/L) after 1.0 mg of LCI699 (-75%; P<0.0001). Plasma 11-deoxycorticosterone concentrations increased by 710% after 0.5 mg of LCI699 (P<0.0001) and by 1427% after 1.0 mg of LCI699 (P<0.0001). The plasma potassium concentration increased from 3.27±0.31 to 4.03±0.33 mmol/L (P<0.0001) after only 1 week on 0.5 mg of LCI699. Twenty-four-hour ambulatory systolic blood pressure decreased by -4.1 mm Hg (95% CI: -8.1 to -0.1 mm Hg) after 4 weeks of treatment (P=0.046). Basal plasma cortisol concentrations remained unchanged, whereas plasma adrenocorticotropic hormone concentrations increased by 35% after 0.5 mg of LCI699 (P=0.08) and by 113% after 1.0 mg of LCI699 (P<0.0001), and the plasma cortisol response to an adrenocorticotropic hormone test was blunted. All of the variables except plasma 11-deoxycorticosterone concentration returned to initial levels after the placebo. LCI699 was well tolerated. In conclusion, the administration of LCI699, up to 1.0 mg BID, effectively and safely inhibits aldosterone synthase in patients with primary aldosteronism. This 4-week treatment corrected the hypokalemia and mildly decreased blood pressure. The effects on the glucocorticoid axis were consistent with a latent inhibition of cortisol synthesis.

An association between primary aldosteronism and metabolism disorders has been reported. The aim of this retrospective study was to test for this association by comparison between large cohorts of patients with primary aldosteronism and with essential hypertension. We retrieved the records of 460 cases with primary aldosteronism (103 lateralized, 150 not lateralized, and 207 undetermined) and of 1363 controls with essential hypertension individually matched for age and sex. We compared clinical history; blood pressure levels; body mass index; levels of fasting plasma glucose and serum triglycerides; total, high-density lipoprotein, and low-density lipoprotein cholesterol; and the prevalence of diabetes mellitus and impaired fasting glucose among subtypes of primary aldosteronism, as well as between cases with primary aldosteronism and their matched controls. Fasting plasma glucose and serum lipid levels did not differ among the 3 subtypes of primary aldosteronism. The prevalence of impaired fasting glucose was lower in patients with primary aldosteronism than their matched controls, but the prevalence of hyperglycemia (impaired fasting glucose or diabetes mellitus) and blood levels of glucose and lipids did not differ between cases and controls. There was no significant difference between preoperative and postoperative levels of either fasting plasma glucose or serum lipids in patients who underwent adrenalectomy and had follow-up data available. The analysis of this large group of patients with primary aldosteronism and essential hypertension does not confirm a higher prevalence of carbohydrate or lipid metabolism disorders in the former. It is unlikely that the prevalence of metabolic syndrome differs significantly between patients with primary aldosteronism and those with essential hypertension.