Hypertension Editors' Picks: Hyperaldosteronism.

Abstract

HomeHypertensionVol. 77, No. 2Hypertension Editors’ Picks Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessIn BriefPDF/EPUBHypertension Editors’ PicksHyperaldosteronism The Editors The Editors Search for more papers by this author Originally published14 Jan 2021https://doi.org/10.1161/HYPERTENSIONAHA.120.15141Hypertension. 2021;77:e17–e28Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 13, 2021: Previous Version of Record These abstracts represent the rich vein of laboratory and clinical research that flows from the celebration in 2003 of the 50th anniversary of the discovery of aldosterone, by the Taits at the Middlesex Hospital in London, followed only 1 year later by Jerome Conn’s recognition of the first patient with an aldosterone-producing adenoma. After the discoveries, 2011 to 2013, of characteristic gain-of-function somatic mutations in aldosterone-producing adenomas, the authors continue to find occasional new mutations. Now we learn of gross ethnic differences in prevalence of the major mutations. Celso Gomez-Sanchez’s monoclonal antibody to CYP11B2 (aldosterone synthase) is essential to most papers about the microscopic aldosterone-producing cell clusters, including the tantalizing observation that mutations in the calcium channel gene, CACNA1D, which are commonest in the adenomas from Black patients with primary aldosteronism, are also the most frequent in aldosterone-producing cell clusters and that these clusters are more likely than hyperplasia to underlie bilateral disease. Whether CACNA1D mutations occur mainly in the metabolically active, pre-adenomatous aldosterone-producing cell clusters is the next question, followed perhaps by the development of selective inhibitors of the encoded Cav1.3 channel. Clinically, authors grapple with the paradox that primary aldosteronism is diagnosed in <1% of patients, and yet newer tests—nonstandard (hybrid) steroids, superselective adrenal vein sampling—are restricted to a few centers. New treatments also feature, including a bench-to-bedside report of an aldosterone synthase inhibitor, now in phase 2. In the decade when aldosterone and aldosterone-producing adenomas were first discovered, a whole organ—the stomach—was commonly removed as treatment of another 1- to 2-cm benign lesion, peptic ulcer. In primary aldosteronism, we still remove a whole organ to effect cure. Could one of the molecular pathways featuring in these articles lead to the omeprazole of the adrenal?Comprehensive Analysis of Steroid Biomarkers for Guiding Primary Aldosteronism Subtyping1AbstractAdrenal vein (AV) sampling (AVS) is required to distinguish unilateral from bilateral aldosterone sources in primary aldosteronism (PA), and cortisol is used for AVS data interpretation, but cortisol has several pitfalls. In this study, we present the utility of several other steroids in PA subtyping, both during AVS and in peripheral serum. We included patients with PA who underwent AVS at the University of Michigan between 2012 and 2018. We used mass spectrometry to simultaneously quantify 17 steroids in AVs and periphery, both at baseline and after cosyntropin administration. PA was classified as unilateral or bilateral based on a lateralization index ≥4 or <4, respectively, separately for baseline and post-cosyntropin administration. Of 131 participants, AV catheterization was deemed failed in 28 (21%) patients (36 AVs) at baseline. Eight steroids demonstrated higher AV/periphery ratios than cortisol (P<0.01 for all); 11β-hydroxyandrostenedione, 11-deoxycortisol, and corticosterone rescued most failed baseline catheterizations. Lateralization was generally consistent when using these alternative steroids. Based on pre- and post-cosyntropin data, the remaining 103 patients were classified as U/U, 37; B/B, 32; U/B, 20; and B/U, 14. Discriminant analysis of multisteroid panels from peripheral serum showed distinct profiles across the 4 groups, with the highest aldosterone, 18-oxocortisol, and 11-deoxycorticosterone in U/U patients. In conclusion, 11β-hydroxyandrostenedione and 11-deoxycortisol are superior to cortisol for AVS data interpretation. Single-assay multisteroid panels measured in peripheral serum are helpful in stratified PA subtyping and have the potential to circumvent AVS in a subset of patients with PA.Mass Spectrometry Imaging Establishes 2 Distinct Metabolic Phenotypes of Aldosterone-Producing Cell Clusters in Primary Aldosteronism2AbstractAldosterone-producing adenomas (APAs) are one of the main causes of primary aldosteronism and the most prevalent surgically correctable form of hypertension. Aldosterone-producing cell clusters (APCCs) comprise tight nests of zona glomerulosa cells, strongly positive for CYP11B2 (aldosterone synthase) in immunohistochemistry. APCCs have been suggested as possible precursors of APAs because they frequently carry driver mutations for constitutive aldosterone production, and a few adrenal lesions with histopathologic features of both APCCs and APAs have been identified. Our objective was to investigate the metabolic phenotypes of APCCs (n=27) compared with APAs (n=6) using in situ matrix-assisted laser desorption/ionization mass spectrometry imaging of formalin-fixed paraffin-embedded adrenals from patients with unilateral primary aldosteronism. Specific distribution patterns of metabolites were associated with APCCs and classified 2 separate APCC subgroups (subgroups 1 and 2) indistinguishable by CYP11B2 immunohistochemistry. Metabolic profiles of APCCs in subgroup 1 were tightly clustered and distinct from subgroup 2 and APAs. Multiple APCCs from the same adrenal displayed metabolic profiles of the same subgroup. Metabolites of APCC subgroup 2 were highly similar to the APA group and indicated enhanced metabolic pathways favoring cell proliferation compared with APCC subgroup 1. In conclusion, we demonstrate specific subgroups of APCCs with strikingly divergent distribution patterns of metabolites. One subgroup displays a metabolic phenotype convergent with APAs and may represent the progression of APCCs to APAs.Presence of Subclinical Hypercortisolism in Clinical Aldosterone-Producing Adenomas Predicts Lower Clinical Success3AbstractThe clinical characteristics and outcomes in patients with clinical aldosterone-producing adenomas harboring KCNJ5 mutations with or without subclinical hypercortisolism remain unclear. This prospective study is aimed at determining factors associated with subclinical hypercortisolism in patients with clinical aldosterone-producing adenomas. Totally, 82 patients were recruited from November 2016 to March 2018 and underwent unilateral laparoscopic adrenalectomy with at least a 12-month follow-up postoperatively. Standard subclinical hypercortisolism (defined as cortisol >1.8 mug/dL after 1 mg dexamethasone suppression test [DST]) was detected in 22 (26.8%) of the 82 patients. Intriguingly, a generalized additive model identified the clinical aldosterone-producing adenoma patients with 1 mg DST >1.5 mug/dL had significantly larger tumors (P=0.02) than those with 1 mg DST <1.5 mug/dL. Multivariable logistic regression showed that the presence of KCNJ5 mutations (odds ratio, 0.22; P=0.010) and body mass index (odds ratio, 0.87; P=0.046) were negatively associated with 1 mg DST >1.5 mug/dL, whereas tumor size was positively associated with it (odds ratio, 2.85; P=0.014). Immunohistochemistry revealed a higher degree of immunoreactivity for CYP11B1 in adenomas with wild-type KCNJ5 (P=0.018), whereas CYP11B2 was more commonly detected in adenomas with KCNJ5 mutation (P=0.007). Patients with wild-type KCNJ5 and 1 mg DST >1.5 mug/dL exhibited the lowest complete clinical success rate (36.8%) after adrenalectomy. In conclusion, subclinical hypercortisolism is common in clinical aldosterone-producing adenoma patients without KCNJ5 mutation or with a relatively larger adrenal tumor. The presence of serum cortisol levels >1.5 mug/dL after 1 mg DST may be linked to a lower clinical complete success rate.Nadir Aldosterone Levels After Confirmatory Tests Are Correlated With Left Ventricular Hypertrophy in Primary Aldosteronism4AbstractLeft ventricular hypertrophy (LVH) is often seen in patients with primary aldosteronism (PA), and the prevalence of LVH is reportedly higher among patients with PA than patients with essential hypertension. However, the correlation between aldosterone levels and LVH is undefined, and how aldosterone affects LVH in patients with PA remains unclear. We, therefore, retrospectively assessed a large PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) to reveal the factors associated with LVH in patients with PA without suspected autonomous cortisol secretion. In the 1186 patients with PA studied, the basal plasma aldosterone concentration, plasma renin activity, and the aldosterone-to-renin ratio did not significantly correlate with left ventricular mass index (LVMI) in single or multiple regression analyses. However, the plasma aldosterone concentration after the captopril challenge test or saline-infusion test, which are associated with autonomous aldosterone secretion, correlated significantly with LVMI, even after adjusting for patients’ backgrounds, including age and blood pressure. In addition, hypokalemia and the unilateral subtype also correlated with LVMI. Longitudinal subanalysis of medically or surgically treated patients with PA showed significant reductions in LVMI in both the surgery (63.0±18.1 to 55.3±19.5 g/m2.7; P<0.001) and drug treatment (56.8±14.1 to 52.1±13.5 g/m2.7; P<0.001) groups. Our results suggest the autonomous aldosterone secretion level, not the basal aldosterone level itself, is relevant to LVH in patients with PA. In addition, the elevated LVMI seen in patients with PA is at least partially reversible with surgical or medical treatment.Somatic CACNA1H Mutation As a Cause of Aldosterone-Producing Adenoma5AbstractDriver somatic mutations for aldosterone excess have been found in ≈90% of aldosterone-producing adenomas (APAs) using a CYP11B2 (aldosterone synthase)-guided sequencing approach. In the present study, we identified a novel somatic CACNA1H mutation (c.T4289C, p.I1430T) in an APA without any currently known aldosterone-driver mutations using CYP11B2 immunohistochemistry-guided whole exome sequencing. The CACNA1H gene encodes a voltage-dependent T-type calcium channel α-1H subunit. Germline variants in this gene are known as a cause of familial hyperaldosteronism IV. Targeted next-generation sequencing detected identical CACNA1H variants in 2 additional APAs in a cohort of the University of Michigan, resulting in a prevalence of 4% (3 of 75) in APAs. We tested the functional effect of the variant on adrenal cell aldosterone production and CYP11B2 mRNA expression using the human adrenocortical HAC15 cell line with a doxycycline-inducible CACNA1H(I1430T) mutation. Doxycycline treatment increased CYP11B2 mRNA levels, as well as aldosterone production, supporting a pathological role of the CACNA1H p.I1430T mutation on the development of primary aldosteronism. In conclusion, somatic CACNA1H mutation is a genetic cause of APAs. Although the prevalence of this mutation is low, this study will provide better understanding of molecular mechanism of inappropriate aldosterone production in APAs.Impaired Glucose Tolerance in Primary Aldosteronism: Mechanism(s) and Clinical Implications6ExtractAldosterone is a potent mineralocorticoid that increases sodium reabsorption and facilitates potassium secretion in epithelial tissue (eg, distal renal tubule, distal colon, and salivary glands). The response to aldosterone is mediated by the mineralocorticoid receptor. Beyond this classic action in sodium-transporting epithelia, aldosterone has direct effects on other tissues, particularly the cardiovascular system, that induce an inflammatory cascade leading to cardiac fibrosis. Although high-affinity binding sites have been identified in nonepithelial tissue, the underlying signaling pathways remain to be fully clarified.Precise Mapping of Intra-Adrenal Aldosterone Activities Provides a Novel Surgical Strategy for Primary Aldosteronism7AbstractSegmental selective adrenal venous sampling (sAVS) elucidates an intra-adrenal aldosterone activity map (IAMap), which allows us to design a novel surgical treatment strategy for patients with primary aldosteronism. We evaluated the usefulness of sAVS by analyzing 278 patients with whom we had prospectively used IAMap using the criteria of sAVS for surgical indication between 2009 and 2015. We evaluated its diagnostic accuracy using pathological and postsurgical biochemical and clinical outcomes. One hundred twenty and 158 patients were diagnosed with unilateral and bilateral disease, respectively, through sAVS. The concordance of lateralization diagnosis with computed tomography imaging was 66.6%. Among the unilateral patients, we performed partial adrenalectomy in 68 patients whose IAMap showed focal aldosterone hypersecretion from computed tomography-detectable tumor in the affected adrenal gland. All of them achieved complete biochemical success 1 year after surgery. Furthermore, 25 of 158 bilateral disease patients underwent surgical resection because they were preoperatively diagnosed as bilateral aldosterone-producing adenomas by IAMap. These cases showed complete or partial biochemical success (28.0% and 72.0%, respectively); 36.0% showed complete clinical success. Pathological studies demonstrated that all 145 resected specimens possessed aldosterone-producing adenoma or multiple nodules (132 and 13 cases, respectively), and none showed diffuse hyperplasia. IAMap accurately diagnosed both bilateral and unilateral aldosterone-producing adenomas and diffuse hyperplasia before surgery. sAVS allows a novel surgical strategy for selected primary aldosteronism patients with favorable outcomes.Screening Rates for Primary Aldosteronism in Resistant Hypertension: a Cohort Study8AbstractResistant hypertension is associated with higher rates of cardiovascular disease, kidney disease, and death than primary hypertension. Although clinical practice guidelines recommend screening for primary aldosteronism among persons with resistant hypertension, rates of screening are unknown. We identified 145 670 people with hypertension and excluded people with congestive heart failure or advanced chronic kidney disease. Among this cohort, we studied 4660 people aged 18 to <90 years from the years 2008 to 2014 with resistant hypertension and available laboratory tests within the following 24 months. The screening rate for primary aldosteronism in people with resistant hypertension was 2.1%. Screened people were younger (55.9±13.3 versus 65.5±11.6 years; P<0.0001) and had higher systolic (145.1±24.3 versus 139.6±20.5 mm Hg; P=0.04) and diastolic blood pressure (81.8±13.6 versus 74.4±13.8 mm Hg; P<0.0001), lower rates of coronary artery disease (5.2% versus 14.2%; P=0.01), and lower serum potassium concentrations (3.9±0.6 versus 4.1±0.5 mmol/L; P=0.04) than unscreened people. Screened people had significantly higher rates of prescription for calcium channel blockers, mixed α/β-adrenergic receptor antagonists, sympatholytics, and vasodilators and lower rates of prescription for loop, thiazide, and thiazide-type diuretics. The prescription of mineralocorticoid receptor antagonists or other potassium-sparing diuretics was not significantly different between groups (P=0.20). In conclusion, only 2.1% of eligible people received a screening test within 2 years of meeting criteria for resistant hypertension. Low rates of screening were not due to the prescription of antihypertensive medications that may potentially interfere with interpretation of the screening test. Efforts to highlight guideline-recommended screening and targeted therapy are warranted.Endoplasmic Reticulum Chaperone Calmegin Is Upregulated in Aldosterone-Producing Adenoma and Associates With Aldosterone Production9AbstractThe endoplasmic reticulum (ER) plays a pivotal role in syntheses of proteins and steroid hormones and regulation of intracellular Ca(2+) level. We aimed to investigate ER-associated genes in aldosterone-producing adenomas (APAs) and clarify their effect on aldosterone production. Microarray analysis targeting 288 ER-associated genes was conducted using nonfunctioning adrenocortical adenomas (n=5) and APAs (n=19). Immunohistochemistry and quantitative polymerase chain reaction analyses were performed with 13 nonfunctioning adrenocortical adenoma and 48 APA samples. Functional studies were performed with human adrenocortical carcinoma (HAC15) cells, some of which were genetically modified using lentiviruses. The ER chaperone calmegin (CLGN) was the most highly expressed ER-associated gene in APAs relative to nonfunctioning adrenocortical adenomas. Analysis with quantitative polymerase chain reaction revealed CLGN to be 9.5-fold upregulated in APAs relative to nonfunctioning adrenocortical adenomas. There were no differences among different APA genotypes affecting aldosterone production. Immunohistochemistry analysis revealed that CLGN was strongly expressed in APAs and aldosterone-producing cell clusters. Angiotensin II stimulation or KCNJ5 T158A overexpression in HAC15 cells did not affect CLGN mRNA levels. CLGN overexpression in HAC15 cells increased aldosterone levels but did not stimulate CYP11B2 (aldosterone synthase) mRNA levels. Pathway and gene ontology analyses using RNA sequencing results showed that tRNA aminoacyl metabolism was the most enriched pathway in CLGN-overexpressing cells. CYP11B2 and HSD3B2 (3 beta-hydroxysteroid dehydrogenase/delta 5->4-isomerase type 2) protein expression were more abundant in CLGN-overexpressing cells. CLGN knockdown using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9) method in HAC15 cells that carry the KCNJ5 mutation did not affect aldosterone production. To summarize, CLGN was upregulated and associated with aldosterone production via translational regulation of CYP11B2 in APAs.Effects of Ramipril on the Aldosterone/Renin Ratio and the Aldosterone/Angiotensin II Ratio in Patients With Primary Aldosteronism10AbstractThe aldosterone/renin ratio (ARR) is currently considered the most reliable approach for case detection of primary aldosteronism (PA). ACE (angiotensin-converting enzyme) inhibitors are known to raise renin and lower aldosterone levels, thereby causing false-negative ARR results. Because ACE inhibitors lower angiotensin II levels, we hypothesized that the aldosterone/equilibrium angiotensin II ratio (AA2R) would remain elevated in PA. Receiver operating characteristic curve analysis involving 60 patients with PA and 40 patients without PA revealed that the AA2R was not inferior to the ARR in screening for PA. When using liquid chromatography–tandem mass spectrometry to measure plasma aldosterone concentration, the predicted optimal AA2R cutoff for PA screening was 8.3 (pmol/L)/(pmol/L). We then compared the diagnostic performance of the AA2R with the ARR among 25 patients with PA administered ramipril (5 mg/day) for 2 weeks. Compared with basally, plasma levels of equilibrium angiotensin I and direct renin concentration increased significantly (P<0.01 or P<0.05) after ramipril treatment, whereas equilibrium angiotensin II and ACE activity (equilibrium angiotensin II/equilibrium angiotensin I) decreased significantly (P<0.01). The changes of plasma renin activity and plasma aldosterone concentration in the current study were not significant. On day 14, 4 patients displayed false-negative results using ARR_direct renin concentration (plasma aldosterone concentration/direct renin concentration), 3 of whom also showed false-negative ARR_plasma renin activity (plasma aldosterone concentration/plasma renin activity). On day 15, 2 patients still demonstrated false-negative ARR_plasma renin activity, one of whom also showed a false-negative ARR_direct renin concentration. No false-negative AA2R results were observed on either day 14 or 15. In conclusion, compared with ARR, which can be affected by ACE inhibitors causing false-negative screening results, the AA2R seems to be superior in detecting PA among subjects receiving ACE inhibitors.Genetic, Cellular, and Molecular Heterogeneity in Adrenals With Aldosterone-Producing Adenoma11AbstractAldosterone-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 (aldosterone synthase) 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 CYP11B2 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.Renin-Angiotensin-Aldosterone System Inhibitors and Risks of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: a Systematic Review and Meta-Analysis12AbstractThe viral spike coat protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engages the human ACE (angiotensin-converting enzyme)-2 cell surface receptor to infect the host cells. Thus, concerns arose regarding theoretically higher risk for coronavirus disease 2019 (COVID-19) in patients taking ACE inhibitors/angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]). We systematically assessed case-population and cohort studies from MEDLINE (Ovid), Cochrane Database of Systematic Reviews PubMed, Embase, medRXIV, the World Health Organization database of COVID-19 publications, and ClinicalTrials.gov through June 1, 2020, with planned ongoing surveillance. We rated the certainty of evidence according to Cochrane methods and the Grading of Recommendations Assessment, Development and Evaluation approach. After pooling the adjusted odds ratios from the included studies, no significant increase was noted in the risk of SARS-CoV-2 infection by the use of ACE inhibitors (adjusted odds ratio, 0.95 [95% CI, 0.86–1.05]) or ARBs (adjusted odds ratio, 1.05 [95% CI, 0.97–1.14]). However, the random-effects meta-regression revealed that age may modify the SARS-CoV-2 infection risk in subjects with the use of ARBs (coefficient, −0.006 [95% CI, −0.016 to 0.004]), that is, the use of ARBs, as opposed to ACE inhibitors, specifically augmented the risk of SARS-CoV-2 infection in younger subjects (<60 years old). The use of ACE inhibitors might not increase the susceptibility of SARS-CoV-2 infection, severity of disease, and mortality in case-population and cohort studies. Additionally, we discovered for the first time that the use of ARBs, as opposed to ACE inhibitors, specifically augmented the risk of SARS-CoV-2 infection in younger subjects, without obvious effects on COVID-19 outcomes.Prevalence of Hypokalemia and Primary Aldosteronism in 5100 Patients Referred to a Tertiary Hypertension Unit13AbstractPrimary aldosteronism (PA) was considered a rare disorder almost always associated with hypokalemia. The widespread screening of patients with hypertension unveiled an increased prevalence of PA with normokalemic hypertension the prevailing phenotype. Many studies have reported the prevalence of hypokalemia in patients with PA; conversely, the prevalence of PA in patients with hypokalemia is unknown. In this retrospective observational study, we define the prevalence of hypokalemia in referred patients with hypertension and the prevalence of PA in patients with hypokalemia and hypertension. Hypokalemia was present in 15.8% of 5100 patients with hypertension, whereas 76.9% were normokalemic and 7.3% hyperkalemic. The prevalence of PA in patients with hypokalemia was 28.1% and increased with decreasing potassium concentrations up to 88.5% of patients with spontaneous hypokalemia and potassium concentrations <2.5 mmol/L. A multivariate regression analysis demonstrated the association of hypokalemia with the occurrence of cardiovascular events independent of PA diagnosis. An association of PA with the occurrence of cardiovascular events and target organ damage independent of hypokalemia was also demonstrated. In conclusion, our results confirm that PA is a frequent cause of secondary hypertension in patients with hypokalemia, and the presence of hypertension and spontaneous hypokalemia are strong indications for PA diagnosis. Finally, we show that PA and hypokalemia are associated with an increased risk of cardiovascular events.Renin-Angiotensin-Aldosterone System Triple-A Analysis for the Screening of Primary Aldosteronism14AbstractPrimary aldosteronism is recognized as the most frequent cause of secondary hypertension, and its screening is expected to become a routine evaluation in most patients with hypertension. The interference of antihypertensive therapies with the aldosterone/renin ratio during screening process is a major confounder. Renin-angiotensin-aldosterone system triple-A analysis is a novel liquid chromatography/tandem mass spectrometry diagnostic assay that allows simultaneous quantification of aldosterone, equilibrium Ang I (angiotensin I), and Equilibrium Ang II (angiotensin II) in a single sample of serum. We performed a comparative evaluation of the diagnostic performance of the aldosterone/Ang II ratio and 5 renin-based diagnostic ratios, differing in methods to determine aldosterone levels and renin activity in a cohort of 110 patients with hypertension (33 patients with confirmed primary aldosteronism and 77 with essential hypertension). All ratios showed comparable areas under the curves ranging between 0.924 and 0.970 without significant differences between each other. The evaluation of the Ang II/Ang I ratio revealed persistent drug intake in some patients as cause for suppressed renin-based diagnostic ratios, while aldosterone/Ang II ratio remained unaffected. The Youden index optimal cutoff value for the aldosterone/Ang II ratio was 6.6 (pmol/L)/(pmol/L) with a sensitivity of 90% and a specificity of 93%, proving noninferiority compared with the aldosterone/renin ratio while pointing to the potential for an interference-free application in patients under the ACE (angiotensin-converting enzyme) inhibitor therapy. This study shows for the first time the accuracy and reliability of renin-angiotensin-aldosterone system triple-A analysis for the screening of primary aldosteronism that can be applied in clinical routine.Primary Aldosteronism Decreases Insulin Secretion and Increases Insulin Clearance in Humans15AbstractPrimary aldosteronism is a frequent cause of resistant hypertension and is associated with an increased risk of developing diabetes. Aldosterone impairs insulin secretion in isolated islets, and insulin secretion is increased in aldosterone synthase–deficient mice. We hypothesized that treatment for primary aldosteronism increases insulin secretion and insulin sensitivity in humans. We conducted a prospective cohort study in patients with primary aldosteronism, with assessment of glucose metabolism before and 3 to 12 months after treatment. Participants underwent treatment for primary aldosteronism with adrenalectomy or a mineralocorticoid receptor antagonist at the discretion of their treating physician. We assessed insulin secretion and insulin sensitivity by hyperglycemic and hyperinsulinemic-euglycemic clamps, respectively, on 2 study days after a 5-day standardized diet. After treatment, the C-peptide and insulin response during the hyperglycemic clamp increased compared with pretreatment (DeltaC-peptide at 90–120 minutes, +530.5±384.1 pmol/L; P=0.004; Deltainsulin at 90–120 minutes, +183.0±122.6; P=0.004). During hyperinsulinemic-euglycemic clamps, insulin sensitivity decreased after treatment (insulin sensitivity index, 30.7±6.2 versus 18.5±4.7 nmol·kg[−1]·min[−1]·pmol[−1]·L; P=0.02). Insulin clearance decreased after treatment (872.8±207.6 versus 632.3±178.6 mL/min; P=0.03), and disposition index was unchanged. We conclude that the insulin response to glucose increases and insulin clearance decreases after treatment for primary aldosteronism, and these effects were not due to alterations in creatinine clearance or plasma cortisol. Thes