Idiopathic Hyperaldosteronism Research Articles

Reversal of cardiac damage after treatment for aldosterone-producing adenoma and idiopathic hyperaldosteronism - A Prospective Cardiac Magnetic Resonance Imaging study

Reversal of cardiac damage after treatment for aldosterone-producing adenoma and idiopathic hyperaldosteronism - A Prospective Cardiac Magnetic Resonance Imaging study

Comparison of Different Doses of ACTH Used in ACTH Stimulation Test to Determine the Subtypes of Primary Aldosteronism

To compare the diagnostic value of adrenocorticotropic hormone (ACTH) stimulation test (AST) with different doses of ACTH combined with midnight administration of 1 mg dexamethasone for the determination of the subtypes of primary hyperaldosteronism (PA). This is a prospective observational study. Patients diagnosed with PA in the Department of Endocrinology, the First Medical Center of of Chinese PLA General Hospital from January 1, 2020 to September 30, 2022 underwent AST with different doses of ACTH. All patients received 1 mg dexamethasone at midnight for inhibition. Then, the patients were randomly assigned to 25-unit and 50-unit ACTH treatment groups by a ratio of 1:2. Subtype classification and diagnosis of aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) was made on the basis of adrenal venous blood samples and/or postoperative pathology and clinical follow-up findings. Receiver operating characteristics (ROC) curves were plotted to examine the diagnostic efficacy and the difference of AST by varying doses of ACTH in distinguishing APA and IHA. A total of 82 patients, including 49 patients with APA (59.8%) and 33 patients with IHA (40.2%), were enrolled. There were 29 patients in the 25-unit ACTH group (35.4%) and 53 patients in the 50-unit ACTH group (64.6%). There were no significant differences in age, sex, blood pressure, minimum serum potassium, and biochemical parameters between the 25-unit and 50-unit groups. After ACTH stimulation, plasma aldosterone concentration (PAC), cortisol (F), and PAC/F at different points of time showed no statistical difference between the two groups (P>0.05). The area under the curve (AUC) of PAC in the 25-unit group was higher than that of PAC/F. The AUC of PAC reached the maximum at 90 minutes (0.948, 95% confidence interval [CI]: 0870-1.000) and the optimal cutoff was 38.0 ng/dL, which had a sensitivity of 92.9% and a specificity of 86.7% for differentiating APA and IHA. Similar to the 25-unit group, the maximum AUC of PAC in the 50-unit group was greater than that of PAC/F. The AUC of PAC reached the maximum 90 minutes (0.930, 95% CI: 0.840-0.994) and the optimal cutoff was 39.6 ng/dL, which had a sensitivity of 91.2% and a specificity of 83.3%. The AUC of PAC at different points of time in the 25-unit ACTH group (0.862-0.948) was greater than that of 50-unit ACTH group (0.823-0.930), but the difference was not statistical significance. AST with 25-unit or 50-unit ACTH combined with small-dose dexamethasone can be used in PA subtype determination, ie, differentiation between APA and IHA. The optimal PAC cut-off values for 25-unit or 50-unit ACTH are similar, being 38.0 ng/dL and 39.6 ng/dL, respectively, and both cutoff values show higher sensitivity and specificity at 90 min. The AST with 25-unit ACTH has the smaller dose and the better safety. Therefore, it is recommended for the diagnosis of PA subtypes.

Comparisons of risk factors for post-treatment renal dysfunction between the two major subtypes of primary aldosteronism.

Aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldosteronism (IHA) are the most common subtypes of primary aldosteronism (PA), and the PA subtype dictates the treatment options. This study aimed to identify predictors of declined estimated glomerular filtration rate (eGFR) following each treatment in patients with APA and IHA. We retrospectively investigated 45 patients with APA who had undergone adrenalectomy (ADX) and 37 patients with IHA who had received treatment with a mineralocorticoid receptor antagonist (MRA) to identify pre-treatment risk factors for eGFR decline during the post-treatment follow-up period. Patients with APA who underwent ADX exhibited higher eGFR declines than patients with IHA treated with MRA at the 6-month post-treatment evaluation point. A high preoperative plasma aldosterone concentration (PAC) in patients with APA and a high body mass index (BMI) in patients with IHA were identified as independent predictors of higher eGFR decline at 6 months post-treatment (β=0.42 and β=0.36, respectively). In patients with APA, the cutoff PAC to best predict a 20% decrease in eGFR following ADX, as determined by receiver operating characteristic analysis, was 524 pg/mL. In patients with IHA, the cutoff BMI to best predict a 10% decrease in eGFR following MRA administration was 25.3 kg/m2. In addition, lower preoperative flow-mediated vasodilation was associated with eGFR decline after ADX in patients with APA. Greater attention should be given to the above-mentioned risk factors to prevent renal impairment following each treatment in patients with both APA and IHA.

Metabolic Outcomes of Primary Aldosteronism Patients Receiving Adrenalectomy or Spironolactone Treatments

To investigate the metabolic outcomes of primary aldosteronism (PA) patients receiving adrenalectomy (ADX) or spironolactone treatment and the contributing factors to the metabolic outcomes. The clinical data of 70 patients with aldosterone-producing adenoma (APA) and 86 patients with idiopathic hyperaldosteronism (IHA) were retrospectively analyzed. All subjects received confirmatory diagnosis of APA or IHA at the Department of Endocrinology and Metabolism, West China Hospital between March 2018 and October 2020. APA patients underwent ADX, while IHA patients were given spironolactone, a mineralocorticoid receptor antagonist (MRA). After ADX or spironolactone treatment, the outcomes of the metabolic indicators and the inter-group differences between the APA patients and IHA patients were studied. There was no significant difference between the baseline data of the APA group and those of the IHA group in terms of age, sex, duration of hypertension, maximum systolic blood pressure (SBP-max), maximum diastolic blood pressure (DBP-max), body mass index (BMI), fasting blood glucose (FBG), lipid parameters, and renal function. IHA patients had higher waist circumference, serum potassium, and plasma renin activity (PRA) than those of the APA patients (all P<0.05). All patients showed significant improvement in blood pressure, blood potassium, and plasma aldosterone at follow-up. However, they also showed increased triglycerides (TG) accompanied by deterioration in renal function (P≤0.001). Multiple regression showed that TG levels were associated with spironolactone treatment for IHA patients and post-treatment BMI and creatinine levels. Furthermore, APA patients showed improvement in their FBG after ADX (P=0.041), while IHA patients showed elevated levels of FBG after spironolactone treatment (P=0.037). After treatment, PA patients still may experience abnormal lipid metabolism and deteriorating renal function. Spironolactone therapy may give rise to worse glucolipid metabolism than ADX therapy does.

Differences between left adrenal vein sampling sites revealed with segmental sampling in primary aldosteronism.

To clarify the differences between two left sampling sites (left adrenal central vein [LCV] and common trunk [CMT], conjunction with LCV and inferior phrenic vein) and their impact on adrenal venous sampling (AVS) in primary aldosteronism by analyzing the results of segmental AVS (sAVS). We retrospectively analyzed a final cohort of 432 patients who underwent cosyntropin-stimulated sAVS from 2017 to 2020. Hormone levels in the LCV and the CMT were compared. Subtype diagnosis was based on the lateralization index with LCV and CMT sampling (a cutoff value of 4) and sAVS after excluding patients with a selectivity index (SI) <3. Compared with the LCV, CMT sampling showed significantly lower aldosterone and cortisol levels and a higher proportion of cases with an SI of <3 (2.8% vs 0.5%, p = 0.025) and <5 (6.9% vs 0.5%, p < 0.001), while the aldosterone to cortisol ratio and the lateralization index were not significantly different. Subtyping of both sites was concordant in 94.7% (393/415) and discordant in the remainder, which included left and right aldosterone-producing adenoma and idiopathic hyperaldosteronism cases referring to the sAVS. There was no significant difference between the concordance rate of the two sampling sites based on the sAVS diagnosis. LCV sampling meets the SI criteria for successful AVS more frequently compared with CMT sampling, but neither was better than the other in terms of diagnosis under conditions of meeting the criteria. LCV sampling would decrease the number of cases judged as AVS failure.

FRI186 Differences Of Body Composition And Comorbidities In Patients With Primary Aldosteronism According To Sex And Subtypes

Abstract Disclosure: S. Park: None. C. Ahn: None. S. Seo: None. S. Kim: None. J. Yoon: None. J. Kim: None. Background: Primary aldosteronism (PA) is associated with metabolic risks such as diabetes and obesity. However, controversy exists as to which subtype of PA has a higher metabolic risk between idiopathic hyperaldosteronism (IHA) and aldosterone-producing adenoma (APA). We aimed to assess the body composition of two PA subtypes according to sex and evaluate autonomous cortisol secretion (ACS) and its contribution to comorbidities. Methods: A total of 400 patients with PA and 1:10 age- and sex-matched healthy controls (n=4,000) were enrolled. Clinical and biochemical data were reveiwed. The skeletal muscle area (SMA), subcutaneous fat area, and visceral fat area (VFA) at the third lumbar spine were calculated using abdominal computed tomography-based body composition analysis. Results: In both sexes, a higher body mass index (BMI) was observed in patients with IHA than in those with APA (P&amp;lt;0.001 in men and P=0.049 in women). Hemoglobin A1c (HbA1c) level and the prevalence of diabetes were higher in female patients with IHA than in those with APA (6.0±0.9 vs. 5.6±0.5%, P=0.005 for HbA1c; 19.0% vs. 6.8%, P=0.016 for diabetes). The VFA/BMI ratio was significantly higher in patients with IHA than in patients with APA (5.77±2.69 vs. 4.56±2.35, P&amp;lt;0.001 in men; 4.03±2.58 vs. 2.53±2.05, P&amp;lt;0.001 in women). In subgroup analysis, decreased SMA was observed in PA patients with ACS compared with those without ACS. Compared with age- and sex-matched healthy controls, all patients with IHA and female patients with APA showed significantly higher VFA and VFA/BMI. Conclusion: Patients with IHA were more obese and had higher visercal adiposity than those with APA. This metabolically unfavorable body composition may contribute to a higher metabolic risk in patients with IHA. The role of adipose tissue in pathogenesis of IHA remains to be elucidated. Presentation: Friday, June 16, 2023

FRI166 Characterization of Aldosterone-producing Cell Cluster (APCC) At Single-cell Resolution

Abstract Disclosure: N. Iwahashi: None. H. Umakoshi: None. T. Seki: None. C. Gomez-Sanchez: None. K. Mukai: None. M. Suematsu: None. Y. Umezawa: None. M. Oya: None. T. Kosaka: None. M. Seki: None. Y. Suzuki: None. Y. Horiuchi: None. K. Nishimoto: None. Y. Ogawa: None. Context: The adrenal cortex consists of zona glomerulosa (ZG), fasciculata (ZF), and reticularis. Aldosterone-producing cell clusters (APCCs) that express aldosterone synthase (CYP11B2) strongly can be frequently found in adult adrenals and harbor somatic mutations that are also present in aldosterone-producing adenomas (APAs). Primary aldosteronism is mainly caused by APAs or idiopathic hyperaldosteronism (IHA). We presume that APCCs are causing IHA and are precursors of APAs. However, the gene expression characteristics and especially the development of APCCs are not well understood. Objective: This study aimed to analyze the transcriptome of APCCs at single-cell resolution and infer the developmental trajectory. Methods: Single-cell RNA sequencing (scRNA-seq) was performed on two adult adrenals. Results: Immunohistochemical analyses confirmed the presence of APCCs in the two adrenals. scRNA-seq data of 6770 adrenal cells were obtained and 2928 high-quality cells were selected after quality control procedures. Unsupervised clustering and marker gene expressions such as CYP11A1 and NR5A1 identified 1765 adrenocortical cells, which were further divided into six clusters (B1-6). Using the list of APCC/ZG upregulated genes from our previously reported DNA microarray study, three clusters (B1, B3, and B6, totaling 923 cells) were identified as APCC/ZG cells. By further subclustering, the APCC/ZG cells were divided into 3 clusters (C1, C2, and C3). The APCC cluster (C3, 64 cells) and ZG cluster (C1, 447 cells) were identified. Cluster C2 seemed to be ZG-to-ZF transitional cells. RNA velocity analysis, which aimed to infer the direction of differentiation, inferred a direction of development from ZG cells to APCCs. Conclusion: Our results revealed the gene expression characteristics of APCC at single-cell resolution and show that some ZG cells remodel into APCCs. Presentation: Friday, June 16, 2023

The Value of Targeting CXCR4 With 68Ga-Pentixafor PET/CT for Subtyping Primary Aldosteronism.

Primary aldosteronism (PA) is one of the leading causes of secondary hypertension, and its diagnostic subtyping consistently presents a clinical challenge. This study aimed to investigate the potential of 68Ga-Pentixafor positron emission tomography/computed tomography (PET/CT) in PA classification and its applicability in guiding the development of clinical treatment plans by increasing the sample size. We prospectively enrolled 120 patients with either PA or nonfunctional adenoma (NFA) for analysis. All patients underwent 68Ga-Pentixafor PET/CT. Of these, 11 patients underwent adrenal venous sampling (AVS), 77 underwent adrenalectomy, 76 received pathological diagnoses, and 71 underwent immunohistochemical detection of aldosterone synthase (CYP11B2). Immunohistochemistry for C-X-C chemokine receptor 4 (CXCR4) was performed in 62 cases. Follow-up was conducted for all patients. Among the 120 patients, 66 were diagnosed with aldosterone-producing adenoma (APA), 33 with idiopathic hyperaldosteronism (IHA), and 21 with NFA. For APA patients, the sensitivity, specificity, and accuracy of visual analysis using 68Ga-Pentixafor PET/CT were 92.40%, 94.40%, and 93.33%, respectively. Furthermore, for APA patients with a nodule greater than 1 cm in diameter, when the maximum standard uptake value was 7.3 or greater, the specificity was 100%; and for APA patients with a nodule less than 1 cm in diameter, 68Ga-Pentixafor PET/CT also exhibited high sensitivity. AVS was successfully performed in 5 patients. Among the 5 patients, the concordance rate between the AVS and 68Ga-Pentixafor PET/CT for PA subtyping was 60%. In the 77 patients who underwent adrenalectomy, 61 PET/CT scans displayed positive lesions, all of which benefited from the surgery. Additionally, the concordance rate between 68Ga-Pentixafor PET/CT imaging and CYP11B2 was 81.69%. 68Ga-Pentixafor PET/CT is a reliable and noninvasive functional imaging technique that demonstrates high accuracy in classifying PA and provides valuable guidance for clinical treatment decision-making.

Establishment and validation of a nomogram-based predictive model for idiopathic aldosteronism

Objective: To establish and validate a nomogram-based predictive model for idiopathic hyperaldosteronism (IHA). Methods: This cross-sectional study was conducted with the collected clinical and biochemical data of patients with primary aldosteronism (PA) including 249 patients with unilateral primary aldosteronism (UPA) and 107 patients with IHA, who were treated at the Department of Endocrinology of the First Affiliated Hospital of Chongqing Medical University from November 2013 to November 2022. Plasma aldosterone concentration (PAC) and plasma renin concentration (PRC) were measured by chemiluminescence. Stepwise regression analysis was applied to select the key predictors of IHA, and a nomogram-based scoring model was developed. The model was validated in another external independent cohort of patients with PA including 62 patients with UPA and 43 patients with IHA, who were diagnosed at the Department of Endocrinology, First Affiliated Hospital of Zhengzhou University. An independent-sample t test, Mann-Whitney U test, and χ2 test were used for statistical analysis. Results: In the training cohort, in comparison with the UPA group, the IHA group showed a higher serum potassium level [M(Q1, Q3), 3.4 (3.1, 3.8) mmol/L vs. 2.7 (2.1, 3.1) mmol/L] and higher PRC [4.0 (2.1, 8.2) mU/L vs. 1.5 (0.6, 3.4) mU/L] and a lower PAC post-saline infusion test (SIT) [305 (222, 416) pmol/L vs. 720 (443, 1 136) pmol/L] and a lower rate of unilateral adrenal nodules [33.6% (36/107) vs. 81.1% (202/249)]; the intergroup differences in these measurements were statistically significant (all P<0.001). Serum potassium level, PRC, PAC post-SIT, and the rate of unilateral adrenal nodules showed similar performance in the IHA group in the validation cohort. After stepwise regression analysis for all significant variables in the training cohort, a scoring model based on a nomogram was constructed, and the predictive parameters included the rate of unilateral adrenal nodules, serum potassium concentration, PAC post-SIT, and PRC in the standing position. When the total score was ≥14, the model showed a sensitivity of 0.65 and specificity of 0.90 in the training cohort and a sensitivity of 0.56 and specificity of 1.00 in the validation cohort. Conclusion: The nomogram was used to successfully develop a model for prediction of IHA that could facilitate selection of patients with IHA who required medication directly.

An Ancillary Method for Adrenal Venous Sampling in Cases in Which Right Adrenal Vein Sampling Is Difficult

Catheterization of the right adrenal vein (rt.AdV) to obtain blood samples can often be difficult. The aim of the present study was to investigate whether blood sampling from the inferior vena cava (IVC) at its juncture with the rt.AdV can be an ancillary to sampling of blood directly from the rt.AdV. This study included 44 patients diagnosed with primary aldosteronism (PA) in whom AVS with adrenocorticotropic hormone (ACTH) was performed, resulting in a diagnosis of idiopathic hyperaldosteronism (IHA) (n = 24), and patients diagnosed with unilateral aldosterone-producing adenoma (APA) (n = 20; rt.APA = 8, lt.APA = 12). In addition to regular blood sampling, blood was also sampled from the IVC, as the substitute rt.AdV [S-rt.AdV]. Diagnostic performance with the conventional lateralized index (LI) and the modified LI using the S-rt.AdV were compared to examine the utility of the modified LI. The modified LI of the rt.APA (0.4 ± 0.4) was significantly lower than those of the IHA (1.4 ± 0.7) (p < 0.001) and the lt.APA (3.5 ± 2.0) (p < 0.001). The modified LI of the lt.APA was significantly higher than those of the IHA (p < 0.001) and rt.APA (p < 0.001). Likelihood ratios to diagnose rt.APA and lt.APA using the modified LI with threshold values of 0.3 and 3.1 were 27.0, and 18.6, respectively. The modified LI has the potential to be an ancillary method for rt.AdV sampling in cases in which rt.AdV sampling is difficult. Obtaining the modified LI is extremely simple, which might complement conventional AVS.

PS-BPR01-1: SUCCESSFUL TREATMENT WITH ESAXERENONE IN A PREGNANT WOMAN WITH PRIMARY ALDOSTERONISM AND SUPERIMPOSED PREECLAMPSIA

Background: During pregnancy, there is no established treatment for idiopathic hyperaldosteronism (IHA), the most common form of primary aldosteronism (PA) due to bilateral adrenal hyperplasia. Here, we report the case of a pregnant patient with IHA who was successfully treated with esaxerenone, a non-steroidal mineralocorticoid receptor (MR) antagonist. Case: A 39-year-old woman was referred to our outpatient clinic for hypertension with high plasma aldosterone concentration (PAC). Her PAC was 204 pg/mL (radioimmunoassay) and plasma renin activity was 1.2 ng/mL/h at the time of referral. She was diagnosed with PA since the saline-loading test for PA was positive. She had no hypokalemia and computed tomography scans showed no adrenal tumors. Adrenal vein sampling indicated overproduction of aldosterone in both adrenal glands leading to the diagnosis of IHA. She was commenced on nifedipine controlled release (CR) 20 mg daily because she desired to be pregnant. After one year, she became pregnant. Her blood pressure was well controlled until 34 weeks of gestation when her home blood pressure became elevated up to 140/90 mmHg. Although the dose of nifedipine CR was increased to 80 mg daily, her blood pressure increased to 151/97 mmHg and urinary test showed proteinuria of 2 + in 35 weeks of gestation. She was diagnosed with superimposed preeclampsia (SPE) and additionally treated with esaxerenone. Her blood pressure decreased to 120–140/98–100 mmHg and the proteinuria improved to +/-. A successful cesarean section at 37 weeks resulted in the delivery of a healthy baby boy. Esaxerenone was discontinued 2 weeks after delivery, because she was eager to breast-feed the baby and no safety data of esaxerenone in breast-feeding woman was available. Her blood pressure has been well controlled by nifedipine CR 80 mg daily even after 100 days of postpartum. Conclusions: This is the first case of a pregnant woman who was successfully treated with esaxerenone despite being an elderly pregnant woman who had been diagnosed with IHA and developed SPE. Further studies are needed to investigate the efficacy and safety of non-steroidal selective MR antagonist in similar pregnant patients with IHA, to establish better treatment strategy for these patients.

PS-BPB06-10: DISTRIBUTION OF CACNA1D SOMATIC MUTATIONS AMONG CYP11B2 IMMUNOHISTOCHEMISTRY-GUIDED SAMPLES OF ALDOSTERONE-PRODUCING ADENOMA (APA)

Objectives: Past studies in Afro-Caribbean primary aldosteronism (PA) patients have found CACNA1D mutations to be the most common aldosterone-driving mutation among their cohort; a striking difference to Caucasian and Oriental cohorts where KCNJ5 mutations are reported to be the most common. However not many studies had used aldosterone synthase (CYP11B2) immunohistochemistry (IHC)-guided sequencing approach of the whole CACNA1D gene, performing instead unguided adenoma sampling and hotspot sequencing. We thus performed CYP11B2 IHC-guided whole gene sequencing on APAs from an Oriental cohort (Malaysia) and a Caucasian cohort (Czech Republic) for comparison. Design and method: Surgically removed adrenals from 100 Malaysian and Czech PA patients with unilateral disease were studied. Genomic DNA was isolated from adenoma FFPE sections that had a positive CYP11B2 IHC staining and somatic mutations analysis were performed by next generation sequencing (NGS) of known aldosterone-driver genes. Predicted pathogenic mutations were verified by Sanger Sequencing. Results: Out of 100 FFPE samples sent for NGS, 36 were excluded due to the quality of the data. In total 58 of 64 APAs (87.5%) had a pathogenic aldosterone-driver somatic mutation. KCNJ5 mutations were the most common (n = 37, 57.8%), followed by CACNA1D (n = 11, 20.3%), ATP1A1 (n = 6, 9.4%), ATP2B3 (n = 3, 4.7%) and CTNNB1 (n = 2, 3.1%) mutations. Of particular interest, one APA sample had two pathogenic somatic mutations, CACNA1D p.Val1373Met and CTNNB1: p.Thr41Ala. SIFT and Polyphen2 scores predicted both mutations to be deleterious. Both mutations have previously been reported separately to cause APAs. The CACNA1D/CTNNB1 mutant APA, was solitary, with homogeneous CYP11B2 expression while negative for CYP17A1 expression. The APA was adrenalectomized from a 53-year-old male Czech patient. The majority of patients with APAs harboring CACNA1D mutations were male (n = 8, 72.7%) and from the Czech cohort (n = 7, 64%). There were no significant differences in age at adrenalectomy between patients harboring a CACNA1D mutant APA (45 ± 3) and those with a non-CACNA1D mutant APA (48 ± 2). Conclusions: Solitary ZG APAs can harbor both a CACNA1D and a CTNNB1 mutation. The prevalence of CACNA1D in this CYP11B2-IHC guided study is consistent with previous results reported in Oriental and Caucasian cohorts. Although CACNA1D is not the top genetic alteration responsible for APAs in these cohorts, CACNA1D may still be a potential key player in idiopathic hyperaldosteronism and aldosterone-producing micronodules. Thus further study is required to characterize the distribution of CACNA1D pathogenic mutations in bilateral PA.

PS-B04-8: YM750, AN ACAT1 INHIBITOR, REDUCES ALDOSTERONE SECRETION BY DECREASING ADRENAL CYP11B2 EXPRESSION

Primary aldosteronism (PA) is a refractory hypertension that accounts for approximately 5%-10% of hypertensive patients. aldosterone-producing adenomas and idiopathic hyperaldosteronism are known causes of PA. In aldosterone-producing adenomas, depolarization due to somatic mutations of ion channels in adrenocortical cells is considered the cause of aldosterone oversecretion. Recently, there have been reports on the expression of various cholesterol-metabolizing enzymes in aldosterone-producing adenomas, suggesting that intracellular cholesterol metabolism is very important for aldosterone secretion. We present here the possibility that an inhibitor of Acetyl-CoA acetyltransferase (ACAT1), an enzyme that converts cholesterol to cholesteryl esters, may inhibit aldosterone secretion by depolarization in adrenal cells. Potassium chloride and YM750, an ACAT1 inhibitor, were added to human adrenocortical carcinoma, H295R cells. Then, we measured aldosterone synthase gene, CYP11B2 mRNA expression level. As a result, the expression level of CYP11B2 decreased. Both NURR1 and NGFIB mRNA expression levels also decreased. Additionally, aldosterone production was also measured and found to be significantly decreased in the YM750 added group. Next, angiotensin II was added and the inhibitory effect of YM750 was examined. The results showed that CYP11B2 expression was not decreased. This indicates that YM750 decreased the induction of CYP11B2 expression in a potassium chloride-induced stimulus-specific manner. The experimental results suggest that YM750 specifically inhibits CYP11B2 gene expression by cell depolarization and suppresses aldosterone secretion. However, there are few reports of cholesterol metabolism affecting CYP11B2 gene expression. In this study, we found that intracellular cholesterol metabolism may affect CYP11B2 gene expression. We plan to investigate the relationship between ACAT inhibition and CYP11B2 gene expression in detail mechanisms in the future.

PS-BPR03-11: A CASE OF MALIGNANT PHASE HYPERTENSION ASSOCIATED WITH PRIMARY ALDOSTERONISM

Background: Primary aldosteronism is associated with low plasma renin levels, while malignant phase hypertension is generally associated with raised renin activity. Therefore, these two conditions are at opposite ends of the renin spectrum, so in theory their co-existence would be unusual. Case presentation: We present a case of a 41-year-old male with uncontrolled hypertension on multiple antihypertensive drugs. He discontinued these drugs for three days, thereafter he admitted to our hospital with congestive heart failure and acute ischemic stroke. He manifested malignant phase hypertension (blood pressure 216/130 mmHg; Keith-Wagener IV) accompanying renal dysfunction (serum creatinine 2.4 mg/dL), high plasma aldosterone concentration (PAC, 221 pg/mL) and mildly elevated plasma renin activity (PRA, 3.0 ng/mL/hr). A computed tomography did not reveal the presence of adrenal mass. After the treatment for congestive heart failure, the reassessment for endocrine causes of hypertension showed high level of PAC (468 pg/mL) and low level of PRA (0.2 ng/mL/hr), resulting in a high PAC/PRA ratio under the treatment with angiotensin-converting enzyme inhibitor. Adrenal venous sampling (AVS) confirmed the excessive aldosterone secretion from bilateral adrenal glands. Given these findings, we diagnosed him with idiopathic aldosteronism. After an addition of the mineralocorticoid receptor antagonist, he could keep his blood pressure under control. Conclusions: PRA in patients with primary aldosteronism could be increased under the conditions in which renin release from the kidney is overstimulated by glomerular ischemia, leading to an incorrect diagnosis of primary aldosteronism. Repeated endocrine assessment including the measurement of PRA and PAC should be considered to reveal the cause of malignant phase hypertension.

ODP611 Combination Of Seated Saline Suppression Test And Computed Tomography In Predicting Subtype Diagnosis Of Primary Aldosteronism In Chinese Population

Abstract Objective The study aimed to evaluate the accuracy of the seated saline suppression test (SSST) combined with adrenal computed tomography (CT) in determining the primary aldosteronism (PA) subtypes. Methods Each patient underwent a SSST and adrenal CT. Logistic diagnostic model (CT finding + post-SSST plasma aldosterone concentration (PAC)) were built, which evaluated the accuracy of the SSST combined with adrenal CT for a subtype classification of PA. Subtype diagnosis of PA was determined by adrenal venous sampling (AVS), pathology and clinical outcomes (primary aldosteronism surgical outcome(PASO)). Results A total of 72 patients with PA were classified into two groups, including 45 aldosterone-producing adenoma (APA) and 27 idiopathic hyperaldosteronism (IHA) patients. By binary logistic regression analysis, adrenal CT (odds ratio (OR)=16.28, 95% confidence interval (CI) 4.18-63.42, P&amp;lt;0. 05) and 4-hours PAC after SSST (OR =1.13, 95% CI 1. 03 to 1.23, P&amp;lt;0. 05) were significantly independent predictors of APA patients. We have successfully developed a diagnostic model based on logistic regression that is able to predict the probability of APA. The area under the receiver operating characteristic (ROC) curve of logistic diagnostic models(AUC=0.907, 95% CI 0.815 to 0.963) was significantly greater either than that for the adrenal CT (AUC=0.807,95% CI 0.696 to 0.890,respectively,P&amp;lt;0. 05) or SSST (AUC=0.799,95% CI 0.688 to 0.884,respectively,P&amp;lt;0. 05). Positive CT finding combined with a post-SSST PAC≥18.2 ng/dL provided sensitivity of 88.89%,specificity of 74. 07%,and positive predictive value (PPV) of 93.9%(31/33) for predicting APA, that determined patients who required AVS prior to surgery. Conclusion The model combining CT finding with post-SSST PAC has superior accuracy in subtype diagnosis of PA compared with SSST or adrenal CT alone. The current study was the first study to investigate the accuracy of the new method on the subtype classification of PA. We are fortunate to find it may be a safe, convenient, sensitive and noninvasive approach in predicting subtype diagnosis of PA in Chinese individuals, especially in primary care where AVS may be unavailable. The results require further confirmation by RCT clinical trials. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Unilateral Adrenalectomy for Primary Aldosteronism Due to Bilateral Adrenal Disease Can Result in Resolution of Hypokalemia and Amelioration of Hypertension.

Bilateral idiopathic hyperaldosteronism (IHA) is responsible for 60% of primary aldosteronism (PA) cases. Medical management is standard of care for IHA. Unilateral adrenalectomy (UA) with the intent of debulking total aldosterone production as a palliative measure remains controversial. Single-center retrospective review (2010-2020) of patients undergoing UA with a diagnosis of PA due to IHA (lateralization index [LI] on adrenal venous sampling [AVS] < 4). Demographic, pre-operative, intra-operative, and post-operative variables were assessed. Hypertensive regimens were converted to the WHO Defined Daily Dose (DDD). Twenty-four patients were identified, 14, 58% male and mean age 52 ± 10years. Preoperative hypokalemia was present in 22, 92% of patients. Median number of antihypertensives taken was 3 (interquartile range [IQR], 2-4) and median DDD was 4 (IQR, 3-5.3). Median lateralization index on AVS was 3.52 (range, 1.19-3.88). All operations were performed in minimally invasive fashion. There were no conversions to open procedure, ICU admissions, or post-operative complications. Median follow-up was 10.5months (range, 1-145months). Hypokalemia resolved in 17, 76% of patients at last follow-up. Post-operative median number of antihypertensives taken was 1 (IQR, 1-3) and median DDD was 2 (IQR, 0.5-2.75) from 4, P = 0.003. Three (%) patients required continuation of mineralocorticoid receptor antagonists post-operatively. Blood pressure control improved in 65% of patients. Unilateral adrenalectomy in the setting of bilateral hyperaldosteronism can improve blood pressure control and stabilize potassium levels in selected patients. Further prospective studies in larger cohorts will be necessary to further define the role of unilateral adrenalectomy in the setting of PA due to bilateral adrenal disease.

The metabolic phenotype of patients with primary aldosteronism: impact of subtype and sex - a multicenter-study of 3566 Caucasian and Asian subjects.

Accumulating evidence suggests that primary aldosteronism (PA) is associated with several features of the metabolic syndrome, in particular with obesity, type 2 diabetes mellitus, and dyslipidemia. Whether these manifestations are primarily linked to aldosterone-producing adenoma (APA) or bilateral idiopathic hyperaldosteronism (IHA) remains unclear. The aim of the present study was to investigate differences in metabolic parameters between APA and IHA patients and to assess the impact of treatment on these clinical characteristics. We conducted a retrospective multicenter study including 3566 patients with APA or IHA of Caucasian and Asian origin. We compared the prevalence of metabolic disorders between APA and IHA patients at the time of diagnosis and 1-year post-intervention, with special references to sex differences. Furthermore, correlations between metabolic parameters and plasma aldosterone, renin, or plasma cortisol levels after 1 mg dexamethasone (DST) were performed. As expected, APA patients were characterized by higher plasma aldosterone and lower serum potassium levels. Only female IHA patients demonstrated significantly worse metabolic parameters than age-matched female APA patients, which were associated with lower cortisol levels upon DST. One-year post-intervention, female adrenalectomized patients showed deterioration of their lipid profile, when compared to patients treated with mineralocorticoid receptor antagonists. Plasma aldosterone levels negatively correlated with the BMI only in APA patients. Metabolic alterations appear more prominent in women with IHA. Although IHA patients have worse metabolic profiles, a correlation with cortisol autonomy is documented only in APAs, suggesting an uncoupling of cortisol action from metabolic traits in IHA patients.

Clinical Translationality of KCNJ5 Mutation in Aldosterone Producing Adenoma.

Hypertension due to primary aldosteronism poses a risk of severe cardiovascular complications compared to essential hypertension. The discovery of the KCNJ5 somatic mutation in aldosteroene producing adenoma (APA) in 2011 and the development of specific CYP11B2 antibodies in 2012 have greatly advanced our understanding of the pathophysiology of primary aldosteronism. In particular, the presence of CYP11B2-positive aldosterone-producing micronodules (APMs) in the adrenal glands of normotensive individuals and the presence of renin-independent aldosterone excess in normotensive subjects demonstrated the continuum of the pathogenesis of PA. Furthermore, among the aldosterone driver mutations which incur excessive aldosterone secretion, KCNJ5 was a major somatic mutation in APA, while CACNA1D is a leading somatic mutation in APMs and idiopathic hyperaldosteronism (IHA), suggesting a distinctive pathogenesis between APA and IHA. Although the functional detail of APMs has not been still uncovered, its impact on the pathogenesis of PA is gradually being revealed. In this review, we summarize the integrated findings regarding APA, APM or diffuse hyperplasia defined by novel CYP11B2, and aldosterone driver mutations. Following this, we discuss the clinical implications of KCNJ5 mutations to support better cardiovascular outcomes of primary aldosteronism.

Characterization of Aldosterone-producing Cell Cluster (APCC) at Single-cell Resolution.

ContextThe adrenal cortex consists of zona glomerulosa (ZG), fasciculata (ZF), and reticularis. Aldosterone-producing cell clusters (APCCs) that strongly express aldosterone synthase (CYP11B2) are frequently found in adult adrenals and harbor somatic mutations that are also detected in aldosterone-producing adenomas (APAs). Primary aldosteronism is mainly caused by APAs or idiopathic hyperaldosteronism (IHA). We presume that APCCs are causing IHA and are precursors of APAs. However, the gene expression characteristics and especially the development of APCCs are not well understood.ObjectiveThis study aimed to analyze the transcriptome of APCCs at single-cell resolution and infer the developmental trajectory.MethodsSingle-cell RNA sequencing (scRNA-seq) of 2 adult adrenals was performed.ResultsImmunohistochemical analyses confirmed the 2 adrenals had APCCs. scRNA-seq data of 2928 adrenal cells were obtained and 1765 adrenocortical cells were identified based on unsupervised clustering and the marker gene expression. The adrenocortical cells were divided into 6 clusters, of which 3 clusters (923 cells) were composed of APCC/ZG cells. By further subclustering, the APCC/ZG cells were divided into 3 clusters (clusters C1, C2, and C3), we finally identified APCC cluster (C3) and ZG cluster (C1). Cluster C2 seemed to be ZG-to-ZF transitional cells. RNA velocity analysis inferred the developmental direction from cluster ZG-cluster-C1 to APCC-cluster-C3. The scRNA-seq additionally revealed that many CYP11B2-positive cells were positive for CYP11B1 and/or CYP17A1, which were essential for cortisol but not for aldosterone production.ConclusionsOur results revealed the gene expression characteristics of APCC at single-cell resolution and show that some ZG cells remodel to APCC.

Sex-specific Association of Primary Aldosteronism With Visceral Adiposity.

ContextThe association between primary aldosteronism and obesity, especially its sex difference, remains unknown.ObjectiveTo assess the association for each subtype of primary aldosteronism with obesity parameters including visceral adipose tissue and differences between sexes.MethodsIn this case-control study, 4 normotensive controls were selected for each case with primary aldosteronism. Multivariable conditional logistic regression models were used to estimate the association between each type of primary aldosteronism and obesity indicators. We used a random forest to identify which visceral or subcutaneous tissue areas had a closer association with disease status.ResultsThe study subjects included 42 aldosterone-producing adenoma cases (22 women) and 68 idiopathic hyperaldosteronism cases (42 women). In multivariable conditional logistic regressions, aldosterone-producing adenoma was significantly associated with body mass index only in men (odds ratio [OR] [95% CI)], 4.62 [1.98-10.80] per 2.89 kg/m2) but not in women (OR [95% CI], 1.09 [0.69-1.72] per 3.93 kg/m2) compared with the matched controls, whereas idiopathic hyperaldosteronism was associated with body mass index in both men (OR [95% CI], 3.96 [2.03-7.73] per 3.75 kg/m2) and women (OR [95% CI], 2.65 [1.77-3.96] per 3.85 kg/m2) compared with the matched controls. In random forests, visceral adipose tissue areas were the better predictor of both aldosterone-producing adenoma and idiopathic hyperaldosteronism than subcutaneous adipose tissue.ConclusionsAldosterone-producing adenoma cases were obese among men, but not among women. Idiopathic hyperaldosteronism cases were obese among both men and women. Visceral adipose tissue may contribute to the pathophysiology of primary aldosteronism.