Unilateral Primary Aldosteronism Research Articles

Role of unilateral‐cannulating adrenal venous sampling for the subtyping of primary aldosteronism for adrenalectomy: Experience from a low‐volume center

AbstractBackgroundCurrent guidelines recommend adrenal venous sampling (AVS) for subtyping primary aldosteronism (PA). However, bilateral adrenal cannulation failure is common especially at low‐volume centers. The role of unilateral‐cannulating AVS in selecting patients for unilateral adrenalectomy is unclear.MethodsFifty consecutive patients underwent AVS between 2009 and 2023 and thirty‐three (66%) underwent unilateral adrenalectomy. We defined unilateral PA (uPA) by the normalized plasma aldosterone and the aldosterone–renin ratio following unilateral adrenalectomy. We examined the effectiveness of unilateral‐cannulating AVS in identifying uPA.Results88%, 50%, and 48% of patients had the left, right, and bilateral adrenal veins successfully cannulated, respectively. Among patients with bilateral successful cannulation, a lateralization index (LI) > 4 provided a sensitivity of 100% and a positive predictive value (PPV) of 86.7% for uPA. Thresholds for the contralateral suppression index (CSI) and relative aldosterone secretion index (RASI) were derived from this subgroup and applied to the entire cohort. CSI <0.5 demonstrated a sensitivity of 76.5% and PPV of 92.9% for uPA, whereas RASI >2.4 showed a sensitivity of 85.0% and PPV of 94.4% for uPA. With CSI <0.5 or RASI >2.4 combined, a higher PPV (95.5%) was achieved when compared to computed tomography and iodocholesterol scintigraphy (86.2% and 62.5%, respectively).ConclusionDespite unsuccessful bilateral cannulation, our study confirms that unilateral‐cannulating AVS can effectively select patients for unilateral adrenalectomy based on a combination of CSI or RASI criteria.

Somatic GNAQ, CTNNB1, and CACNA1C Mutations in Cat Aldosterone-Secreting Tumors.

Primary aldosteronism (PA) is a common cause of human hypertension. Somatic mutations in KCNJ5, CACNA1D, ATP1A1, and ATP2B3 are found in at least 80% of aldosterone-producing adenomas, which cause unilateral PA in humans. Somatic mutations have been identified infrequently in 7 other genes; few of these were known to play a role in aldosterone secretion before the discovery of their mutations. Interrogating somatic mutations in the domestic cat, in which spontaneous PA is also known to occur, might improve the understanding of normal adrenal gland physiology and the pathophysiology of PA. DNA and RNA extracted from tissue from 13 cats with unilateral aldosterone-secreting tumors, including 8 carcinomas and 5 adenomas, underwent whole genome sequencing, targeted Sanger sequencing, and RNA sequencing. Single-nucleotide substitution variants were filtered to select those with a predicted deleterious effect on protein function and a suspected role in aldosterone secretion. Probable functional somatic single-nucleotide polymorphisms (n=8) were found in 3 adenomas and 2 carcinomas. Mutations with predicted significant effects were identified in 2 genes also mutated in human PA; GNAQ and CTNNB1, and in a residue of CACNA1C analogous to a common CACNA1D mutation. In contrast to humans, CACNA1C expression was much greater than CACNA1D in both feline tumor and nontumor adrenal tissue. No mutations were identified in KCNJ5, CACNA1D, ATP1A1, or ATP2B3. Similar mutations were identified in cats to those found in humans. It is, therefore, likely that both species have shared underlying selection pressures for mutations that increase aldosterone secretion.

Circulating miRNAs and Machine Learning for Lateralizing Primary Aldosteronism.

Distinguishing between unilateral and bilateral primary aldosteronism, a major cause of secondary hypertension, is crucial due to different treatment approaches. While adrenal venous sampling is the gold standard, its invasiveness, limited availability, and often difficult interpretation pose challenges. This study explores the utility of circulating microRNAs (miRNAs) and machine learning in distinguishing between unilateral and bilateral forms of primary aldosteronism. MiRNA profiling was conducted on plasma samples from 18 patients with primary aldosteronism taken during adrenal venous sampling on an Illumina MiSeq platform. Bioinformatics and machine learning identified 9 miRNAs for validation by reverse transcription real-time quantitative polymerase chain reaction. Validation was performed on a cohort consisting of 108 patients with known subdifferentiation. A 30-patient subset of the validation cohort involved both adrenal venous sampling and peripheral, the rest only peripheral samples. A neural network model was used for feature selection and comparison between adrenal venous sampling and peripheral samples, while a deep-learning model was used for classification. Our model identified 10 miRNA combinations achieving >85% accuracy in distinguishing unilateral primary aldosteronism and bilateral adrenal hyperplasia on a 30-sample subset, while also confirming the suitability of peripheral samples for analysis. The best model, involving 6 miRNAs, achieved an area under curve of 87.1%. Deep learning resulted in 100% accuracy on the subset and 90.9% sensitivity and 81.8% specificity on all 108 samples, with an area under curve of 86.7%. Machine learning analysis of circulating miRNAs offers a minimally invasive alternative for primary aldosteronism lateralization. Early identification of bilateral adrenal hyperplasia could expedite treatment initiation without the need for further localization, benefiting both patients and health care providers.

A comparative study of postadrenalectomy hyperuricemia and renal impairment in patients with unilateral primary aldosteronism: does histopathology subtype matter?

BackgroundPrimary aldosteronism (PA), which is present in 5–18% of hypertensive patients, is a leading cause of secondary hypertension. Adrenalectomy is often recommended for patients with unilateral primary aldosteronism (uPA), yielding good long-term outcomes. PA patients without hyperuricemia and chronic renal failure before adrenalectomy were enrolled in this cohort study. Serum uric acid (SUA) and renal filtration were measured one year post-adrenalectomy. Their relationships with pathologic features, histopathological subtype (classical or nonclassical (HISTALDO consensus)), and vessel stiffness were explored. The aim of this cohort study is to evaluate the correlation between post-adrenalectomy serum uric acid (SUA) levels and estimated glomerular filtration rate (eGFR) with the pathologic features delineated by the HISTALDO consensus. Additionally, the study seeks to assess the impact of these biochemical markers on peripheral vessel stiffness and brachial-ankle pulse wave velocity (baPWV) at a one-year follow-up visit.MethodsThis prospective cohort study included patients (N = 100) diagnosed with uPA who underwent adrenalectomy from Jan 1, 2007 to Dec 31, 2022.ResultsAt follow-up, elevated SUA, hyperuricemia, and a > 25% eGFR decrease were significantly more common in the classical than the nonclassical group. The incidence of postoperative hyperuricemia, herein referred to as post-adrenalectomy hyperuricemia (PAHU), was 29% (29/100) overall, 34.8% (23/66) in the classical group and 17.6% (6/34) in the nonclassical group. The incidence of eGFR reduction > 25% was 33% (33/100), 43.9% (29/66), and 11.8% (4/34), respectively. baPWV decreased more in the classical group than the nonclassical group.ConclusionFor PA patients with PAHU and/or renal impairment, we suggest monitoring SUA, pH, urine uric acid, and urine crystals and performing a KUB study and peripheral vascular and renal sonography (on which pure uric acid stones in the KUB are radiolucent) to determine whether drug intervention is required for cases of asymptomatic PAHU, especially patients in male gender, classical histopathology, or renal impairment.

Staining patterns of aldosterone synthase in patients undergoing surgery for primary aldosteronism: Proposal for system of categorization and investigation of clinical and biochemical correlation

BackgroundHow aldosterone synthase (CYP11B2) staining patterns impact patient outcomes in those with unilateral primary aldosteronism is not well described. We hypothesized that a system of categorization would benefit future research and that clinical and biochemical outcomes after unilateral adrenalectomy are impacted by different CYP11B2 staining patterns. MethodsA retrospective review of patients undergoing adrenalectomy for primary aldosteronism from January 2015 to September 2023 was conducted. Demographics, clinical, and pathologic data were analyzed. A system of categorization of staining patterns was developed. Clinical and biochemical outcomes were compared with staining patterns to assess differences and determine correlation. Descriptive and statistical analyses were performed using SPSS. ResultsForty-three patients were included. The following CYP11B2 staining patterns were identified: (1) single adenoma; (2) aldosterone producing nodule(s) or micronodule(s); (3) combination of type 1 and type 2; (4) hyperplasia; and (5) aldosterone-producing adrenocortical cancer. In total, 23 of 43 revealed CYP11B2 staining in a single adenoma only. Staining in 3/23 involved a portion of the adenoma. 4/9 patients age <40 had areas of CYP11B2 staining in nonadenomatous tissue. Complete biochemical cure was noted in 37 of 43 (86%) and complete clinical cure in 23.2%. There were no differences between staining pattern and sex, race, or age. CYP11B2 staining pattern did not correlate with early clinical or biochemical outcomes. ConclusionAdrenalectomy specimens from patients treated for primary aldosteronism reveal multiple CYP11B2 staining patterns, including in nonadenomatous tissue in many patients. The impact of these patterns on clinical outcomes requires additional investigation. Uniform categorization of staining patterns will allow for consistent reporting across studies.

7454 Angiotensin AT1 Receptor Type 1 (AT1) Autoantibodies In Patients with Primary Aldosteronism

Abstract Disclosure: J.K. Waraich: None. G. Kline: None. M.Y. Choi: None. R.J. Sigal: None. C. Caughlin: None. S.J. Przybojewski: None. A. Leung: None. Background: Primary aldosteronism (PA) is a condition characterized by excessive aldosterone secretion, and accounts for at least 10% - 20% of all cases of hypertension. Determination of PA subtype (i.e., unilateral vs. bilateral aldosterone hypersecretion) is clinically important to inform targeted treatment. We hypothesized that pathogenesis of PA is immune-mediated and autoantibodies to angiotensin receptor type 1 (AT1) may determine PA subtype. Aims: The aim of this study was to examine whether AT1 autoantibodies predict PA subtype. Methods: We conducted a cross-sectional study of patients with PA who were referred for adrenal vein sampling (AVS) for subtyping. AT1 autoantibody titres were measured using an enzyme-linked immunosorbent assay. AT1 antibodies were defined as present when the titre was &amp;gt;17 U/mL, negative if &amp;lt;10 U/mL, and indeterminate if between 10-17 U/mL. AVS was used as a gold standard to determine lateralization and PA . The frequency of positive AT1 autoantibodies was determined according to PA subtype and clinical predictors of lateralization. Baseline patient characteristics were reported as means (and standard deviations) for normally distributed variables, and medians (and interquartile ranges) for non-normally distributed variables. Fisher’s exact test was performed for categorical variables and Kruskal-Wallis test for continuous variables. Results: 54 patients had successful cannulation of both adrenal veins (mean age, 52.7 years; 46.3% male; mean body mass index, 31.2 kg/m2). AT1 antibodies were detected in 14 (25.9%) of the patients, absent in 32 (59.3%), and indeterminate in 8 (14.8%). Among the 25 patients with unilateral PA, 8 (32.0%) had positive AT1 antibodies, 15 (60.0%) negative, and 2 (8.0%) indeterminate. Similarly, among the 29 patients with bilateral PA, 6 (20.7%) had positive AT1 antibodies, 17 (58.6%) negative, and 6 (20.7%) indeterminate. There was no significant association detected between AT1 antibody status and lateralization (p=0.39). There were no associations between AT1 autoantibody status and any of the clinical factors traditionally predictive of PA, including sex (p=0.94), older age (p=0.76), hypokalemia (p=0.91), higher estimated glomerular filtration rate (p=0.46), or magnitude of aldosterone-to-renin ratio elevation (p=0.58). There was also no association between AT1 titres and these factors. Conclusion: AT1 autoantibodies are common in patients with PA; over a quarter of patients who underwent AVS in our study. Although they were not predictive of PA subtype, these results may still suggest that PA is immune-mediated. Future studies comparing AT1 autoantibodies in PA to other controls are underway. Presentation: 6/1/2024

7798 A Prospective Within-Patient Comparison of Molecular Imaging Ligands for Detection Of Surgically Curable Primary Aldosteronism (PA), and an Assessment of Accuracy in Cortisol Co-Secretors

Abstract Disclosure: E. Goodchild: None. X. Wu: None. R. Senanayake: None. J. MacFarlane: None. G. Argentesi: None. K. Laycock: None. C. Cabrera: None. S.M. O'Toole: None. J. Salsbury: None. D. Benu: None. Y. Lee: None. A. Chua: None. M. Mattson: None. P. Laila: None. N. Hilliard: None. M. Alison: None. D. Berney: None. K. Drew: None. C. Mein: None. E. Wozniak: None. J. Kearney: None. A. Sahdev: None. N. Bird: None. G. Smith: None. M. Hird: None. V. Warnes: None. D. Gillett: None. F. Aigbirhio: None. A. McIntosh: None. A. McConnachie: None. K. Cruickshank: None. H. Cheow: None. M. Gurnell: None. W. Drake: None. M.J. Brown: None. Introduction: Molecular imaging could reduce the need for invasive, scarcely-available adrenal sampling (AVS) to identify aldosterone-producing adenomas (APAs). Easily-distributable ligands for widespread use will be needed. Imidazole ligands lacking selectivity ex vivo for CYP11B1 and CYP11B2 are rendered selective in vivo by pre-treatment with dexamethasone. Aims To determine whether post-dexamethasone para-chloro-2-[[1]8F]fluoroethyletomidate PET-CT (CETO) (T ½ 110min), is interchangeable with previously validated [[1][1]C]-metomidate PET-CT (MTO) (T ½ 20min) for the diagnosis of APA. To identify whether a non-fully-suppressed cortisol after prolonged (72h) low-dose dexamethasone forewarns of an increased risk of a false-positive MTO result, in the MATCH study cohort.1Experimental design Prospective within-patient comparison of diagnostic interventions (n=31), with independent scoring of each as high, medium, low probability of unilateral PA, blind to scoring of the other scan or AVS. Prospective measurements of cortisol after prolonged low-dose dexamethasone suppression (PLDDF) and urinary hybrid steroids, with 6-month post-operative PASO biochemical outcomes and APA somatic genotyping when high probability (MTO or AVS) mandated surgery. Major results MTO and CETO agreed in 29/31, kappa=0.85 [95%CI 0.68,1.00]. Scatter was evenly distributed on either side of zero on Bland-Altman analysis (bias -0.04, [95% CI -0.12,0.04]. Of all 174 MATCH-study patients (n=174) PLDDF was available in 156, 32 had PLDDF &amp;gt;25nmol/L. Of these, MTO scored 16 as high probability of unilateral PA, in whom there was complete PASO biochemical success in 14 (88%), and absent in 2 (12%), indicating possible false-positives (AVS had failed in both). In patients with PLDDF &amp;lt;/=25nmol/L, MTO identified unilateral disease in 22, 19 (86.3%) of whom had complete biochemical success at 6 months, 3 (13.6%) with partial or absent success. 22 patients had both an elevated PLDDF and urinary hybrid steroid profiles measured, of whom 4 had an elevated 18OH/F ratio. PLDDF in unilateral and not-unilateral MTO outcome were comparable (unpaired T test p= 0.92). A known somatic genotype mutation was found in 21 patients with PLDDF &amp;gt;25nmol/l. PLDDF was highest in KCNJ5 mutants (12/21, mean 55.3nmol/L), compared to ATP1A1 (3/21, mean 44nmol/L), CACNA1D (4/21, mean 31nmol/L), ATP2B3 (1/21, 36nmol/L) and GNAQ (1/21, 28nmol/L). All had complete biochemical success at 6 months post-op. Conclusion: CETO is interchangeable with MTO, which is non-inferior to AVS, in lateralising aldosterone excess in PA patients. False-positives rarely occurred by MTO, and autonomous cortisol secretion did not increase the chance of a false-positive MTO result, compared to patients without, in this cohort. Reference: (1) Wu X et al. Nature Medicine. 2023;29:190-202. Presentation: 6/3/2024

5156 Circulating MicroRNA-based Biomarker Combinations for Differentiating Uni- and Bilateral Primary Aldosteronism Using a Machine Learning Approach

Abstract Disclosure: B. Vekony: None. G. Nyiro: None. Z. Herold: None. J. Fekete: None. F. Ceccato: None. S. Gruber: None. L. Kurzinger: None. M. Parasiliti-Caprino: None. B. Szeredas: None. S.K. Nazri: None. V. Fell: None. M. Bassiony: None. E.A. Azizan: None. I. Bancos: None. F. Beuschlein: None. P. Igaz: None. Background: The differentiation of uni- and bilateral forms of primary aldosteronism (PA) is of pivotal clinical relevance. Whereas unilateral PA warrants surgical treatment, bilateral PA is treated by aldosterone antagonists. The most reliable way to differentiate these two entities is adrenal venous sampling (AVS) that is an invasive method with limited availability and requiring great expertise. Aim: To develop a circulating blood-borne microRNA-based approach using machine learning for the differentiation of uni- and bilateral PA. Methods: Circulating microRNA profiling on an Illumina MiSeq platform was performed on total RNA samples isolated from EDTA-anticoagulated blood specimens taken by AVS from 18 pairs of right and left suprarenal veins (10 uni-, 8 bilateral PA). Significantly differentially expressed microRNAs were analyzed by a neural network (90-10% learner-tester cross-validation simulation). From the top 29 significantly differentially expressed microRNAs, 9 were selected for validation by Taqman RT-qPCR on a separate cohort of 30 AVS-confirmed samples (15-15 uni- and bilateral forms) both on plasma samples from adrenal as well as from peripheral veins. The method was finally tested on another independent cohort of peripheral blood samples from 80 patients (40 uni- and 40 bilateral PA). Results: Regarding the 9 microRNAs selected for validation, microRNA abundance was non-significantly lower in peripheral samples compared to AVS samples. By analyzing peripheral plasma samples, ten combinations of 4-8 microRNAs from the pool of 9 microRNAs turned out to have maximal sensitivity and specificity values over 85 %. The best combination included 6 microRNAs with a sensitivity of 86.3 % and a specificity of 87.91 % (AUC = 0.871). The inclusion of further parameters such as imaging, potassium and renin levels did not improve the model’s performance. Conclusion: The analysis of circulating blood-borne microRNAs represents a minimally invasive and potentially reliable way of differentiating uni- and bilateral PA. If bilateral PA is confirmed by the model, no more localization efforts would be necessary thus simplifying the management of PA patients. This would be relevant both from the patient’s and a public health perspective. Presentation: 6/3/2024

Bilateral superselective adrenal artery embolization for bilateral primary aldosteronism: a novel approach in an efficacy and safety proof-of-principle trial.

Superselective adrenal artery embolization (SAAE) offers a novel approach for treating primary aldosteronism (PA). In this study, we aimed to assess the efficacy and safety of SAAE for the treatment of PA based on the lateralization results obtained from adrenal vein sampling (AVS).In this prospective study, we enrolled 40 patients with PA who underwent SAAE. The patients were categorized into two groups, unilateral PA and bilateral PA, based on AVS results. Clinical parameters and biochemical markers were assessed at 3 and 12 months postoperatively. The primary outcomes were changes in blood pressure and defined daily dose (DDD) of antihypertensive medications compared to baseline. Thirty-eight patients achieved technical success, with favorable clinical and biochemical efficacy rates. At three months postoperatively, the clinical efficacy rates were 79.2% and 78.6% for the UPA and BPA groups, respectively. At 12 months, the rates were 83.3% and 71.4%, respectively. Both groups exhibited a significant decrease in average blood pressure at 3 and 12 months compared with baseline (P < 0.001), and there was also a notable reduction in DDD (P < 0.05). At three months, the biochemical efficacy rates were 61.9% and 58.3% in the UPA and BPA groups, respectively. Due to loss to follow-up, biochemical indicators were not assessed at 12 months postoperatively. No severe adverse reactions occurred during or after SAAE. Patients with both UPA and BPA can benefit from SAAE. The superiority of bilateral adrenal artery embolization in the treatment of BPA over unilateral adrenal artery embolization requires further investigation.

Typing diagnostic value of 68Ga-pentixafor PET/CT for patients with primary aldosteronism and unilateral nodules.

Our goal was to compare the lateralization of 68Ga-pentixafor PET/CT with adrenal vein sampling (AVS) in primary aldosteronism (PA) patients with unilateral lesions. We retrospectively enrolled 61 patients with PA and all patients showed unilateral nodular lesions on CT and underwent 68Ga-Pentixafor PET/CT. The general clinical data, imaging and AVS results were collected. The diagnostic efficiency of 68Ga-Pentixafor PET/CT imaging in PA patients was calculated by visual and semi-quantitative analysis to compare the consistency with AVS, and the correlation between CXCR4 express and 68Ga-Pentixafor uptake was performed. The study included 42 unilateral PA (UPA) and 19 bilateral PA (BPA). The area under curve (AUC) of 68Ga-Pentixafor PET/CT to diagnosis UPA with 10 min maximum standardized uptake value (SUVmax) > 8.17 was 0.82 ([0.70-0.90], P < 0.001), and the sensitivity and specificity were 0.64 and 0.90, respectively. The maximal AUC of 68Ga-pentixafor PET/CT for the diagnosis UPA in patients with nodules with a diameter ≥1 cm was 0.87 ([0.73-0.95],P both <0.001,[10 min SUVmax=8.17 and 10 min mean standardized uptake value (SUVmean)=5.57]), and the sensitivity and specificity were 0.73 and 0.93, respectively. Unilateral adrenalectomy and significant CXCR4 expression were present in 32 UPA, including 27 aldosterone-producing adenoma and 5 idiopathic adrenal hyperplasia. Additionally, 68Ga-pentixafor uptake in adrenal lesions was significantly correlated with CXCR4 expression, and statistical differences in 68Ga-pentixafor uptake among IRS subgroups. 68Ga-Pentixafor PET/CT can be helpful for subtyping diagnosis of PA patients with unilateral adrenal nodular, showing significant potential in non-invasive PA classification.

P052 OPTIMAL ADRENAL VEIN SAMPLING LATERALIZATION CRITERIA FOR DIAGNOSIS OF UNILATERAL PRIMARY ALDOSTERONISM USING ALDOSTERONE CONCENTRATION MEASURED BY LC-MS/MS POST-ACTH STIMULATION

Background: Primary aldosteronism (PA) is characterized by excessive, autonomous secretion of aldosterone from one or both adrenal glands. Identification of unilateral disease and surgical resection can lead to cure, and is dependent on accurate criteria for lateralization of excess aldosterone during adrenal vein (AV) sampling (AVS). Current evidence for AVS lateralization cut-offs using plasma aldosterone concentration (PAC) measured by LC-MS/MS and post-surgical outcomes is limited. Aim: To determine optimal cut-off criteria to define lateralization of PA on AVS based on PAC measured by LC-MS/MS post-ACTH stimulation and post-surgical outcomes data. Methods: This study involved 60 subjects with PA who had PAC measured by LC-MS/MS post ACTH-stimulation during bilaterally-cannulated AVS, underwent unilateral adrenalectomy between July 2015-July 2021 and were followed up for ≥6 months. AVS lateralization parameters (lateralization index [LI; dominant PAC/cortisol(AV) ÷ non-dominant PAC/cortisol(AV)], contralateral suppression index [CSI; non-dominant PAC/cortisol(AV) ÷ PAC/cortisol(Peripheral Vein)], lateralization ratio [LR; dominant PAC/cortisol(AV) ÷ PAC/cortisol(Peripheral Vein)] and post-surgical outcome data were examined. Complete biochemical remission (CR) of PA post-surgery was defined using PASO International Consensus Criteria. Receiver operating characteristic (ROC) analysis was performed to determine optimal cut-offs for LI, CSI and LR based on cases who achieved CR of PA post-surgery (n=55) vs those who did not (n=5). Results: Optimal cut-off LI during ACTH-stimulated AVS to identify unilateral PA cases who achieved CR post-surgery was 5.1 (AUC=0.92, P&lt;0.001; 92.7% sensitivity, 80.0% specificity) while the optimal cut-off for CSI was 0.6 (AUC=0.887, P&lt;0.001; 82.1% sensitivity, 100.0% specificity), and for LR was 3.3 (AUC=0.695, P=0.202; 80.0% sensitivity, 80.0% specificity). Cases with LR of 2.0-3.3 also achieved CR post-surgery if it was associated with CSI &lt;0.6. Conclusion: LI of &gt;5.1 provides high sensitivity and CSI &lt;0.6 high specificity for identification of surgically curable unilateral PA during ACTH-stimulated AVS when PAC is analyzed by LC-MS/MS.

Utility of Adrenal Vein Sampling With and Without Ultra-Low Dose ACTH Infusion in the Diagnostic Evaluation of Primary Aldosteronism.

Adrenal vein sampling (AVS), integral to identifying surgically remediable unilateral primary aldosteronism (PA), is technically challenging and subject to fluctuations in cortisol and aldosterone secretion. Intra-procedural adrenocorticotropic hormone (ACTH), conventionally administered as a 250-μg bolus and/or 50 μg per hour infusion, increases cortisol and aldosterone secretion and can improve AVS success, but may cause discordant lateralisation compared to unstimulated AVS. To assess if AVS performed with ultra-low dose ACTH infusion causes discordant lateralisation. Here, we describe our preliminary experience using an ultra-low dose ACTH infusion AVS protocol. We retrospectively reviewed the results of consecutive AVS procedures (n = 37) performed with and without ultra-low dose ACTH (1-μg bolus followed by 1.25 μg per hour infusion). Bilateral AV cannulation was successful in 70% of procedures pre-ACTH and 89% post-ACTH (p < 0.01). Sixty-nine percent of studies lateralised pre-ACTH and 55% post-ACTH, improving to 79% when both groups were combined. Lateralisation was discordant in 11 cases, including eight in which lateralisation was present only on basal sampling, and three in which lateralisation occurred only with ACTH stimulation. Overall, the decrease in lateralisation rates with ACTH was higher than previously reported for some protocols utilising conventional doses of ACTH. Our results suggest that AVS performed with ultra-low dose ACTH can cause discordant lateralisation similar to AVS performed with conventional doses of ACTH. Prospective studies directly comparing low and conventional dose ACTH AVS protocols and long-term patient outcomes are needed to help define the optimal ACTH dose for accurate PA subtyping.

Rationality and implication of catheter-based adrenal ablation for bilateral primary aldosteronism.

Mineralocorticoid receptor antagonists (MRAs) for bilateral primary aldosteronism (PA) are the mainstay option recommended by guidelines, but poor compliance occurs due to numerous side effects. We aimed to examine whether catheter-based adrenal ablation could be an alternative treatment for bilateral PA.644 PA patients were included from a total of 6054 hypertensive patients. Adrenal CT scan and adrenal venous sampling (AVS) were both performed for PA subtype classification. Clinical and biochemical outcomes were assessed at 6 months after treatment according to the Primary Aldosteronism Surgical Outcome (PASO) criteria.93 patients with PA were recruited to be treated by adrenal ablation, including 25 bilateral PA and 68 unilateral PA according to AVS results. Office SBP and DBP significantly decreased from baseline levels, serum potassium levels increased and ARR significantly decreased (p < 0.01) in both the bilateral and unilateral groups. In the bilateral group, complete, partial and absent clinical success was achieved in 6 (24.0%), 11 (44.0%) and 8(32.0%) patients, respectively. In the unilateral group, complete, partial and absent clinical success was achieved in 12 (17.6%), 37 (54.4%), and 19 (27.9%) patients, respectively. The numbers of patients achieving complete, partial, and absent biochemical success were 15 (60.0%), 6 (24.0%), and 4 (16.0%), respectively, in the bilateral group versus 37 (54.4%), 9 (13.2%), and 22 (32.3%), respectively, in the unilateral group. In conclusion, we provide evidence for the beneficial outcomes of unilateral adrenal ablation for patients with bilateral PA. Our findings provide insight into an alternative option for patients with bilateral excess aldosterone.

Clinical Management of Primary Aldosteronism: An Update.

Despite carrying an excess risk of cardiovascular events, primary aldosteronism (PA) is a commonly overlooked secondary form of arterial hypertension. An increased awareness of its high prevalence and broader screening strategies are urgently needed to improve its detection rate and allow early diagnosis and targeted treatment. For patients with unilateral PA, these measures can correct hyperaldosteronism and ensure cure of hypertension, even when resistant to drug treatment, thus preventing adverse cardiovascular events. Among these, atrial fibrillation is the most common, but left ventricular hypertrophy, stroke, chronic kidney disease, and myocardial infarction also occur more often than in patients with hypertension and no PA. Young patients, who have higher chances of being cured long term, and high-risk patients, such as those with stage III or resistant hypertension, are those who will benefit most from an early diagnosis of PA. Therefore, the implementation of strategies to detect PA by a simplified diagnostic algorithm is necessary. In the patients who seek for surgical cure, adrenal vein sampling is key for the identification of unilateral PA and the achievement of optimal outcomes. Unfortunately, being technically demanding and poorly available, adrenal vein sampling represents the bottleneck in the workup of PA. Considering the novel knowledge generated in the past 5 years in many studies, particularly in the AVIS-2 study (Adrenal Vein Sampling International Study-2), based on 4 decades of experience at our center and on the last guidelines, we herein provide an update on the management of PA with recommendations for drug treatment and strategies to avoid adrenal vein sampling wherever it is poorly, or not, available.

Clinical characteristics of primary aldosteronism screened from Chinese patients with hypertension: The China primary aldosteronism prospective study.

We investigated the clinical characteristics of primary aldosteronism (PA) screened from patients with hypertension in China. The participants were hypertensive patients who were suspected of PA and registered in the China Primary Aldosteronism Prospective Study. Plasma aldosterone-to-renin ratio (ARR) was used as the screening test. In patients screened positive for PA, that is, an ARR exceeding the thresholds and plasma aldosterone concentration (PAC)>100 pg/mL, a confirmatory test was performed for diagnosis. Patients with PA underwent a CT scan and adrenal venous sampling for subtyping. Of the 1497 screened patients, 754 (50.4%) had an ARR exceeding the diagnostic threshold and 637 (84.5% of those eligible) were registered. These registered hypertensive patients with suspected PA had a mean (standard deviation) age of 52.6±12.1 years, and included 442 (58.6%) women. In multiple stepwise logistic regression, the significant odds ratios for the presence of diagnosed (n=490) versus suspected and non-diagnosed PA (n=147) were 4.54 (95% CI: 2.78-7.39) for a history of hypokalemia, 0.79 (95% CI: 0.64-0.98) for a 0.9mmol/l higher serum total cholesterol, and 2.25 (95% CI: 1.63-3.10) for a doubling of PAC in the supine or standing/sitting position. In multiple stepwise logistic regression, the significant odds ratios for the presence of unilateral (n=135) versus bilateral PA (n=53) were 3.04 (95% CI: 1.90-4.87) for a 0.4mmol/l lower minimum serum potassium concentration and 1.86 (95% CI: 1.20-2.86) for a 0.3mmol/l higher serum high-density lipoprotein cholesterol. PA might be a biochemical continuum in the adrenal hypersecretion of aldosterone as well as hypokalemia.

Targeted Treatment Reverses Increased Left Cardiac Work in Unilateral vs. Bilateral Primary Aldosteronism.

The incidence of cardiovascular complications may be higher in unilateral than bilateral primary aldosteronism (PA). We compared noninvasive hemodynamics after targeted therapy of bilateral vs. unilateral PA. Adrenal vein sampling was performed, and hemodynamics recorded using radial artery pulse wave analysis and whole-body impedance cardiography (n = 114). In 40 patients (adrenalectomy n = 20, spironolactone-based treatment n = 20), hemodynamic recordings were performed after 33 months of PA treatment. In initial cross-sectional analysis, 51 patients had bilateral and 63 unilateral PA. The mean ages were 50.6 and 54.3 years (P = 0.081), and body mass indexes 30.3 and 30.6 kg/m2 (P = 0.724), respectively. Aortic blood pressure (BP) and cardiac output did not differ between the groups, but left cardiac work was ~10% higher in unilateral PA (P = 0.022). In the follow-up study, initial and final BPs in the aorta were not significantly different, while initial cardiac output (+13%, P = 0.015) and left cardiac work (+17%, P = 0.009) were higher in unilateral than bilateral PA. After median treatment of 33 months, the differences in cardiac load were abolished, and extracellular water volume was reduced by 1.3 and 1.4 l in bilateral vs. unilateral PA, respectively (P = 0.814). These results suggest that unilateral PA burdens the heart more than bilateral PA, providing a possible explanation for the higher incidence of cardiac complications in unilateral disease. A similar reduction in aldosterone-induced volume excess was obtained with targeted surgical and medical treatment of PA.

Establishment of a scoring model for predicting clinical outcomes in patients with unilateral primary aldosteronism after superselective adrenal artery embolization.

Superselective adrenal arterial embolization (SAAE) is a potential alternative treatment for patients with unilateral primary aldosteronism (PA) who refuse unilateral adrenalectomy. Therefore, we aimed to establish a scoring model to differentiate between hypertensive remission after SAAE. This prospective cohort study involved 240 patients who underwent SAAE for unilateral PA. Patients were randomly divided into a model training set and a validation set at a ratio of 7:3. The clinical outcome was a response to hypertension remission, defined as complete, partial, or absent success at 6 months after SAAE. Multivariate logistic regression was performed to identify independent parameters and develop a nomogram to predict clinical outcomes after SAAE. The discrimination, calibration efficacy, and clinical utility of the predictive model were assessed. Five independent predictors were identified: female sex, duration of hypertension, defined daily dose of antihypertensive medication, diabetes, and target organ damage. The above five independent predictors were put into a predictive model that was presented as a nomogram. Using bootstrapping for internal validation, the C-statistic for the predictive model was 0.866 (95% confidence interval [CI]: 0.834 to 0.898). In the validation cohort, the area under the curve (AUC) of the nomogram for predicting hypertension remission after SAAE was 0.809. The present model is the first nomogram-based score that specifically predicts hypertension remission after SAAE in patients with unilateral PA using conventional parameters. This is an effective risk stratification tool that can be used by clinicians for timely and tailored preoperative risk discussions.

#357 Sex differences in the aldosterone-renin system must be taken into account during screening for primary aldosteronism

Abstract Background and Aims Primary aldosteronism (PA) is one of the most frequent causes of secondary hypertension. Patients with PA are at higher risk for cardiovascular and renal complications than those with essential hypertension. Screening for PA is rarely considered in the assessment of a hypertensive patient, in part because of difficulties in the diagnostic process. Nevertheless, identification of PA is crucial to guide patients towards optimal management, either by mineralocorticoid receptor blockade or by unilateral adrenalectomy, with the latter offering potential cure for patients with aldosterone-producing adenomas (APAs). Numerous studies show inadequate diagnostic accuracy of the aldosterone:renin ratio (ARR) for screening for PA, particularly in females, who have higher ARR variability and lower renin compared to males. Women have a higher risk of false-positive screening results leading to unnecessary confirmatory tests. Use of oral contraception (OC) or hormone replacement therapy (HRT) may also confound the ARR. The aim of this study was to develop improved screening tools for PA, including adjustments for sex-specific differences. Method PROSALDO is a multicenter prospective cohort study designed to test new diagnostic procedures for patients with suspected PA. Medication that interfere with the renin-angiotensin-aldosterone system are withdrawn before laboratory measurements. For screening, the routine ARR is calculated along with additional probability scores based on a peripheral venous steroid hormone profile (PVSP). The latter allows for identification of potentially false-negative ARR results. After a positive screening result of the ARR and/or a high probability score based on the PVSP, PA is confirmed or excluded with a saline infusion test (SIT). PA confirmation is followed by adrenal venous sampling (AVS) to identify patients with unilateral PA. We compared aldosterone, renin and ARR levels between females and males with and without PA. Renin- and sex dependent formulas for aldosterone screening cut-offs were derived from the study population. Logistic regression and the corresponding receiver operating characteristic (ROC) curves were used to determine and compare diagnostic accuracies. Results PA was confirmed in 159 (24.5%) of 649 (328 (50.5%) females and 321 (49.5%) males). Lateralization was shown in 58 out of 117 patients who underwent AVS. In hypertensive patients without PA, ARR was higher in females vs. males (26.4 vs. 11.7 pmol/mU, P &amp;lt; 0.0001), mainly due to a lower renin (9.2 vs. 16.2 mU/L, P &amp;lt; 0.0001). Furthermore, ARRs in patients with vs. without PA showed more overlap in females compared to males. Areas under ROC curves (AUROCs) for the ARR were 0.857 (CI 95%: 0.797-0.902) vs. 0.912 (CI 95%: 0.876-0.938) for females and males respectively. Using liquid chromatography mass spectrometry measurements (LC-MS/MS) of aldosterone, an ARR cut-off of 21.75 pmol/L yielded a sensitivity of 93% with only 45% specificity in females, while for males, a specificity of 66% was obtained for a sensitivity of 97.7%. This meant for females having a higher risk of false-positive screening results (OR 2.36 (CI 95%: 1.65-3.41)), even after excluding patients on OC or HRT (OR 2.17 (CI 95%: 1.5-3.17)). We derived a renin- and sex-dependent formula for the calculation of aldosterone cut-offs, which improved diagnostic accuracy for both males and females (ΔAUROC = 0.05 and 0.045, P &amp;lt; 0.0001 and 0.02 respectively): for a diagnostic sensitivity of 94-95%, specificity was improved to 61% in females and 82% in males. Conclusion Lower renin in females without PA leads to higher ARRs and thus a higher risk of false-positive screening results. Higher overlap of the ARR between females with and without PA compared to their male counterparts weakens utility of the ARR for discrimination of patients with and without PA. Sex- and renin-specific aldosterone cut-offs for screening for PA offer improved diagnostic accuracy. Diagnostic accuracy remains however superior in males, which highlights the need for further optimization of diagnostic procedures specifically in women.

EVALUATION OF CHORIORETINAL VASCULARIZATION WITH OCT AND ANGIO-OCT IN PRIMARY ALDOSTERONISM

Objective: Primary aldosteronism (PA), the most common cause of secondary hypertension, is associated with excess cardiovascular damage and, when unilateral, is amenable to surgical cure. Our objective was to determine whether the chorioretinal microvasculature is also affected. Design and method: Ocular CT-scan (OCT) and angio-OCT images of the superficial and deep retinal plexi were obtained in PA patients at diagnosis, in wash-out from RAAS-confounding drugs (WO), and again during mineralocorticoid receptor antagonist (MRA) therapy and 4-6 months after surgical cure (PS). The images were analysed for choroidal thickness and, upon automated ImageJ processing, for indexes of total vascular area density (VAD) and length fraction (VLF), a surrogate for the number of open vessels. Results: We enrolled 11 patients with PA (51±10 yrs; 27%F); of these, 10 who had unilateral PA underwent curative surgery (p&lt;0.05 for BP, sK+ and ARR). We found that MRA therapy had no effect on any of the investigated parameters. At variance, curative surgery determined a reduction of VAD in both superficial and deep plexi (-6.4% retinal area, p=0.017 and -3.5%, p=0.023, respectively) and of VLF in the superficial plexus (-2.2%, p=0.033). Moreover, choroidal thickness (on average: -21μm, p=0.003 at 2-way ANOVA) decreased after adrenalectomy. Conclusions: OCT and angio-OCT images, which can accurately track changes in choroid- retinal vascularization, highlighted a decrease of retinal microvascular area and choroidal thickness in patients with unilateral PA, who were cured from PA.

FEASIBILITY OF SUBTYPING OF PRIMARY ALDOSTERONISM BY ADRENAL VEIN SAMPLING DURING MINERALOCORTICOID RECEPTOR ANTAGONIST TREATMENT

Objective: Current guidelines and consensus documents recommend withdrawal of mineralocorticoid receptor antagonists (MRA) before primary aldosteronism (PA) subtyping by adrenal venous sampling (AVS), but this practice can cause severe hypokalemia and/or uncontrolled high blood pressure (BP) values in PA patients. The aim of the study was to investigate if identification of unilateral PA (uPA) by means of AVS is feasible in patients on MRA treatment. Design and method: We compared the rate of uPA identification between patients with and without MRA treatment in two large datasets of patients who were submitted to AVS from 2000 to 2023 without renin-angiotensin system blockers and beta-blockers. In sensitivity analyses, the between-groups differences of lateralization index (LI) values after propensity score matching and the rate of uPA identification in subgroups with undetectable (&lt; 2 mUI/L), suppressed (&lt; 8.2 mUI/L) and unsuppressed (&gt; 8.2 mUI/L), direct renin concentration (DRC) levels were also evaluated. Results: A minority of the PA patients (n = 61, 7.3%) underwent AVS on MRA treatment, while the majority were off MRA (n = 779, 92.7%). Compared to non-MRA patients, those with MRA showed a higher daily drug dose (2.25 vs 1.5, p = 0.001), a higher rate of adrenal nodules at imaging (82 vs 67, p = 0.022) and of adrenalectomy (72 vs 54%, p = 0.01). The AUROC of lateralization index (LI) showed no significant differences between groups, either under unstimulated conditions (0.960 vs 0.937, p = 0.590) or after cosyntropin (0.923 vs 0.917, p = 0.938). Sensitivity analyses confirmed these results after propensity score matching in several adjusted models and in patients with undetectable, suppressed or unsuppressed renin levels. Conclusions: MRAs, at doses that controlled blood pressure and potassium levels in PA patients, did not preclude the identification of uPA at AVS.