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Objective: To determine whether antihypertensives will affect diagnostic accuracy of the aldosterone-to-renin ratio (ARR) to an extent that is clinically relevant., Methods: Confirmatory tests were used to confirm or exclude PA diagnosis. Area under the receiver operating characteristic curve (AUC), specificity and sensitivity of ARR performance in different conditions were calculated., Results: 208 PA and 78 essential hypertension (EH), and 125 PA and 206 EH patients, were included in the retrospective and prospective cohort, respectively. AUC of ARR on interfering medications was comparable to ARR off interfering medications (retrospective: 0.82 vs. 0.87, p = 0.20; prospective: 0.78 vs. 0.84, p = 0.07). At a threshold of 20 pg/μIU, the sensitivity of ARR on interfering medications was lower (11.1-23.2%) while the specificity was higher (10.2-15.2%) than ARR off interfering medications. However, when the ARR threshold on interfering medications was lowered to 10 pg/μIU, both the sensitivity (retrospective: 0.91 vs. 0.90, p = 0.61; prospective: 0.86 vs. 0.82, p = 0.39) and specificity (retrospective: 0.49 vs. 0.59, p = 0.20; prospective: 0.58 vs. 0.66, p = 0.10) were comparable to the ARR threshold off interfering medications., Conclusion: Using ARR to screen for PA whilst taking interfering antihypertensive drugs is feasible in most cases, but the ARR threshold needs to be reduced., Trial Registration: ClinicalTrials.gov identifier: NCT04991961., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Aldosterone-producing adenoma (APA) is a benign adrenal tumor with autonomous aldosterone production which causes hypertension and excess cardiovascular risk. Protein phosphorylation regulates aldosterone secretion from adrenal cortical cells, but how signaling networks are remodeled in APA remains unknown., Methods: We performed an integrated proteomic and phosphoproteomic profiling of 15 APA and 10 matched nonfunctioning adrenocortical tumors (NFAT) based on the 4-dimensional label-free technique. We further validated our main findings in enlarged APA samples, mice, and adrenocortical cell line., Results: The proteomic and phosphoproteomic profiling of APA and NFAT quantified 5989 proteins and 9011 phosphopeptides. We highlighted differentially expressed and phosphorylated proteins which modulated aldosterone synthesis and secretion from APA. As intracellular calcium is the central signal for aldosterone synthesis, our integrated calcium signaling network implicated wolframin in the control of calcium influx and CYP11B2 (aldosterone synthase) activation in APA (ratio of wolframin expression in APA to NFAT: 6.411, P <0.001). Among 97 APA cases for validation, a higher expression level of wolframin was associated with a higher plasma aldosterone concentration postcaptopril challenge test and a higher systolic blood pressure. In vitro, the secretion of aldosterone was enhanced by wolframin overexpression, while aldosterone secretion in response to potassium or angiotensin II was inhibited by the knockdown of wolframin. Further in vivo and in vitro data demonstrated the wolframin-calcium axis as an important regulator of CYP11B2 expression and aldosterone production., Conclusions: Wolframin is a regulatory protein in aldosterone hypersecretion. Remodeled calcium transportation and mitochondrial function are involved in wolframin-related aldosterone secretion.

Importance: Adrenal vein sampling (AVS) is the recommended procedure for subtyping primary aldosteronism (PA) as unilateral PA (UPA) or bilateral PA (BPA), with different treatment needed for each: adrenalectomy for UPA and medication for BPA. However, AVS is invasive and technically difficult, and how to subtype PA noninvasively is currently a great challenge., Objective: To evaluate the accuracy of gallium-68 pentixafor positron emission tomography-computed tomography (PET-CT) in subtyping PA using AVS as a reference standard., Design, Setting, and Participants: This diagnostic study was conducted at a tertiary hospital in China among patients diagnosed with PA. Enrollment was started in November 2021, with follow-up ending in May 2022., Exposures: : Patients were recruited to undergo gallium-68 pentixafor PET-CT and AVS., Main Outcomes and Measures: Maximum standardized uptake value (SUVmax) of each adrenal gland during PET-CT was measured to calculate the lateralization index of SUVmax. Area under the receiver operating characteristic curve (AUROC), specificity, and sensitivity were used to analyze the accuracy of the lateralization index based on SUVmax for subtyping PA., Results: Among 100 patients with PA who completed the study (47 female [47.0%] and 53 male [53.0%]; median [IQR] age, 49 [38-56] years), 43 individuals had UPA and 57 individuals had BPA. Aldosterone-cortisol ratio (Spearman ρ = 0.26; P < .001) in adrenal veins was positively correlated with SUVmax of adrenal glands at 10 minutes during PET-CT. Using lateralization index based on SUVmax at 10 minutes to identify UPA, the AUROC was 0.90 (95% CI, 0.83-0.97). A cutoff value for lateralization index based on SUVmax at 10 minutes set at 1.65 conferred a specificity of 1.00 (95% CI, 0.94-1.00) and sensitivity of 0.77 (95% CI, 0.61-0.88). The diagnostic concordance rate of PET-CT and AVS was 90 patients (90.0%) compared with 54 patients (54.0%) between traditional CT and AVS., Conclusions and Relevance: This study found good diagnostic accuracy of gallium-68 pentixafor PET-CT in differentiating UPA from BPA. These findings suggest that gallium-68 pentixafor PET-CT may be used to avoid invasive AVS in some patients with PA.