Primary Aldosteronism Subtypes: Pathophysiology and Steroid Signatures

摘要 原发性醛固酮增多症（PA）是最常见的肾上腺疾病，也是最常见的原因。 内分泌性高血压PA与心血管发病率和死亡率相关， 高血压患者的血压水平高于相似程度的原发性高血压患者。两大 PA类型为单侧PA（通常为醛固酮腺瘤，阿帕，约占PA病例的40%）， 双侧醛固酮增多症（BHA，约60%的PA病例），这需要终身 有针对性的药物治疗。尽管PA的患病率很高，并有严重的心肾并发症， 诊断不足，部分原因是诊断和分型的步骤复杂、昂贵且具有侵入性。 肾上腺成像在确定过量醛固酮产生的来源方面是不准确的。因此，委员会认为， 目前PA亚型的标准治疗是肾上腺静脉采样（AVS），这是一种侵入性的，技术上 具有挑战性，标准化程度低，仅限于三级转诊中心。 本申请的总体目标是：1）确定各种APA的类固醇合成能力 通过对阿帕组织进行全面的组织学、基因组和类固醇分析; 2）联合收割机 基线和动态血液检查，以确定外周血中PA亚型的类固醇特征。这 这种方法将消除60%以上PA患者（BHA）对AVS的需求。制定了两个具体目标 以解决PA患者护理中的关键差距。·在目标1中，我们将探讨APA的工作假设， 具有不同的潜在醛固酮驱动体细胞突变的人具有特定的类固醇指纹。落实 CYP 11B 2酶化学指导的下一代测序（NGS），以表征体细胞 APAs潜在的突变。同时，我们会用最先进的质谱分析来确定类固醇的成分 APA的特征：（a）最佳切割温度（OCT）包埋的阿帕组织;（B）肾上腺血液 引流这些肿瘤的静脉;和（c）外周血。·在目标2中，我们将检验小组的工作假设， 在外周血中测量的类固醇生物标志物可以区分APA与BHA和必需的 高血压我们将实施基线和动态测试（ACTH刺激和地塞米松 抑制）以鉴定PA亚型的类固醇特征之间的差异。质谱分析将是 用于定量PA和原发性高血压患者的类固醇。这种方法将直接解决 简化PA诊断和亚型分型的关键临床需求，并将为我们的长期目标采取重要步骤 目标是扩大个性化PA治疗，最大限度地提高治愈PA病例的数量。

ABSTRACT Primary aldosteronism (PA) is the most common adrenal disorder and the most common cause of endocrine hypertension. PA is associated with cardiovascular morbidity and mortality that are disproportionately higher compared to those observed in patients with similar degree of essential hypertension. The two major types of PA are unilateral PA (typically an aldosterone producing adenoma, APA, ~40% of PA cases), which can be cured with surgery, and bilateral hyperaldosteronism (BHA, ~60% of PA cases), which requires life-long targeted medical therapy. Despite its high prevalence and serious cardio-renal complications, PA is underdiagnosed, in part because the steps for diagnosis and subtyping are complicated, costly, and invasive. Adrenal imaging is inaccurate in identifying the source(s) of excessive aldosterone production. Consequently, the current standard-of-care for PA subtyping is adrenal vein sampling (AVS), which is an invasive, technically challenging, and poorly standardized procedure, with availability limited to tertiary referral centers. The overall objectives of this application are: 1) to define the steroid synthetic capacity of various APAs by implementing comprehensive histologic, genomic and steroid profiling analyses of APA tissue; 2) combine baseline and dynamic blood tests to define the steroid signatures of PA subtypes in peripheral blood. This approach will eliminate the need for AVS in over 60% PA patients (BHA). Two specific aims have been designed to address critical gaps in the care of PA patients. • In Aim 1, we will probe the working hypothesis that APAs with distinct underlying aldosterone-driver somatic mutations have specific steroid fingerprints. We will implement CYP11B2 immunohistochemistry-guided next-generation sequencing (NGS) to characterize the somatic mutations underlying APAs. In parallel, we will use state-of-the-art mass spectrometry to define the steroid profiles of APAs from: (a) optimal cutting temperature (OCT)-embedded APA tissue; (b) blood from the adrenal veins draining these tumors; and (c) peripheral blood. • In Aim 2, we will test the working hypothesis that panels of steroid biomarkers measured in peripheral blood can distinguish APAs from both BHA and essential hypertension. We will implement baseline and dynamic testing (ACTH stimulation and Dexamethasone suppression) to identify differences between the steroid signatures of PA subtypes. Mass spectrometry will be used to quantify steroids in patients with PA and essential hypertension. This approach will directly address the critical clinical need to simplify PA diagnosis and subtyping and will take essential steps towards our long-term goal, of expanding personalized PA treatment and maximizing the number of cured PA cases.