Subclinical Autonomous Aldosterone Secretion: Physiology, Pathogenesis, and Progression

醛固酮的自主和非生理性分泌导致矿皮质激素受体的过度激活和随之而来的心血管疾病。目前的临床标准只承认明显和严重的“原发性醛固酮增多症”；然而，调查小组已经描述了一种扩展的轻度和亚临床自主醛固酮分泌连续体，延伸到相当大比例的正常血压个体。研究小组已经表明，自主醛固酮增多症的严重程度随着年龄的增长而增加，并代表了一种可改变的机制，有助于高血压和心血管疾病的发生。此外，研究小组还表明，这种自主分泌醛固酮的发病机制可能是醛固酮产生细胞簇（APCCs）：在形态正常的肾上腺中发现的醛固酮合成酶异常表达簇，在近一半的个体中发现。本研究计划的目的是探讨亚临床自主醛固酮分泌的生理、发病机制和进展。该建议的第一个目标是纵向队列研究，其中具有亚临床自主醛固酮分泌的正常血压参与者（n=50）和没有自主醛固酮分泌证据的正常血压参与者（n=50）将在3年的过程中进行表型表征。预计自主醛固酮分泌和过度矿皮质激素受体激活的表型将随着时间的推移而严重恶化，并导致血压和MR活性生物标志物升高。本提案的目的2涉及40例计划接受选择性肾上腺切除术的患者的表型特征。所有参与者将接受术前详细的醛固酮分泌表型分析。手术后，他们的正常肾上腺组织将被分析apcc。预计apcc的负担将与术前自主醛固酮分泌的生化表型独立相关。本研究的完成将：1)扩大自主醛固酮分泌的临床病理疾病谱，并有可能重新定义“原发性醛固酮增多症”的连续性；2)证实亚临床自主醛固酮分泌相对常见，起源于血压正常者，并随时间以年龄依赖性方式加重；3)提示组织病理学apcc可能是亚临床醛固酮分泌的机制基础。这种对自主醛固酮分泌的扩展理解将支持未来的研究，以确定和瞄准醛固酮介导的心血管疾病的发生风险，这些风险可能通过矿皮质激素受体拮抗剂减轻。

The autonomous and non-physiologic secretion of aldosterone results in excessive activation of the mineralocorticoid receptor and consequent cardiovascular disease. Current clinical standards only recognize overt and severe “primary aldosteronism;” however, the investigative team has described an expanded continuum of milder and subclinical autonomous aldosterone secretion that extends to a substantial proportion of normotensive individuals. The research team has shown that the severity of autonomous aldosteronism progresses with aging, and represents a modifiable mechanism that contributes to incident hypertension and cardiovascular disease. Further, the investigative team has shown that the pathogenesis of this autonomous aldosterone secretion may be aldosterone producing cell clusters (APCCs): clusters of abnormal aldosterone synthase expression in morphologically normal adrenal glands that are found in nearly one half of all individuals. The aim of this research proposal is to investigate the physiology, pathogenesis, and progression of subclinical autonomous aldosterone secretion. The first aim of this proposal is a longitudinal cohort study, whereby normotensive participants enriched to have subclinical autonomous aldosterone secretion (n=50), and normotensive participants without evidence of autonomous aldosterone secretion (n=50), will be phenotypically characterized over the course of 3 years. It is anticipated that the phenotype of autonomous aldosterone secretion and excessive mineralocorticoid receptor activation will progress in severity over time and contribute to elevations in blood pressure and biomarkers of MR activity. Aim 2 of this proposal involves the phenotypic characterization of 40 patients scheduled to undergo an elective adrenalectomy. All participants will undergo pre-operative detailed phenotyping for autonomous aldosterone secretion. Following their surgery, their normal adrenal tissue will be analyzed for APCCs. It is anticipated that the burden of APCCs will be independently associated with the pre- operative biochemical phenotype of autonomous aldosterone secretion. The completion of the proposed research will: 1) Expand the clinico-pathologic disease spectrum of autonomous aldosterone secretion and potentially redefine the continuum of “primary aldosteronism”; 2) Confirm that subclinical autonomous aldosterone secretion is relatively common, originates in normotension, and progresses in severity over time in an age-dependent manner; and 3) Implicate histopathologic APCCs as the likely mechanistic basis for subclinical aldosterone secretion. This expanded understanding of autonomous aldosterone secretion will support future investigations to identify and target the risk for developing aldosterone-mediated cardiovascular disease that may be mitigated by mineralocorticoid receptor antagonists.