Subclinical Autonomous Aldosterone Secretion: Physiology, Pathogenesis, and Progression

醛固酮的自主性和非生理性分泌导致盐皮质激素受体的过度激活和随后的心血管疾病。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，研究小组已经描述了一个扩大的连续性的温和和亚临床自主醛固酮分泌，延伸到相当大比例的血压正常的个人。研究小组已经表明，自主性醛固酮增多症的严重程度随着年龄的增长而进展，并且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，研究小组已经表明，这种自主醛固酮分泌的发病机制可能是醛固酮产生细胞簇（APCC）：在近一半的个体中发现的形态正常的肾上腺中异常醛固酮合酶表达的簇。本研究的目的是探讨亚临床自主性醛固酮分泌的生理学、发病机制和进展。该提案的第一个目的是一项纵向队列研究，其中富含亚临床自主性醛固酮分泌的血压正常参与者（n=50）和没有自主性醛固酮分泌证据的血压正常参与者（n=50）将在3年内进行表型表征。预计自发性醛固酮分泌和盐皮质激素受体过度激活的表型的严重程度将随时间推移而进展，并导致血压和MR活动生物标志物升高。本建议的目的2涉及40例择期肾上腺切除术患者的表型特征。所有参与者将接受术前详细的自主醛固酮分泌表型分析。手术后，将对他们的正常肾上腺组织进行APCC分析。预期APCC的负荷将独立地与自主性醛固酮分泌的术前生化表型相关。该研究的完成将：1）扩大自主性醛固酮分泌的临床病理疾病谱，并可能重新定义“原发性醛固酮增多症”的连续性; 2）证实亚临床自主性醛固酮分泌相对常见，起源于正常血压，并以年龄依赖性方式随时间推移而严重进展;和3）暗示组织病理学APCCs作为亚临床醛固酮分泌的可能机制基础。这种对自主性醛固酮分泌的扩展理解将支持未来的研究，以确定和靶向开发醛固酮介导的心血管疾病的风险，盐皮质激素受体拮抗剂可以减轻。

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.