Subclinical Autonomous Aldosterone Secretion: Physiology, Pathogenesis, and Progression

醛固酮的自主和非生理性分泌导致盐皮质激素受体的过度激活，从而导致心血管疾病。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，研究小组描述了一种较轻微和亚临床自主的醛固酮分泌的扩展连续统，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发展，并代表了一种导致高血压和心血管疾病的可修改机制。此外，研究小组还表明，这种自主的醛固酮分泌的发病机制可能是醛固酮产生细胞团(APCCs)：在形态正常的肾上腺中异常表达的醛固酮合成酶，在近一半的人中发现。本研究的目的是探讨亚临床自主的醛固酮分泌的生理学、发病机制和进展。这项建议的第一个目标是一项纵向队列研究，在这项研究中，血压正常的参与者在3年的时间里将表现为有亚临床自主的醛固酮分泌(n=50)，而血压正常的参与者(n=50)没有自主的醛固酮分泌的证据。可以预见，醛固酮自主分泌和盐皮质激素受体过度激活的表型将随着时间的推移而加重，并有助于血压和MR活动的生物标志物的升高。这项建议的目标2涉及40名计划接受选择性肾上腺切除术的患者的表型特征。所有参与者都将在手术前接受自主醛固酮分泌的详细表型鉴定。手术后，他们的正常肾上腺组织将被分析APCCs。预计APCCs的负担将与术前自主分泌醛固酮的生化表型独立相关。这项拟议研究的完成将：1)扩大醛固酮自主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”的连续体；2)确认亚临床自主的醛固酮分泌相对常见，起源于正常血压，并以年龄相关的方式随着时间的推移而加重；3)组织病理学APCCs可能是亚临床醛固酮分泌的机制基础。这种对醛固酮自主分泌的深入了解将支持未来的研究，以确定并针对发生醛固酮介导的心血管疾病的风险，这些疾病可能会被盐皮质激素受体拮抗剂缓解。

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.