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.
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 healthy normotensive individuals. The completion of the proposed research will expand the current understanding of autonomous aldosterone secretion and will support future investigations to identify and target the risk for developing aldosterone-mediated cardiovascular disease that may be mitigated by mineralocorticoid receptor antagonists.
| Hundemer, Gregory L; Curhan, Gary C; Yozamp, Nicholas et al. (2018) Incidence of Atrial Fibrillation and Mineralocorticoid Receptor Activity in Patients With Medically and Surgically Treated Primary Aldosteronism. JAMA Cardiol 3:768-774 |
| Vaidya, Anand; Mulatero, Paolo; Baudrand, Rene et al. (2018) The Expanding Spectrum of Primary Aldosteronism: Implications for Diagnosis, Pathogenesis, and Treatment. Endocr Rev 39:1057-1088 |
| Hundemer, Gregory L; Curhan, Gary C; Yozamp, Nicholas et al. (2018) Renal Outcomes in Medically and Surgically Treated Primary Aldosteronism. Hypertension 72:658-666 |
| Vaidya, Anand; Malchoff, Carl D; Auchus, Richard J et al. (2017) AN INDIVIDUALIZED APPROACH TO THE EVALUATION AND MANAGEMENT OF PRIMARY ALDOSTERONISM. Endocr Pract 23:680-689 |
