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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK115392-01
Application #
9419587
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Malozowski, Saul N
Project Start
2018-04-01
Project End
2023-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115