R01HL155834

Primary Aldosteronism Subtypes: Pathophysiology and Steroid Signatures - Abstract

Primary aldosteronism (PA) is the most common adrenal disorder and the most common cause of endocrine hypertension. PA is associated with cardiovascular morbidity and mortality that are disproportionately higher compared to those observed in patients with a similar degree of essential hypertension.

The two major types of PA are unilateral PA (typically an aldosterone-producing adenoma, APA, ~40% of PA cases), which can be cured with surgery, and bilateral hyperaldosteronism (BHA, ~60% of PA cases), which requires lifelong targeted medical therapy.

Despite its high prevalence and serious cardio-renal complications, PA is underdiagnosed, in part because the steps for diagnosis and subtyping are complicated, costly, and invasive. Adrenal imaging is inaccurate in identifying the source(s) of excessive aldosterone production. Consequently, the current standard-of-care for PA subtyping is adrenal vein sampling (AVS), which is an invasive, technically challenging, and poorly standardized procedure, with availability limited to tertiary referral centers.

The overall objectives of this application are:

1) To define the steroid synthetic capacity of various APAs by implementing comprehensive histologic, genomic, and steroid profiling analyses of APA tissue.

2) Combine baseline and dynamic blood tests to define the steroid signatures of PA subtypes in peripheral blood. This approach will eliminate the need for AVS in over 60% of PA patients (BHA).

Two specific aims have been designed to address critical gaps in the care of PA patients.

- In Aim 1, we will probe the working hypothesis that APAs with distinct underlying aldosterone-driver somatic mutations have specific steroid fingerprints. We will implement CYP11B2 immunohistochemistry-guided next-generation sequencing (NGS) to characterize the somatic mutations underlying APAs. In parallel, we will use state-of-the-art mass spectrometry to define the steroid profiles of APAs from: (a) optimal cutting temperature (OCT)-embedded APA tissue; (b) blood from the adrenal veins draining these tumors; and (c) peripheral blood.

- In Aim 2, we will test the working hypothesis that panels of steroid biomarkers measured in peripheral blood can distinguish APAs from both BHA and essential hypertension. We will implement baseline and dynamic testing (ACTH stimulation and dexamethasone suppression) to identify differences between the steroid signatures of PA subtypes. Mass spectrometry will be used to quantify steroids in patients with PA and essential hypertension.

This approach will directly address the critical clinical need to simplify PA diagnosis and subtyping and will take essential steps towards our long-term goal of expanding personalized PA treatment and maximizing the number of cured PA cases.

Regents Of The University Of Michigan

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Michigan United States

State-Wide

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the End Date has been extended from 03/31/25 to 03/31/26 and the total obligations have increased 365% from $751,696 to $3,494,786.