Clinical and Mechanistic Understanding of Right Ventricular Steatosis in Pulmonary Arterial Hypertension (PAH)
Overview
- Phase
- Not Applicable
- Intervention
- Not specified
- Conditions
- Idiopathic Pulmonary Arterial Hypertension
- Sponsor
- Vanderbilt University Medical Center
- Enrollment
- 75
- Locations
- 1
- Primary Endpoint
- Change in Right Ventricular (RV) Ejection Fraction
- Status
- Recruiting
- Last Updated
- 11 months ago
Overview
Brief Summary
The investigators propose to study the relationship between right ventricle (RV) steatosis and RV function, exercise capacity, and outcomes in humans with pulmonary arterial hypertension (PAH) and to identify potential drivers of lipid accumulation.
Detailed Description
The investigators propose to test the hypothesis that abnormal lipid metabolism in PAH leads to delivery of fatty acids in excess of RV oxidative capacity, resulting in steatosis and lipotoxicity. The objectives of the study are to: 1) Define the relationships between RV steatosis, RV function, and exercise capacity; 2) Identify mechanistic drivers of RV steatosis including BMPR2 expression and lipid metabolism; 3) Examine lipid metabolism in PAH skeletal muscle as a potential driver of reduced functional capacity. In Aim 1 (clinical relevance) the investigators will measure RV and left ventricle (LV) lipid in participants with heritable, idiopathic, and scleroderma- associated PAH. Participants will undergo the 6-minute walk test, cardiopulmonary exercise testing, and will be followed for clinical events. A subgroup will undergo repeat MRS at four timepoints over three years to determine the natural history of steatosis. In Aim 2 (mechanism), the investigators will perform metabolomic/lipidomic profiling of peripheral and coronary sinus plasma and measure BMPR2 expression to identify potential drivers of steatosis. In Aim 3 (specificity), the investigators will perform MRS on skeletal muscle in Aim 1 participants and matched healthy controls to clarify the systemic effects of lipid metabolic defects in PAH.
Investigators
Evan Brittain
Associate Professor of Medicine
Vanderbilt University Medical Center
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Outcomes
Primary Outcomes
Change in Right Ventricular (RV) Ejection Fraction
Time Frame: Baseline to 36 months
Change in RV ejection fraction will be measured by cardiac MRI.
Change in Right Ventricular (RV) Lipid Content
Time Frame: Baseline to 36 months
Change in RV lipid content will be measured by cardiac proton magnetic resonance spectroscopy (MRS). Lipid content is expressed as a percent of the voxel occupied by lipid.
Ratio of BMPR2 isoform B/A.
Time Frame: Baseline to 36 months
BMPR2 isoforms A and B and wild type gene expression will be measured by real-time polymerase chain reaction (PCR) and validated by measuring protein content using Western blot test.
Change in skeletal muscle lipid content.
Time Frame: Baseline to 36 months
Change in skeletal muscle lipid content will be measured by skeletal muscle proton MRS. Lipid content is expressed as percent triglyceride (%TG)
Identification of metabolic markers (dihyroxybutyrate, acetylputriscene, hydroxystearate and glucuronate) in the peripheral circulation and coronary sinus.
Time Frame: Baseline to 36 months
Metabolite markers will be measured by ultrahigh performance liquid chromatography and mass spectrometry.