Right Ventricle Lipid in Pulmonary Arterial Hypertension (PAH)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Clinical and Mechanistic Understanding of Right Ventricular Steatosis in Pulmonary Arterial Hypertension (PAH)

Conditions
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Idiopathic Pulmonary Arterial Hypertension, Heritable Pulmonary Arterial Hypertension, Scleroderma Associated Pulmonary Arterial Hypertension

Intervention / Treatment
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* Other: No Intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years old Diagnosed with idiopathic, heritable, connective tissue disease - associated PAH, associated pulmonary arterial hypertension (PAH) according to World Health Organization consensus recommendations. Stable PAH-specific medication regimen for three months prior to enrollment. Adjustments in IV prostacyclin for side effect management are allowed. Diuretic adjustments are permitted. World Health Organization (WHO) Functional Class I-III Ambulatory Able to have an MRI/MRS, perform a six minute walk distance (6MWD) test and cardiopulmonary exercise test Exclusion Criteria: Pregnancy Diagnosis of PAH etiology other than idiopathic, heritable, connective tissue disease - associated PAH WHO Functional class IV heart failure Requirement for continuous oxygen Unable to have an MRI/MRS, perform a 6MWD test or cardiopulmonary exercise test. Patients with implanted/embedded ferromagnetic material that would preclude cardiac MRI

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Participants with Pulmonary Arterial Hypertension (PAH)<br>Participants with heritable, idiopathic, and scleroderma associated PAH. | Other: No Intervention<br>* No Intervention<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Right Ventricular (RV) Ejection Fraction | Change in RV ejection fraction will be measured by cardiac MRI. | Baseline to 36 months | 
| Change in Right Ventricular (RV) Lipid Content | 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. | Baseline to 36 months | 
| Identification of metabolic markers (dihyroxybutyrate, acetylputriscene, hydroxystearate and glucuronate) in the peripheral circulation and coronary sinus. | Metabolite markers will be measured by ultrahigh performance liquid chromatography and mass spectrometry. | Baseline to 36 months | 
| Ratio of BMPR2 isoform B/A. | 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. | Baseline to 36 months | 
| Change in skeletal muscle lipid content. | Change in skeletal muscle lipid content will be measured by skeletal muscle proton MRS. Lipid content is expressed as percent triglyceride (%TG) | Baseline to 36 months |