Right Ventricle Lipid in Pulmonary Arterial Hypertension (PAH)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Idiopathic Pulmonary Arterial Hypertension; Heritable Pulmonary Arterial Hypertension; Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
• Intervention / Treatment: Other: No Intervention

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.

• Study Type: Observational
• Enrollment (Estimated): 75

Contacts and Locations

• Study Contact: Name: Evan Brittain, MD, MSCI; Phone Number: (615) 322-4382; Email: evan.brittain@vumc.org
• Study Contact Backup: Name: Natasha Billard; Phone Number: (434) 851-3306; Email: natasha.billard.1@vumc.org

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with PAH will be recruited from the Center for Pulmonary Vascular Disease (CPVD) at Vanderbilt University Medical Center.

Description

Inclusion criteria:

• ≥ 18 years old
• Diagnosed with idiopathic, heritable, connective tissue disease-associated PAH, associated pulmonary arterial hypertension (PAH), or drug-or toxin-associated PAH according to World Health Organization (WHO) 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.
• WHO Functional Class I-III
• Ambulatory
• Able to have an MRI/MRS, perform a 6MWD test, and cardiopulmonary exercise test

Exclusion criteria:

• Pregnancy
• Diagnosis of PAH etiology other than idiopathic, heritable, connective tissue disease - associated PAH or associated with drugs and toxins
• 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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Participants with Pulmonary Arterial Hypertension (PAH); Participants with heritable, idiopathic, and scleroderma associated PAH.	Other: No Intervention; No Intervention

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Evan Brittain, MD, MSCI, Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2023
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: July 14, 2022
• First Submitted That Met QC Criteria: July 14, 2022
• First Posted (Actual): July 18, 2022

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 26, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Familial Primary Pulmonary Hypertension
• Other Study ID Numbers: 221138; HL155278 (Other Grant/Funding Number: NHLBI)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No