Right Ventricle Lipid in Pulmonary Arterial Hypertension (PAH)

Idiopathic Pulmonary Arterial Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05462574
• Other study ID #: 221138
• Secondary ID: HL155278
• Status: Recruiting
• Start date: January 17, 2023
• Est. completion date: September 30, 2027

Study information

• Verified date: May 2024
• Source: Vanderbilt University Medical Center
• Contact: Natasha Billard
• Phone: (434) 851-3306
• Email: natasha.billard.1[@]vumc.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 75
• Est. completion date: September 30, 2027
• Est. primary completion date: September 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Connective Tissue Diseases
• Familial Primary Pulmonary Hypertension
• Heritable Pulmonary Arterial Hypertension
• Hypertension
• Idiopathic Pulmonary Arterial Hypertension
• Pulmonary Arterial Hypertension

Intervention

Other:
• No Intervention
No Intervention

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (2)

Lead Sponsor	Collaborator
Vanderbilt University Medical Center	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Right Ventricular (RV) Ejection Fraction	Change in RV ejection fraction will be measured by cardiac MRI.	Baseline to 36 months
Primary	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
Primary	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
Primary	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
Primary	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