Clinical trial NCT05462574: Right Ventricle Lipid in Pulmonary Arterial Hypertension (PAH)
Official title: Clinical and Mechanistic Understanding of Right Ventricular Steatosis in Pulmonary Arterial Hypertension (PAH)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Idiopathic Pulmonary Arterial Hypertension
Heritable Pulmonary Arterial Hypertension
Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2022-07-18
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Right Ventricular (RV) Ejection Fraction
timeFrame: Baseline to 36 months
measure: Change in Right Ventricular (RV) Lipid Content
timeFrame: Baseline to 36 months
measure: Identification of metabolic markers (dihyroxybutyrate, acetylputriscene, hydroxystearate and glucuronate) in the peripheral circulation and coronary sinus.
timeFrame: Baseline to 36 months
measure: Ratio of BMPR2 isoform B/A.
timeFrame: Baseline to 36 months
measure: Change in skeletal muscle lipid content.
timeFrame: Baseline to 36 months
Secondary outcomes:
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: Evan Brittain, MD, MSCI
role: PRINCIPAL_INVESTIGATOR
References: