Heritable Pulmonary Arterial Hypertension, Idiopathic Pulmonary Arterial Hypertension, Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
Conditions
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.
Interventions
OTHERNo Intervention
No Intervention
Sponsors
Vanderbilt University Medical Center
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Right Ventricular (RV) Ejection Fraction | Baseline to 36 months | Change in RV ejection fraction will be measured by cardiac MRI. |
| Change in Right Ventricular (RV) Lipid Content | 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. |
| Identification of metabolic markers (dihyroxybutyrate, acetylputriscene, hydroxystearate and glucuronate) in the peripheral circulation and coronary sinus. | Baseline to 36 months | Metabolite markers will be measured by ultrahigh performance liquid chromatography and mass spectrometry. |
| Ratio of BMPR2 isoform B/A. | 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. | 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) |
Countries
United States
Contacts
CONTACTNatasha Billard
CONTACTEvan Brittain, MD, MSCI
PRINCIPAL_INVESTIGATOREvan Brittain, MD, MSCI
Vanderbilt University Medical Center
Outcome results
None listed