Clinical and Mechanistic Understanding of Right Ventricular Steatosis in Pulmonary Arterial Hypertension (PAH)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 75
- 试验地点
- 2
- 主要终点
- Change in Right Ventricular (RV) Ejection Fraction
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •≥ 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
排除标准
- •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
结局指标
主要结局
Change in Right Ventricular (RV) Ejection Fraction
时间窗: Baseline to 36 months
Change in RV ejection fraction will be measured by cardiac MRI.
Change in Right Ventricular (RV) Lipid Content
时间窗: 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.
Ratio of BMPR2 isoform B/A.
时间窗: 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.
时间窗: 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)
Identification of metabolic markers (dihyroxybutyrate, acetylputriscene, hydroxystearate and glucuronate) in the peripheral circulation and coronary sinus.
时间窗: Baseline to 36 months
Metabolite markers will be measured by ultrahigh performance liquid chromatography and mass spectrometry.
次要结局
未报告次要终点
研究者
Evan Brittain
Associate Professor of Medicine
Vanderbilt University Medical Center