R01HL155278

Clinical and Mechanistic Understanding of Right Ventricular Steatosis in Pulmonary Arterial Hypertension - Abstract

Most patients with pulmonary arterial hypertension (PAH) die from right ventricular (RV) failure and all experience exercise limitation. No RV-specific therapies exist because the mechanisms underlying RV failure are poorly understood.

The discovery of novel, potentially treatable causes of RV failure and exercise limitation would be an important advance in the treatment of PAH. RV steatosis may be a novel mechanism of RV failure in human PAH.

We and others reported a high prevalence of insulin resistance in patients with PAH. We recently published that insulin resistance in PAH manifests primarily as abnormalities in lipid metabolism. Patients with PAH had elevated circulating free fatty acids and long-chain acylcarnitines, and we found impaired mitochondrial fatty acid oxidation and RV lipid accumulation (steatosis) in a rodent model of PAH.

We used proton magnetic resonance spectroscopy (MRS) to quantify RV lipid in vivo and showed that RV lipid content is over 10-fold higher in humans with PAH compared with matched controls and may be modifiable with metformin. In autopsy RV specimens, we found increased ceramide, a mediator of lipotoxicity, and identified candidate plasma surrogates for RV steatosis.

Finally, we present new evidence of skeletal muscle steatosis in humans to demonstrate that insulin resistance is a systemic feature of PAH. The clinical relevance of RV steatosis in human PAH is unknown. RV steatosis is common in both heritable and idiopathic PAH and is not an end-stage phenomenon, which suggests potential for therapeutic intervention.

We hypothesize that abnormal lipid metabolism in PAH leads to delivery of fatty acids in excess of RV oxidative capacity, resulting in steatosis and lipotoxicity. Our objectives 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; and 4) test the response of RV and skeletal muscle steatosis to metformin.

In Aim 1 (Clinical Relevance), we will measure RV and 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. We will measure RV lipid in participants before and after metformin therapy in a separate ongoing study.

In Aim 2 (Mechanism), we 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), we 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. We will also test the effect of metformin on skeletal muscle lipid content and fatigue.

The proposed studies address an important knowledge gap in PAH pathophysiology by interrogating a newly discovered, novel mechanism of RV failure in humans.

Vanderbilt University Medical Center

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Nashville, Tennessee 372152691 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 306% from $752,441 to $3,053,152.