Right ventricular failure is the primary cause of mortality in patients with pulmonary arterial hypertension and there currently are no therapies to reverse right ventricular dysfunction. Other's work and our own preliminary data have suggested altered metabolism including decreased fatty acid oxidation and lipid deposition may contribute to right ventricular failure in both human pulmonary arterial hypertension and in rodent models of RV dysfunction associated with pulmonary arterial hypertension. We have identified both fatty acid oxidation and increased lipid transport into cardiomyocytes as mechanisms that promote right ventricular lipid accumulation. Moreover, in preliminary data we have used MR spectroscopy to measure lipid deposition in the right ventricle of a patient with pulmonary arterial hypertension and found 10 fold higher percent triglyceride compared with controls. Based on these preliminary data, we now hypothesize that cardiomyocyte lipid deposition promotes RV failure in pulmonary arterial hypertension. Multiple mechanisms may result in right ventricular myocyte lipid deposition including Western diet resulting in increased lipid import or genetic mutations associated with impaired fatty acid oxidation with resultant accumulation of fatty acid metabolites and we propose two specific aims to study the mechanisms leading to lipid accumulation and the effect of deposition on right ventricular dysfunction. Our third specifi aim will translate these findings to humans in a trial of metabolic therapy for right ventricular failure with metformin and test the effect of this fatty acid oxidation enhancer on right ventriculr lipid measured by cardiac magnetic resonance spectroscopy. We will use cell culture, rodent model and human studies to study the mechanisms by which lipid deposition occurs, the functional consequences of lipid accumulation and if metabolic interventions to decrease lipid accumulation will improve right ventricular function in both rodent models and human disease. The long-term goal of these studies is to develop effective metabolic therapy for right heart failure in pulmonary arterial hypertension.

Public Health Relevance

Nearly half of patient with pulmonary arterial hypertension die within five years of their diagnosis. The primary cause of death is right heart failure, yet right heart failure remains poorly understood and without specific therapies. Recent work by our group and others has demonstrated that intracellular lipid accumulation and decreased fatty acid oxidation are features of right heart failure related to pulmonary hypertension. This grant aims to demonstrate that lipid deposition in the right ventricle promotes failure and can be reversed by metabolic interventions. The long-term goal of these studies is to develop effective metabolic therapy for right heart failure in human pulmonary arterial hypertension.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL122417-04
Application #
9197665
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Xiao, Lei
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Brittain, Evan L; Talati, Megha; Fessel, Joshua P et al. (2016) Fatty Acid Metabolic Defects and Right Ventricular Lipotoxicity in Human Pulmonary Arterial Hypertension. Circulation 133:1936-44
Talati, Megha H; Brittain, Evan L; Fessel, Joshua P et al. (2016) Mechanisms of Lipid Accumulation in the Bone Morphogenetic Protein Receptor Type 2 Mutant Right Ventricle. Am J Respir Crit Care Med 194:719-28
Brittain, Evan L; Hemnes, Anna R (2015) Vasodilator-responsive idiopathic pulmonary arterial hypertension: evidence for a new disease? Ann Intern Med 162:148-9
Talati, Megha; Hemnes, Anna (2015) Fatty acid metabolism in pulmonary arterial hypertension: role in right ventricular dysfunction and hypertrophy. Pulm Circ 5:269-78
Su, Yan Ru; Chiusa, Manuel; Brittain, Evan et al. (2015) Right ventricular protein expression profile in end-stage heart failure. Pulm Circ 5:481-97