Abstract 18041: Dysregulated Fatty Acid Metabolism in Pulmonary Arterial Hypertension is Associated with Right Ventricular Steatosis and Lipotoxicity
Introduction: The mechanisms of right ventricular (RV) failure in pulmonary arterial hypertension (PAH) are poorly understood. We have previously shown that heritable PAH is associated with RV lipotoxicity. Abnormalities in fatty acid metabolism have been described in experimental PAH, but systemic and myocardial fatty acid metabolism have not been well described in human PAH. We hypothesized that abnormal fatty acid metabolism in PAH is associated with altered peripheral lipid metabolism and lipotoxic cardiac steatosis.
Methods and Results: We measured plasma free fatty acids (FFA) and acylcarnitine (fatty acid metabolites) profiles in PAH patients and age, gender, and body mass index-matched controls. In a transgenic murine model of PAH, we measured RV FAs and acylcarnitines. Using proton magnetic resonance spectroscopy we quantified in vivo myocardial triglyceride content in 6 PAH patients and 5 healthy controls. To test the functional consequences of lipid accumulation, we stained explanted human PAH and control RVs for annexin V (apoptosis) and ceramide, a fatty acid metabolite and mediator of apoptosis and lipotoxicity. FFAs (0.91±0.35 vs. 0.48±0.30, p < 0.001) and the long-chain acylcarnitines C16 to C18:2 (p < 0.0003 for all) were 1.5-2 fold higher in PAH patients versus matched controls. RV long chain FAs were increased in murine PAH versus control and pulmonary artery banded mice and associated with lower cardiac index. In vivo myocardial triglyceride content (1.4 ± 1.3 %TG vs. 0.21 ± 0.13 %TG, p = 0.05) was elevated in human PAH versus controls (Figure). Lipotoxicity markers ceramide and annexin V were increased in the PAH patient RVs versus controls.
Conclusions: Abnormalities in fatty acid metabolism can be detected in the blood and myocardium in human PAH and are associated with marked in vivo cardiac steatosis and lipotoxicity. Further study is needed to determine the impact of altered fatty acid metabolism on RV function and clinical outcomes in PAH.
- Pulmonary hypertension
- Magnetic resonance spectroscopy
- Pulmonary heart disease
- Cardiac imaging
Author Disclosures: E.L. Brittain: None. M. Talati: None. H. Zhu: None. J. West: None. J.P. Fessel: Research Grant; Significant; Actelion Pharmaceuticals through the Entelligence program. N. Penner: None. M. Funke: None. G.D. Lewis: None. R.E. Gerszten: None. R. Hamid: None. M.E. Pugh: Consultant/Advisory Board; Modest; Gilead. E.D. Austin: Research Grant; Significant; American Thoracic Society, NIH/NHLBI. J.H. Newman: None. A.R. Hemnes: Research Grant; Significant; Pfizer. Consultant/Advisory Board; Modest; Pfizer, United Therapeutics.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.