Abstract 14564: Bone Morphogenetic Protein Receptor Type II-Associated Heritable Pulmonary Arterial Hypertension is Associated with Fatty Acid Oxidation Defects and Cardiac Steatosis
Background: We have previously demonstrated in endothelial cells that impaired fatty acid oxidation(FAO) and increased glycolysis are direct consequences of mutation in Bone Morphogenetic Protein Receptor Type II (BMPR2), which underlies most cases of heritable pulmonary arterial hypertension (HPAH). Mutant BMPR2 is expressed in all tissues in vivo. Thus, cell types dependent on FAO such as cardiac myocytes may be adversely affected by these metabolic derangements and peripheral blood may demonstrate abnormalities of FAO. Hypothesis: We hypothesized that FAO impairment in BMPR2-associated HPAH (B-HPAH) patients can be measured in peripheral blood and demonstrated in pathologic right ventricular (RV) specimens.
Methods: Using neonatal metabolic screening cards, we collected blood samples from patients with B-HPAH and quantified acylcarnitine levels. Because FAO defects are exacerbated when glucose stores are low, we tested fasting and post-prandial levels in one patient. Two post-mortem RVs from B-HPAH patients and two non-ischemic cardiomyopathy patients were stained with Oil red O for lipid accumulation.
Results: 14 patients with HPAH (mean age 40 ± 14 years, 64% female) were tested; 7/14 had one or more elevated medium chain acylcarnitine level, suggesting impairment of medium chain acyl-coA dehydrogenases (Figure A). In one fasting patient, medium-chain acyclcarnitine levels were 1.5-3x normal, all of which normalized post-prandially. Intra-myocyte Oil red O staining was prominent in 2 patients with B-HPAH and was not found in disease controls (Figure B).
Conclusion: Defects in oxidation of medium-chain fatty acids are present at baseline in some patients with B-HPAH, and fasting may unmask defects not detected in the fed state. Human BMPR2 mutation is associated with marked intra-myocyte lipid accumulation in the RV. Further study is needed to determine if these abnormalities are related to the elevated mortality demonstrated in HPAH.
- © 2012 by American Heart Association, Inc.