Abstract 11501: Dilated Cardiomyopathy Due to Medium-Chain Triglyceride Diet in Mice With a Defect in β-Oxidation
Patients with long-chain fatty acid oxidation disorders are prone to develop cardiac and skeletal myopathy. Therapeutical approaches include fat-modified diets, in which long-chain triglycerides (LCT) are replaced by medium-chain triglycerides (MCT). MCTs are able to bypass the first steps of β-oxidation catalyzed by long-chain acyl-CoA dehydrogenases and thus limit metabolic derangements in the heart. MCTs are considered as safe dietary intervention although long-term observations are still missing. To investigate the consequences of a prolonged MCT diet we used very long-chain acyl-CoA dehydrogenase deficient (VLCAD-/-) mice and analyzed the dietary effects on cardiac function and abdominal fat distribution and composition by in vivo 1H/13C MRI and MRS at 9.4 Tesla. We show that MCT supplementation, without increasing the total fat content of the diet, induces a dramatic accumulation of visceral fat and liver lipids in VLCAD-/- mice when applied over one year. Furthermore, MCT diet leads to a profound shift in body triglyceride composition in that levels of physiological important polyunsaturated fatty acids dramatically decrease. Concomitant to the alterations in fat distribution and composition, we demonstrate severe liver damage in VLCAD-/- mice with substantial signs of oxidative stress and steatohepatitis. Beyond these metabolic deteriorations, MCT diet could not prevent cardiomyopathy in VLCAD-/- mice (EF 58.9±6.5%, LCT diet), but rather aggravated the functional consequences of the metabolic defect (EF 48.3±5.3% (MCT diet), n=9, P<0.05) and leads to severe dilated cardiomyopathy (diastolic wall thickness 0.97±0.04 (MCT) vs 1.12±0.14 mm (LCT)). Histology revealed significant cardiac lipid accumulation and fibrosis after long-term MCT diet. Despite the fact that all MCT-induced effects were exceptionally pronounced in VLCAD-/- mice, we noted that also wild-type mice displayed a tendency to a similar phenotype (EF 66.4±6.2 (MCT) vs 75.4±4.7% (LCT)) as VLCAD-deficient mice. In summary, we demonstrate that MCT therapy of mice with a defect in ß-oxidation provokes a severe phenotype similar to the metabolic syndrome associated with dilated cardiomyopathy, casting doubt that MCTs are suitable for long-term supplementation.
- © 2012 by American Heart Association, Inc.