title: Development and pathomechanisms of cardiomyopathy in very long-chain acyl-CoA dehydrogenase deficient (VLCAD(-/-)) mice.
abstract: Hypertrophic cardiomyopathy is a typical manifestation of very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), the most common long-chain β-oxidation defects in humans; however in some patients cardiac function is fully compensated. Cardiomyopathy may also be reversed by supplementation of medium-chain triglycerides (MCT). We here characterize cardiac function of VLCAD-deficient (VLCAD(-/-)) mice over one year. Furthermore, we investigate the long-term effect of a continuous MCT diet on the cardiac phenotype. We assessed cardiac morphology and function in VLCAD(-/-) mice by in vivo MRI. Cardiac energetics were measured by (31)P-MRS and myocardial glucose uptake was quantified by positron-emission-tomography (PET). Metabolic adaptations were identified by the expression of genes regulating glucose and lipid metabolism using real-time-PCR. VLCAD(-/-) mice showed a progressive decrease in heart function over 12 months accompanied by a reduced phosphocreatine-to-ATP-ratio indicative of chronic energy deficiency. Long-term MCT supplementation aggravated the cardiac phenotype into dilated cardiomyopathy with features similar to diabetic heart disease. Cardiac energy production and function in mice with a β-oxidation defect cannot be maintained with age. Compensatory mechanisms are insufficient to preserve the cardiac energy state over time. However, energy deficiency by impaired β-oxidation and long-term MCT induce cardiomyopathy by different mechanisms. Cardiac MRI and MRS may be excellent tools to assess minor changes in cardiac function and energetics in patients with β-oxidation defects for preventive therapy.
authors: Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, 79106 Freiburg, Germany; Department of General Pediatrics, University Children's Hospital Duesseldorf, 40225 Duesseldorf, Germany. Electronic address: sara.tucci@uniklinik-freiburg.de.
authors: Sara
authors: S
authors: Tucci
authors: Department of Molecular Cardiology, Heinrich Heine University Duesseldorf, 40225 Duesseldorf, Germany.
authors: Ulrich
authors: U
authors: Flögel
authors: European Institute for Molecular Imaging - EIMI, University of Muenster, 48149 Muenster, Germany.
authors: Sven
authors: S
authors: Hermann
authors: Department of General Pediatrics, University Children's Hospital Duesseldorf, 40225 Duesseldorf, Germany.
authors: Marga
authors: M
authors: Sturm
authors: European Institute for Molecular Imaging - EIMI, University of Muenster, 48149 Muenster, Germany.
authors: Michael
authors: M
authors: Schäfers
authors: Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, 79106 Freiburg, Germany.
authors: Ute
authors: U
authors: Spiekerkoetter
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000503:physiopathology*; D000080984:Congenital Bone Marrow Failure Syndromes; D004734:Energy Metabolism; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D028361:Mitochondrial Diseases / Q000235:genetics / Q000503:physiopathology*; D009135:Muscular Diseases / Q000235:genetics / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D016133:Polymerase Chain Reaction; D049268:Positron-Emission Tomography; D013599:Systole
chemical_list: D044942:Acyl-CoA Dehydrogenase, Long-Chain; D005947:Glucose
keywords: Dilated cardiomyopathy; Energy metabolism; MCT-supplementation; MRI; PET; VLCAD-deficiency