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Biochim Biophys Acta. 2014 May;1842(5):677-85. doi: 10.1016/j.bbadis.2014.02.001. Epub 2014 Feb 12.

Development and pathomechanisms of cardiomyopathy in very long-chain acyl-CoA dehydrogenase deficient (VLCAD(-/-)) mice.

Author information

1
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.
2
Department of Molecular Cardiology, Heinrich Heine University Duesseldorf, 40225 Duesseldorf, Germany.
3
European Institute for Molecular Imaging - EIMI, University of Muenster, 48149 Muenster, Germany.
4
Department of General Pediatrics, University Children's Hospital Duesseldorf, 40225 Duesseldorf, Germany.
5
Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, 79106 Freiburg, Germany.

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.

KEYWORDS:

Dilated cardiomyopathy; Energy metabolism; MCT-supplementation; MRI; PET; VLCAD-deficiency

PMID:
24530811
DOI:
10.1016/j.bbadis.2014.02.001
[Indexed for MEDLINE]
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