Development and pathomechanisms of cardiomyopathy in very long-chain acyl-CoA dehydrogenase deficient (VLCAD^{鈭?鈭?/sup>) mice}

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• 作者：Sara Tucci^a ; ^b ; ¹ ; ^{sara.tucci@uniklinik-freiburg.de" class="auth_mail} ; Ulrich Flö ; gel^c ; ¹ ; Sven Hermann^d ; Marga Sturm^b ; Michael Schä ; fers^d ; Ute Spiekerkoetter^a
• 关键词：VLCAD-deficiency ; Dilated cardiomyopathy ; MRI ; PET ; MCT-supplementation ; Energy metabolism
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：May, 2014
• 年：2014
• 卷：1842
• 期：5
• 页码：677-685
• 全文大小：1331 K

文摘

Hypertrophic cardiomyopathy is a typical manifestation of very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), the most common long-chain 尾-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^{鈭?鈭?/sup>) 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鈭?鈭?/sup> mice by in vivo MRI. Cardiac energetics were measured by 31P-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鈭?鈭?/sup> 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 尾-oxidation defect cannot be maintained with age. Compensatory mechanisms are insufficient to preserve the cardiac energy state over time. However, energy deficiency by impaired 尾-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 尾-oxidation defects for preventive therapy.}