Abstract 9376: Cardiac-Specific Very Long Chain Acyl-CoA Dehydrogenase Deficiency Induces Dilated Cardiomyopathy and Cold Intolerance in Mice
BACKGROUND: Very long chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial step of mitochondrial beta-oxidation of fatty acids with chain lengths of 14 to 20 carbons. Patients with VLCAD deficiency present with hypoketotic hypoglycemia, cardiomyopathy and sudden death that can be exacerbated by the stresses of fasting and cold. Global VLCAD knockout (KO) mice recapitulate these phenotypes. However, the contribution of cardiac VLCAD in the development of cardiomyopathy and the response to the environmental stressors is unclear. In this study, we assessed the hypothesis that cardiac-specific VLCAD deficiency is sufficient to induce cardiomyopathy and cold intolerance.
METHODS AND RESULTS: A cardiac-specific homozygous VLCAD KO (csVLCAD KO) mouse was generated by crossing a VLCAD floxed-allele mouse with a transgenic mouse expressing Cre recombinase under the control of the α-myosin heavy chain promoter. Echocardiographic analysis at 6 months of age demonstrated left ventricular dilation and decreased fractional shortening (FS) in csVLCAD KO mice (for FS, 21±1% vs 29±4% in wild-type mice, p<0.05). Ultrastructural analysis of ventricular myocardium showed widening of the sarcomeric I band, increased sarcomere length and substantial lipid deposits in csVLCAD KO mice. To test if cardiac VLCAD deficiency leads to susceptibility to death caused by cold stress, csVLCAD-KO mice and controls were placed at 4°C. All csVLCAD-KO mice (n=9) became moribund within 4-10 hours, whereas only 1/9 hemizygous and 1/9 wild-type mice died. Unlike global VLCAD KO mice, csVLCAD KO mice did not develop hypoglycemia. To determine if VLCAD deficiency alters mitochondrial fatty acid oxidation in cardiomyocytes, oxygen consumption rates in response to palmitate and glutamate administration were measured. The results indicated that while mitochondrial function was largely preserved, the fatty acid oxidation rate was markedly reduced in csVLCAD-KO mice, measuring 10-15% of WT.
CONCLUSIONS: Cardiac-specific VLCAD deficiency is sufficient to induce ventricular dilation and cardiac dysfunction as well as cold intolerance, which may be related to reduced fatty acid oxidation and increased lipid deposition in cardiomyocytes.
- © 2011 by American Heart Association, Inc.