TY - JOUR
T1 - Fasting-induced myocardial lipid accumulation in long-chain acyl-CoA dehydrogenase knockout mice is accompanied by impaired left ventricular function
AU - Bakermans, Adrianus J.
AU - Geraedts, Tom R.
AU - van Weeghel, Michel
AU - Denis, Simone
AU - João Ferraz, Maria
AU - Aerts, Johannes M. F. G.
AU - Aten, Jan
AU - Nicolay, Klaas
AU - Houten, Sander M.
AU - Prompers, Jeanine J.
PY - 2011
Y1 - 2011
N2 - Lipotoxicity may be a key contributor to the pathogenesis of cardiac abnormalities in mitochondrial long-chain fatty acid β-oxidation (FAO) disorders. Few data are available on myocardial lipid levels and cardiac performance in FAO deficiencies. The purpose of this animal study is to assess fasting-induced changes in cardiac morphology, function, and triglyceride (TG) storage as a consequence of FAO deficiency in a noninvasive fashion. MRI and proton magnetic resonance spectroscopy ((1)H-MRS) were applied in vivo in long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mice and wild-type (WT) mice (n=8 per genotype). Fasting was used to increase the heart's dependency on FAO for maintenance of energy homeostasis. In vivo data were complemented with ex vivo measurements of myocardial lipids. Left ventricular (LV) mass was higher in LCAD KO mice compared with WT mice (P <0.05), indicating LV myocardial hypertrophy. Myocardial TG content was higher in LCAD KO mice at baseline (P <0.001) and further increased in fasted LCAD KO mice (P <0.05). Concomitantly, LV ejection fraction (P <0.01) and diastolic filling rate (P <0.01) decreased after fasting, whereas these functional parameters did not change in fasted WT mice. Myocardial ceramide content was higher in fasted LCAD KO mice compared with fasted WT mice (P <0.05). Using a noninvasive approach, this study reveals accumulation of myocardial TG in LCAD KO mice. Toxicity of accumulating lipid metabolites such as ceramides may be responsible for the fasting-induced impairment of cardiac function observed in the LCAD KO mouse
AB - Lipotoxicity may be a key contributor to the pathogenesis of cardiac abnormalities in mitochondrial long-chain fatty acid β-oxidation (FAO) disorders. Few data are available on myocardial lipid levels and cardiac performance in FAO deficiencies. The purpose of this animal study is to assess fasting-induced changes in cardiac morphology, function, and triglyceride (TG) storage as a consequence of FAO deficiency in a noninvasive fashion. MRI and proton magnetic resonance spectroscopy ((1)H-MRS) were applied in vivo in long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mice and wild-type (WT) mice (n=8 per genotype). Fasting was used to increase the heart's dependency on FAO for maintenance of energy homeostasis. In vivo data were complemented with ex vivo measurements of myocardial lipids. Left ventricular (LV) mass was higher in LCAD KO mice compared with WT mice (P <0.05), indicating LV myocardial hypertrophy. Myocardial TG content was higher in LCAD KO mice at baseline (P <0.001) and further increased in fasted LCAD KO mice (P <0.05). Concomitantly, LV ejection fraction (P <0.01) and diastolic filling rate (P <0.01) decreased after fasting, whereas these functional parameters did not change in fasted WT mice. Myocardial ceramide content was higher in fasted LCAD KO mice compared with fasted WT mice (P <0.05). Using a noninvasive approach, this study reveals accumulation of myocardial TG in LCAD KO mice. Toxicity of accumulating lipid metabolites such as ceramides may be responsible for the fasting-induced impairment of cardiac function observed in the LCAD KO mouse
U2 - https://doi.org/10.1161/CIRCIMAGING.111.963751
DO - https://doi.org/10.1161/CIRCIMAGING.111.963751
M3 - Article
C2 - 21737602
SN - 1941-9651
VL - 4
SP - 558
EP - 565
JO - Circulation. Cardiovascular imaging
JF - Circulation. Cardiovascular imaging
IS - 5
ER -