Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
Circ Cardiovasc Imaging. 2011 Sep;4(5):558-65. doi: 10.1161/CIRCIMAGING.111.963751. Epub 2011 Jul 7.
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.
脂毒性可能是线粒体长链脂肪酸β氧化（FAO）障碍导致心脏异常发病机制的关键因素。FAO 缺乏症中心肌脂质水平和心脏功能的数据很少。本动物研究的目的是以非侵入性方式评估 FAO 缺乏症时空腹引起的心脏形态、功能和甘油三酯（TG）储存的变化。
在长链酰基辅酶 A 脱氢酶（LCAD）敲除（KO）小鼠和野生型（WT）小鼠（每组 8 只）体内应用 MRI 和质子磁共振波谱（1H-MRS）。禁食用于增加心脏对 FAO 的依赖，以维持能量稳态。体内数据用心肌脂质的离体测量结果补充。与 WT 小鼠相比，LCAD KO 小鼠的左心室（LV）质量更高（P<0.05），表明 LV 心肌肥大。LCAD KO 小鼠的心肌 TG 含量在基线时更高（P<0.001），禁食后进一步增加（P<0.05）。同时，禁食后 LV 射血分数（P<0.01）和舒张充盈率（P<0.01）降低，而禁食 WT 小鼠的这些功能参数没有变化。禁食 LCAD KO 小鼠的心肌神经酰胺含量高于禁食 WT 小鼠（P<0.05）。
本研究采用非侵入性方法，揭示了 LCAD KO 小鼠心肌 TG 的积累。蓄积脂质代谢物（如神经酰胺）的毒性可能是导致 LCAD KO 小鼠空腹时心脏功能受损的原因。
