Heterogeneous abnormalities of in-vivo left ventricular calcium influx and function in mouse models of muscular dystrophy cardiomyopathy.
Heterogeneous abnormalities of in-vivo left ventricular calcium influx and function in mouse models of muscular dystrophy cardiomyopathy.
复制标题
DOI：
10.1186/1532-429x-15-4
复制
发表时间：
2013-01-16
期刊：
影响因子：
--
通讯作者：
MacGowan GA
中科院分区：
文献类型：
--
作者：
Greally E;Davison BJ;Blain A;Laval S;Blamire A;Straub V;MacGowan GA
锰增强心血管磁共振（MECMR）可以无创地评估心肌钙内流，并且基于细胞研究，已知肌营养不良性心肌病中钙水平升高。在mdx小鼠（杜氏肌营养不良模型，24和40周）和Sgcd−/−小鼠（肢带肌营养不良2 F，16和32周）中进行左心室功能研究和MECMR，并与野生型对照（C57 Bl/10，WT）进行比较。与WT相比，两种模型在较晚的年龄都有左心室肥大，尽管mdx小鼠的每搏输出量减少，而Sgcd−/−小鼠的心率和心脏指数增加。尤其是在年轻时，两种模型的MECMR均显著升高（均P<0.05 vs WT）。L-型钙通道抑制剂地尔硫卓（5 mg/kg i. p.）显著降低mdx小鼠中的MECMR（P<0.01），尽管仅使用较高剂量（10 mg/kg i. p.）在Sgcd−/−小鼠中（P<0.05）。由于Sgcd−/−小鼠的心率增加，为了确定心率在MECMR中的作用，我们研究了超极化激活的环核苷酸门控通道抑制剂ZD 7288，它选择性地降低心率。这降低了所有小鼠组的心率和MECMR。然而，当心率与WT小鼠匹配时，当观察Sgcd-/-小鼠在锰输注长达5分钟时MECMR降低的时间过程时，Sgcd-/-小鼠的MECMR仍然显着升高（P<0.01）），这表明心率本身并不能解释所有MECMR的增加。尽管两种小鼠模型在左心室肥大之前的心肌病发展的早期阶段表现出体内钙内流增加，但在心率、血流动力学和对钙通道抑制剂的反应方面，两种模型之间存在明显的表型差异。
Manganese-enhanced cardiovascular magnetic resonance (MECMR) can non-invasively assess myocardial calcium influx, and calcium levels are known to be elevated in muscular dystrophy cardiomyopathy based on cellular studies. Left ventricular functional studies and MECMR were performed in mdx mice (model of Duchenne Muscular Dystrophy, 24 and 40 weeks) and Sgcd−/− mice (Limb Girdle Muscular Dystrophy 2 F, 16 and 32 weeks), compared to wild type controls (C57Bl/10, WT). Both models had left ventricular hypertrophy at the later age compared to WT, though the mdx mice had reduced stroke volumes and the Sgcd−/− mice increased heart rate and cardiac index. Especially at the younger ages, MECMR was significantly elevated in both models (both P<0.05 versus WT). The L-type calcium channel inhibitor diltiazem (5 mg/kg i.p.) significantly reduced MECMR in the mdx mice (P<0.01), though only with a higher dose (10 mg/kg i.p.) in the Sgcd−/− mice (P<0.05). As the Sgcd−/− mice had increased heart rates, to determine the role of heart rate in MECMR we studied the hyperpolarization-activated cyclic nucleotide-gated channel inhibitor ZD 7288 which selectively reduces heart rate. This reduced heart rate and MECMR in all mouse groups. However, when looking at the time course of reduction of MECMR in the Sgcd−/− mice at up to 5 minutes of the manganese infusion when heart rates were matched to the WT mice, MECMR was still significantly elevated in the Sgcd−/− mice (P<0.01) indicating that heart rate alone could not account for all the increased MECMR. Despite both mouse models exhibiting increased in-vivo calcium influx at an early stage in the development of the cardiomyopathy before left ventricular hypertrophy, there are distinct phenotypical differences between the 2 models in terms of heart rates, hemodynamics and responses to calcium channel inhibitors.