Heterogeneous abnormalities of in-vivo left ventricular calcium influx and function in mouse models of muscular dystrophy cardiomyopathy

Journal of Cardiovascular Magnetic Resonance

Research

Volker Straub¹  Benjamin J Davison¹  Alison Blain¹  Steve Laval¹  Elizabeth Greally¹  Guy A MacGowan²  Andrew Blamire³ 

[1] Institute of Genetic Medicine, Newcastle University, International Center for Life, Newcastle, UK;Institute of Genetic Medicine, Newcastle University, International Center for Life, Newcastle, UK;Dept of Cardiology, Freeman Hospital and Newcastle University, NE7 7DN, Newcastle upon Tyne, UK;MR Centre, Newcastle University, Newcastle, UK;

关键词: Muscular dystrophy;    Cardiomyopathy;    Magnetic resonance imaging;    Calcium;   

DOI  :  10.1186/1532-429X-15-4

 received in 2012-06-15, accepted in 2012-12-14,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundManganese-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.MethodsLeft 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).ResultsBoth 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.ConclusionsDespite 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.

【 授权许可】

Unknown   
© Greally et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.