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

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.