Cardiovascular phenotype of the Dmdmdx rat – a suitable animal model for Duchenne muscular dystrophy

Besides skeletal muscle abnormalities, Duchenne muscular dystrophy (DMD) patients present with dilated cardiomyopathy development, which considerably contributes to morbidity and mortality. Because the mechanisms responsible for the cardiac complications in the context of DMD are largely unknown, evidence-based therapy approaches are still lacking. This has increased the need for basic research efforts into animal models for DMD. Here, we characterized in detail the cardiovascular abnormalities of Dmd mdx rats, with the aim of determining the suitability of this recently established dystrophin-deficient small animal as a model for DMD. Various methods were applied to compare cardiovascular properties between wild-type and Dmd mdx rats, and to characterize the Dmd mdx cardiomyopathy. These methods comprised echocardiography, invasive assessment of left ventricular hemodynamics, examination of adverse remodeling and endothelial cell inflammation, and evaluation of vascular function, employing wire myography. Finally, intracellular Ca 2+ transient measurements, and recordings of currents through L-type Ca 2+ channels were performed in isolated single ventricular cardiomyocytes. We found that, similar to respective observations in DMD patients, the hearts of Dmd mdx rats show significantly impaired cardiac function, fibrosis and inflammation, consistent with the development of a dilated cardiomyopathy. Moreover, in Dmd mdx rats, vascular endothelial function is impaired, which may relate to inflammation and oxidative stress, and Ca 2+ handling in Dmd mdx cardiomyocytes is abnormal. These findings indicate that Dmd mdx rats represent a promising small-animal model to elucidate mechanisms of cardiomyopathy development in the dystrophic heart, and to test mechanism-based therapies aiming to combat cardiovascular complications in DMD.