Progression of the cardiac phenotype of the DE50-MD dog model of Duchenne Muscular Dystrophy, corroborating results of cardiac magnetic resonance imaging with pathology up to 36 months of age.

Abstract

Cardiomyopathy is an expected consequence of the invariably fatal, X-linked muscle-wasting disease, Duchenne Muscular Dystrophy, (DMD) but onset and progression vary between individuals. Cardiac magnetic resonance imaging (CMR) is invaluable for identification of subclinical myocardial abnormalities, to stratify disease and to identify patients needing early therapeutic intervention. The dystrophin-deficient DE50-MD canine model harbours a mutation in the major hot spot region for mutations in DMD patients and mimics the preclinical cardiac and skeletal muscle of DMD boys. We performed serial parametric (T1, T2 and extracellular volume) mapping and late gadolinium enhancement (LGE) studies to characterise myocardial pathology in 15-to-36-month-old DE50-MD, (n=8) and wild type (WT, n=6) dogs. In 6/8 DE50-MD dogs left ventricular (LV) subepicardial LGE identified myocardial fibrofatty infiltration, (confirmed with histopathology post-mortem) with the characteristic distribution reported in DMD cardiomyopathy. Parametric mapping techniques exposed diffuse myocardial pathology that was most pronounced in DE50-MD dogs of 30 months and older and supported extracellular matrix expansion due to fibrosis, with or without regional myocardial oedema and /or fatty infiltration in individual dogs. All CMR markers of fibrosis worsened with age in DE50-MD dogs and paralleled deterioration in ventricular function evaluated with conventional and speckle tracking (circumferential strain) echocardiography, the burden of fragmented QRS complexes in 12-lead electrocardiography studies and the severity of pathological lesions. LGE and parametric mapping studies accurately identified a spectrum of myocardial abnormalities encountered in young DE50-MD dogs, further validating the relevance of these dogs as a preclinical model of DMD cardiomyopathy.