The preclinical cardiac phenotype of the DE50-MD dog model of Duchenne muscular dystrophy.

Abstract

Cardiomyopathy is the leading cause of death in the X-linked disorder, Duchenne Muscular Dystrophy (DMD) yet optimal management strategies remain undetermined. Advances in the search for novel DMD treatments, particularly at cell and molecular levels, rely heavily on the use of translational animal models. It is crucial that these models faithfully recapitulate the human clinical phenotype to best expedite the development of promising treatments. We sought comprehensively to describe the cardiac phenotype of DE50-MD dogs, a novel dystrophin-deficient model that harbours a mutation within the principal DMD mutational hotspot. Cardiac magnetic resonance imaging and echocardiographic studies were performed at approximately 12-week intervals in male, 3- to 18-month-old DE50-MD (n=17) and age-matched littermates, wild type (WT, n=14) dogs. Late gadolinium enhancement (LGE) imaging was performed in a subpopulation of DE50-MD (n=10) and WT (n=11) dogs aged 9 to 18 months. The DE50-MD dogs had smaller left ventricular (LV) mass and LV dimensions than WT dogs. While global ventricular systolic function was preserved, DE50-MD dogs showed early differences in strain and strain rate parameters. Only DE50-MD dogs demonstrated LGE (3/8 dogs studied at 18 months); the subepicardial to transmural, mid-to-basal LV LGE distribution resembling that of DMD patients and of other dystrophic dog models. Histopathological assessment confirmed that LGE corresponded to fibrofatty myocardial scarring, as described in DMD patients and other canine models of dystrophin-deficient cardiomyopathy. The DE50-MD early preclinical cardiac phenotype shares key features of DMD cardiomyopathy prior to onset of global LV systolic dysfunction. Their disproportionately low LV volume to mass supports possible combined physiological hypotrophy and tonic contraction in affected animals.