P.320Cardiac phenotypic expressions in female carriers of a canine model of Duchenne muscular dystrophy

Abstract

Golden Retriever muscular dystrophy (GRMD) represents an animal model that recapitulates human Duchenne muscular dystrophy (DMD) and provides a unique tool to investigate the pathogenic mechanisms and clues to understand the disease process. The primary presenting symptom in most dystrophinopathies is skeletal muscle weakness. However, cardiac muscle is similarly affected in DMD. Human female carriers of DMD, although frequently asymptomatic, can develop cardiac abnormalities. Our primary goal was to use female GRMD carriers as a test model for this subset of patients and establish a comprehensive reference dataset on a population of young adult GRMD carriers (N=19, 2 to 8 years) compared to healthy controls (N=8). Methodological approach was based on structural and functional evaluations, involving cardiac MRI as well as ECG Holter monitoring. Necropsy data should be correlated to the in vivo observations. In the context of cardiomyopathies, alterations of the cardiac rhythm as well as modifications of the cardiac interstitium like fibrosis, usually precede the appearance of overt systolic dysfunction. Preliminary results reveal quantifiable abnormalities in myocardial structure, contractile function or cardiac rhythm in all female carriers. Whereas, global ejection fractions were preserved, alterations of segmental contractility were observed. The longitudinal relaxation time constant (T1) of the myocardium was altered and might be due to increased water content or other changes of the local molecular environment related to fibrosis. All the carrier females presented with severe ventricular arrhythmias grading from 3a (polymorphism) to 4b (salvos) in the Lown classification. Some animals also presented with supraventricular arrhythmias. At necropsy, all female carriers had obvious myocardial fibrosis. Thus, female GRMD carriers appear as a valuable animal model to explore further the pathophysiology of the subset of female patients carrying a dystrophin mutation.