Cardiomyopathy in the Golden Retriever Model of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder affecting approximately 1/3500-5000 boys, causing progressive muscle wasting. Affected boys typically die from respiratory or cardiac failure. Golden retriever muscular dystrophy (GRMD) is a genetically homologous model used to study pathogenesis and treatments for DMD. Dogs with GRMD develop cardiomyopathy similar to DMD, but the disease progression has not been well characterized. In this dissertation, we characterized the natural history of GRMD cardiomyopathy and developed a method that can detect early cardiac abnormalities in young GRMD dogs. Initially, we investigated adult GRMD dogs using echocardiography and cardiac magnetic resonance (CMR) and found ejection fraction (EF) and fractional shortening (FS) correlated well with age. Systolic dysfunction typically occurred between 30 to 45 months of age. Circumferential strain was more sensitive than EF in early disease detection. Leftventricular (LV) chamber dilatation provided proof of dilated cardiomyopathy. Late gadolinium enhancement (LGE) on CMR showed DMD-like LV lateral wall lesions and earlier involvement of the anterior septum. A cardiac scoring system was developed to provide a standardized index of disease severity regardless of age. Consistent with DMD, there was parallel skeletal muscle involvement, as tibiotarsal joint flexion torque declined in tandem with cardiac function. Next, we characterized the natural history of cardiomyopathy over the first year of life using electrocardiography (ECG), echocardiography, and CMR on GRMD dogs. We found increased heart rate and Q/R ratios, smaller cardiac chamber size, and less myocardial mass in GRMD dogs. A hyperdynamic state was identified around 6 to 12 months, reflecting a compensatory process of the dystrophic heart. While establishing advanced imaging techniques for juvenile GRMD dogs, no myocardial fibrosis was identified on LGE and extracellular volume assessments. Finally, we investigated a dobutamine test in young GRMD dogs to identify sensitive echocardiographic and CMR markers for early disease detection. Dogs with GRMD had a less pronounced inotropic stress response with dosages as low as 5 or 10 µg/kg/min, reflecting a blunted effect on cardiac beta receptors identified with changes of EF and FS in different imaging modalities. In conclusion, we characterized the natural history of cardiomyopathy in juvenile and adult GRMD dogs, providing the most comprehensive cardiac imaging study to date, and also established a stress protocol for future therapeutic testing. This dissertation revealed remarkable parallels between dystrophic dogs and boys, validating GRMD as a model of DMD