Early Natural History of Cardiomyopathy and Cardiac Stress Response in Young Dogs with Golden Retriever Muscular Dystrophy

Background Duchenne muscular dystrophy (DMD) and genetically homologous golden retriever muscular dystrophy (GRMD) are X-linked conditions causing progressive muscle wasting and cardiomyopathy. We previously defined a DMD-like dilated cardiomyopathy in adult GRMD dogs. The goal of this study was to extend our work and characterize the early natural history and cardiac stress response in young GRMD dogs. Methods Age-matched GRMD (N=7), carrier (N=10), and normal (N=8) littermates at 3, 6, and 12 months of age were prospectively enrolled. Electrocardiography (ECG), echocardiography, and cardiac magnetic resonance (CMR) were assessed. To identify early evidence of cardiomyopathy, we conducted a dobutamine stress test in a subset of 17 GRMD and 6 normal dogs. Systolic functions were assessed during dobutamine infusion at 2 months of age, with follow ups (4 GRMD vs. 6 normal) at 4.5 and 6 months. Results Heart rate and ECG Q/R ratios were greater in GRMD dogs at 12 months, and PR interval was shortened at ≥6 months. There were no differences of echocardiographic systolic function nor circumferential strain in GRMD dogs. CMR left ventricular volumes and myocardial mass were smaller in GRMD dogs ≥6 months, but LGE and T1 mapping did not differ. A diminished inotropic response was seen in GRMD dogs during stress test at 2 months, but not at 4.5 and 6 months. Conclusions We demonstrated GRMD dogs had a blunted inotropic response at 2 months, and ECG changes and reduced heart sizes ≥6 months. This study substantiated GRMD as a valid animal model for early DMD cardiomyopathy. Clinical Perspective What Is New? This study demonstrates the early natural history of the dystrophin-deficient cardiomyopathy in GRMD model, with early ECG changes and higher heart rate, reduced cardiac chamber sizes, and disproportionally reduced myocardial mass. While with phenotypic variations, imaging markers from ECG, echocardiography, and CMR differentiated the GRMD dogs as early as 6 months of age. Systolic function was preserved and no clear evidence of myocardial fibrosis was identified during the subclinical stage of GRMD cardiomyopathy. No cardiac abnormalities were seen in GRMD carriers over the first year of age, aligning with the late-onset cardiomyopathy to carriers. A dobutamine stress protocol was established whereby dosages as low as 5 or 10 µg/kg/min intravenous infusion can be used to early differentiate GRMD dogs at 2 months of age. A blunted inotropic response and increased cardiac troponin I to the stress test were found in young GRMD dogs. What Are the Clinical Implications? This study documented the early natural history of GRMD cardiomyopathy, providing a comprehensive dataset and identifying many cardiac imaging markers for preclinical research use. The study further demonstrates the young GRMD dog is a valid animal model for early investigations of DMD cardiac disease. The dobutamine stress test and the blunted inotropic response, shown by the changes of fractional shortening (ΔFS) and ejection fraction (ΔEF), provide subclinical markers to detect early cardiomyopathy in very young GRMD dogs.