Abstract 17108: Natural History of Cardiomyopathy and Cardiac Stress Response in Young Dogs With Golden Retriever Muscular Dystrophy

Abstract

Introduction: Duchenne muscular dystrophy (DMD) and the genetically homologous model, golden retriever muscular dystrophy (GRMD), are x-linked conditions that cause progressive muscle wasting and cardiomyopathy. We previously defined a late onset DMD-like dilated cardiomyopathy in adult GRMD dogs and aimed to extend that work to young dogs used for preclinical studies. The goal of this study was to characterize the early natural history and cardiac stress response of GRMD cardiomyopathy. Methods: A prospective imaging study was completed in 10 GRMD dogs and 8 age-matched normal littermates at 3, 6, and 12 months of age. Electrocardiography (ECG), echocardiography with speckle tracking, and cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) and myocardial T1 mapping were assessed. In an effort to identify early subclinical evidence of cardiomyopathy, we conducted a dobutamine stress test in an additional subset of dogs (17 GRMD vs. 6 normal). Fractional shortening (FS) was assessed using echocardiography during dobutamine infusion (5-25 μg/kg/min) at 2 months of age, with follow up studies (4 GRMD vs. 6 normal) at 4.5 and 6 months. Results: Heart rate and ECG Q/R ratios (lead II, III, and aVF) were greater in GRMD dogs at 12 months (p<0.04 for all), and PR interval was shortened at 6 months (p=0.02). No systolic functional differences were seen between GRMD and normal dogs using echocardiography. No differences in circumferential strain were seen. CMR left ventricular end-diastolic volume, end-systolic volume, and myocardial mass were smaller in GRMD dogs from 6 months onward (p=0.014, 0.008, and 0.0013). LGE and extracellular volume calculated from T1 mapping did not differ on CMR. A diminished inotropic response, shown by a lower increase of FS (ΔFS), was seen in GRMD dogs during the dobutamine stress test (beginning at a dose of 5 μg/kg/min, 13.9±4.8% vs. 21.8±3.0%, p=0.003) at 2 months of age but not at 4.5 and 6 months. Conclusions: We demonstrated ECG changes and heart size differences in GRMD dogs as early as 6-12 months of age. While cardiac function was preserved, the inotropic response to dobutamine stress was blunted in 2-month-old GRMD dogs, potentially providing an early subclinical marker for DMD therapeutic research.