Abstract 16904: Low-Dose Isoproterenol Administration in the Murine MDX Model Unmasks Progression of Duchenne-Associated Cardiomyopathy

Abstract

Introduction: The cardiovascular phenotype resulting from Duchenne muscular dystrophy (DMD) includes cardiomyopathy (CMP) leading to congestive heart failure and early mortality. CMP is the leading cause of death in DMD. Our objective was to characterize the progression of CMP in a murine model of DMD. We hypothesized that a genetic mouse model of DMD will exhibit significantly lower function over time as measured by ejection fraction when given an isoproterenol (IPT) challenge. Methods: We examined a mouse model of DMD from the Jackson Laboratory: C57BL/10ScSn- Dmd mdx /J (B10.mdx; n=6 female). The genetic group was paired with the wild type control strain C57BL/10ScSnJ (B10; n=6 female mice). B10.mdx (MDX) and B10 (WT) mice received intraperitoneal IPT administered via daily injections at 3 mg/kg. Cardiac function was assessed by 2D ultrasound using a Vevo3100 imaging system (FUJIFILM, VisualSonics) from the baseline, immediate effects of IPT injection at 1 minute, after 7, 14, and 21 days. Results: At 1 minute following the first IPT injection in WT and MDX, we observed increases in EF and HR for both groups ( Figure 1 ). While the changes in EF were notable yet not reaching significance, the differences within groups between baseline and 1 minute after injection were significant due to HR response ( p <0.05).We observed decreases in EF for both groups between baseline and day 7 following IPT injections ( Figure 1 ). The changes in MDX EF between baseline and day 7 approached significance. The EF in both groups was maintained through day 7, day 14, and day 21. 2 deaths in MDX occurred during the treatment period and 1 death followed day 7. A WT sacrifice was made after day 14 due to severe dermatitis. Conclusion: Murine mdx models exhibit DMD-associated CMP comparable to humans. Associated humanlike phenotype includes decreased EF, FS, ESV, EDS, and SV. A low dose of IPT in MDW mice has the potential to unmask these changes within 7 days, reducing the need for longer term murine studies.