(G-279) Low-dose isoproterenol administration in the murine mdx model unmasks progression of Duchenne-associated cardiomyopathy

Introduction:: The cardiovascular phenotype resulting from Duchenne muscular dystrophy (DMD) includes cardiomyopathy, arrhythmias, and congestive heart failure [1]. While therapies aimed at improving skeletal muscle degradation have improved outcomes, cardiomyopathy (CMP) is the number one cause of death in DMD. Our objective was to characterize the progression of CMP in murine models 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 challenge.

Materials and Methods:: We examined two mouse models of DMD: D2.B10-Dmd^mdx/J (D2.mdx; n=5 male) and C57BL/10ScSn-Dmd^mdx/J (B10.mdx; n=6 female), both from the Jackson Laboratory. Each genetic group was paired with appropriate background wild type control strain (n=5 DBA/2J and n=6 B10 female mice, respectively). We imaged DBA/2J wild type control strain and D2.mdx mice as they aged to 17 weeks old using a Vevo3100 imaging system (FUJIFILM, VisualSonics). 2D ultrasound images of the left ventricle were used to calculate left ventricular ejection fraction (EF), stroke volume (SV), end-diastolic volume (EDV), end-systolic volume (ESV), cardiac output (CO), fractional shortening (FS), mass, and body weight. A separate seven-day study was conducted to unmask left ventricular cardiomyopathy in the B10.mdx mouse exacerbated by intraperitoneal isoproterenol administer via daily injections at 3 mg/kg compared to a B10 control group. Preliminary results from the baseline, immediate effects of the isoproterenol injection at 1 minute, and after 7 days are reported.

Results, Conclusions, and Discussions:: D2.mdx mice had a significantly reduced left ventricular ejection fraction and stroke volume at 14 weeks of age compared to wild-type controls (p< 0.05, Figure 1). At 1 minute time following the first isoproterenol injection in the B10 and B10.mdx mouse groups, we observed increases in ejection fraction and heart rate for both B10.mdx and controls (Figure 2). While the changes in EF were notable yet not reaching statistical significance, the differences within groups between baseline and 1 minute after injection were significant due to tachycardia (p< 0.05). After seven days, both B10.mdx and wild type mice exhibited a decrease in EF which was significantly lower than baseline and 1 minute.
Murine mdx models exhibit DMD-associated cardiomyopathy comparable to humans. Associated human-like phenotype includes decreased EF and FS and decreased ESV, EDS, and SV. A low dose of isoproterenol in B10.mdx mice has the potential to unmask these changes within 7 days, reducing the need for longer term murine studies.

Acknowledgements (Optional): : We would like to acknowledge Neurodon, LLC and Riley Children's Foundation for funding this research project.

References (Optional): : [1] R. Adorisio et al., “Duchenne dilated cardiomyopathy: Cardiac management from prevention to advanced cardiovascular therapies,” Journal of Clinical Medicine, vol. 9, no. 10. MDPI, pp. 1–18, Oct. 01, 2020. doi: 10.3390/jcm9103186.