• DOI:10.1161/CIRCULATIONAHA.111.031716
• Corpus ID: 2577132

Early treatment with lisinopril and spironolactone preserves cardiac and skeletal muscle in Duchenne muscular dystrophy mice.

@article{RafaelFortney2011EarlyTW,
  title={Early treatment with lisinopril and spironolactone preserves cardiac and skeletal muscle in Duchenne muscular dystrophy mice.},
  author={Jill A. Rafael-Fortney and Neeraj S. Chimanji and Kevin E. Schill and Christopher D. Martin and Jason D. Murray and Ranjit Ganguly and Jenna E. Stangland and Tam Tran and Ying Xu and Benjamin D. Canan and Tessily A Mays and Dawn A. Delf{\'i}n and Paul M. L. Janssen and Subha V. Raman},
  journal={Circulation},
  year={2011},
  volume={124 5},
  pages={
          582-8
        }
}

• J. Rafael-Fortney, Neeraj S. Chimanji, +11 authors S. Raman
• Published 2 August 2011
• Medicine, Biology
• Circulation

BACKGROUND
Nearly universal cardiomyopathy in Duchenne muscular dystrophy (DMD) contributes to heart failure and death. Because DMD patients show myocardial fibrosis well before functional impairment, we postulated that earlier treatment using drugs with antifibrotic effect may be beneficial.

METHODS AND RESULTS
Three groups of 10 utrn(+/-);mdx, or "het" mice, deficient for dystrophin and haploinsufficient for utrophin with skeletal myopathy and cardiomyopathy that closely mimics clinical DMD were studied. One het group received spironolactone and lisinopril starting at 8 weeks of life (het-treated-8); a second received the same starting at 4 weeks of life (het-treated-4), and the third het group was untreated. At 20 weeks, all mice had normal ejection fractions though circumferential strain rate was abnormal (-0.21±0.08) in untreated hets. This improved to -0.40±0.07 in het-treated-8 mice (P=0.003) and further improved to -0.56±0.10 in het-treated-4 mice (P=0.014 for het-treated-4 versus het-treated-8). Treated mice showed less cardiomyocyte damage, with a 44% reduction in intracardiomyocyte serum immunoglobulin G localization in het-treated-8 mice (P<0.0001) and a further 53% reduction in het-treated-4 mice (P=0.0003 versus het-treated-8); matrix metalloproteinases were similarly reduced. Cardiac, limb, and diaphragm function by ex vivo muscle testing remained at 80% of normal with early treatment compared to a decline to 40% of normal skeletal muscle function without treatment.

CONCLUSIONS
These findings offer clinically available medications with proven antifibrotic effect as a new therapeutic strategy in DMD. Early initiation greatly attenuated myocardial disease and, for the first time with these drugs, improved skeletal myopathy. Thus, early initiation of such agents warrants further clinical evaluation to maintain ambulatory, respiratory, and cardiac function for patients with DMD and related myopathies.