title: Early treatment with lisinopril and spironolactone preserves cardiac and skeletal muscle in Duchenne muscular dystrophy mice.
abstract: 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.
  
  
  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.
authors.affiliation: Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rafael-Fortney
authors.forename: Neeraj S
authors.initials: NS
authors.lastname: Chimanji
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Schill
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Martin
authors.forename: Jason D
authors.initials: JD
authors.lastname: Murray
authors.forename: Ranjit
authors.initials: R
authors.lastname: Ganguly
authors.forename: Jenna E
authors.initials: JE
authors.lastname: Stangland
authors.forename: Tam
authors.initials: T
authors.lastname: Tran
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Canan
authors.forename: Tessily A
authors.initials: TA
authors.lastname: Mays
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Delfín
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.forename: Subha V
authors.initials: SV
authors.lastname: Raman
mesh_terms: D000818:Animals; D057791:Cardiac Imaging Techniques; D009202:Cardiomyopathies / Q000188:drug therapy / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004232:Diuretics / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D017706:Lisinopril / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D013148:Spironolactone / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D004232:Diuretics; D013148:Spironolactone; D017706:Lisinopril; D007545:Isoproterenol