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European Journal of Heart Failure Advance Access originally published online on February 20, 2009
European Journal of Heart Failure 2009 11(5):463-471; doi:10.1093/eurjhf/hfp028
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Contrasting effects of steroids and angiotensin-converting-enzyme inhibitors in a mouse model of dystrophin-deficient cardiomyopathy

Ralf Bauer1, Volker Straub1, Alison Blain1, Kate Bushby1 and Guy A. MacGowan1,2,*

1 Institute of Human Genetics, Newcastle University, International Center for Life, Newcastle upon Tyne, UK
2 Department of Cardiology, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK

* Corresponding author. Tel: +44 191 2137140, Email: guy.macgowan{at}nuth.nhs.uk


  Abstract

Aims: Duchenne muscular dystrophy (DMD) is associated with progressive cardiomyopathy. Oral corticosteroids are the gold standard for the treatment of skeletal muscle weakness; however, the effects of steroids on cardiac function have not been prospectively studied. In addition, the early role of ACE-inhibitors (ACE-I) is controversial. We aimed to determine the effects of steroids and ACE-I on development of left ventricular dysfunction in the mdx mouse, a model for dystrophin-deficient cardiomyopathy.

Methods and results: Orally administered captopril or prednisolone was given for 8 weeks to 16-week-old, male mdx mice. In vivo pressure–volume loops, fibrosis, in vivo myocyte sarcolemmal injury, and cytokine expression were assessed in treated and untreated mdx mice and age-matched controls. Untreated mdx mice showed compensated cardiomyopathy with reduced myocardial contractility, patchy myocardial fibrosis but preserved stroke volume. Captopril treatment resulted in indirect myocardial effects of reduced afterload and direct effects of increased contractility. Prednisolone caused acute sarcolemmal injury, increased expression of myocardial TNF alpha and fibrosis, resulting in left ventricular dilatation and diastolic dysfunction.

Conclusion: In a mouse model of dystrophin-deficient cardiomyopathy, ACE-I produced haemodynamic benefit, whereas steroids accelerated progression of cardiomyopathy. Although mouse models may not entirely replicate the human condition, comprehensive monitoring of cardiac function with these therapies is essential.

Key Words: Cardiomyopathy • Corticosteroids • ACE inhibitors • Muscular dystrophy

Received June 10, 2008; Revised December 29, 2008; Accepted January 8, 2009


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