Dystrophic heart failure blocked by membrane sealant poloxamer

Soichiro Yasuda, De Wayne Townsend, Daniel E. Michele, Elizabeth G. Favre, Sharlene M. Day, Joseph M. Metzger

Research output: Contribution to journalArticlepeer-review

228 Scopus citations

Abstract

Dystrophin deficiency causes Duchenne muscular dystrophy (DMD) in humans, an inherited and progressive disease of striated muscle deterioration that frequently involves pronounced cardiomyopathy. Heart failure is the second leading cause of fatalities in DMD. Progress towards defining the molecular basis of disease in DMD has mostly come from studies on skeletal muscle, with comparatively little attention directed to cardiac muscle. The pathophysiological mechanisms involved in cardiac myocytes may differ significantly from skeletal myofibres; this is underscored by the presence of significant cardiac disease in patients with truncated or reduced levels of dystrophin but without skeletal muscle disease. Here we show that intact, isolated dystrophin-deficient cardiac myocytes have reduced compliance and increased susceptibility to stretch-mediated calcium overload, leading to cell contracture and death, and that application of the membrane sealant poloxamer 188 corrects these defects in vitro. In vivo administration of poloxamer 188 to dystrophic mice instantly improved ventricular geometry and blocked the development of acute cardiac failure during a dobutamine-mediated stress protocol. Once issues relating to optimal dosing and long-term effects of poloxamer 188 in humans have been resolved, chemical-based membrane sealants could represent a new therapeutic approach for preventing or reversing the progression of cardiomyopathy and heart failure in muscular dystrophy.

Original languageEnglish (US)
Pages (from-to)1025-1029
Number of pages5
JournalNature
Volume436
Issue number7053
DOIs
StatePublished - Aug 18 2005

Bibliographical note

Funding Information:
Acknowledgements This work was supported by a grant from the National Institute on Aging (J.M.M.). D.T. was supported by an NIH National Research Service Award, and S.M.D. was supported by an American Heart Association Fellow-to-Faculty Transition Award.

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