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Dystrophic heart failure blocked by membrane sealant poloxamer


Dystrophin deficiency causes Duchenne muscular dystrophy (DMD) in humans, an inherited and progressive disease of striated muscle deterioration that frequently involves pronounced cardiomyopathy1. Heart failure is the second leading cause of fatalities in DMD1,2. 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 disease3. 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.

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Figure 1: Active and passive tension and [Ca2+]i in single cardiac myocytes from control and mdx mice.
Figure 2: Effects of P188 on passive tension and [Ca2+]i during sarcomere length stretch in control and mdx single cardiac myocytes.
Figure 3: Acute effects of P188 on in vivo haemodynamics and mdx survival.

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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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Correspondence to Joseph M. Metzger.

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Supplementary information

Supplementary Figure S1

Schematic of experimental apparatus.

Supplementary Figure S2

Cardiac myocyte force decline upon single stretch during active contractions

Supplementary Figures Legends

Legends to accompany the above Supplementary Figures.

Supplementary Table S1

Summary of baseline haemodynamic function.

Supplementary Video S1

Single cardiac myocyte passive stretch video.

Supplementary Video S2

Mdx myocyte hypercontracture video.

Supplementary Video S3

Mdx myocyte fibrillation video.

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Yasuda, S., Townsend, D., Michele, D. et al. Dystrophic heart failure blocked by membrane sealant poloxamer. Nature 436, 1025–1029 (2005).

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