Dystrophic Heart Failure Blocked by Membrane Sealant Poloxamer

Nature. 2005 Aug 18;436(7053):1025-9. doi: 10.1038/nature03844. Epub 2005 Jul 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cardiomyopathies / chemically induced
  • Cardiomyopathies / drug therapy*
  • Cardiomyopathies / pathology
  • Cardiomyopathies / physiopathology*
  • Dobutamine / pharmacology
  • Dystrophin / deficiency*
  • Hemodynamics / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Muscular Dystrophy, Duchenne / complications
  • Muscular Dystrophy, Duchenne / pathology
  • Myocardial Contraction / drug effects
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Myocytes, Cardiac / physiology
  • Poloxamer / pharmacology
  • Poloxamer / therapeutic use*

Substances

  • Dystrophin
  • Poloxamer
  • Dobutamine
  • Calcium