title: Voltage-gated ion channel dysfunction precedes cardiomyopathy development in the dystrophic heart.
abstract: BACKGROUND
  Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is associated with severe cardiac complications including cardiomyopathy and cardiac arrhythmias. Recent research suggests that impaired voltage-gated ion channels in dystrophic cardiomyocytes accompany cardiac pathology. It is, however, unknown if the ion channel defects are primary effects of dystrophic gene mutations, or secondary effects of the developing cardiac pathology.
  
  
  RESULTS
  To address this question, we first investigated sodium channel impairments in cardiomyocytes derived from dystrophic neonatal mice prior to cardiomyopahty development, by using the whole cell patch clamp technique. Besides the most common model for DMD, the dystrophin-deficient mdx mouse, we also used mice additionally carrying an utrophin mutation. In neonatal cardiomyocytes, dystrophin-deficiency generated a 25% reduction in sodium current density. In addition, extra utrophin-deficiency significantly altered sodium channel gating parameters. Moreover, also calcium channel inactivation was considerably reduced in dystrophic neonatal cardiomyocytes, suggesting that ion channel abnormalities are universal primary effects of dystrophic gene mutations. To assess developmental changes, we also studied sodium channel impairments in cardiomyocytes derived from dystrophic adult mice, and compared them with the respective abnormalities in dystrophic neonatal cells. Here, we found a much stronger sodium current reduction in adult cardiomyocytes. The described sodium channel impairments slowed the upstroke of the action potential in adult cardiomyocytes, and only in dystrophic adult mice, the QRS interval of the electrocardiogram was prolonged.
  
  
  CONCLUSIONS
  Ion channel impairments precede pathology development in the dystrophic heart, and may thus be considered potential cardiomyopathy triggers.
authors.affiliation: Center for Physiology and Pharmacology, Department of Neurophysiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Xaver
authors.initials: X
authors.lastname: Koenig
authors.forename: Sandra
authors.initials: S
authors.lastname: Dysek
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kimbacher
authors.forename: Agnes K
authors.initials: AK
authors.lastname: Mike
authors.forename: Rene
authors.initials: R
authors.lastname: Cervenka
authors.forename: Peter
authors.initials: P
authors.lastname: Lukacs
authors.forename: Katrin
authors.initials: K
authors.lastname: Nagl
authors.forename: Xuan B
authors.initials: XB
authors.lastname: Dang
authors.forename: Hannes
authors.initials: H
authors.lastname: Todt
authors.forename: Reginald E
authors.initials: RE
authors.lastname: Bittner
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Hilber
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001464:Barium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D009202:Cardiomyopathies / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D016189:Dystrophin / Q000235:genetics; D004562:Electrocardiography; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D049411:Utrophin / Q000172:deficiency
chemical_list: D020746:Calcium Channels, L-Type; D016189:Dystrophin; D015222:Sodium Channels; D049411:Utrophin; D001464:Barium; D012964:Sodium