title: Unique topographical distribution of M cells underlies reentrant mechanism of torsade de pointes in the long-QT syndrome.
abstract: BACKGROUND
  Specific ion channel mutations underlie the congenital long-QT syndrome (LQTS). However, the mechanisms by which dysfunction at the molecular level translates into functional electrical instability leading to torsade de pointes (TdP) in LQTS are poorly understood.
  
  
  RESULTS
  The cellular basis of TdP was investigated using a novel approach of transmural optical imaging in the canine wedge preparation (n=14). The spatial organization of repolarization and arrhythmogenesis were determined in a surrogate model of LQT2. Action potentials were recorded simultaneously from 128 sites spanning the transmural wall of the left ventricle. In LQT2, QT interval prolongation was paralleled by an abrupt rise in transmural dispersion of repolarization (DOR) from 2.7 plus/minus 0.9 ms/mm (controls) to 12.2 plus/minus 2.1 ms/mm (LQT2). Islands of midmyocardial (M) cells formed zones of increased refractoriness in LQT2, producing steep spatial gradients of repolarization that were directly responsible for conduction block and self-sustained intramural reentrant circuits underlying TdP.
  
  
  CONCLUSIONS
  These data provide direct evidence supporting the functional expression of M cells in intact myocardium and a central role for M cells in the development of reentrant TdP arrhythmias in LQTS.
authors.affiliation: Heart and Vascular Research Center and Departments of Medicine and Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44109-1998, USA.
authors.forename: Fadi G
authors.initials: FG
authors.lastname: Akar
authors.forename: Gan-Xin
authors.initials: GX
authors.lastname: Yan
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenbaum
mesh_terms: D000200:Action Potentials; D000818:Animals; D018780:Body Surface Potential Mapping; D004195:Disease Models, Animal; D004285:Dogs; D004558:Electric Stimulation; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D006329:Heart Conduction System / Q000503:physiopathology*; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000150:complications / Q000503:physiopathology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D013015:Sotalol; D016171:Torsades de Pointes / Q000209:etiology / Q000503:physiopathology*
chemical_list: D013015:Sotalol