title: Cell therapy for modification of the myocardial electrophysiological substrate.
abstract: BACKGROUND
  Traditional antiarrhythmic pharmacological therapies are limited by their global cardiac action, low efficacy, and significant proarrhythmic effects. We present a novel approach for the modification of the myocardial electrophysiological substrate using cell grafts genetically engineered to express specific ionic channels.
  
  
  RESULTS
  To test the aforementioned concept, we performed ex vivo, in vivo, and computer simulation studies to determine the ability of fibroblasts transfected to express the voltage-sensitive potassium channel Kv1.3 to modify the local myocardial excitable properties. Coculturing of the transfected fibroblasts with neonatal rat ventricular myocyte cultures resulted in a significant reduction (68%) in the spontaneous beating frequency of the cultures compared with baseline values and cocultures seeded with naive fibroblasts. In vivo grafting of the transfected fibroblasts in the rat ventricular myocardium significantly prolonged the local effective refractory period from an initial value of 84+/-8 ms (cycle length, 200 ms) to 154+/-13 ms (P<0.01). Margatoxin partially reversed this effect (effective refractory period, 117+/-8 ms; P<0.01). In contrast, effective refractory period did not change in nontransplanted sites (86+/-7 ms) and was only mildly increased in the animals injected with wild-type fibroblasts (73+/-5 to 88+/-4 ms; P<0.05). Similar effective refractory period prolongation also was found during slower pacing drives (cycle length, 350 to 500 ms) after transplantation of the potassium channels expressing fibroblasts (Kv1.3 and Kir2.1) in pigs. Computer modeling studies confirmed the in vivo results.
  
  
  CONCLUSIONS
  Genetically engineered cell grafts, transfected to express potassium channels, can couple with host cardiomyocytes and alter the local myocardial electrophysiological properties by reducing cardiac automaticity and prolonging refractoriness.
authors.affiliation: Sohnis Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Yankelson
authors.forename: Yair
authors.initials: Y
authors.lastname: Feld
authors.forename: Tal
authors.initials: T
authors.lastname: Bressler-Stramer
authors.forename: Ilanit
authors.initials: I
authors.lastname: Itzhaki
authors.forename: Irit
authors.initials: I
authors.lastname: Huber
authors.forename: Amira
authors.initials: A
authors.lastname: Gepstein
authors.forename: Doron
authors.initials: D
authors.lastname: Aronson
authors.forename: Shimon
authors.initials: S
authors.lastname: Marom
authors.forename: Lior
authors.initials: L
authors.lastname: Gepstein
mesh_terms: D000200:Action Potentials; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001145:Arrhythmias, Cardiac / Q000503:physiopathology / Q000628:therapy*; D002478:Cells, Cultured; D003198:Computer Simulation; D004594:Electrophysiology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D015316:Genetic Therapy; D008297:Male; D032383:Myocytes, Cardiac / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
chemical_list: D024642:Potassium Channels, Voltage-Gated