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(Circulation. 2008;117:720-731.)
© 2008 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Cell Therapy for Modification of the Myocardial Electrophysiological Substrate

Lior Yankelson, BSc^*; Yair Feld, MD, PhD^*; Tal Bressler-Stramer, PhD; Ilanit Itzhaki, MSc; Irit Huber, PhD; Amira Gepstein, PhD; Doron Aronson, MD; Shimon Marom, MD, PhD; Lior Gepstein, MD, PhD

From the Sohnis Laboratory for Cardiac Electrophysiology and Regenerative Medicine (L.Y., Y.F., T.B.-S., I.I., I.H., A.G., L.G.), Minerva Center for Cell Biophysics (S.M.), and the Cardiology Department (Rambam Medical Center) (D.A., L.G.), Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Correspondence to Lior Gepstein, MD, PhD, Technion’s Faculty of Medicine, POB 9649, Haifa, 31096, Israel. E-mail mdlior{at}tx.technion.ac.il

Received August 24, 2004; accepted November 28, 2007.

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.

Methods and 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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
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