This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Feld, Y. Articles by Gepstein, L. Search for Related Content PubMed PubMed Citation Articles by Feld, Y. Articles by Gepstein, L. Related Collections Gene therapy Arrythmias-basic studies Ion channels/membrane transport

(Circulation. 2002;105:522.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Electrophysiological Modulation of Cardiomyocytic Tissue by Transfected Fibroblasts Expressing Potassium Channels

A Novel Strategy to Manipulate Excitability

Yair Feld, MSc; Meira Melamed-Frank, PhD; Izhak Kehat, MD; Dror Tal, PhD; Shimon Marom, MD, DSc; Lior Gepstein, MD, PhD

From the Cardiovascular Research Laboratory (Y.F., I.K., L.G.) and the Sir Bernard Katz Minerva Center for Cell Biophysics (M.M.-F., D.T., S.M.), Department of Physiology and Biophysics, Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.

Correspondence to Lior Gepstein MD, PhD, Cardiovascular System Laboratory, the Bruce Rappaport Faculty of Medicine, Technion, 2 Efron St, POB 9649, Haifa 31096, Israel. E-mail mdlior{at}tx.technion.ac.il

Background— Traditional pharmacological therapies aiming to modify the abnormal electrophysiological substrate underlying cardiac arrhythmias may be limited by their relatively low efficacy, global cardiac activity, and significant proarrhythmic effects. We suggest a new approach, in which transfected cellular grafts expressing various ionic channels may be used to manipulate the local electrophysiological properties of cardiac tissue. To examine the feasibility of this concept, we tested the hypothesis that transfected fibroblasts expressing the voltage-sensitive potassium channel Kv1.3 can modify the electrophysiological properties of cardiomyocytic cultures.

Methods and Results— A high-resolution multielectrode mapping technique was used to assess the electrophysiological and structural properties of primary cultures of neonatal rat ventricular myocytes. The transfected fibroblasts, added to the cardiomyocytic cultures, caused a significant effect on the conduction properties of the hybrid cultures. These changes were manifested by significant reduction in extracellular signal amplitude and by the appearance of multiple local conduction blocks. The location of all conduction blocks correlated with the spatial distribution of the transfected fibroblasts assessed by vital staining. All electrophysiological changes were reversed after the application of Charybdotoxin, a specific Kv1.3 blocker. In contrast, conduction remained uniform in the control hybrid cultures when nontransfected fibroblasts were used.

Conclusions— Transfected fibroblasts are able to electrically couple with cardiac myocytes, causing a significant local and reversible modification of the tissue’s electrophysiological properties. More broadly, this study suggests that transfected cellular grafts expressing various ionic channels may be used to modify cardiac excitability, providing a possible future novel cell therapy strategy.

Key Words: electrophysiology • gene therapy • arrhythmia • ion channels • mapping

This article has been cited by other articles:

				M. E. Mangoni and J. Nargeot Genesis and Regulation of the Heart Automaticity Physiol Rev, July 1, 2008; 88(3): 919 - 982. [Abstract] [Full Text] [PDF]

				V. Jacquemet and C. S. Henriquez Loading effect of fibroblast-myocyte coupling on resting potential, impulse propagation, and repolarization: insights from a microstructure model Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2040 - H2052. [Abstract] [Full Text] [PDF]

				C. Cabo Modulation of impulse propagation by fibroblasts Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H1992 - H1993. [Full Text] [PDF]

				L. Yankelson, Y. Feld, T. Bressler-Stramer, I. Itzhaki, I. Huber, A. Gepstein, D. Aronson, S. Marom, and L. Gepstein Cell Therapy for Modification of the Myocardial Electrophysiological Substrate Circulation, February 12, 2008; 117(6): 720 - 731. [Abstract] [Full Text] [PDF]

				J. P. Fahrenbach, R. Mejia-Alvarez, and K. Banach The relevance of non-excitable cells for cardiac pacemaker function J. Physiol., December 1, 2007; 585(2): 565 - 578. [Abstract] [Full Text] [PDF]

				S. E. Lehnart, M. J. Ackerman, D. W. Benson Jr, R. Brugada, C. E. Clancy, J. K. Donahue, A. L. George Jr, A. O. Grant, S. C. Groft, C. T. January, et al. Inherited Arrhythmias: A National Heart, Lung, and Blood Institute and Office of Rare Diseases Workshop Consensus Report About the Diagnosis, Phenotyping, Molecular Mechanisms, and Therapeutic Approaches for Primary Cardiomyopathies of Gene Mutations Affecting Ion Channel Function Circulation, November 13, 2007; 116(20): 2325 - 2345. [Abstract] [Full Text] [PDF]

				I. Huber, I. Itzhaki, O. Caspi, G. Arbel, M. Tzukerman, A. Gepstein, M. Habib, L. Yankelson, I. Kehat, and L. Gepstein Identification and selection of cardiomyocytes during human embryonic stem cell differentiation FASEB J, August 1, 2007; 21(10): 2551 - 2563. [Abstract] [Full Text] [PDF]

				K. A. MacCannell, H. Bazzazi, L. Chilton, Y. Shibukawa, R. B. Clark, and W. R. Giles A Mathematical Model of Electrotonic Interactions between Ventricular Myocytes and Fibroblasts Biophys. J., June 1, 2007; 92(11): 4121 - 4132. [Abstract] [Full Text] [PDF]

				C. K. Sen, S. Khanna, and S. Roy Perceived hyperoxia: Oxygen-induced remodeling of the reoxygenated heart Cardiovasc Res, July 15, 2006; 71(2): 280 - 288. [Abstract] [Full Text] [PDF]

				T. J. Bunch, S. Mahapatra, G. K. Bruce, S. B. Johnson, D. V. Miller, B. D. Horne, X.-L. Wang, H.-C. Lee, N. M. Caplice, and D. L. Packer Impact of Transforming Growth Factor-{beta}1 on Atrioventricular Node Conduction Modification by Injected Autologous Fibroblasts in the Canine Heart Circulation, May 30, 2006; 113(21): 2485 - 2494. [Abstract] [Full Text] [PDF]

				M. Miragoli, G. Gaudesius, and S. Rohr Electrotonic Modulation of Cardiac Impulse Conduction by Myofibroblasts Circ. Res., March 31, 2006; 98(6): 801 - 810. [Abstract] [Full Text] [PDF]

				S. L.M.A. Beeres, D. E. Atsma, A. van der Laarse, D. A. Pijnappels, J. van Tuyn, W. E. Fibbe, A. A.F. de Vries, D. L. Ypey, E. E. van der Wall, and M. J. Schalij Human Adult Bone Marrow Mesenchymal Stem Cells Repair Experimental Conduction Block in Rat Cardiomyocyte Cultures J. Am. Coll. Cardiol., November 15, 2005; 46(10): 1943 - 1952. [Abstract] [Full Text] [PDF]

				E. Kizana, S. L. Ginn, D. G. Allen, D. L. Ross, and I. E. Alexander Fibroblasts Can Be Genetically Modified to Produce Excitable Cells Capable of Electrical Coupling Circulation, February 1, 2005; 111(4): 394 - 398. [Abstract] [Full Text] [PDF]

				P. Camelliti, T. K. Borg, and P. Kohl Structural and functional characterisation of cardiac fibroblasts Cardiovasc Res, January 1, 2005; 65(1): 40 - 51. [Abstract] [Full Text] [PDF]

				J. Satin, I. Kehat, O. Caspi, I. Huber, G. Arbel, I. Itzhaki, J. Magyar, E. A. Schroder, I. Perlman, and L. Gepstein Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes J. Physiol., September 1, 2004; 559(2): 479 - 496. [Abstract] [Full Text] [PDF]

				L. Gepstein, Y. Feld, and L. Yankelson Somatic gene and cell therapy strategies for the treatment of cardiac arrhythmias Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H815 - H822. [Full Text] [PDF]

				G. Gaudesius, M. Miragoli, S. P. Thomas, and S. Rohr Coupling of Cardiac Electrical Activity Over Extended Distances by Fibroblasts of Cardiac Origin Circ. Res., September 5, 2003; 93(5): 421 - 428. [Abstract] [Full Text] [PDF]