Electrophysiological modulation of cardiomyocytic tissue by transfected fibroblasts expressing potassium channels: a novel strategy to manipulate excitability.
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.


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.
Feld
Yair
Y
Cardiovascular Research Laboratory, Department of Physiology, Technion, Israel.
Melamed-Frank
Meira
M
Kehat
Izhak
I
Tal
Dror
D
Marom
Shimon
S
Gepstein
Lior
L
D000818:Animals; D000831:Animals, Newborn; D018780:Body Surface Potential Mapping; D017690:Cell Transplantation / Q000379:methods; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods*; D004553:Electric Conductivity; D004594:Electrophysiology; D005240:Feasibility Studies; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006321:Heart / Q000502:physiology*; D006822:Hybrid Cells; D007700:Kinetics; D051664:Kv1.3 Potassium Channel; D009206:Myocardium / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
C496975:Kcna3 protein, rat; D051664:Kv1.3 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated