טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentFeld Yair
SubjectLong Term Electromechanical and Structural Evaluation of
Hybrid Cardiomyocytic Cultures
DepartmentDepartment of Medicine
Supervisor Professor Lior Gepstein


Abstract

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 novel high-resolution multielectrode mapping technique was used to assess the electrophysiological and structural properties of primary cultures of neonatal rat ventricular myocyte. 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 as assessed by vital staining. All electrophysiological changes were reversed following the application of Charybdotoxin, a specific Kv1.3 blocker. In contrast, conduction remained uniform in the control hybrid cultures when non-transfected fibroblasts were used. Conclusions: These results demonstrate that 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.