Arrhythmia Susceptibility in Mice after Therapy with β-Catenin-Transduced Hematopoietic Progenitor Cells after Myocardial Ischemia/Reperfusion

Abstract

Background: Hematopoietic progenitor cells (HPCs) can improve cardiac function after myocardial infarction. However, occurrence of arrhythmias is a potential limitation of cell therapy. In this study, we investigated the cardiac electrophysiological properties of ex vivo expanded HPCs, generated by β-catenin gene transfer, after transcoronary delivery in a murine model of ischemia/reperfusion (I/R) injury. Methods and Results: To assess arrhythmia inducibility of ex vivo expanded HPCs, mice were subjected to I/R and assigned to sham operation (n = 8), I/R (n = 21) and HPC (n = 15) treatment. Six weeks later, mice were subjected to long-term electrocardiogram recording and in vivo transvenous electrophysiological study. After I/R, mice showed a significant prolongation of conduction and repolarization compared with sham-operated mice. There was a marked increase in ventricular ectopic activity in infarcted mice as compared with sham-operated mice. Cardiac electrophysiological parameters and ventricular ectopic activity were not altered in mice treated with HPCs in comparison with control I/R mice. Conclusion: Transcoronary delivery of genetically ex vivoexpanded HPCs did not alter the electrophysiological properties in mice after I/R. Therefore, ex vivo β-catenin-mediated HPC expansion may represent an attractive therapeutic option for cell transplantation treatment of myocardial infarction without electrophysiological side effects.

The Utility of the Small Rodent Electrocardiogram in Toxicology

“…Some of the common IR-related abnormal changes in the ECG include R-wave enlargement, development of Q-waves, and ST-segment elevation. This model has proven useful in the assessment of the efficacy of antiarrhythmic and anti-ischemic drugs (Burger et al, 2009;Dhalla et al, 2009;Gardiwal et al, 2009;Gandhi et al, 2009;Wajima et al, 2004;Wehrens et al, 2000). IR has also been used as a challenge procedure to determine if toxicant treatment can modify responses to myocardial injury.…”

Combining stem cells in myocardial infarction: The road to superior repair?

“…In this context, it was demonstrated that β-catenin modification of HSCs can significantly improve cardiac function in mice models of ischemia-reperfusion without changing electrophysiological properties of cardiomyocytes. 27,28 Unfortunately, subsequent clinical trials using HSCs had the same negative outcome. Both intracoronary 66 and intramyocardial 67 autologous transplantation of HSCs did not improve cardiac performance and the latter even showed an increased frequency and severity in adverse events.…”

“…Researchers tried to improve HSC therapeutic efficiency by genetic transduction. In this context, it was demonstrated that β‐catenin modification of HSCs can significantly improve cardiac function in mice models of ischemia‐reperfusion without changing electrophysiological properties of cardiomyocytes 27,28 . Unfortunately, subsequent clinical trials using HSCs had the same negative outcome.…”