The epicardial delivery of cardiosphere derived cells or their extracellular vesicles is safe but of limited value in experimental infarction

Verónica Crisóstomo,Antoni Bayes-Genis,Verónica Álvarez,Francisco M. Sánchez-Margallo,Javier G. Casado,Virginia Blanco-Blázquez,Juan Maestre,Claudia Baéz-Diaz,Esther López-Nieto,Carolina Gálvez-Montón

doi:10.1038/s41598-021-01728-y

Abstract

The epicardial administration of therapeutics via the pericardial sac offers an attractive route, since it is minimally invasive and carries no risks of coronary embolization. The aim of this study was to assess viability, safety and effectiveness of cardiosphere-derived cells (CDCs), their extracellular vesicles (EVs) or placebo administered via a mini-thoracotomy 72 h after experimental infarction in swine. The epicardial administration was completed successfully in all cases in a surgery time (knife-to-skin) below 30 min. No significant differences between groups were found in cardiac function parameters evaluated using magnetic resonance imaging before therapy and at the end of the study, despite a trend towards improved function in CDC-treated animals. Moreover, infarct size at 10 weeks was smaller in treated animals, albeit not significantly. Arrhythmia inducibility did not differ between groups. Pathological examination showed no differences, nor were there any pericardial adhesions evidenced in any case 10 weeks after surgery. These results show that the epicardial delivery of CDCs or their EVs is safe and technically easy 3 days after experimental myocardial infarction in swine, but it does not appear to have any beneficial effect on cardiac function. Our results do not support clinical translation of these therapies as implemented in this work.

Highlights

The epicardial administration of therapeutics via the pericardial sac offers an attractive route, since it is minimally invasive and carries no risks of coronary embolization
5 animals died during infarction due to refractory malignant arrhythmias (14% of model-related mortality), so that 30 animals were subjected to the 72 h Cardiac magnetic resonance (CMR) examination
The use of clinically relevant imaging techniques and a large animal model ensured that our results could be translatable to the clinical scenario

Summary

Introduction

The epicardial administration of therapeutics via the pericardial sac offers an attractive route, since it is minimally invasive and carries no risks of coronary embolization. The aim of this study was to assess viability, safety and effectiveness of cardiosphere-derived cells (CDCs), their extracellular vesicles (EVs) or placebo administered via a mini-thoracotomy 72 h after experimental infarction in swine. Pathological examination showed no differences, nor were there any pericardial adhesions evidenced in any case 10 weeks after surgery. These results show that the epicardial delivery of CDCs or their EVs is safe and technically easy 3 days after experimental myocardial infarction in swine, but it does not appear to have any beneficial effect on cardiac function. Our results do not support clinical translation of these therapies as implemented in this work To this day, the potential of cardiac cell therapy as an ancillary treatment for acute myocardial infarction patients has not been consistently proved.

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Conclusion