Optimization of delivery strategies for cardiac cell therapy in ischemic heart disease

Abstract

Cardiac cell therapy has been proposed as an alternative treatment option for patients after acute myocardial infarction (MI). Irrespective of the chosen regenerative strategy, it is essential to deliver sufficient number of cells to the infarcted myocardium to become effective which is important since low survival and retention of therapeutic cells after transplantation have been reported. To address this issue we have explored three approaches namely: detailed analysis of current literature, evaluation of clinical available delivery techniques and application of state-of the-art imaging techniques. First, we evaluated non-invasive imaging and percutaneous delivery methods used for cardiac repair and postulated that an experimental study on delivery efficiency was necessary. Next, a comparison between transendocardial and intracoronary cell delivery was performed using Indium-oxine labeled MSC to observe short-term cell biodistribution at four hours after transplantation. The results of this study demonstrated no significant differences in delivery efficiency to the heart or in myocardial damage between both techniques. In addition, results were presented of a systematic review and meta-analysis performed on large animals to evaluate the effect of cell therapy in ischemic heart disease. Our analysis confirmed that cell therapy was safe and improved left ventricular ejection fraction (LVEF) as was observed in a clinical setting. Cell type and type of infarction were significant predictors of functional outcome. Moreover, this study provided the indication that indeed large animal models can accurately predict human clinical outcome upon cell transplantation therapy. We therefore performed a comparison between mesenchymal stem cells (MSC) and bone marrow mononucleair (BMMNC) cells in a post MI model to evaluate short and long-term efficacy including a repeated strategy. Myocardial function was assessed at different time-points by pressure-volume loops and echocardiography. Results showed that the differences in LVEF after MSC injection was significantly enhanced compared to bone marrow treatment and this effect was maintained during follow-up. No additional benefit on LVEF of repeated cell injections compared to single cell injection was observed. Thus, injection of MSC was more effective compared to BMMNC treatment and the positive effect was sustained during follow-up. The aim of the final chapter was to provide more functional insight on top-off prognostic relevant LVEF in local wall changes caused by MI as a first step using a novel echocardiographic deformation technique. In pigs, radiofrequency (RF) ultrasound epicardial images were acquired twelve weeks after MI in normal and infarcted regions. Radial and longitudional strains were estimated at three levels namely; endocardium, midwall and epicardium. We demonstrated that layer specific peak radial and longitudinal strain differences can be assessed by RF strain estimation and shows a clear difference between healthy and infarcted tissue. In conclusion, this thesis provides some answers to the unresolved issue as outlined by the ESC Task Force on cardiac repair thereby advancing cardiac cell therapy to the next level. Nevertheless, much more research is necessary since there is still room for improvement of the magnitude of effect of cardiac cell therapy.