Optimising cell therapy for treating heart failure

Abstract

Cell therapy is a promising strategy for treating ischaemic chronic heart failure. However, its therapeutic efficacy has not been fully established. In addition, arrhythmia occurrence is a concern of this treatment. In this work, therapeutic benefits, arrhythmogenicity and underlying mechanisms, which were hypothesised to be modulated by cell-delivery route into the heart, were investigated with the aim of optimising cell therapy. Injection of either skeletal myoblasts or mononuclear bone marrow cells into the rat ischaemic chronically failing heart via either direct intramyocardial or retrograde intracoronary route similarly improved both cardiac function and physical activity over the 84 days analysed. Survival of the grafted cells in the myocardium was extremely poor and trans-differentiation or fusion of the grafted cells into cardiomyocytes or vessels were only rarely identified via either celldelivery route. Therefore, paracrine effects including increased neovascular formation and attenuated fibrosis in the myocardium were considered to play an important role in the therapeutic benefits of cell therapy using either cell-type. Of note, direct intramyocardial injection of either cell-type, but not retrograde intracoronary injection, produced spontaneous ventricular arrhythmias including ventricular tachycardia in the early periods following cell injection. Local heterogeneity in the myocardium induced by clusters of grafted cells, which also involved inflammatory response, was considered to be a cause of the arrhythmias following intramyocardial cell injection. In contrast, in the late periods, injection of skeletal myoblasts via either route, but not mononuclear bone marrow cells, caused latent ventricular tachycardia possibly via regression of connexin43 in the native myocardium. Efficiency of engraftment of mononuclear bone marrow cells in the myocardium following intracoronary injection was very poor in the normal heart, but was enhanced by induction of ischaemia-reperfusion prior to cell injection. Most of the enhanced cell-engraftment was dependent on P-selectin-mediated cellular interaction between donor cells and endothelium