Current clinical trials of cell-based therapies in cardiac repair: too many variables spoil the stem cell broth.

Even the staunchest advocate of the use of cell-based therapies in cardiac repair would be forced to admit that progress has thus far been slow. Both use of therapeutic stem cells and gene-based approaches have met with significant hurdles in their clinical development. However, significant progress does continue to be made towards the ultimate goal of a safe and efficacious cell-based therapy for routine clinical use in cardiac repair. In the area of stem cells, a number of approaches have been proposed, testedpre-clinically, and thenclinically evaluated, albeit in relatively small studies thus far. These include use of skeletal muscle myoblasts (SKMs), bone marrow-derived mononuclear cells (BMCs), mesenchymal stem cells (MSCs, both bone marrow and adipose tissue derived), and cardiac stem cells. Amongst these, the most rigorously evaluated thus far have undoubtedly been the BMCs. Bone marrow-derived mononuclear cells used therapeutically may be unselected or selected according to characteristic cell surface markers, e.g. CD34+, CD133+, and/or CXCR4+, amongst many other identifiers. Putative mechanisms of benefit of BMCs in the post-myocardial infarction (MI) cardiac repair setting have been variously ascribed to both direct transdifferentiation into cardiomyocytes (likely to playonly aminimal, if any, role), indirect actions such as vasculogenesis and angiogenesis, antiapoptotic and antinecrotic effects, and favourable paracrine effects on the extracellular matrix. Intravascular delivery methods invariably result in only minimal local accumulation and retention of cells within the heart in general and the peri-infarct region specifically post-MI. In addition, the cardiac microenvironment in the early post-infarct setting is relatively hostile to stem cell engraftment and differentiation, with local proinflammatory cytokine activation further diminishing therapeutic activity of delivered cells. Further, the presence of cardiac disease itself, not to mention the co-morbidities commonly associated with it, including advanced age, appear to impair the ability of stem cells to release critical homing and engraftment factors, e.g. stromal cell-derived factor-1, that may be contributory to their success in cardiac repair. Nevertheless, despite the above seemingly major limitations to the potential benefit of these cells post-MI, advances have been made with BMCs in this setting. Delewi and colleagues have now undertaken a collaborative meta-analysis whereby original data were sent to the researchers from the individual contributing BMC study groups. This approach, although time consuming, is vastly superior to conventional meta-analysis where group data from individual studies are pooled, with inferencesoften having to be made regarding data not readily extractable from the relevant publication. This collaborative approach therefore permits a more robust and probably more accurate analysis of the true impact of BMCs in the post-MI setting as well as the ability to cut the data into relevant subgroups to generate hypotheses of clinical and mechanistic interest. The key findings of the meta-analysis were modest beneficial effects on the post-MI left ventricular (LV) remodelling process, specifically increased LV ejection fraction (LVEF) and reductions in LV end-systolic and end-diastolic volume index (LVESVI and LVEDVI). Furthermore, subgroup analysis supported younger patients (perhaps because of better preservation of stem cell functional capacity) and those with lower baseline LVEF as having the greatest antiremodelling benefit. Interestingly, timing of administration in relation to the occurrence of the acute coronary syndrome (ACS) event as well as the subsequent percutaneous coronary intervention did not appear to be particularly critical regarding subsequent remodelling endpoints, suggesting that any putative benefits of early administration of stem cells may be offset by loss of quality of therapeutic cells in the immediate post-MI proinflammatory environment. For this reason, temporal remoteness from MI such as in the chronic