Changing of the guard.

Abstract

Cell therapy continues to hold promise as a future therapeutic modality for patients with heart failure. The first cells to be utilised in clinical trials in cardiovascular disease were autologous bone marrow-derived mononuclear cells (ABMMNCs). 3 This was likely due to the fact that these cells are readily accessible and can be easily processed and given back to patients as an autologous fresh product in a short amount of time. In the absence of clinical experience, this was a good starting point. Over the next decade, important additional data were obtained with the use of ABMMNCs, 6 and the initial positive results were tempered by negative results. Nonetheless, after much scrutiny, there seems to be a therapeutic signal, albeit a weak one. Overall, treated patients have shown relatively small but statistically significant improvements in LV function and reductions in future major adverse cardiac events (MACE). Because of the limitations of ABMMNCs and a general drive towards finding more effective treatments based on preclinical work, there has been a parallel and progressive development of single-cell therapies from both bone marrow and other tissues. The therapeutic properties of mesenchymal stromal cells have been extensively investigated in a wide range of disease conditions (Figure 1). In this issue of the European Heart Journal, Dr Mathiasen and colleagues showed that transendocardial injections of autologous bone marrow-derived mesenchymal cells (MCS) resulted in positive effects on left ventricular (LV) contractility in patients with ischemic cardiomyopathy and no other treatment options. Treated patients received a mean of 77.5+ 67.9 × 10 cells. The primary endpoint of their trial was a change in LV end-systolic volume (LVESV), as measured by magnetic resonance imaging or computed tomography at the 6-month follow-up. In this placebocontrolled, randomised trial comprising 55 patients (37 treated with MSCs and 18 treated with placebo), they found that LVESV decreased by 7.6 mL in the MSC-treated group and increased by 5.4 mL in the placebo-treated group. The difference between the 2 groups was 13.0 mL (P 1⁄40.001). Compared to the placebo group, the treated group also showed a 6% increase in LV ejection fraction (P , 0.001), an 18 mL increase in stroke volume (P , 0.0001), and a 5.7 g increase in myocardial mass (P 1⁄40.001). No significant differences were found in New York Heart Association classification, 6-minute walk time, or the Kansas City cardiomyopathy questionnaire. No side-effects attributable to the treatment were identified. These findings are in agreement with those from several previous clinical studies that also assessed the use of mesenchymal cells in similar patients. – 14 In these previous studies, allogeneic and autologous bone marrow-derived and adipose tissue-derived mesenchymal stem cells showed beneficial effects on various aspects of LV function and the occurrence of MACE in patients with ischemic cardiomyopathies and no other option for revascularization. Taken together, these newer studies represent a shift away from ABMMNC therapy. The mesenchymal cell has taken centre stage. Based on more robust results, a large phase 3 trial is currently underway to investigate the therapeutic role of these cells in heart failure patients (DREAM HF, NCT02032004). However, one must always be cautious as this is a very dynamic field, and another cell type, such as cardiac-derived stem cells or iPS cells, may take over as the best candidate after further development. In addition to the progress in pursuing more potent single-cell therapies, it also seems possible that combinations of stem cells may be more effective than a single cell type alone. In a pre-clinical study, Williams and colleagues showed that the combination of cardiac resident c-kit cells and mesenchymal cells administered transendocardially reduced infarct size and improved LV function more than either stem cell type alone in a porcine model of myocardial infarction. The Cardiovascular Cell Therapy Research Network will soon begin a clinical trial in the United States in which patients with ischemic cardiomyopathies will receive similar treatments (ie, mesenchymal cells, c-kit+ cells, or the 2 cell types in combination) (CONCERT-HF). This trial will help determine the potential benefits of combining mesenchymal and c-kit+ stem cells for treating patients with heart failure due to coronary heart disease and no other treatment options. In summary, important progress has been made in the search for the ideal cell type, or combinations thereof, to obtain the best therapeutic effect for patients with heart failure. Mathiasen et al’s positive

DOI: 10.1093/eurheartj/ehv219

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Cite this paper

@article{Kahn2005ChangingOT, title={Changing of the guard.}, author={Charles N Kahn}, journal={European heart journal}, year={2005}, volume={36 27}, pages={1711-3} }