5.21 Stem Cell Therapy to Treat Heart Failure q

stem-cell homing factors. 84,85 In a clinical study, autologous bone marrow improved left ventricular function in 69 post-myocardial patients. Results from a small phase II clinical trial Prochymal using intravenous allogeneic MSC hints at an improvement in ventricular function in treated patients at a 6-month midpoint. 88,89 2 endothelial identi ﬁ cation, CD34 and CD133 cells these markers by haematopoietic cells. EPC, types, comparisons dif ﬁ Some in both mice and humans of EPC no speci ﬁ c cell surface marker pattern or unique gene expression panel exists. Recent studies proved that EPCs are heterogeneous population and can be divided into early and late EPC population group. Mononuclear cells were isolated from human peripheral blood and the two populations of EPC gained different characteristics when cultured in vitro: early EPCs show spin like morphology, while late EPC take up cobblestone form. The two EPC populations differed in survival and proliferation rate and also in angiogenic properties. EPCs are mobilized from bone marrow in response to injuries, MI and cancer. 99 VEGF and granulocyte colony-stimulating factor (G-CSF) can also boost EPC mobilization. 100,101 It has clinical relevance that widely-used pleiotropic statins (3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors) can induce the mobilization of EPC. 102,103 They may promote neovascularization by secreting proangiogenic factors and by inducing re-endothelialisation 20,104 ; some data further supports that in addition to vasculogenesis, CD34 þ cells may differentiate to cardiomyocytes as well. be a clear that the stem cell pool for EPC is limited, and the scarcity needs to be overcome ﬁ rst by in vitro cell use ﬁ in ventricular function structure. The cells form gap host cardiac however, formation of protective ﬁ brotic tissue around the grafts can prevent complete electrophysiological coupling. 144 Yet, transplantation also appears to normalize electrical conduction through the infarct zone, reducing susceptibility to arrhythmias. 145 The bene ﬁ cial effects in MI have been reported 1 month after transplantation. 143 However, in a study with a longer follow up, no effect on cardiac function could be documented 3 months after transplantation of GFP-tagged cells into the hearts of immunode ﬁ cient mice. 146 Thus, post-transplantation expansion, maturation, survival, and long-term effects of grafted ESC-derived cardiomyocytes to injured myocardium need to be further evaluated. In a study by Murry and colleagues, myocardial infarction has been induced in non-human primates via LAD balloon-occlusion, followed by direct myocardial implantation of hESC-CM in open-chest surgery. The results proved promising electromechanical and histological coupling between the host and grafted human cells. At the same time, malignant ventricular arrhythmias (ventricular tachycardia and ﬁ brillation) were registered which cast doubt on the success. 147 The same group made further direct comparison between hESC-CM, hESC-derived cardiovascular progenitor cells and bone marrow-derived mononuclear cells in a myocardial infarction model of nude rats. All the cell types were safe, but hESC derivatives were found to be superior to bone marrow derivatives as they improved left ventricular systolic function, while bone marrow derivatives only attenuated LV dilatation. 148 The latest preclinical data suggest that co-transplantation of hESC derived cardiovascular cells with mesenchymal stem cells may enhance the bene ﬁ cial effects of hESC derivatives. MSC may support the engraftment and survival of implanted hESC derivatives by advanced real-time imaging techniques such as MRI and electromechanical voltage mapping, 198 200 and a recently implemented approach of transvenous injection into coronary veins. MI of the anterior wall treated with percutaneous coronary intervention were randomized to the group that underwent intracoronary infusion of autologous mononuclear BMC or sham injections 3 – 5 days later. 205 After 6 months, echocardiography, ECG-gated SPECT, and MRI were used to assess left ventricular function, end-diastolic volume, and infarct size. With the largest volume, randomized REPAIR-AMI (Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction) trial included 204 patients with ST-elevation MI to an intracoronary infusion into the infarct-related artery with either heterogeneous population of haematopoietic, mesenchymal and mononuclear cells or placebo vehicle medium 3 – 7 days after reperfusion therapy. 206 At 4 month follow-up, patients treated with BMC had a signi ﬁ cant improvement in LVEF compared with placebo ( þ 5.5 vs þ 3.0%, absolute difference þ 2.5%). In further subgroup analyses, the improvement in LVEF was most prominent in patients with poorer baseline LVEF and in those treated (cid:4) 5 days after MI. The results also showed a reduction in the combined clinical endpoint of mortality, a trend toward a reduction in recurrent MI or repeated revascularisation. Bene ﬁ cial effects of BMC administration on cardiovascular outcome are preserved even after an observation period of 2 years after MI 207 and several trials showed further improvement in angina or left ventricular function in chronic ischaemic heart disease even with preserved or decreased ejection fraction. In a controlled crossover study patients with stable ischemic heart disease with at least 3 months after an MI were randomized to receive BMC, circulating progenitor blood cells, or placebo into the patent coronary artery. 208 This study suggested that intracoronary infusion of progenitor cells is safe in patients with previous MI and infusion of BMC is associated with moderate improvement in the LVEF. Patients receiving BMC had a 2 percentage point increase in LVEF, while the ones in placebo group had a 1% decrease in LVEF. Fewer randomized trials of transplants of blood- or bone marrow-derived stem cells have been performed in the setting of chronic coronary artery disease and chronic heart failure. Some controversial results brought publication bias and clinical data from Strauer et al. were withdrawn due to publication fraud. Janssens and colleagues used infusion of autologous bone marrow mononuclear cells in patients with MI 24 h after successful percutaneous coronary intervention, showed no bene ﬁ t in LVEF, but a signi ﬁ cant reduction in infarct size and improved regional left ventricular function. The BAMI study is due to end in 2018 and will clarify effects of these cells in intracoronary implantation after ischemic events. Four recent meta-analyses of these trials, incorporating 5, 10, 13, and 18 randomized and non-randomized trials, respec-tively, and involving altogether 999 patients with acute MI or chronic ischaemic cardiomyopathy help to place the results of indi-vidual trials into perspective. These meta-analyses showed that transplantation of BMC improved LVEF by 5.4%, decreased infarct scar size by 5.5% and lowered left ventricular end-systolic volume by 4.8 mL. 211 Other meta-analyses 215 indicated that BMC treatment is bene ﬁ cial; however, the typical modest increase in ejection fraction is of uncertain clinical signi ﬁ cance. The overall bene ﬁ t on ventricular function demonstrated in the meta-analyses needs to be tempered by the ASTAMI (Autologous Stem Cell Transplantation in Acute Myocardial Infarction), 192 REGENT (Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction) 216 and BOOST (BOne marrOw transfer to enhance ST-elevation MI regeneration) trials showing either no bene ﬁ t or a temporary improvement for less than 6 months. The post hoc analysis of data from the REPAIR-AMI and REGENT trials also revealed that BMC had substantial treatment effects only in areas with the greatest damage or extent of scar-ring.