Efficacy and Safety of Mesenchymal Stem Cell Therapy in Patients with Acute Myocardial Infarction: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

The adjuvant treatment of stem cell therapy for acute myocardial infarction (AMI) has been studied in multiple clinical trials, but many questions remain to be addressed, such as efficacy, safety, identification of the optimal cell type, tractable route of delivery, transplant dosage, and transplant timing. The current meta-analysis aimed to explore the issues of mesenchymal stem cells (MSCs) transplantation in patients with AMI based on published randomized controlled trials (RCTs) and guide the design of subsequent clinical trials of MSCs therapy for AMI. The Cochrane Library, PubMed, EMBASE databases were searched for relevant clinical trials from January 1, 2000, to January 23, 2021. Results from RCTs involving MSCs transplantation for the treatment of AMI were identified. According to the Cochrane systematic review method, the literature quality, including studies, was evaluated and valid data was extracted. Rev- Man 5.3 and Stata 15.1 software were used for Meta-analysis. After literature search and detailed evaluation, 9 randomized controlled trials enrolling 460 patients were included in the quantitative analysis. Pooled analyses indicated that MSCs therapy was associated with a significantly greater improvement in overall left ventricular ejection fraction (LVEF), and the effect was maintained for up to 24 months. No significant difference in favor of MSCs treatment in left ventricular (LV) volume and in the risk of rehospitalization as a result of heart failure (HF) was noted, compared with the controls. For transplantation dose, the LVEF of patients accepting a MSCs dose of 107-108 cells was significantly increased by 2.62% (95% CI 1.54 to 3.70; P < 0.00001; I2 =0%), but this increase was insignificant in the subgroup that accepted a MSCs dose of < 107 cells (1.65% in LVEF, 95% CI, 0.03 to 3.27; P =0.05; I2 =75%) or >108 cells (4.65% in LVEF, 95% CI, -4.55 to 13.48; P =0.32; I2 =95%), compared with the controls. For transplantation timing, a significant improvement of LVEF of 3.18% was achieved in the group of patients accepting a MSCs infusion within 2 to 14 days after percutaneous coronary intervention (PCI) (95% CI, 2.89 to 3.47; P <0.00001; I2 = 0). There was no association between MSCs therapy and major adverse events. Results from our systematic review suggest that MSCs therapy for patients with AMI appears to be safe and might induce a significant increase in LVEF with a limited impact on LV volume and rehospitalization caused by HF. The effect was maintained for up to 24 months. MSCs dose of 107-108 cells was more likely to achieve better clinical endpoints than <107 or >108 cells. The optimal time window for cell transplantation might be within 2-14 days after PCI. This meta-analysis was registered with PROSPERO, number CRD 42021241104.

Yu J ，Zhang RF ，Mao YL ，Zhang H ... -  《-》

Rational transplant timing and dose of mesenchymal stromal cells in patients with acute myocardial infarction: a meta-analysis of randomized controlled trials.

Wang Z ，Wang L ，Su X ，Pu J ，Jiang M ，He B ... -  《-》

A Systematic Review and Meta-Analysis: Safety and Efficacy of Mesenchymal Stem Cells Therapy for Heart Failure.

Preclinical and clinical evidence suggests that mesenchymal stem cells (MSCs) may be beneficial in treating Heart Failure (HF). However, the effects of stem cell therapy in patients with heart failure is an ongoing debate and the safety and efficacy of MSCs therapy are not well-known. We conducted a systematic review of clinical trials that evaluated the safety and efficacy of MSCs for HF. This study aimed to assess the safety and efficacy of MSCs therapy compared to the placebo in heart failure patients. We searched PubMed, Embase, Cochrane library systematically, with no language restrictions. Randomized Controlled Trials (RCTs) assessing the influence of MSCs treatment function controlled with placebo in heart failure were included in this analysis. We included RCTs with data on safety and efficacy in patients with heart failure after mesenchymal stem cell transplantation. Two investigators independently searched the articles, extracted data, and assessed the quality of the included studies. Pooled data was performed using the fixed-effect model or random-effect model by the use of Review Manager 5.3. The Cochrane risk of bias tool was used to assess the bias of included studies. The primary outcome was safely assessed by death and rehospitalization and the secondary outcome was efficacy, which was assessed by six-minute walk distance and Left Ventricular Ejection Fraction (LVEF), Left Ventricular End-systolic Volume (LVESV), Left Ventricular End-diastolic Volume (LVEDV) and Brain Natriuretic Peptide (BNP). A total of twelve studies were included, involving 823 patients who underwent MSCs or placebo treatment. The overall rate of death showed a trend of reduction of 27% (RR [CI]=0.73 [0.49, 1.09], p=0.12) in the MSCs treatment group. The incidence of rehospitalization was reduced by 47% (RR [CI]=0.53[0.38, 0.75], p=0.0004). The patients in the MSCs treatment group realised an average of 117.01m (MD [95% CI]=117.01m [94.87, 139.14], p<0.00001) improvement in 6MWT. MSCs transplantation significantly improved Left Ventricular Ejection Fraction (LVEF) by 5.66 % (MD [95% CI]=5.66 [4.39, 6.92], p<0.00001), decreased Left Ventricular End-Systolic Volume (LVESV) by 14.75 ml (MD [95% CI]=-14.75 [-16.18, - 12.83], p<0.00001) and Left Ventricular End-Diastolic Volume (LVEDV) by 5.78 ml (MD [95% CI]=- 5.78[-12.00, 0.43], p=0.07), in the MSCs group, BNP was decreased by 133.51 pg/ml MD [95% CI]= - 133.51 [-228.17,-38.85], p=0.54, I2= 0.0%) than did in the placebo group. Our results suggested that mesenchymal stem cells as a regenerative therapeutic approach for heart failure are safe and effective by virtue of their self-renewal potential, vast differentiation capacity and immune modulating properties. Allogenic MSCs have superior therapeutic effects and intracoronary injection is the optimum delivery approach. In the tissue origin, patients who received treatment with umbilical cord MSCs seem more effective than bone marrow MSCs. As to dosage injected, (1-10)*10^8 cells were of better effect.

Shen T ，Xia L ，Dong W ，Wang J ，Su F ，Niu S ，Wang Q ，Fang Y ... -  《-》

Effects of timing on intracoronary autologous bone marrow-derived cell transplantation in acute myocardial infarction: a meta-analysis of randomized controlled trials.

Xu JY ，Liu D ，Zhong Y ，Huang RC ... -  《-》

Comparing the effect of bone marrow mono-nuclear cells with mesenchymal stem cells after acute myocardial infarction on improvement of left ventricular function: a meta-analysis of clinical trials.

The effect of transplantation of bone-marrow mononuclear cells (BM-MNCs) and mesenchymal stem cells (MSCs) on ejection fraction (LVEF) has been studied in patients with acute myocardial infarction (AMI) in clinical trials. This raises the question that which type of cell may help improve LVEF better in AMI patients. No meta-analysis of clinical trials has yet addressed this question. Electronic databases were searched thoroughly to find eligible trials on the effects of transplantation of BM-MNCs and MSCs in patients with AMI. The primary outcome was improvement in LVEF. Data were synthesized using random-effects meta-analysis. For maximizing the credibility of subgroup analysis, we used the instrument for assessing the Credibility of Effect Modification of Analyses (ICEMAN) for meta-analyses. A total of 36 trials (26 on BM-MNCs and 10 on MSCs) with 2489 patients (1466 were transplanted [1241 with BM-MNCs and 225 with MSCs] and 1023 as controls) were included. Both types of cells showed significant improvements in ejection fraction in short-term follow-up (BM-MNCs: WMD = 2.13%, 95% CI = 1.23 to 3.04, p < 0.001; MSCs: WMD = 3.71%, 95% CI = 2.32 to 5.09, p < 0.001), and according to ICEMAN criteria, MSCs are more effective. For selected population of patients who received stem cell transplantation in early course after AMI (less than 11 days), this effect was even more pronounced (BM-MNC: WMD = 3.07%, 95% CI = 1.97 to 4.17, p < 0.001, I2 = 40.7%; MSCs: WMD = 5.65%, 95% CI = 3.47 to 7.84, p < 0.001, I2 = 84.6%). Our results showed that transplantation of MSCs after AMI might increase LVEF more than BM-MNCs; also, based on ICEMAN, there was likely effect modification between subgroups although uncertainty still remained.

Hosseinpour A ，Kheshti F ，Kazemi A ，Attar A ... -  《-》