Effects of bone marrow cells transplantation for acute myocardial infarction on cardiac function, infarct size, and clinical events: a meta-analysis

To the Editor: Acute myocardial infarction (AMI) poses a substantial threat to human health.[1] At present, AMI is mainly treated by reperfusion, drugs, and surgery,[2] which only temporarily delay cell death and deterioration. Sian Harding at el[3] suggested that myocardial transfer of specific bone marrow cells (BMCs) and progenitor cell populations may enhance recovery of systolic and diastolic function after AMI. Although a few previous meta-analysis studies of BMCs transplantation for AMI have been published, the quality of these studies was varied due to marked heterogeneity[4,5] or because they focused on a single outcome (e.g., cardiac function)[5] and very few evaluated the clinical evens.[6] In addition, the effects of BMCs transplantation over different lengths of follow-up periods were unclear. In an attempt to reach more reliable conclusions, we performed an updated meta-analysis of randomized controlled trials (RCTs) and conducted subgroup analyses according to follow-up periods. Seven databases (PubMed, Cochrane Library, Clinical Trial Registry, EMBASE, MEDLINE, Wanfang, and CNKI) were searched through March 2022 for RCT studies of BMCs transplantation in patients with AMI. Search terms were listed as "stem cells", "bone marrow cells", "bone marrow stem cells", "progenitor cells", "acute myocardial infarction" and "myocardial infarction". The literature search finally identified 1910 studies, of which 54RCTs with Alejandro Jadadad-Bechara (JADAD) score ≥3[7] met inclusion criteria for meta-analysis, after excluding 126 duplicate published papers and 1730 papers that did not meet the criteria of high quality. Using the Cochrane Review risk-of-bias assessment tool and JADAD scale[7] to evaluate the quality of included studies and of which studies with scores ≥3 were considered high-quality [Supplementary Figure 1, https://links.lww.com/CM9/B670]. Two researchers independently identified and classified studies and the following data were extracted: (1) first author, year of publication, etc., and (2) primary outcomes, including left ventricular ejection fraction (LVEF, %), left ventricular end-diastolic volume (LVEDV, mL), left ventricular end-systolic volume (LVESV, mL), wall motion score index (WMSI, %), left ventricular end-diastolic internal diameter (LVDd, mm), infarct size (%), and the incidence of clinical events including death, recurrent myocardial infarction (MI), target vessel revascularization (TVR), and rehospitalization for heart failure (HF). Fifty-four RCTs comprised 3572 patients,with a median follow-up period of 6 months after AMI (range: 1–62 months). Basic details and the quality evaluation of these studies are presented in Supplementary Tables 1 and 2, https://links.lww.com/CM9/B670. All statistical analyses were performed by using Review Manager (Version 5.3; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). Mean differences (MD) with 95% confidence intervals (CIs) were calculated for LVEF, LVESV, LVEDV, WMSI, LVDd, and infarct size. Odds ratio (OR) with 95% CI was calculated for clinical events. Subgroup analyses were performed for different follow-up periods after BMCs transplantation (short-term: <3 months, medium-term: 3–6 months, and long-term: ≥12 months). Depending on the results from the tests of heterogeneity, a fixed effect model or a random effect model was chosen. The chi-squared test and I2 were used to evaluate the heterogeneity of included studies. Statistically significant difference was evaluated based on two-tailed P <0.05 for hypotheses and P <0.10 for the heterogeneity test. Begg's test was used to assess publication bias by using STATA software (version 15.1; StataCorp., College Station, TX, USA). In meta-analysis, BMCs transplantation can significantly increase LVEF (46 studies; MD: 1.84, 95% CI 1.19–2.48; I2: 30%, P = 0.03), and significantly reduced LVESV (35 studies; MD:–1.96, 95% CI –3.41 to –0.50; I2: 0%, P = 0.65), moreover LVDd (4 studies; MD = –1.59, 95% CI –3.08 to –0.11; I2: 1%, P = 0.39), WMSI (11 studies; MD: –0.08, 95% CI –0.14 to –0.01; I2: 44%, P = 0.06), and infarct size (16 studies; MD: –3.16, 95% CI –4.22 to –2.10; I2: 0%, P = 0.57), but no difference in LVEDV (37 studies; MD: –1.37, 95% CI –2.84 to 0.09; I2: 0%, P = 0.97) [Supplementary Table 3, https://links.lww.com/CM9/B670]. It suggested that BMCs transplantation can improve left ventricular function and reduce infarct size beyond what is achievable with conventional treatment with PCI, with weak and moderate heterogeneity. Furthermore, the different effects were observed over different follow-up periods and were highest over the short term. For LVEF, significant improvements were shown in all time points and persisted beyond 12 months: short term (4 studies; MD: 3.42, 95% CI 1.57–5.27; I2: 20%, P = 0.29), medium term (40 studies; MD: 1.40, 95% CI 0.80–1.99; I2: 23%, P = 0.10), and long term (4 studies; MD: 2.67, 95% CI 0.28–5.07; I2: 0%, P = 0.86). For LVEDV and LVESV, it seemed that the effects over the long term were greater than over the medium term, even though there was a trend toward significant effects on LVEDV (31 studies; MD: –1.33, 95% CI –2.87 to 0.21; I2: 0%, P = 0.91) and LVESV (28 studies; MD: –1.47, 95% CI –3.05 to 0.12; I2: 0%, P = 0.94) over the medium term. For infarct size, effects seemed higher over the medium term (11 studies; MD: –3.04, 95% CI –4.25 to –1.83; I2: 13%, P = 0.32) than over the short term (4 studies; MD: –2.62, 95% CI –4.96 to –0.27; I2: 0%, P = 0.98), and improvement persisted beyond 6 months. Over the medium term, BMCs transplantation was associated with significantly reduced WMSI (8 studies; MD: –0.02, 95% CI –0.06 to 0.03; I2: 0%, P = 0.93), and LVDd (3 studies; MD: –1.79, 95% CI –3.40 to –0.19; I2: 23%, P = 0.27) [Supplementary Figure 2A–F, https://links.lww.com/CM9/B670]. Long-term changes in infarct size, WMSI, and LVDd could not be assessed due to a lack of data. Differences in effects among different follow-up time periods suggest that compensatory functional improvement occurred soon after BMCs transplantation and then decreased until new cardiomyocytes differentiated from transplanted BMCs, which led to further improvements. Clinical events for evaluating the effects of BMCs transplantation on AMI are essential and critical. Transplantation of BMCs was associated with a significant reduction in the odds of rehospitalization for HF (14 studies; OR: 0.35, 95% CI 0.20–0.63; I2: 1%; P = 0.43), and demonstrated a trend toward decreased odds of recurrent MI (13 studies; OR: 0.59, 95% CI 0.33–1.06; I2: 0%, P = 0.86) that approached statistical significance (P = 0.08) [Supplementary Table 3, https://links.lww.com/CM9/B670]. Moreover, over the medium term, BMCs transplantation was associated with a significant reduction in recurrent MI (4 studies; OR: 0.31, 95% CI 0.10–0.99; I2: 0%, P = 0.62), but not in death (5 studies; OR: 0.96, 95% CI 0.31–3.00; I2: 0%, P = 0.47), TVR (4 studies; OR: 0.74, 95% CI 0.42–1.32; I2: 0%, P = 0.66), and rehospitalization for HF (5 studies; OR: 0.36, 95% CI 0.10–1.27; I2: 0%, P = 0.90). Over the long term, BMCs transplantation was associated with a significant decrease in rehospitalization for HF (7 studies; OR: 0.27, 95% CI 0.14–0.54; I2: 0%, P = 0.46), but not in death (7 studies; OR: 0.92, 95% CI 0.43–1.96; I2: 0%, P = 0.81), recurrent MI (8 studies; OR: 0.76, 95% CI 0.39–1.50; I2: 0%, P = 0.85), and TVR (5 studies; OR: 1.07, 95% CI 0.66–1.73; I2: 0%, P = 0.93) [Supplementary Figure 2G–I, https://links.lww.com/CM9/B670]. The effect of BMCs transplantation on recurrent MI clearly varied, suggesting the influence of factors such as dose and timing of BMCs injection, follow-up periods, and AMI severity, that merit further exploration. BMCs transplantation was associated with a significant reduction in risk for rehospitalization for HF, but there was no significant decrease in the risk of death and TVR, and it might be because this meta-analysis included few long-term studies. Begg's test showed that there was no publication bias among studies of LVEF, LVEDV, LVESV, WMSI, infarct size, LVDd, death, recurrent MI, TVR, and rehospitalization for HF (all P >0.05) [Supplementary Figure 3, https://links.lww.com/CM9/B670]. In summary, BMCs transplantation after AMI leads to significant clinical improvements in cardiac function and infarct size and also is associated with a significant reduction in adverse cardiac outcomes that extends beyond the benefits of PCI. Effects size appears to be influenced by different follow-up periods after transplantation and that needs further verification, particularly for long-term measures. However, due to lack of information on injected doses makes analysis of dose–response relationship impossible. More and larger studies of the clinical effects of BMCs transplantation could help confirm and characterize benefits over different time periods and injection doses. Funding This study was supported by grants from the National Natural Science Foundation of China (No.81960614) and International scientific and technological cooperation project (No.20YF3WA020).