Autologous bone marrow stem cell transplantation for patients undergoing coronary artery bypass grafting: a meta-analysis of 22 randomized controlled trials

Ischemic heart disease (IHD) remains one of the leading causes of morbidity and mortality worldwide, imposing both economic and healthy burdens on either developed and developing countries [1‐3]. Myocardial ischemia often results in irreversible loss of viable myocardium and replacement by noncontractile scar tissue, leading to the impairment of left ventricular and cardiac dysfunction. Despite the advances in revascularization techniques and pharmacological treatment, patients with poor cardiac function struggle to achieve desirable outcomes. The aim of bone marrow stem cells (BMSCs) therapy is to repair damaged myocardium, prevent ventricular remodeling, and improve overall cardiac function [1].

Bone marrow cells are the first choice for bypass combined stem cell transplantation because they are autologous and readily available. The efficacy of CABG combined with BMSC transplantation remains controversial. Studies have shown that CABG combined with BMSC transplantation is beneficial to cardiac function without adverse reactions, and is a safe and feasible clinical adjuvant therapy [4‐14]. However, other studies have reported no effect of CABG combined with BMSC transplantation on overall left ventricular function and clinical symptoms [13, 15‐24]. Since the publication of these meta-analyses, several new randomized controlled trials (RCTs) have been published [11, 14, 22‐24]. The purpose of this meta-analysis was to reevaluate the efficacy of CABG combined with BMSC transplantation by incorporating updated RCTs results.

In this meta-analysis, CABG combined with BMSC transplantation showed an improved cardiac function in patients with IHD compared with CABG alone. The change of LVEF from baseline to follow-up in the BMSC group increased by 3.87% (CI: 1.93–5.80%) compared with that in the CABG group. But the results were highly heterogeneous (I² = 80%). A detailed subgroup analysis was performed to explore differences in LVEF change and revealed that these results were consistent regardless of the follow-up time, type of stem cells, route of cell injection (IM or IC), dose of stem cells and baseline LVEF.

Subgroup analysis of LVEF measurements (echocardiography, SPECT, or MRI) showed that the choice of method influenced the determined effectiveness of CABG combined with BMSC transplantation in IHD patients. Method of LVEF measurements was revealed as a significant factor contributing to the heterogeneity of the results. In addition, subgroup analysis of echocardiographic tests demonstrated higher values of LVEF improvement but poor homogeneous results. However, subgroup analysis of MRI did not show any significant improvement of LVEF and more homogeneous results. Echocardiography, SPECT and MRI have important diagnostic value in assessing cardiac function. Nonetheless, echocardiographic measurements are affected by the ultrasonographer, whereas MRI and SPECT are more reliable and accurate for measuring cardiac function in IHD patients. The source of heterogeneity in these results cannot be identified sufficiently. Although the subgroup analysis showed the method of LVEF and SPECT assessment as significant factors, this finding could not clinically explain the differences in the outcomes reported by different trials. The high SD values in some trials may demonstrate that the cause of the different outcomes reported by the trials might be due to variation in patient response to BMSC transplantation.

Subgroup analysis suggested that the use of BMMNCs or BMCs may lead to a more pronounced improvement in LVEF compared to CD133 + or CD34 + cells, that 2 of the 7 studies that included CD133 + or CD34 + cells in the meta-analysis had an unfavorable MD, and 2 of the 10 studies using BMMNCs or BMCs had an unfavorable MD. But the study of Naseri et al. [12] suggested that CD133 + cells had slightly greater efficacy compared to BMMNCs. Naseri et al. [12] have commented that the heterogeneous population of the BMMNCs may affect homing of the desired cells and previous human studies have shown that intracoronary transplantation with a small concentration of bone marrow progenitor cells has a sevenfold higher homing ability compared to larger numbers of BMMNCs. Noiseux et al. [20] suggested that selected CD133+, CD34+ , CD45+ hematopoietic progenitor cells have vasculogenic properties that may improve perfusion in ischemic cardiomyopathy. However, results may be limited by the small sample size of groups treated with CD133+ or CD34+ cells and autologous cell agents are medical products characterized by the complexity of cell isolation protocols and cell product storage, and the methods used to evaluate the results may be inhomogeneous. These factors may affect the effectiveness of cell therapy in improving heart function. In addition, subgroup analysis of dose of stem cells demonstrated that the number of injected BMSCs was not a significant factor affecting the heterogeneity of the data, and the change of LVEF may be independent of the dose of BMSCs.

Subgroup analysis of IC injection demonstrated higher values of LVEF improvement but poor homogeneous results [MD 5.07% (2.34 to 7.80%), I² = 0%], while MD of IM injection group is 3.80%(1.53 to 6.06, I² = 84%). Hu et al. [7] have commented that stem cells in the process of operation were shipped to the myocardial, mainly around the infarction area, while a large number of transplanted cells by intramyocardial in situ, but a large number of cells during ischemia or infarction area reducing survival and impairing proliferation ability, in addition, the uneven distribution of delivery within myocardial cells, some parts need to cell therapy can't reach. In their study [7], the aorta was open 5 min after cell injection, extending the contact time between BMMNCs and small coronary vessels and enhancing the adhesion of BMMNCs, thereby reducing the number of BMMNCs washed out of the heart. They [7] hypothesized that in a cardiac arrest, capillaries dilate and blood vessel permeability increases, so transplanted cells attached to the blood vessel wall migrate easily to the myocardium. Naseri et al. [12] hold the opposite view that intramuscular injection was the most effective method because cells are more reliably located in the heart by direct visualization and delivery to the target site, while many of the injected cells deliver to the lungs or liver with intracoronary injections. More high-quality research is needed to determine which approach is better.

LVESV_change and LVEDV_change decreased in the BMSC group, but the difference was not statistically significant compared with the CABG group. Our meta-analysis demonstrated that there was a statistical difference in LVEDVI_change (MD = −10.57 ml/m²; 95% CI: −19.86 to −1.28 ml/m²; P = 0.03) and LVESVI_change (MD = −9.49 ml/m²; 95% CI: −16.95 to −2.03 ml/m²; P = 0.01) between the BMSC and CABG groups, while the meta-analysis of Wu et al. [1] with 14 RCTs revealed no statistically difference between two groups. These indexes are more reflective regarding the heart function compared with LVEDV and LVESV, as each individual's body surface area is different. This may be one of the reasons for the difference in LVEDV and LVESV not being statistically significant.

LVESD_change and LVEDD_change decreased in the BMSC group compared with the CABG group. There was a statistically difference in LVESD_change (MD = −3.50 mm; 95% CI: −5.58 to −1.42 mm; P = 0.001) and no statistically difference in LVEDD_change (MD = −2.49 mm; 95% CI: −7.27 to 2.28 mm; P = 0.31). This meant the BMSC group may benefit more than the CABG group in LVESD.

There are some points of view in previous studies. Wang et al. [30] have commented that paracrine effects of BMMNCs transplantation and the intervention time may play a key role in the outcome, the left ventricular remodeling is more likely to be prohibited and the left ventricular systolic function obtains the opportunity to improve steadily in the long term while transplanted at the acute myocardial infarction setting, limited reduction in MI size, short-term improvement in LV function, and disappearance of paracrine effects over time when BMMNCs is transplanted at old myocardial infarction setting in which the left ventricular remodeling has already developed and the paracrine effect of BMMNCs is mainly acting on the transitional zone of old myocardial infarction. Wang et al. [10] suggested that transplantation during off-pump coronary artery bypass grafts could reduce ischemia and reperfusion injury and restore vascular supply, thereby increasing stem cell survival rate and avoiding inflammation, loss of survival signal of extracellular matrix components and release of ischemic cardiac cytotoxic factors leading to high mortality of stem cells after transplantation.

BMSCs are an ideal cell resource for cell therapy. BMSCs are easy to harvest, and the biological characteristics are not affected after isolation. There are several important subclasses, such as endothelial progenitor cells, mesenchymal stem cells, and hemopoietic progenitor cells; each type may be capable of improving heart function [7].

The detailed mechanism of autologous bone marrow stem cell transplantation for patients undergoing coronary artery bypass grafting has not been fully elucidated. The role of CD133+ cells in reducing nonviable segments, improving LVEF and wall thickening is unclear. Naseri et al. [12] have commented that previous animal experiments have shown that the transplanted cells integrate into the new environment and form new vasculature and myocardium. Wang et al. [30] have commented that a series of experimental studies have shown that BMMNCs can express a large number of cytokines, prevent cardiomyocyte apoptosis, promote angiogenesis, and recruit endogenous stem cells for cell regeneration and fusion. Wang et al. [10] have suggested that the suppression of fibrosis and the improvement of ventricular remodeling induced by BMCs transplantation may play important roles in improving cardiac function. Lu et al. [11] have commented that autologous BMMNCs transplantation increased viable myocardium and improved microcirculation of infarcted myocardium. Previous animal studies have suggested that exogenous Shh protein may promote the improvement of cardiac function of CD34+ cells after bone marrow stem cell transplantation [11]. Previous studies have shown that erythropoietin combined with granulocyte-colony-stimulating factor can enhance vascular formation and reduce infarct area after bone marrow stem cell transplantation in myocardial infarction area by increasing endothelial progenitor cell mobilization and up-regulating vascular endothelial growth factor and other microenvironments [11].

Overall, the results of this meta-analysis should be interpreted with caution, especially the results of subgroup analyses, as the number of studies per subgroup is further reduced. Therefore, future meta-analyses must include more studies to obtain significant results.

While the results of this study seem promising for the efficacy of BMSC transplantation, there were also certain limitations: There was significant heterogeneity in the present meta-analysis. Follow-up work in most studies is relatively short, and the continued efficacy of BMSC transplantation in patients treated with CABG remains to be demonstrated.

Based on current evidence, autologous BMSC transplantation in patients receiving CABG appears to be associated with improved LV function, and this improvement is beyond that achieved by CABG alone. BMSC transplantation seems to be beneficial for patients receiving CABG. However, the differences in patients' responses to this treatment require further study. Future research should focus on patient profiling and response to treatment to identify the patient population that could benefit most from this approach and the mechanisms of action of BMSC transplantation.