Intramyocardial Stem Cell Transplantation during Coronary Artery Bypass Surgery Safely Improves Cardiac Function: Meta-Analysis of 20 Randomized Clinical Trials

Abstract

IMSC transplantation during CABG is considered one of the most promising methods to effectively deliver stem cells and has been widely studied in many trials. But the results of outcomes and safety of this modality still vary widely. We conducted this meta-analysis of randomized controlled trials (RCTs) to evaluate not only the outcome but also the safety of this promising method. A meta-analysis was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. A comprehensive literature search was undertaken using the PubMed, Scopus, and Cochrane databases. Articles were thoroughly evaluated and analyzed. Twenty publications about IMSC during CABG were included. Primary outcomes were measured using LVEF, LVESV, LVESVI, LVESD, LVEDV, LVEDVI, LVEDD, WMSI, and 6-MWT. Safety measures were depicted by total deaths, MACE, CRD, CVA, myocardial infarction, ventricular arrhythmia, and cardiac-related readmission. IMSC transplantation during CABG significantly improved LVEF (MD = 3.89%; 95% CI = 1.31% to 6.46%; p = 0.003) and WMSI (MD = 0.28; 95% CI = 0.01-0.56; p = 0.04). Most of the other outcomes showed favorable results for the IMSC group but were not statistically significant. The safety analysis also showed no significant risk difference for IMSC transplantation compared to CABG alone. IMSC during CABG can safely improve cardiac function and tend to improve cardiac volumes and dimensions. The analysis and application of influencing factors that increase patients' responses to IMSC transplantation are important to achieve long-term improvement.

Keywords: coronary artery bypass; intramyocardial; ischemic heart disease; outcome; safety; stem cell.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines flowchart.

Figure 2

Forest plot of LVEF change (%) difference between ISMC and control group [3,4,8,9,10,18,19,20,21,23,24,25,26,27,28,29,30,31,32].

Figure 3

Forest plot of WMSI change difference between ISMC and control group [3,23,26].

Figure 4

Forest plot of LVESV (mL) change difference between ISMC and control group [3,4,18,19,20,23,24,25,31].

Figure 5

Forest plot of LVESVI change difference between ISMC and control group [8,19,29,32].

Figure 6

Forest plot of LVESD (mm) change difference between ISMC and control group [27,31].

Figure 7

Forest plot of LVEDV (mL) change difference between ISMC and control group [3,4,18,19,20,23,24,25,28,30,31].

Figure 8

Forest plot of LVEDVI change difference between ISMC and control group [8,19,29,32].

Figure 9

Forest plot of LVEDD (mm) change difference between ISMC and control group [27,28,31].

Figure 10

Forest plot of 6-MWT change difference between ISMC and control group [3,19,22,28,32].

Figure 11

Forest plot of total death incidence difference between ISMC and control group [3,4,10,11,18,19,20,21,25,26,27,28,29,30,31,32].

Figure 12

Forest plot of MACE incidence difference between ISMC and control group [3,4,8,9,10,18,19,20,21,23,24,25,26,27,28,29,30,31,32].

Figure 13

Forest plot of myocardial infarct incidence difference between ISMC and control group [3,4,10,11,18,19,20,21,23,25,26,27,28,29,30,31,32].

Figure 14

Forest plot of cerebrovascular incidence difference between ISMC and control group [4,19,20,21,23,25,27,28,29,30,32].

Figure 15

Forest plot of cardiac-related death incidence difference between ISMC and control group [3,4,8,9,10,18,19,21,25,26,27,28,29,30,31,32].

Figure 16

Forest plot of cardiac-related readmission incidence difference between ISMC and control group [4,18,25].

Figure 17

Forest plot of ventricular arrhythmia incidence difference between ISMC and control group [3,4,8,18,19,20,23,24,25,27,28,30,31].

Figure 18

Results of RoB2 assessment. (A) Risk of bias summary: review authors’ judgments about each risk of bias item for each included study using RoB2 for randomized studies. (B) Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies using RoB2 for randomized studies [3,4,8,9,10,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32].

Figure 19

How IMSC transplantation improves patient’s outcomes. Transplanted stem cells can directly differentiate into many kinds of tissues, including cardiomyocytes and endothelial cells [3,9,21,26,27]. This in turn supports myocardial tissue and vasculature repair [3,9,21,26,27]. The transplanted stem cells also release cytokines that exert paracrine effects [3,25,26,27,30,31,32]. Paracrine effects on damaged but viable and hibernating myocardial tissue lead to tissue repair and remodeling attenuation, resulting in LV reverse remodeling [26,30]. This is supported by the paracrine effect on cardiac vessels, which stimulates vasculature repair and angiogenesis, increasing myocardial tissue perfusion and ensuring continuous LV reverse remodeling [3,27,31]. All of these mechanisms together will lead to global LV function improvement, which will result in an overall improvement of patients’ outcomes.