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Introduction

Coronary artery disease (CAD) is a common condition, affecting an estimated 315 million individuals worldwide, with a prevalence of 3,605 cases per 100,000 population in 2022(1). In the USA, the prevalence rate of CAD in 2022 was 4.9% (2). Coronary artery bypass grafting (CABG) is a treatment aimed at revascularizing the coronary arteries. CABG is recommended in several situations, including left main disease with >50% stenosis (3). In a previous study the mortality rates of CABG at 30 days and 1 year were reported to be 3.1 and 7.6%, respectively (4). Notably, the mortality rate of CABG may vary among hospitals.

Currently, stem cell therapy has been shown to be effective in CAD. Of note, two meta-analysis studies found that stem cell therapy significantly improved left ventricular ejection fraction (LVEF) compared with the control (5,6). The LVEF in the stem cell therapy group improved by 3.89-4.8% compared with the control (P=0.003 and P=0.001, respectively). However, the cardiac-related mortality was not significantly different between both groups; risk ratio of 0.78 (95% CI of 0.17, 3.56). Heart failure is a condition that may decrease LVEF or diastolic dysfunction. A previous meta-analysis revealed that stem cell therapy significantly improved LVEF by 6.23% (P<0.0001) in patients with CAD who underwent CABG with heart failure (7). As stem cell therapy may improve LVEF by 5%, patients with CAD treated with CABG may receive benefits from stem cell therapy (8). To the best of our knowledge, there is no previous systematic review evaluating the effects of stem cell therapy in this setting. The aim of this study was to evaluate whether stem cell therapy is effective in patients with CAD who underwent CABG and had no heart failure.

Materials and methods

Purpose

The present research was a systematic review to study whether there was any improvement in cardiac function or mortality in patients with CAD who underwent CABG. This study was exempted from ethical approval by the Ethics Committee of Khon Kaen University (Khon Kaen, Thailand).

Eligibility criteria. Population

The inclusion criteria were studies conducted on whether patients with CAD who underwent CABG, using stem cell therapy from bone marrow, peripheral blood, or muscle and had no heart failure either preserved or reduced LVEF. All studies, regardless of the types of CAD and the types of CABG reported, were included. Any research papers of the following categories: Systematic review, case reports, and case series were excluded.

Intervention and control groups

The intervention group was defined by the use of stem cells; which could be performed before or after the CABG. There was no specification as to what type of stem cell therapy or how the stem cells were introduced to the heart, as well as dosage or numbers of injection. The control group was defined as receiving no stem cells due to sham needles, placebo substance injections, or nothing at all.

Outcomes

The outcomes of interest were cardiac function represented by LVEF and mortality.

Study types

The only study types included in this study were randomized controlled trials (RCTs). Non-randomized trials, observation studies, systematic reviews, and meta-analyses were excluded.

Search strategy

In total, four databases were used for systematic searching; these were PubMed (https://pubmed.ncbi.nlm.nih.gov/), CENTRAL database (https://www.cochranelibrary.com/central/), Scopus (https://www.scopus.com/), and CINAHL Plus (https://www.ebsco.com/). Search terms included ‘coronary artery disease’, ‘coronary artery bypass’, and ‘stem cells’. The full list of search terms is shown in the Appendix. The final search was conducted on October 22, 2022 (9,10).

Selection process

After duplicate removal, initial screening was conducted for irrelevant articles. The initial screening process was performed independently by two authors (TJ and SK). Studies selected by the reviewer were compared and entered into the full-text review process, then full-text reviews and data extraction were performed independently by the two authors (TJ and SK). In the event a final agreement could not be reached, consensus would be made by the third reviewer (KS). A PRISMA flowchart of articles searching and data collection is illustrated in Fig. 1.

Figure 1 PRISMA flowchart for cardiac function and mortality of stem cell therapy in patients with coronary artery disease without heart failure who underwent coronary artery bypasss grafting. EF, ejection fraction; RCT, randomized controlled trial.

Data collection

Data collection included publication characteristics, study characteristics, and outcome characteristics. The publication characteristics contained the first author, year of publication, and the country of origin. The study characteristics were comprised of research design, research duration, inclusion criteria, exclusion criteria, stem cell type, site of injection, stem-cell dosage, and other outcomes of interest. The outcome characteristics were methods of ejection fraction measurement.

Data analysis

There were two groups assessed in the present study: A stem cell therapy group and a control group. Cardiac function was calculated by the standardized mean difference (SMD) of the LVEF from both groups with a 95% confidence interval (CI). Mortality was calculated by the risk ratio of death from both groups with a 95% CI. I2 was used as a formal test of heterogeneity among the results of the included trials. The following guide was used: 0-40% might not be important; 30-60% may represent moderate heterogeneity; 50-90% may represent substantial heterogeneity; and 75-100% may represent considerable heterogeneity (11). A random-effect model was used to perform a meta-analysis. A forest plot was created to show differences between both groups. The analyses were performed by Review Manager 5.4 (The Nordic Cochrane Centre, The Cochrane Collaboration).

Risk of bias

The study quality of RCTs was evaluated using a revised Cochrane risk-of-bias tool for randomized trials Version 2 (RoB 2) (12). The RoB 2 tool was structured into five different domains of bias: Randomization process, deviations from the intended interventions, missing outcome data, measurement of the outcome, and selection of reported results. Judgment of bias can be made from low to some concerns to high. A risk-of-bias analysis was independently performed by two authors (TJ and SK), and discrepancies were verified using the Excel tool to implement RoB 2; in the event an agreement could not be made, the final decision would be made by the third author (KS). This evaluation was separately performed on both outcomes (namely ejection fraction and mortality).

Results

There were 125 studies from a search in four databases related to stem cell therapy in patients with CAD who had undergone CABG treatment, and 118 remained after the removal of duplicated studies. Of these, 50 of those were eligible for a full-text review, and 10 were excluded due to the inclusion of patients with heart failure (two), having no comparison group (three), having no ejection fraction and mortality outcome (three), written in Turkish (one), and not being an RCT (one). Thus, a total of seven studies remained for evaluation (13-19). These were published from 2007-2021 and were mostly conducted in Europe (five studies), two studies were multicentered, and two studies were conducted in Indonesia (Table I). The longest duration for the research was 5 years, with an average duration of 3.29±1.25 years (Table I). Most studies had as inclusion criteria an LVEF of <35% (five out of seven studies) and exhibiting akinetic left ventricular myocardium (five out of seven studies) (Table I). Notably, all included studies used autologous stem cell therapy.

Table I Study characteristics of included studies on stem cell therapy in patients with coronary artery disease without heart failure who underwent CABG.

Table I

Study characteristics of included studies on stem cell therapy in patients with coronary artery disease without heart failure who underwent CABG.

First author, year	Country	Research design	Setting	EF	Research duration	Comparison	Mean age stem cell group	Male/total (%): stem cell group	Mean age control group	Male/total (%) Control group	(Refs.)
Soetisna et al, 2020	Indonesia	Single-blind randomized clinical trial	Age, <70 years; triple vessel disease	<35% (cardiac MRI)	2 years	Stem cell vs. CABG	54.61 (8.07)	12/13 (92.30)	57.46 (6.33)	12/13 (92.30)	(17)
Soetisna, 2021	Indonesia	Randomized trial	Triple vessel disease	<35%	2 years	Stem cell vs. CABG	54.61 (8.07)	12/13 (92.30)	57.46 (6.33)	12/13 (92.30)	(18)
Nasseri et al, 2014	Germany	Randomized, placebo-controlled, and double-blinded trial	NA	<35% (Echo)	4 years	Stem cell vs. Placebo	61.9 (7.3)	28/30 (93.33)	62.7 (10.6)	29/30 (96.67)	(19)
Ang et al, 2008	United Kingdom	Blinded randomized controlled trial (physician and data analyzer blinded)	Post-myocardial infarction (at least one vessel)	NA	5 years	Stem cell vs. CABG	IM, 64.7 (8.7); IC, 62.1 (8.7)	IM, 15/21 (71.4); IC, 19/21 (90.5)	61.3 (8.3)	18/20 (90.0)	(14)
Stamm et al, 2007	Germany	Single-blind randomized clinical trial	Post-myocardial infarction	NA	4 years	Stem cell vs. CABG	62 (10.2)	15/20(75)	63.5 (8.4)	16/20(80)	(13)
Menasché et al, 2008	France, Germany, Belgium, United Kingdom, and Italy	Randomized, placebo-controlled, 3-arm, double-blind trial	Age, 18-80 years; NYHA class I-III	15-35% (Echo)	4 years	Stem cell vs. Placebo	High dose, 59 (53-67) Low dose, 61 (54-70)	High dose; 28/30(93); Low dose, 33/33(100)	61 (55-72)	32/34(94)	(15)
Brickwedel et al, 2014	France, Germany, Belgium, United Kingdom, and Italy	Randomized, placebo-controlled, 3-arm, double-blind trial	Age, 18-80 years; NYHA class I-III; post-myocardial infarction	15-35% (Echo)	2 years	Stem cell vs. Placebo	56.5 (5.1)	4/4(100)	62.0 (6.6)	3/3(100)	(16)

[i] CABG, coronary artery bypass graft; EF, ejection fraction; MRI, magnetic resonance imaging; Echo, echocardiography; NA, not available; IM, intramuscular; IC, intracoronary; NYHA, New York Heart Association.

The most commonly used stem cell therapy was autologous CD133+ cells from the bone marrow (five out of seven studies) (Table II). Additionally, the average injection volume was 14.86±14.32 ml. Cardiac MRI and transthoracic echocardiography were both used for the evaluation of the ejection fraction; the former was used slightly more often (Table II). Almost all studies (six out of seven studies) had both ejection fraction and mortality as an outcome measurement, with the exception of the study by Soetisna (18), which did not include mortality (Table II).

Table II Intervention and outcome measurements of included studies on stem cell therapy in patients with coronary artery disease without heart failure who underwent coronary artery bypass graft.

Table II

Intervention and outcome measurements of included studies on stem cell therapy in patients with coronary artery disease without heart failure who underwent coronary artery bypass graft.

First author, year	Stem cells type	Site of injection	Stem cell dosage	No. of injections	EF measurement method	(Refs.)
Soetisna et al, 2020	Bone marrow CD 133+ cells from the posterior iliac crest	(1) Transepicardial segments (2) Transeptal segments (3) Hypokinetic/hypoperfused segments	0.5 ml of CD 133+ cells	60	Philips Achieva® 1.5T MRI	(17)
Soetisna, 2021	Autologous CD133+ marrow cells	Hypoperfusion area	1 ml	40	1.5 T cardiac MRI	(18)
Nasseri et al, 2014	Autologous CD133+ marrow cells	Intramyocardial	0.5 ml	20	Cardiac MRI	(19)
Ang et al, 2008	Autologous CD133+ bone marrow cells	Intramuscular, intracoronary	500 μl (IM)	20 (IM)	Cardiac MRI	(14)
Stamm et al, 2007	Autologous CD133+ marrow cells	Intramyocardial	0.2 ml	10	Cardiac transthoracic ultrasonography validated with cardiac MRI	(13)
Menasché et al, 2008	Autologous CD 56+ skeletal myoblasts	Intramyocardial	1 ml	30	Transthoracic echocardiography	(15)
Brickwedel et al, 2014	Autologous CD 56+ skeletal myoblasts	Intramyocardial	1 ml	30	Transthoracic echocardiography	(16)

[i] CD, cluster of differentiation; MRI, magnetic resonance imaging; IM, intramuscular.

For the included studies without meta-analysis calculations, a total of seven trials for the LVEF and seven trials for the mortality outcomes are presented in Tables III and IV, respectively. Despite the discrepancies in some characteristics in the research by Soetisna et al (17) and Soetisna (18) (Tables I and II), all the numerical data with regard to baseline values, the number of participants, and the outcomes were similar between studies (Tables III and IV). As aforementioned, since the study by Soetisna (18) did not analyze mortality as an outcome, the dataset from this study was therefore excluded from the meta-analysis. As a result, six trials were included in the evaluation of cardiac function and mortality. Some trials such as Ang et al (14), Menasché et al (15), and Brickwedel et al (16) were a three-arm study; all intervention arms from these trials were compared against their control in the meta-analysis as well (Fig. 2 and Fig. 3).

Figure 2 Forest plot of left ventricular ejection fraction between the stem cell therapy and control groups in patients with coronary artery disease without heart failure who underwent coronary artery bypass graft. Std., standardized; df, degree of freedom; IC, intracoronary; IM intramuscular.

Figure 3 Forest plot of the mortality rate between the stem cell therapy and control groups in patients with coronary artery disease without heart failure who underwent coronary artery bypass graft. Std., standardized; df, degree of freedom; IC, intracoronary; IM intramuscular.

Table III LVEF of included studies on stem cell therapy in patients with coronary artery disease without heart failure who underwent underwent coronary artery bypass graft.

Table III

LVEF of included studies on stem cell therapy in patients with coronary artery disease without heart failure who underwent underwent coronary artery bypass graft.

	Stem cell therapy group				Control group
First author, year	Baseline LVEF (%)	Total (n)	LVEF after treatment (%)	Total (n)	Baseline LVEF (%)	Total (n)	LVEF after treatment (%)	Total (n)	(Refs.)
Soetisna et al, 2020	25.88±5.66	13	Δ 8.69±9.49	13	30.18±3.85	13	Δ 1.43±7.87	13	(17)
Soetisna, 2021	25.88±5.66	13	34.58±11.32	13	30.18±3.85	13	31.62±7.89	13	(18)
Nasseri et al, 2014	27±6	30	31±7	26	26±6	30	33±8	22	(19)
Ang et al, 2008	25.4±8.1 (IM); 28.5±6.5 (IC)	10 (IM) 8 (IC)	29.7±9.1 (IM); 27.3±7.7 (IC)	10 (IM); 8 (IC)	20.9±8.9	7	22.3±5.8	7	(14)
Stamm et al, 2007	37.4±8.4	20	47.1±8.3	20	37.9±10.3	20	41.3±9.1	20	(13)
Menasché et al, 2008	27.08±7.25 (LD); 28.83±7.64 (HD)	28 (LD) 26 (HD)	32.54±9.37 (LD); 33.66±8.92 (HD)	28 (LD); 26 (HD)	29.67±4.49	32	33.50±7.10	32	(15)
Brickwedel et al, 2014	33±1.41 (LD); 29±5.66 (HD)	2 (LD) 2 (HD)	35±8.49 (LD); 32±7.07 (HD)	2 (LD); 2 (HD)	31±4.62	3	25±13.43	3	(16)

[i] LVEF, left ventricular ejection fraction; IM, intramuscular; IC, intracoronary; LD, low dose; HD, high dose.

Table IV Mortality of included studies of stem cell therapy in patients with coronary artery disease without heart failure who underwent underwent coronary artery bypass graft.

Table IV

Mortality of included studies of stem cell therapy in patients with coronary artery disease without heart failure who underwent underwent coronary artery bypass graft.

	Stem cell therapy group		Control group
First author, year	Deceased (n)	Total (n)	Deceased (n)	Total (n)	(Refs.)
Soetisna et al, 2020	2	15	1	14	(17)
Soetisna, 2021	Not stated	Not stated	Not stated	Not stated	(18)
Nasseri et al, 2014	0	28	2	28	(19)
Ang et al, 2008	2 (IC group); 0 (IM group)	21 (IC group); 21 (IM group)	1	20	(14)
Stamm et al, 2007	0	20	0	20	(13)
Menasché et al, 2008	Low dose group, 5; High dose group, 4	Low dose group, 33; High dose group, 30	2	34	(15)
Brickwedel et al, 2014	Low dose group, 0; High dose group, 0	Low dose group, 2; High dose group, 2	0	3	(16)

[i] IC, intracoronary; IM, intramuscular.

Regarding the outcome of cardiac function, which is measured by LVEF, the SMD between the experimental and the control groups was not statistically significant [SMD, 0.17; CI (-0.09, 0.44)], as shown in Fig. 2. The formal test for heterogeneity showed a degree of freedom of 8 (P=0.34) and an I2 of 12% (Fig. 2). The risk ratio of mortality was also not statistically significant [1.59; CI (0.68, 3.73)] (Fig. 3). The formal test for heterogeneity revealed a degree of freedom of 5 (P=0.62) and an I2 of 0% (Fig. 3). Since there was no significant heterogeneity observed, further subgroup analyses were not indicated. In total, five out of six studies had some concerns regarding the overall risk of bias for the LVEF, while one study had a high risk of overall bias for LVEF (Figs. 4 and 5) according to The Cochrane Collaboration's tool for assessing risk of bias in randomized trials (12). In addition, one study in the overall bias evaluation for the mortality outcome had low risk, while the majority (four out of six studies) had some concerns, as shown in Fig. 5.

Figure 4 Bias assessment of included studies on stem cell therapy in patients with coronary artery disease without heart failure who underwent coronary artery bypass graft: Ejection fraction as an outcome.

Figure 5 Bias assessment of included studies on stem cell therapy in patients with coronary artery disease without heart failure who underwent coronary artery bypass graft: Mortality as an outcome.

Discussion

The present meta-analysis determined that stem cell therapy did not significantly improve LVEF and mortality compared with the control treatment (Figs. 2 and 3). These results imply that in patients with CAD who underwent CABG, this therapy may not be beneficial in the patients without heart failure.

Stem cell therapy significantly improved LVEF by several mechanisms, primarily related to cytokines. Stem cells may differentiate into cardiomyocytes and improve cardiomyocyte regeneration, suppress myocardial fibrosis or hypertrophy, and improve angiogenesis of cardiac tissue (6). However, the findings of the present study did not identify significant improvement of LVEF, although the LVEF in the stem cell therapy group nearly reached a significant increase of 0.17%, compared with the control group (Fig. 2). These findings may be due to the small sample size and the low average LVEF (Fig. 2); these two factors may require larger differences of LVEF to be statistically significant.

As previously reported (6), stem cell therapy did not significantly improve mortality compared with the control group (4.76% vs. 5.88%; risk ratio, 0.78; 95% CI, 0.17, 3.56). By contrast, the present study had a higher mortality rate in the stem-cell therapy group than the control with a risk ratio of 1.59 and a 95% CI of 0.68-3.73, as shown in Fig. 3. These differences may be attributed to two factors: First, the mortality of patients undergoing CABG may vary depending on the hospital and the expertise of the surgeon (4); second, several factors, such as age or comorbidities, may also influence the mortality of patients with CAD who undergo CABG (20-22).

Overall, the studies that were included had limited and small sample sizes, which may have reduced the power to detect significant differences between the stem cell therapy and control treatment. Although stem cell therapy may be beneficial, the sample size in each study was generally small probably due to the high cost and difficult preparation of stem cells, particularly those from bone marrow (23). Previous systematic reviews revealed that most included studies had a sample size between 20 and 40 patients per study (5-7).

There are several potential reasons for the lack of significant improvement in LVEF and mortality in the present study, other than the small sample size. As there are varied stem cell therapy regimens in terms of timing, dosage, or type of stem cell therapy, these factors may have affected both study outcomes. Only one study (13) showed significant improvement in LVEF (Fig. 2), while none of the studies included reported favorable outcomes concerning mortality (Fig. 3). Of note the study by Stamm et al (13) used 0.2 ml of stem cells with 10 injections in intramyocardial areas (13). Additionally, patients with CAD who did not have heart failure may survive longer than those with heart failure. Previous research revealed that patients with CAD and heart failure had a 48.7% survival rate at 720 days (24,25). To achieve statistical significance in patients without heart failure, a long follow-up duration and a large sample size may be required. Similarly, left ventricular function in patients without heart failure may not reveal marked improvement.

There were some limitations in the present study. First, broad inclusion criteria were used to reduce selection bias, resulting in variations in stem cell therapy, including dosage, number of injections, sites of injection, and type of stem cell therapy employed. Therefore, the results of the present study may not be specific to any particular stem cell therapy. Currently, factors such as dosage and the source of stem cells for CAD treatment remain uncertain (26). Second, the included studies were limited and had a small sample size. Additionally, as five studies were conducted in Europe and two studies were conducted in Indonesia, evaluating racial differences in this systematic review was challenging; future additional RCTs in diverse settings are required to update the meta-analysis for both outcomes. Finally, personal factors such as hypertension and obstructive sleep apnea were not evaluated (27-29), nor was any other intervention implemented (30,31).

In conclusion, stem cell therapy did not exert significant improvement of LVEF or the mortality rate compared with the control in patients with CAD who underwent CABG and did not have heart failure. Further studies are required to confirm the findings of the present study and to provide greater insights into the potential benefits of stem cell therapy by investigating other patient subgroups or different stem cell therapy protocols.

Supplementary Material

Searching method for PubMed, Central, Scopus and CINAHL (on October 22, 2022).

Acknowledgements

The authors would like to thank Dr Chetta Ngamjarus, Khon Kaen University (Khon Kaen, Thailand) for assistance in the literature search.

Funding

Funding: No funding was received.

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

TJ, SK, and KS designed the study, collected and analyzed the data, and wrote the manuscript. TJ and SK confirm the authenticity of all the raw data. All authors read and approved the final version of the manuscript.

Ethical approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References