Pursuing meaningful end-points for stem cell therapy assessment in ischemic cardiac disease

Table 1 Meta-analysis evaluating left ventricle ejection fraction and other outcomes in acute myocardial infarction settings

Ref.	Included studies	Cell type	Pathology	Mean change in LVEF	Other outcomes
Hristov et al[104] (2007)	5 RCTs	BMMNCs	AMI	4.21%
	482 subjects			(P < 0.00001)
Abdel Latif et al[105] (2007)	18 trials (RCTs/CSs)	BMMNCs	AMI	3.66%	Reduced infarct size
	999 subjects	MSCs		(P < 0.01)	Reduced LVESV
		BM-derived circulating progenitor cells
Lipinski et al[106] (2007)	10 trials (RCTs/CSs)	BMMNCs	AMI	3%	Reduced infarct size
	698 subjects	PMCs		(P < 0.01)	Reduced LVESV
					Reduced recurrent AMI
Martin Rendon et al[107,108] (2008)	13 RCTs	BMMNCs	AMI	2.99%	Reduced LVESV
	811 subjects			(P = 0.0007)	Reduced infarct size
Zhang et al[109] (2009)	7 RCTs	BMMNCs	AMI	4.63%	Reduced LVEDV
	660 subjects			(P = 0.01)	Reduced MACE
Bai et al[110] (2010)	10 RCTs	BMMNCs	AMI	3.79
	814 subjects			(P < 0.01)
Takagi et al[111] (2011)	15 RCTs	BMMNCs	AMI	2.87%	Reduced LVEDV
	877 subjects			(P < 0.00001)	Reduced LVESV
Kuswardhani et al[10] (2011)	10 RCTs	BMMNCs	AMI	2.07%	Reduced LVESV
	906 subjects	Nucleated BMCs		(P = 0.008)	Reduced LVEDV
		BMCs			No reduced mortality
		MSCs			Reduced recurrent MI and
					rehospitalization for HF
Clifford et al[70] (2012)	33 RCTs	BMMNCs	AMI	2.87% maintained at	Reduced LVESV
	1765 subjects	BM-CD34+		12-61 mo	Reduced LVEDV
		BM-CD34+CXCR4+			Reduced infarct size
		MSCs
		BM-CD133+
Zimmet et al[11] (2012)	29 RCTs	BM-CD34+	AMI	2.70%	No reduced LVEDV
	1830 subjects			(P < 0.001)	No reduced LVESV
Chen et al[112] (2013)	5 RCTs	BMMNCs	AMI	4.18%	No reduced LVESV
	510 subjects			(P = 0.0002)	No reduced LVEDV
Jeong et al[113] (2013)	17 RCTs	BMMNCs	AMI	2.51%	Reduced LVESV
	1072 patients			(P = 0.0002)	Reduced LVEDV
Delewi et al[114] (2013)	24 RCTs	BMMNCs	AMI	2.23%	Reduced LVESV at 6 and 12 mo
	1624 subjects	BM-CD133+		(P < 0.01)	Reduced recurrent AMI
		BM-CD134+			Reduced readmission for HF, unstable angina/chest pain
		BM-CD34+/CXCR4			No reduction in infarct size
					No reduction in LVEDV
Jong et al[18] (2014)	30 RCTs	BMMNCs	AMI	2.10%	Reduced LVESV
	2037 subjects	MSCs		(P = 0.004)	Reduced infarct size
		BM progenitor cells			No reduced LVEDV/LVESV (MRI)
					No reduced infarct size (MRI)
					No effect on MACE at 6 mo
Liu et al[115] (2014)	8 RCTs	MSCs	AMI	3.17	A trend toward reduced LVESV
	262 subjects	BM-CD34+		(P = 0.02)	Reduced MACEs
		BM-CD133+
		BM-CD133+ CD34+
Delewi et al[116] (2014)	16 RCTs	BMMNCs	AMI	2.55%	Reduced LVEDV
	1641 subjects	CD34+/CXCR4+		(P < 0.001)	Reduced LVESV
		Nucleated BMCs
Gyöngyösi et al[117] (2015)	12 RCTs	BMMNCs	AMI	No improvement	No impact on MACE
	1252	BM-CD34+CXCR4			No reduction on LVESV/LVEDV
Fisher et al[17] (2015)	41 RCTs	BMMNCs	AMI	No improvement in LVEF measured by MRI;	No reduced MACE
	2732 subjects	BM-CD34+		2%-5% increase by echo, PET CT and LV angiography	No effect on morbidity, quality of life/performance
		BM-CD133+
		MSCs
Cong et al[12] (2015)	17 RCTs	BMMNCs	AMI	2.74%	Reduced LVESV at 3-6 mo
	1393 subjects	BM-CD34+		(P < 0.00001, 3-6 mo)	Reduced WMSI at 3-6 mo
				5.1% (P < 0.00001,
				12 mo)
Lee et al[118] (2016)	43 RCTs	BMMNCs	AMI	2.75%	No reduced infarct size at 6 mo
	2635 subjects	BM-CD133+		(P < 0.001) 6 mo	Reduced infarct size at 1 yr
		BM-CD34+		1.34 % (P = 0.03) at 1 yr	No reduced infarct size at 3 or 5 yr
		MSCs		No reduction at 3 and 5 yr	No reduced mortality at 6 mo and 1 yr
					Reduced all-cause mortality at 5 yr

AMI: Acute myocardial infarction; BM: Bone marrow; BMCs: Bone marrow cells; BMMNCs: Bone marrow mononuclear cells; CSs: Cohort studies; CXCR4: Chemokine receptor type 4; BM-EPC: Bone marrow endothelial progenitor cells; LVEDV: Left ventricular end-diastolic volume; LVEF: Left ventricular ejection fraction; LVESV: Left ventricular end-systolic volume; MACE: Major adverse cardiac events; MSCs: Mesenchymal stem cells; PMCs: Peripheral mononuclear cells; RCTs: Randomized control trials; WMSI: Wall motion score index.