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.

Table 2 Meta-analysis evaluating left ventricular ejection fraction and other outcomes in chronic, or chronic and acute settings

Ref.	Included studies	Cell type	Pathology	Mean change in LVEF	Other outcomes
Wen et al[119] (2011)	8 RCTs	BMMNCs	CIHD	8.40%	Reduced LVESV
	307 subjects	BM-CD34+	HF	(P < 0.01)	Reduced LVEDV
Zhao et al[120] (2011)	10 RCTs	BM-CD34+/CD133+	CIHD	4.02%	Reduced LVEDV Reduced LVESV
	422 subjects	BMMNCs
		CPCs
Donndorf et al[121] (2011)	6 trials	BMMNCs	CIHD	5.40%	No reduced LVESV
	(4 RCTs and 2 CSs)	BM-CD34+		(P = 0.09)	No reduced MACEs
	179	BM-CD133+
	subjects
Jeevanantham et al[122] (2012)	50 trials (RCTs, CSs)	BMMNCs	AMI	3.96%	Reduced infarct size
	2625	BM-CD133+ and/or BM-CD34+	CIHD	(P < 0.00001)	Reduced LVESV
	subjects	MSCs			Reduced LVEDV
		MSCs and EPCs
Jiang et al[123] (2010)	18 RCTs	BMCs	AMI or CIHD	2.93%	Reduced LVESV
	980 subjects	BMMNCs		(P < 0.00001)	Reduced LVEDV
		MSCs			Reduced infarct area
Cheng et al[124] (2013)	5 RCTs	BMMNCs	Chronic ischemic HF	No significant increase	Increased 6-min walk distance
	210 subjects	SM			Improved MLHF score
					Reduced NYHA class
					No reduce in all-cause mortality
Kandala et al[125] (2013)	10 RCTs	Unselected BMCs	CIHD	4.48%	Reduced LVESV
		Enriched BMCs		(P < 0.0001)	Reduced LVEDV
Sadat et al[126] (2014)	32 trials (24 RCTs and 8 non-RCTs)	BMMNCs	ACS and	4.6 ± 0.7	Improved perfusion
	2306 subjects	BM-CD34+	CAD/HF	(P < 0.05)
		BM-CD133+
		CPCs
		HSCs
		MSCs
Xu et al[127] (2014)	19 RCTs	BMMNCs	CIHD	3.54%	Reduced LVESV
	886 subjects	CD133+		(P < 0.001)	No reduced LVEDV
		CD34+
		Circulating CPCs
		Peripheral blood SCs
Tian et al[128] (2014)	11 RCTs	BMMNCs	CIHD	4.91%	Reduced LVESV
	492 subjects	CD34+		(P < 0.00001)	Reduced LVEDV
		ALDH
		CD133+
Fisher et al[129] (2014)	23 RCTs	BMMNCs	CIHD	2.62%	Reduced mortality
	1255 subjects	CPCs	HF	(P = 0.02, ≥ 12 mo)	Reduced hospitalization HF
		HSCs			(≥ 12 mo)
		MSCs			No effect on mortality, rehospitalization for HF at short term (< 12 mo)
					Reduced LVESV
					Reduced stroke volume index (≥ 12 mo)
					Reduced NYHA class
					Reduced CCS score
Fisher et al[67] (2015)	31 RCTs	BMMNCs	HF	2.06%	Reduced mortality
	1521 subjects	BMMNCs/CPCs		(P < 0.0001)	Reduced rehospitalization for HF
		BM-CD34+			Improved performance status
		MSCs			Improved QOL
		BMMNCs			Reduced BNP
		(enriched CD34+)
		CSCs
		BM-EPCs
		BM-CD133+
		SM
		ALHDs
		ADRCs
Rendon et al[130] (2016)	6	BMMNCs	IHD	No significant increase in LVEF in IHD/HF	Reduced mortality in IHD/HF
	systematic reviews	BM-CD133+ and/or BM-CD34+	AMI		No reduce mortality in AMI
		MSCs	HF
		BM-EPCs
		Peripheral blood-derived cells
		CPCs
		SM
		ALHDs
		ADRCs
		BMMNCs
		(enriched CD34+)
Fisher et al[80] (2016)	38 RCTs	BMMNCs	CIHD	Improvement (MRI analysis)	Reduced mortality
	1907 subjects	MSCs	HF	on short-term	(≥ 12 mo)
		BM-CD133+	Refractory angina	No improvement on long-term	Reduced non-fatal AMI
		BM-CD34+			Reduced arrhythmias risk
		CPC			No reduced rehospitalization
		ALDH			for HF
					No reduced MACE
Fisher et al[81] (2017)	38 RCTs	BMMNCs	CIHD	Improvement (MRI analysis)	Reduced long-term
	1907 subjects	Progenitor cells	HF	on short-term	mortality
			Refractory angina	No improvement on long-term	Reduced refractory angina
					Reduced non-fatal MI
					Reduced arrhythmias
					Reduced rehospitalization for HF/MACE
					No impact on QOL
					Improved exercise capacity at long-term

ACS: Acute coronary syndrome; ADRCs: Adult adipose-derived regenerative cells; ALHDs: Aldehyde dehydrogenase positive stem cells; AMI: Acute myocardial infarction; BM: Bone marrow; BMCs: Bone-marrow derived cells; BM-EPCs: Bone marrow endothelial progenitor cells; BMMNCs: Bone marrow mononuclear cells; CAD: Coronary artery disease; CCS: Canadian Cardiovascular Society grading of angina pectoris; CIHD: Chronic ischemic heart disease; CPCs: Cardiac progenitor cells; CSs: Cohort study; CSCs: Cardiac stem cells; HSCs: Hematopoietic stem cells; HF: Heart failure; LVEDV: Left ventricular end-diastolic volume; LVESV: Left ventricular end-systolic volume; LVEF: Left ventricular ejection fraction; MACE: Major adverse cardiac events; MLHF: Minnesota living with heart failure questionnaire; MSCs: Mesenchymal stem cells; QOL: Quality of life; RCTs: Randomized control trials; SM: Skeletal myoblasts.