Present and future of stem cells for cardiovascular therapy

Figures & data

Figure 1 The most used adult stem cell sources in clinical trials have been skeletal myoblasts(top) and mononuclear bone marrow (bottom) stem cells.

Table I. Flow cytometry surface expression profile of the different bone marrow cell types used in clinical practice.

Antigen	CD 34	CD 117	CD 133	Mononuclear	Mesenchymal
CD 3	−	−		+	−
CD 14	−	−		+	−
CD 19	−	−		+	−
CD 29	−	−		+	++
CD 34	++	+	+	+	−
CD 44				+	++
CD 45	+	+	+	+	−
CD 56				+	−
CD 90				+	++
CD 105					+
CD 106					+
CD 117	+	++	+	+	−
CD 133	+	+	++	+	−
HLA‐II	+	+	+	+	−

++ Markers positive in the majority of cells; + Markers positive in some cells; − Markers expressed in less than 2% of cells.

Table II. Cell therapy clinical trials in humans after acute myocardial infarction.

Author	Design ^a and groups	Dose	LVEF (%) ^b		Timing ^c	F‐U ^d	Results
			Baseline	F‐U
Strauer 42, 43	Phase I				5–9	3	Cell‐treated: ↓ infarct size and ↑ contractility of infarcted area.
	i.c. BMMC (10 p.)	2.8±2.2×10^7	57±8	62±10
	NR control (10 p.)	No placebo	60±7	64±7
Assmus 44, 45	Phase I				5±2	4, 12	Both types of cells: ↑ LVEF, ↓ ESV, infarct size reduction and absence of reactive hypertrophy. Sustained benefits at 12‐month F‐U.
	i.c. BMMC (29 p.)	1.6±1.2×10^7	51±10	59±10
	i.c. CPC (30 p.)	21.3±7.5×10^7	49±10	57±10
	NR control (11 p.)	No placebo	51±10	54±8
Chen 46	Phase II				18	6	Cell‐treated: ↑ LVEF, ↓ ESV and EDV, ↑ perfusion and contractility of infarcted area.
	i.c. MSC (34 p.)	4.8–6.0×10^10	49±9	67±3
	R control (35 p.)	Standard saline	48±10	54±5
Kuethe 47	Phase I				6	12	No changes in LVEF and contractility of infarcted area.
	i.c. BMMC (5 p.)	3.9±2.3×10^7	42±8	46±7
Fernández‐Avilés 15, 48	Phase I				14±6	6	Cell‐treated: ↑ LVEF, ↓ ESV, ↑ contractility and thickness of infarcted wall.
	i.c. BMMC (20 p.)	7.8±4.1×10^7	51±7	57±10
	NR control (13 p.)	No placebo	50±7	52±7
Wollert 49, 50	Phase II				6±1	18	Cell‐treated: acceleration of systolic function recovery (6‐month F‐U: ↑ LVEF, ↑ regional contractility), no difference with controls at long term.
	i.c. BMNC (30 p.)	246±94×10^7	50±10	56±15
	R control (30 p.)	No placebo	51±9	54±13
Bartunek 36	Phase I				12±1	4	Cell‐treated: ↑ LVEF, ↓ ESV, ↑ perfusion and contractility of infarcted area. Besides, ↑ incidence of coronary events, ISR, de novo lesions.
	i.c. CD133+(19 p.)	1.3±0.2×10^7	45±3	52±4
	NR control (16 p.)	No placebo	44±3	49±4
Katritsis 51	Phase I				8–1,560	4	Recent AMI cell‐treated patients: ↑ regional contractility, viability, and reversible ischemia.
	i.c. MSC+EPC (11 p., 6 of them with recent AMI)	2–4×10^6 e	40±9	41±10
	NR control (11 p.)	No placebo	42±11	42±10
Ge 52	Phase II, double‐blinded				0–1	6	Cell‐treated: ↑ LVEF, ↑ regional perfusion. Left ventricular dilatation in controls.
	i.c. BMMC (10 p.)	4×10^7	54±9	59±10
	R control (10 p.)	Placebo	58±8	56±4
Janssens 53	Phase II, double‐blinded				2	4	Cell‐treated: ↑ perfusion and contractility of infarcted area. No difference in LVEF recovery.
	i.c. BMMC (33 p.)	172±72×10^6	49±7	52±9
	R control (34 p.)	Placebo	47±8	49±11
Lunde 27	Phase II				5–8	6	No changes in LVEF assessed by 3 methods (MRI, SPECT, 2D‐echo).
	i.c. BMMC (50 p.)	87±47×10^6	55±14	56±15
	R control (50 p.)	No placebo	54±12	58±11
Schächinger 26, 54	Phase II, double‐blinded				3–6	4	↑ LVEF and contractility of infarcted area, ↓ combined end point: death, reinfarction, and rehospitalization.
	i.c. BMMC (101 p.)	236±174×10^6	48±9	54±10
	R control (103 p.)	Placebo	47±10	50±13
Kuethe 55, 56	Phase I				2 (for 7±1 days)	3	G‐CSF group: ↑ perfusion and contractility of infarcted area; Both groups: ↑ LVEF.
	G‐CSF (14 p.)	10 µg/kg/d	40±11	48±13
	NR control (9 p.)	No placebo	40±13	43±13
Valgimigli 57	Phase I, single‐blinded				2±3 (for 4 days)	6	Nonsignificant trend in treated patients to ↑ LVEF and ↓ EDV.
	G‐CSF sc. (10 p.)	5 µg/kg/d	NA	NA ^f
	R control (10 p.)	Placebo	NA	NA
Suárez de Lezo 58	Phase I				5 (for 10 days)	3	↑ Contractility of infarcted area; spontaneous spleen rupture on day 8 on G‐CSF (1 p.).
	G‐CSF sc. (13 p.)	10 µg/kg/d	40±7	46±15
Ince 38, 59	Phase II				<1 (for 6 days)	4, 12	G‐CSF group: ↑ LVEF, perfusion, thickness, and contractility of infarcted wall.
	G‐CSF sc. (25 p.)	10 µg/kg/d	48±4	54±8
	R control (25 p.)	No placebo	47±5	43±5
Jorgensen 29, 60	Phase II, double‐blinded				1–2 (for 6 days)	6	No differences in LVEF, volumes, ventricular mass, and systolic thickening between groups. No neointimal hyperplasia with G‐CSF.
	G‐CSF sc. (39 p.)	10 µg/kg/d	51±15	60 ^g
	R control (39 p.)	Placebo	56±10	64
Zohlnhöfer 30	Phase II, double‐blinded				5 (for 5 days)	4, 6	No differences in LVEF, volumes, and perfusion between groups.
	G‐CSF sc. (56 p.)	10 µg/kg/d	51±8	52±8
	R control (58 p.)	Placebo	49±9	51±9
Engelmann 32	Phase II, double‐blinded				0–7 (for 5 days)	3	G‐CSF group: ↑ perfusion in infarcted area at 1‐month follow‐up. No differences in LVEF and volumes between groups.
	G‐CSF sc. (23 p.)	10 µg/kg/d	41±12	47±12
	R control (21 p.)	Placebo	44±9	50±12
Ellis 31	Phase II double‐blinded				<2 (for 5 days)	1	No differences in LVEF, regional contractility, volumes, and infarct wall thickness between groups.
	G‐CSF 10 µg/kg/d (6 p.)	10 µg/kg/d	37±8	39±7
	G‐CSF 5 µg/kg/d (6 p.)	5 µg/kg/d	42±8	34±5
	R control (6 p.)	Placebo	34±2	41±10
Kang 37, 39	Phase II				4—6 (G‐CSF for 4 days) ^h	6	Combined treatment group: ↑ LVEF, ↓ EDV, ↑ perfusion of infarcted area, ↑ exercise capacity. Study prematurely stopped due to high rate of in‐stent restenosis (G‐CSF groups).
	G‐CSF sc.+i.c. CPC (7 p.)	10 µg/kg/d	49±9	55±7
	G‐CSF sc. (3 p.)	CPC: 100×10^7	45±14	44±16
	R control (2 p.)	No placebo	40±9	NA
Kang 61	Phase II				7±1 (G‐CSF for 3 days) ^i	6	Recent AMI cell‐treated patients: ↑ LVEF, ↓ ESV.
	G‐CSF sc.+i.c. CPC (25 p.)	10 µg/kg/d	52±10	57±9
		CPC: >7×10^6
	R control (25 p.)	No placebo	53±13	53±12
Steinwender 62	Phase I				6—8 (G‐CSF for 4–6 days) ^k	6	↑ LVEF and regional contractility. High incidence of ISR and reinfarction.
	G‐CSF sc.+i.c. CPC (20 p.)	10 µg/kg/d and CPC ^j	46±8	54±11

Values are mean±standard deviation or range. LVEF = left ventricular ejection fraction; F‐U = follow‐up; BMMC = bone marrow mononuclear cells; BMNC = bone marrow‐nucleated cells; G‐CSF = granulocyte colony‐stimulating factor; NR control = nonrandomized control group; R control = randomized control group; CPC = circulating progenitor cells; ESV = end‐systolic volume; EDV = end‐diastolic volume; MSC = mesenchymal stem cells; AMI = acute myocardial infarction; MRI = magnetic resonance imaging; SPECT = single photon emission computerized tomography; 2D‐echo = two‐dimensional echocardiography; ISR = in‐stent restenosis; sc. = subcutaneous administration; i.c. = intracoronary administration; p. = patients; NA = not available; NS = no significant; PCI = percutaneous coronary intervention.

^a All studies were open label unless stated otherwise.

^b LVEF data showed in the table were calculated or measured by left ventricular angiography 26, 36, 42–47, 54, 58, 62, 2‐dimensional echocardiography 31, 38, 52, 59, radionuclide ventriculography 51, 55, 56, cardiac magnetic resonance 15, 27, 30, 49, 50, 53, 60, 61, and gated‐SPECT 37, 57.

^c Timing indicates the number of days from the onset of symptoms to the administration of the treatment (and its duration in the case of G‐CSF).

^d F‐U indicates the number of months from treatment administration to follow‐up imaging assessment.

^e Including mesenchymal stem cells (66±19%) and endothelial progenitor cells (28±11%).

^f Only relative changes of LVEF at 6‐month follow‐up were reported; no significant differences were found between G‐CSF patients and controls.

^g Absolute changes in LVEF reported (8.5% and 8% in G‐CSF and control group respectively; P = NS), standard deviation not mentioned at follow‐up.

^h Cell transplantation was carried out immediately after G‐CSF completion (10 µg/kg/d for 4 days prior to stent implant) and PCI‐stenting.

ⁱ G‐CSF treatment (10 µg/kg/d for 3 days) started after successful PCI (7±1 days postinfarction); cell transplantation was carried out immediately after G‐CSF completion.

^j CPC obtained by apheresis included 49±37×10⁶ CD34+ cells.

^k G‐CSF treatment for 5.5±1.2 days was initiated 2 days after the onset of symptoms; intracoronary transplantation of progenitors collected by apheresis was carried out immediately after C‐CSF completion.

Table III. Clinical trials with direct intramyocardial stem cell injection in humans with chronic ischemic heart disease.

Author	Type of patients (n)	Timing (months)	Cell type and dose ^a	Delivery method	LVEF (%)		Results
					Baseline	F‐U
Menasché and Hagege 8, 63	ICM, OMI, and indication for CABG in remote reas (10 p.)	3–229	Myoblasts 871±62×10^6 (86%)	TEP ^b	24±1	32±1	At 11±5 months of F‐U: ↑ LVEF ^c and systolic thickening. NYHA functional class improvement. 4 cases with delayed SVT (ICD).
Herreros and Gavira 34, 64	ICM, OMI, and indication or CABG in remote areas (11 p.)	3–168	Myoblasts 221±100×10^6 (66%)	TEP	36±2	54±5	At 3 and 12 months of F‐U: ↑ LVEF, regional contractility, and viability.^d
	Historical NR control (14 p.)
Siminiak 65	ICM, OMI, and indication for CABG in remote areas (10 p.)	4–108	Myoblasts 0.4–50×10^6 (65%)	TEP	35 (25–40) ^e	42 (29–47) ^e	At 12 months of F‐U: ↑ LVEF and regional contractility. SVT in 2 patients, controlled with amiodarone.
Cachques 66	ICM, OMI, and indication for CABG in remote areas (20 p.)	NA	Myoblasts 300±20×10^6 (>70%)	TEP	28±3	52±5	At 6 months of F‐U: ↑ LVEF, regional contractility, and viability.
Dib 67	ICM, OMI, and indication for CABG (24 p.), or for LVAD (6 p.) ^f	NA	Myoblasts Escalating dose (1, 3, 10, 30×10^7) (79%) ^g	TEP	28±9	36±11	At 24 months of F‐U: ↑ LVEF, ↑ viability, ↓ LV volumes. NYHA functional class improvement. Delayed episodes of NSVT in 3 patients (ICD implanted).
Stamm 68, 69	Recent MI and indication for CABG (12 p.)	0.6–3	CD133+ escalating dose (0.12–5×10^6)	TEP	40±9	49±6	At 2 weeks of F‐U: ↑ LVEF and perfusion, ↓ LV volumes. NYHA functional class improvement.^h
Mocini 70	Recent MI and indication for CABG in remote areas (18 p.)	1–6	BMMC (292±232×10^6)	TEP	46±6	51±9	At 3 months of F‐U: ↑ LVEF and regional contractility when compared to controls.
	NR control (18 p.)
Patel 71	Phase II trial, single‐blinded.	NA ^i	CD34+ (22×10^6)	TEP	29±4	46±2	At 6 months of F‐U: ↑ LVEF and NYHA functional class improvement.^d
	ICM, symptomatic HF, and indication for CABG in remote areas (10 p.)
	R control (10 p.)
Archundia 72	ICM, OMI and symptomatic HF (5 p.)	13–19	CPC (400×10^6) ^j	TEP	38–45	55–60	At 7 months of F‐U: ↑ LVEF, perfusion, and systolic thickening of infarcted area, ↓ LV volumes in treated patients.
	NR control (10 p.)
Galinanes 73	OMI and indication for CABG in remote areas due to angina (14 p.)	23±17	BMMC (32±4×10^6 per segment) ^k	TEP	47±4	48±4	At 10 months of F‐U: NYHA and Canadian functional class improvements, ↑ contractile reserve and WMSI whenever CABG and cell injection were combined.
Hamano and Li 74, 75	Severe ischemic heart disease with indication for CABG and ungraftable area/s (5 p.)	NA	BMMC (30‐200×10^7)	TEP	NA	NA	At 6 months of F‐U: ↑ perfusion in treated area in 3 of the 5 patients. Safety proven at 1 year of F‐U.
Ozbaran 76	HF and ICM not suitable for CABG (6 p.)	NA	CPC (5–64×10^9) ^j	TEP+i.c.	21±3	28±10	At 4 months: increase in life quality and NYHA functional class.
Pompilio 77	Ischemia not suitable for standard revascularization or recent MI with indication for CABG in remote areas (4 p.)	NA	CD133+ (13–200×10^6) ^l	TEP	NA	NA	Safety of this strategy proven.
Siminiak 78	ICM, OMI, and symptomatic HF (10 p.)	5–96	Myoblasts 17–106×10^6 (>65%)	Transcoronary venous ^m	40±7	43±8	At 6 months of F‐U: ↑ LVEF in 66% of the patients. NYHA functional class improvement. SVT in 1 p. with ICD previously implanted.
Smits 79	ICM, OMI, and symptomatic HF (5 p.)	24–132	Myoblasts 196±105×10^6 (55%)	TEND ^n	36±11	45±8	At 6 months of F‐U: ↑LVEF, contractility, and systolic thickening of infarcted area. NSVT in 1 patient (ICD implanted).
Ince 80	ICM, OMI, and symptomatic HF (6 p.).	79±59	Myoblasts 210±150×10^6 (70%)	TEND ^o	24±7	32±10	^p At 12 months of F‐U: ↑ LVEF, contractility, and contractile reserve of infarcted area. NYHA functional class improvement. SVT episodes in 2 p. with ICD previously implanted.
	NR control (6 p.)
Perin 81, 82	ICM, OMI, and symptomatic HF with no option for conventional revascularization (14 p.)	>3	BMMC (26±6×10^6)	TEND ^n	30±6	36±8	At 4 and 12 months of F‐U: ↑ contractility and perfusion of infarcted area, and NYHA and Canadian functional class improvement. Sudden cardiac death (1 p.) at 14 weeks of F‐U.
	NR control (7 p.)
Silva 83	ICM, OMI, and HF with no option for conventional revascularization awaiting cardiac transplantation (5 p.)	NA	BMMC (30×10^6)	TEND ^n	30±8	28±12	At 6 months of F‐U: ↑ myocardial volume oxygen consumption and exercise capacity, and 4 of the 5 patients were no longer eligible for cardiac transplantation.
Tse 84, 85	Refractory stable angina (8 p.)	NA	BMMC (dose NA)	TEND ^n	58±11	61±15	At 3 months of F‐U: ↑ contractility, perfusion, and thickening of treated area. Symptomatic improvement. Safety proven at very long term.^q
Fuchs 86, 87	Refractory stable angina with no option for conventional revascularization (27 p.)	NA	BMMC (67±65×10^6)	TEND ^n	48±9	50±7	At 3 and 12 months of F‐U: ↑ exercise capacity, ↓ angina score, and ↓ stress‐induced ischemia in treated areas.
Briguori 88	Refractory stable angina with no option for conventional revascularization (10 p.)	NA	BMNC (127–350×10^6)	TEND ^r	53±10	57±16	At 12 months of F‐U: ↑ perfusion, improvement in the physical limitation, angina frequency, angina stability scores.

All studies mentioned are open label phase I trials unless stated otherwise. Timing indicates the number of months from myocardial infarction to the administration of cell therapy; delivery method is shown as TEP (transepicardial injection), TEND (transendocardial injection), transcoronary venous approach, and i.c. (intracoronary). LVEF indicates left ventricular ejection fraction, and data showed in the table were calculated or measured by left ventricular angiography 79, 2‐dimensional echocardiography 8, 34, 63–65, 67–73, 76, 78, 80–85, radionuclide ventriculography 66, and cardiac magnetic resonance 86, 87.

F‐U = follow‐up; ICM = ischemic cardiomyopathy; OMI = old myocardial infarction; HF = heart failure; CABG = coronary artery bypass graft; LVAD = left ventricular assist device; NR control = nonrandomized control group; p. = patients; SVT = sustained ventricular tachycardia; NSVT = nonsustained ventricular tachycardia; ICD = implantable cardioverter defibrillator; LV = left ventricular; BMMC = bone marrow mononuclear cells; BMNC = bone marrow‐nucleated cells; G‐CSF = granulocyte colony‐stimulating factor; CPC = circulating progenitor cells; MI = myocardial infarction; NA = not available; NYHA = New York Heart Association; WMSI = Wall Motion Systolic Index.

^a Values are mean dose±standard deviation or range or escalating dose as indicated; in the case of studies using myoblasts, the mean percentage of myoblasts injected is shown between parentheses.

^b Unique study of transepicardial injection of myoblasts during CABG in which the grafted scar was not bypassed.

^c Sustained benefit at long‐term follow‐up (median time 52 months).

^d Significant benefit when compared to control group of isolated CABG patients.

^e Mean LVEF (and range).

^f As a bridge to heart transplantation.

^g Cell dose in LVAD group was 30×10⁷, except for 1 patient, who received only 2.2×10⁶ cells.

^h Sustained benefit more than 1 year afterwards in 5 patients.

ⁱ 90% of treated patients had previous myocardial infarction.

^j Circulating progenitor cells obtained by apheresis after stimulation with G‐CSF.

^k Including 0.6±0.1×10⁶ CD34+/CD117+ cells/segment.

^l Circulating progenitor cells obtained by apheresis after stimulation with Hematopoietic Growth Factor Lanogastrim.

^m TransAccess (TransVascular Inc.) catheter system.

ⁿ Guided by electromechanical mapping with NOGA catheter system (Biosense‐Webster).

^o MyoCath injection catheter system (Bioheart).

^p Significant improvements at follow‐up versus baseline and versus controls.

^q Mean follow‐up of 44±10 months in 12 patients.

^r Guided by electromechanical mapping with NOGA catheter system and performed with percutaneous injection using a MYOSTAR injection catheter (Biosense Webster).

Table IV. Clinical trials with intracoronary administration and/or intravascular mobilization of stem cells in humans with chronic ischemic heart disease.

Author	Design ^a and groups	Dose	LVEF (%) ^b		Timing ^c	F‐U ^d	Results
			Baseline	F‐U
Kuethe 89	Phase I				16±6	3, 12	No changes in LVEF, regional contractility, microvascular function, and peak oxygen uptake at F‐U.
	i.c. BMMC (5 p.)	29±9×10^6	29±8	34±8
Strauer 90	Phase I				27±31 (5–102)	3	Cell‐treated group: ↑ LVEF, contractility, and perfusion of infarcted area.
	i.c. BMMC (18 p.)	90×10^6	52±9	60±7
	NR control (18 p.)	No placebo	51±10	52±10
Katritsis 51	Phase I				0.2–52	4	OMI cell‐treated patients: ↑ reversible ischemia in treated area.
	i.c. MSC+EPC (11 p., 5 of them with OMI)	2–4×10^6 e	40±9	41±10
	NR control (11 p.)	No placebo	42±11	42±10
Blatt 91	Phase I				58±2 (12–120)	4	NYHA functional class improvement. In hibernating segments also ↑ regional contractility and contractile reserve.
	i.c. BMNC (6 p.) ^f	13–65×10^8	25±7	28±8
Assmus 33	Phase II				>3 (3–300)	3	BMC‐treated patients: ↑ LVEF and contractility of treated area, also in a crossover phase.
	i.c. BMMC (28 p.)	205±110×10^6	41±11	43±10
	i.c. CPC (24 p.)	22±10×10^6	39±10	39±10
	R control (23 p.)	No placebo	43±13	42±13
Erbs 92	Phase II, double‐blinded				8±3^g	3	Cell‐treated group: ↑ LVEF, contractility, and perfusion of treated area, and improvement of microvascular function.
	G‐CSF sc.+i.c. CPC (13 p.)	G‐CSF 300 µg/d for 4 days and CPC: 69±14×10^6	52±4	59±3
	R control (13 p.)	Placebo	56±3	56±3
Kang 61	Phase II				17±17 ^h	6	OMI cell‐treated patients showed microvascular function improvement. No changes in LVEF or LV dimensions.
	G‐CSF sc.+i.c. CPC (16 p.)	10 µg/kg/d for 3 days and CPC (>7×10^6)	49±13	49±13
	R control (16 p.)	No placebo	45±10	45±11
Seiler 93	Phase II, double‐blinded				NA ^i	0.5	GM‐CSF group improved collateral flow.
	GM‐CSF sc. (10 p.)	10 µg/kg/48h	65±10	NA
	R control (11 p.)	Placebo	58±18	NA
Wang 94	Phase I				NA	2	G‐CSF group: ↓ nitroglycerin consumption, angina attacks. No effect on perfusion or LVEF.
	G‐CSF sc. (13 p.)	5 µg/kg/d for 6 days	48±10	44±12
	NR control (16 p.)	No placebo	46±11	43±20
Hill 95	Phase I				NA	1	2 patients presented serious coronary events after treatment. No positive effect on regional perfusion, contractility, or exercise capacity.
	G‐CSF sc. (16 p.)	10 µg/kg/d for 5 days	52±3	51±3
Joseph 96	Phase I				NA	9	The increase in LVEF was significant in the 4 patients with ischemic cardiomyopathy.
	G‐CSF sc. (6 p.)	5 µg/kg/d for 5 days	19±2 ^j	25±4 ^j

References 33, 51, 61, 89, 90 and 92 included patients with old myocardial infarction and chronic total coronary occlusion, respectively, and patent culprit artery when undergoing stem cell therapy; reference 91 included patients with ischemic cardiomyopathy, symptomatic heart failure, and no options for conventional revascularization; reference 93 included patients with stable coronary artery disease not eligible for or unwilling to undergo bypass surgery (patients with previous myocardial infarction or systolic dysfunction were excluded); reference 94 and 95 included patients with coronary artery disease, severe stable angina, and reproducible ischemia on stress test, not suitable for conventional revascularization and/or unwilling to undergo bypass surgery, respectively; finally, reference 96 included patients with advanced chronic heart failure.

Values are mean±standard deviation or range. LVEF = left ventricular ejection fraction; F‐U = follow‐up; BMMC = bone marrow mononuclear cells; BMNC = bone marrow‐nucleated cells; G‐CSF = granulocyte colony‐stimulating factor; GM‐CSF = granulocyte‐macrophage colony‐stimulating factor; NR control = nonrandomized control group; R control = randomized control group; CPC = circulating progenitor cells; MSC = mesenchymal stem cells; OMI = old myocardial infarction; sc. = subcutaneous administration; i.c. = intracoronary administration; p. = patients; NA = not available.

^a All studies were open label unless stated otherwise.

^b LVEF data showed in the table were calculated or measured by left ventricular angiography 90, 92, 93, 2‐dimensional echocardiography 89, 91, 96, radionuclide ventriculography 51, cardiac magnetic resonance 33, 61, 95, and gated‐SPECT 94.

^c Timing indicates the number of months from myocardial infarction to the administration of the treatment.

^d F‐U indicates the number of months from treatment administration to follow‐up imaging assessment.

^e Including mesenchymal stem cells (66±19%) and endothelial progenitor cells (28±11%).

^f with preconditioning of treated areas by means of induction of previous short ischemia.

^g CPC were intracoronarily infused after recanalization of coronaries with chronic coronary occlusion for 8±3 months.

^h Cell transplantation was carried out immediately after G‐CSF completion.

ⁱ Cell‐therapy trial aimed at assessing the effect of GM‐CSF treatment on angiogenesis, patients with previous myocardial infarction or systolic dysfunction were excluded.

^j LVEF data from the 4 patients with ischemic cardiomyopathy.

Figure 2 The principal differences between cardiovascular stem cell therapy clinical studies have been the type of patients studied, the type of cell used, the delivery approach, and the method of measurement. Three different clinical scenarios have been investigated to date: acute myocardial infarction, myocardial ischemia without revascularization possibilities, and ischemic cardiomyopathy with a depressed contractile function. The type of stem cell used could be classified in two groups: those bone marrow‐derived and myoblast. In conditions where reperfusion is the primary objective or chronic ischemia prevails, the angiogenic potential of bone marrow‐derived may be of high priority. In contrast, in patients where additional restoration of contractile function is the clinical goal, delivering cells with contractile potential like myoblast seems a more reasonable approach. The routes of stem cell delivery experimented have been percutaneous intracoronary infusion, transendocardial delivery through a left ventricle catheter, transvenous catheter approach, transepicardial delivery during surgery, and pharmacological mobilization with stimulating factors. Finally, to assess the efficacy of stem cell therapy, different imaging techniques have been used either to measure perfusion or left ventricular function.

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