Unmodified autologous stem cells at point of care for chronic myocardial infarction

Table 1 Results of statistical analysis

Parameter	Group 1 (delivery of UA-ADRCs)				Group 2 (delivery of saline as control)				P values of repeated measures two-way analysis of variance
	T1		T2		T1		T2
	Mean	SEM	Mean	SEM	Mean	SEM	Mean	SEM	I	Time	Tr	SM
LVEF	343	289	404	264	378	257	362	245	0.036	0.207	0.912	0.006
CO	273	022	378	023	339	030	363	032	0.049	0.004	0.458	0.019
SV	314	202	443	239	346	299	380	343	0.036	0.001	0.638	0.048
EDV	936	507	1119	624	926	645	1061	717	0.358	< 0.001	0.696	< 0.001
ESV	621	528	676	649	580	524	681	603	0.327	0.005	0.821	< 0.001
HR	870	293	854	419	974	396	955	361	0.940	0.400	0.051	0001
MLV	553	499	713	449	632	335	684	397	0.042	0.001	0.665	0.001
ScVol	209	229	166	119	176	138	227	176	0.002	0.739	0.509	0.019

The time points T1 and T2 are explained in detail in the main text. P values < 0.05 are given boldface. T1: Delivery of UA-ADRCs (group 1) or saline (group 2) 4 wk after induction of myocardial infarction; T2, 6 wk after T1 (i.e. 10 wk after induction of myocardial infarction); LVEF: Left ventricular ejection fraction (%) (primary objective); CO: Cardiac output (L/min); SV: Stroke volume (mL); EDV: End diastolic volume (mL); ESV: End systolic volume (mL); HR: Heart rate (min^-1); M_LV: Left ventricular mass (g); ScVol: Relative amount of scar volume of the left ventricular wall (%); I: Interaction; Tr: Treatment; SM: Subject matching; UA-ADRCs: Fresh, uncultured, unmodified autologous adipose-derived regenerative cells.

Table 2 Details of studies that addressed delivery of cultured cells (adipose-derived stem cells, bone marrow-derived stem cells, cardiosphere-derived cells, and c-Kit-positive cardiac stem cells) at a later time after experimentally-induced myocardial infarction in porcine models

Ref.	Johnston et al[38]
Species	Swine (farm and miniature pigs; age and body weight of the animals not provided)
Duration of LAD occlusion	150 min
Cells	CDCs
Source of cells
No. of cells	300000 cells/kg body weight
Delivery time	4 wk after MI
Delivery route	Intracoronary
Investigated groups of animals	Group B (group 3 in Figure 14): 300000 cells/kg body weight
	Group A (group 4 in Figure 14): Control group
Follow-up	8 wk after delivery of cells (12 wk post-MI)
Use of cardiac MRI	Yes (3T; Siemens, Erlangen, Germany)
mLVEF before MI
mLVEF after MI	37.8% (group A) and 39.5% (group B)
mLVEF at follow-up	37.6% (group A) and 37.0% (group B)
ΔmLVEF (absolute numbers)	-0.2% (group A) and -1.5% (group B)
ΔmLVEF (relative numbers)	-0.5% (group A) and -6.3% (group B)
mScVol after MI	19.2% (group A) and 17.7% (group B)
mScVol at follow-up	14.2% (group A) and 15.3% (group B)
ΔmScVol (absolute numbers)	-5.0% (group A) and -2.4% (group B)
ΔmScVol (relative numbers)	-26.0% (group A) and -13.6% (group B)
Ref.	Blázquez et al[39]
Species	Large white pigs (3-4 mo old; body weight 30-35 kg)
Duration of LAD occlusion	90 min
Cells	Allogeneic CDCs
Source of cells	Large White pigs
No. of cells	300000 cells/kg body weight
Delivery time	7 wk after MI
Delivery route	Intrapericardial injection
Investigated groups of animals	Group A (group 5 in Figure 14): 300000 cells/kg body weight (n = 4)
Follow-up	4 wk after delivery of cells (11 wk post-MI)
Use of cardiac MRI	Yes (1.5 T; Intera, Philips Medical System, Eindhoven, Netherlands)
mLVEF before MI
mLVEF after MI	39.4
mLVEF at follow-up (4 wk)	40.2
ΔmLVEF (absolute numbers)	+0.8%
ΔmLVEF (relative numbers)	+2.0%
mScVol after MI	10.2%
mScVol at follow-up	8.7%
ΔmScVol (absolute numbers)	-1.5%
ΔmScVol (relative numbers)	-17.2%
Notes	No control group
Ref.	Tseliou et al[40]
Species	Female Yucatan mini pigs (body weight 40-45 kg); age of the animals not provided
Duration of LAD occlusion	150 min
Cells	Allogeneic CDCs
Source of cells	Male donor Sinclair pigs
No. of cells	12.5 × 106
Delivery time	3 wk after MI
Delivery route	Intracoronary
Investigated groups of animals	Group A: Single-vessel LAD arterial infusion under stop-flow (n = 5)
	Group B: Single-vessel LAD arterial infusion under continuous flow (n = 5)
	Group C: Multi-vessel control group (n = 5)
	Group D: Multi-vessel (LAD, LCX and RCA) under stop-flow (n = 5)
	Group E (group 6 in Figure 14): Multi-vessel (LAD, LCX and RCA) under continuous flow (n = 6)
	Group F (group 7 in Figure 14): Control group (n = 5)
Follow-up	7 wk after delivery of cells (4 wk post-MI)
Use of cardiac MRI	Yes (3T; Siemens, Erlangen, Germany)
mLVEF before MI
mLVEF after MI	47.7% (group A), 43.5% (group B), 46.2% (group C), 48.1% (group D) and 47.4% (group E) and 44.8% (group F)
mLVEF at follow-up	44.9% (group A), 41.6% (group B), 40.3% (group C), 45.6% (group D) and 46.9% (group E) and 37.9% (group F)
ΔmLVEF (absolute numbers)	-2.76% (group A), -1.9% (group B), -5.9% (group C), -2.4% (group D) and -0.5% (group E) and -6.9% (group F)
ΔmLVEF (relative numbers)	-6.1% (group A), -4.5% (group B), -14.5% (group C), -5.3% (group D) and -1.0% (group E) and -18.3% (group F)
mScVol after MI	17.1% (group A), 17.0% (group B), 17.6% (group C), 15.8% (group D) and 14.6% (group E) and 16.0% (group F)
mScVol at follow-up	14.7% (group A), 15.9% (group B), 14.2% (group C), 11.4% (group D) and 11.9% (group E) and 12.1% (group F)
ΔmScVol (absolute numbers)	-2.4% (group A), -1.1% (group B), -3.4% (group C), -4.4% (group D) and -2.7% (group F) and -3.9% (group F)
ΔmScVol (relative numbers)	-16.4% (group A), -6.9% (group B), -24.1% (group C), -38.1% (group D) and -22.5% (group E) and -31.8% (group F)
Ref.	Dariolli et al[41]
Species	Female Sus scrofa domestica pigs (body weight 15-20 kg); age of the animals not provided
Duration of LCX occlusion	Permanent occlusion
Cells	Allogeneic ASCs (passage 4)
Source of cells	Not provided
No. of cells	Between 1 × 106 and 4 × 106
Delivery time	4 wk after MI
Delivery route	Transpericardial intramyocardial injection (20 different sites around the border of MI)
Investigated groups of animals	Group A: 1 × 106 cells/kg body weight (n = 6)
	Group B: 2 × 106 cells/kg body weight (n = 7)
	Group C (group 8 in Figure 14): 4 × 106 cells/kg body weight (n = 5)
	Group D (group 9 in Figure 14): Control group (n = 7)
Follow-up	4 wk after delivery of cells (8 wk post-MI)
Use of cardiac MRI	No
mLVEF before MI
mLVEF after MI	48.4% (group A), 46.7% (group B), 48.7% (group C) and 44.9% (group D)
mLVEF at follow-up	40.6% (group A), 42.2% (group B), 50.0% (group C) and 35.9% (group D)
ΔmLVEF (absolute numbers)	-8.2% (group A), -4.5% (group B), +1.3% (group C) and -9.0% (group D)
ΔmLVEF (relative numbers)	-20.2% (group A), -10.7% (group B), +2.6% (group C) and -25.1% (group D),
mScVol after MI	Not provided
mScVol at follow-up	Not provided
ΔmScVol (absolute numbers)	Not provided
ΔmScVol (relative numbers)	Not provided
Notes	Measurements of LVEF were performed with echocardiography
Ref.	Natsumeda et al[42]
Species	Female Göttingen swine; age and body weight of the animals not provided
Duration of LAD occlusion	150 min
Cells	Allogeneic BMSCs and allogeneic CSCs
Source of cells	Male Yorkshire swine
No. of cells	Between 1 × 106 and 2 × 108
Delivery time	3 mo after MI
Delivery route	Transendomyocardial intramyocardial injection (TESI) 10 different sites around the border of MI
Investigated groups of animals	Group A: 2 × 108 BMSCs (n = 8)
	Group B: 1 × 106 CSCs (n = 4)
	Group C (group 10 in Figure 14): 1 × 106 CSCs + 2 × 108 BMSCs (n = 7)
	Group D (group 11 in Figure 14): Control group (n = 6)
Follow-up	3 mo after delivery of cells (6 mo post-MI)
Use of cardiac MRI	Yes (3T; TIM Trio; Siemens, Erlangen, Germany)
mLVEF before MI	55.3% (group A), 55.2% (group B), 53.8% (group C) and 57.7% (group D)
mLVEF after MI	37.1% (group A), 43.3% (group B), 39.7% (group C) and 41.7% (group D)
mLVEF at follow-up	36.5% (group A), 43.1% (group B), 41.6% (group C) and 40.7% (group D)
ΔmLVEF (absolute numbers)	-0.6% (group A), -0.2% (group B), +1.9% (group C) and -1.0% (group D)
ΔmLVEF (relative numbers)	-1.6%( group A), -0.5% (group B), +4.6% (group C) and -2.5% (group D)
mScVol after MI	16.9% (group A), 12.8% (group B),15.5% (group C) and 17.5% (group D)
mScVol at follow-up	13.7% (group A), 12.4% (group B), 12.5% (group C) and 19.9% (group D)
ΔmScVol (absolute numbers)	-3.2% (group A), -0.4% (group B), -3.0% (group C) and +2.4% (group D)
ΔmScVol (relative numbers)	-23.4% (group A), -3.2% (group B), -24.0% (group C) and +12.1% (group D)

Unlike in the present study, Johnston et al[38] identified hyper-enhancement as areas of signal intensity > 2 standard deviations greater than normal myocardium (> 5 standard deviations in the present study). LAD: Left anterior descending artery; LCX: Left circumflex artery; mLVEF: Mean left ventricular ejection fraction; MI: Myocardial infarction; mScVol: Mean relative amount of scar volume of the left ventricular wall.