Clinical experience with cryopreserved mesenchymal stem cells for cardiovascular applications: A systematic review

Table 1 Baseline characteristics of randomized clinical trials with cryopreserved human umbilical cord-derived mesenchymal stem cells for heart disease, n (%)

Ref.		He et al[20], 2020, China	Bartolucci et al[21], 2017, Chile	Ulus et al[19], 2020, Turkey
Study type		RCT	RCT	Open-label RCT
Phase		I	I/II	I/II
Condition		MI	HF	MI
Sample size	Total	50	30	41
	Intervention (% male)	35 (71.42)	15 (80.0)	25 (100)
	Control (% male)	15 (46.67)	15 (93.3)	16 (100)
Age (mean ± SD)	Intervention	61 ± 8.2	57.33 ± 10.05	61.8 ± 10
	Control	65.2 ± 7.9	57.20 ± 11.64	65.3 ± 6.8
BMI (mean ± SD)	Intervention	25 ± 3.35	29.12 ± 2.88	26.5 ± 4.5
	Control	23.59 ± 2.28	29.52 ± 4.00	26.6 ± 4.8
Number of smokers	Intervention	11 (31.43)	7 (46.7)	21 (84)
	Control	3 (25.0)	4 (26.7)	15 (88.2)
HTN	Intervention	24 (68.57)	7 (46.7)	15 (60)
	Control	9 (75.0)	8 (53.3)	11 (64.7)
DM	Intervention	12 (34.29)	5 (33.3)	16 (66.7)
	Control	8 (66.7)	7 (46.7)	9 (52.9)
NYHA; I (n), II (n), III (n), IV (n)	Intervention	III (4/8), IV (12/8)	N/S: 2.03 ± 0.61	N/S: 1.9 ± 0.44
	Control	III (7) IV (5)	N/S: 1.67 ± 0.49	N/S: 2.1 ± 0.37
Comparison		CABG only	Placebo	CABG only
Follow-up		3, 6, and 12 months	3, 6, and 12 months	1, 3, 6, and 12 months
Assessment modality (yes/no)	ECG	No	Yes	Yes
	Echo	No	Yes	Yes
	MRI	Yes (CMR)	Yes (CMR)	Yes
	Cardiac CT	No	No	No
	SPECT	No	No	Yes
Measured outcomes		Serious adverse events at 12 months (primary), the efficacy of hUC-MSCs and collagen scaffold assessed according to the CV-CMR–based LVEF and infarct size at 3, 6, and 12 months after treatment, and NYHA (secondary)	Safety: Adverse events after IV infusion -/-. Efficacy: Primary, changes in LVEF, LVESV & LVEDV by Echo; LVEF, LVESV, and LVEDV by CMR; NYHA score (secondary)	LVEF, LV remodeling, myocardial mass, 6MWD, NYHA score change

RCT: Randomized controlled trial; MI: Myocardial infarction; HF: Heart failure; BMI: Body mass index; HTN: Hypertension; DM: Diabetes mellitus; NYHA: New York Heart Association; N/S: Not specified; CABG: Coronary artery bypass graft; ECG: Electrocardiogram; MRI: Magnetic resonance imaging; CT: Computed tomography; SPECT: Single-photon emission computed tomography; CMR: Cardiac magnetic resonance; hUC-MSCs: Human umbilical cord-derived mesenchymal stem cells; LV: Left ventricle; LVEF: Left ventricular ejection fraction; LVESV: Left Ventricular end-systolic volume; LVEDV: Left ventricular end-diastolic volume; 6MWD: Six-minute walk distance.

Table 2 Baseline characteristics of randomized clinical trials with cryopreserved human bone marrow mesenchymal stem cells for heart disease, n (%)

Ref.		Chullikana et al[16], 2015, India	Hare et al[17], 2009, United States	Bolli et al[15], 2020, United States	Perin et al[18], 2015, United States
Study type		RCT	RCT	RCT	RCT
Phase		I/II	I	I	II
Condition		MI	MI	HF	HF
Sample size	Total	20	53	31	60
	Intervention (% male)	10 (100)	34 (82.4)	14 (43)	45 (97.8)
	Control (% male)	10 (80)	19 (78.9)	17 (24)	15 (73.3)
Age (mean ± SD)	Intervention	47.31 ± 12.10	59 ± 12.3	54.7 ± 12.8	62.2 ± 10.3
	Control	47.79 ± 6.48	55 ± 10.2	58.2 ± 11.2	62.7 ± 11.2
BMI (mean ± SD)	Intervention	23.32 ± 3.74	29.8 ± 6.7	30.2 ± 9.0	29.8 ± 4.1
	Control	24.86 ± 1.88	30.3 ± 4.3	30.4 ± 6.5	31.3 ± 9.2
Number of smokers	Intervention	N/A	3 (8.8)	5 (36)	7 (15.6)
	Control	N/A	2 (10.5)	3 (18)	2 (13.3)
HTN	Intervention	N/A	16 (17.6)	6 (43)	29 (64.4)
	Control	N/A	9 (47.4)	10 (59)	9 (60)
DM	Intervention	N/A	6 (17.6)	3 (21)	13 (28.9)
	Control	N/A	1 (5.3)	5 (29)	2 (13.3)
NYHA; I (n), II (n), III (n), IV (n)	Intervention	N/A	N/A	II (13), III (1)	II (31), III (14)
	Control	N/A	N/A	II (13), III (4)	II (6), III (9)
Comparison		Placebo (multiple electrolytes injection)	Placebo	Placebo	Placebo
Follow-up, months		Six months till two years	Six months	6 and 12 months	3, 6, 12 months
Assessment modality (yes/no)	ECG	No	Yes	Yes	No
	Echo	Yes	Yes	No	Yes
	MRI	Yes	Yes	Yes (CMR)	No
	Cardiac CT	No	Yes	No	No
	SPECT	Yes	No	No	Yes
Measured outcomes		Adverse events, LVEF (Echo & SPECT), total perfusion score, and total volume of infarct	Safety, adverse events, LVEF (Echo), and 6MWD	Safety and feasibility of allogenic MSC administration in this population (primary). Effects of allogenic MSC administration on LV function (LVEF, LVEDV, LVESV, scar morphology) and functional status (6MWD, MLHFQ) (secondary)	Safety (primary), LV volume, LVEF, 6MWD (secondary)

RCT: Randomized controlled trial; MI: Myocardial infarction; HF: Heart failure; BMI: Body mass index; N/A: Not applicable; HTN: Hypertension; DM: Diabetes mellitus; NYHA: New York Heart Association; ECG: Electrocardiogram; MRI: Magnetic resonance imaging; CT: Computed tomography; SPECT: Single-photon emission computed tomography; CMR: Cardiac magnetic resonance; MSCs: Mesenchymal stem cells; LV: Left ventricle; LVEF: Left ventricular ejection fraction; LVESV: Left Ventricular end-systolic volume; LVEDV: Left ventricular end-diastolic volume; 6MWD: Six-minute walk distance; MLHFQ: Minnesota Living with Heart Failure Questionnaire.