| Study | Trial Type | NIDCM Phenotype | MSC Type and Concen-Tration | Admini-Stration Route | Functional Outcome | Molecular Outcome |
| Carmona, 2017 | Preclinical (Wistar rats, 8 weeks) | NIDCM induced by autoimmune myocarditis | Syngeneic BM-MNCs, BM-MSCs or AT-MSCs, 5 × 106 | Intramyocardial | BM-MSCs and AT-MSCs increased LVEF to 79.8% and 75.1%, respectively | BM-MSCs and AT-MSCs increased serum VEGF at 24 h (peak) and at four weeks post treatment. BM-MSC decreased BNP after four weeks and improved cardiac fiber organization, number of vessels and reduced fibrosis (IHC) |
| Deng, 2017 | Preclinical (Sprague Dawley rats, 8 weeks) | Adriamycin induced NIDCM | Syngeneic BM-MSCs, 1 × 107 | Intravenous | BM-MSCs increased LVEF | BM-MSCs upregulated Cx43, MEF2 and GATA4 and downregulated, TGF-β and Col-I (qPCR). BM-MSCs reduced CVF (IHC) |
| Fatkhutdinov, 2009 | Clinical (27 NIDCM patients) | Idiopathic NIDCM with LVEF ≤35% | Allogeneic BM-MSCs, dose N/A | Intracoronary | BM-MSCs increased walk distance and reduced NYHA class at one and three months follow-up | BM-MSCs reduced serum BNP one week after transplantation |
| Florea, 2020 (POSIEDON-DCM) | Clinical (34 NIDCM patients) | NIDCM with LVEF <40% | Allogeneic and autologous BM-MSCs, 1 × 108 | Trans-endocardial | LVEF was significantly increased in both males and females | BM-MSCs decreased serum TNF-α after six months in both males and females. EPC-CFU increased and FMD improved 3 months post treatment |
| Guo, 2013 | Preclinical (C57/BL6 mice, 10 weeks) | Doxorubicin induced NIDCM | Syngeneic BM-MSCs, 5 × 107 | Intravenous | BM-MSCs increased FS% and reduced LVDd and LVEDP | BM-MSCs reduced cardiac fibrosis and CVF (IHC) |
| Hare, 2017 (Poseidon-DCM) | Clinical (37 NIDCM patients) | NIDCM with LVEF <40% | Allogeneic and autologous BM-MSCs, 1 × 108 | Trans-endocardial | Allogeneic BM-MSCs increased LVEF to a greater degree than autologous BM-MSCs | Serum TNF-α decreased to a greater extent in the allogeneic group compared to the autologous group at six months follow-up. EPC-CFU increased in the allogeneic group compared to the autologous at three months follow-up. Both groups had a reduced percentage of T and B cell subtypes, normally associated with chronic inflammation, at six months follow-up |
| Kong, 2010 | Preclinical (Wistar rats, 3 months, 250 g) | Adriamycin induced NIDCM | Transplant type N/A, BM-MSCs, 2 × 106 | Intravenous for three days | BM-MSCs increased LVEF |
BM-MSCs significantly reduced cardiac norepinephrine content and increased GAP-43, ChaT, and SYN density (IHC and WB) |
| Li, 2009 | Preclinical (Wistar rats, 180–200 g) | Isoproterenol induced HF | Syngeneic BM-MSCs, 3 × 106 | Intramyocardial | BM-MSCs increased LVEF and FS | BM-MSC attenuated myocardial fibrosis (IHC) and upregulated adrenomodullin (qPCR) |
| Mao, 2017 | Preclinical (Sprague Dawley rats, 180 g) | Doxorubicin induced NIDCM | Xenogeneic hUCB-MSCs or CM, 2.5 × 105 (low dose) or 1 × 106 (high dose) or 2.0 mL (CM) | Intramyocardial | Both low-dose and high-dose of hUCB-MSCs increased FS% and LVEF. | hUCB-MSCs attenuated mitochondrial swelling and maintained sarcolemma integrity (IHC). BM-MSCs increased serum LIF at both doses, HGF, GM-CSF, and VEGF at low dose and reduced BNP, cTNI (ELISA). Treatment increased HGF, VEGF, IGF-1 (qPCR) |
| Mörschbächer, 2016 | Preclinical (New Zealand rabbits, 3–4 months, 2–3.5 kg) | Doxorubicin induced NIDCM | Syngeneic AT-MSCs, 1 × 106 | Intramyocardial | No significant change in LVEF | AT-MSCs reduced histological lesions (IHC) |
| Premer, 2019 (POSEIDON-DCM) | Clinical (21 NIDCM patients) | NIDCM with LVEF <40% | Allogeneic and autologous BM-MSCs, 1 × 108 | Trans-endocardial | N/A | Allogeneic BM-MSCs increased EPC-CFUs and decreased plasma SDF-1α in both treatment groups. Plasma TNF-α negatively correlated with EPC-CFUs |
| Premer, 2015 (POSEIDON-DCM + TRIDENT) | Clinical (12 NIDCM patients) | Idiopathic NIDCM (inclusion criteria from POSEIDON-DCM) | Allogeneic and autologous BM-MSCs, 1 × 108 | Trans-endocardial | N/A | Allogeneic BM-MSCs led to increased EPC-CFUs and improved FMD compared to autologous BM-MSCs |
| Rieger, 2019 (POSEIDON-DCM) | Clinical (34 NIDCM patients) | NIDCM with LVEF <40% | Allogeneic and autologous BM-MSCs, 1 × 108 | Trans-endocardial | BM-MSCs increased LVEF in patients negative for any pathological variants (V-) and variants of uncertain significance at one year follow up, and improved MLHFQ score and NYHA class in V- patients only | N/A |
| Shabbir, 2009 | Preclinical (TO2 (cardiomyopathic) male hamsters, 4 months) | TO2 (cardiomyopathic) male hamsters | Xenogeneic BM-MSCs, 0.25 × 106, 1 × 106 or 4 × 106 or 0.8 mL CM | Two intramuscular injections (hamstring muscle) with 2 weeks interval or CM three times per week for 4 weeks | BM-MSCs increased FS% at all concentrations. 4 × 106 BM-MSCs increased FS% to the greatest degree | BM-MSCs decreased myocyte diameter, apoptotic myocytes, fibrosis (IHC), and circulating cTnI (ELISA). BM-MSCs downregulated Col3a1, MMP-9, MMP-13, TIMP-2, TIMP-3 (qPCR) |
| Xiao, 2017 | Clinical (53 NIDCM patients) | NIDCM with LVEF <40% | Autologous BM-MSCs or BM-MNCs, number of adherent cells in passage 3 | Intramyocardial | LVEF, LVEDd, NYHA class were improved after three and 12 months in both groups. Myocardial perfusion had increased in the BM-MSC group |
N/A |
| Yu, 2014 | Preclinical (Sprague Dawley rats, 8 weeks) | Doxorubicin induced NIDCM | Syngeneic BM-MSCs, 5 × 106 | Intravenous every other day for 10 days | Repeated infusions of BM-MSCs increased LVEF to 79.6% and decreased LVEDd | BM-MSCs reduced CVF and Col-I/III ratio (IHC) MSCs downregulated Col-I, AT1, CYP11B2, TGF-β1 and upregulated Col-III (qPCR) |
| Yu, 2015 | Preclinical (Sprague Dawley rats, 37 g) | Furazolidone induced NIDCM | Syngeneic BM-MSCs, 1 × 105 | Intramyocardial | BM-MSCs increased LVEF to 74% | BM-MSCs reduced CVF (IHC), Col-I/III ratio and downregulated myocardial TGF-β1 (qPCR) |
| Zhang, 2019 | Preclinical (Lewis rats) | NIDCM induced by autoimmune myocarditis | Xenogeneic hUCB-MSCs, 1 × 106 | Intravenous | N/A | hUCB-MSCs decreased myocardial fibrosis (IHC) and activity of TGF-β1/ERK1/2 signaling |
| Labelled cells | ||||||
| Abd Allah, 2017 | Preclinical (Male albino rats, 150–200 g) | Doxorubicin induced NIDCM | Xenogeneic, PKH26-labelled c hUCB-MSCs, 1 × 106 | Intravenous | EDP, dP/dt max, and dP/dt min increased after six weeks | hUCB-MSCs decreased serum cTnI (ELISA) and collagen area (IHC) |
| Abdelmonem, 2019 | Preclinical (Wistar rats, 12 weeks old) | Isoprenaline induced HF | Syngeneic, PKH26-labelled BM-MSCs, 1 × 107 | Intravenous | BM-MSC increased LVEF to 74.47% and decreased LVESd | BM-MSCs decreased fibrosis and increased GATA4, desmin and cTNI (IHC) and increased eNOS (WB) and MEF2c (qPCR) |
| Ammar, 2015 | Preclinical (Wistar rats, 200–220 g) | Diabetic mellitus + doxorubicin induced NIDCM | Xenogeneic GFP labelled hBM-MSCs, 2 × 106, or GFP labelled hAT-MSCs, 1 × 106 | Intravenous | Both MSC types increased FS% and decreased arterial blood pressure (systolic and diastolic) | Both MSC groups led to an increased number of capillaries and decreased immune cell infiltration, collagen deposition and αSMA (IHC) |
| Chen, 2010 | Preclinical (Inbred Japanese rabbits, 1800–2000 g) | Doxorubicin induced NIDCM | Autologous BrdU labelled BM-MSCs, 5 × 105 | Intramyocardial | BM-MSCs increased LVEF to 68.38% and decreased LVESd | BM-MSCs were present in the myocardium four weeks after treatment, indicated by BrdU (IHC) |
| Gong, 2016 | Preclinical (cTnTR141W transgenic mice, 4 months) | Genetic NIDCM | Xenogeneic eGFP labelled hUCB-MSCs, 1.5 × 106 | Intramyocardial | hUCB-MSCs increased LVEF to 56.96% and decreased heart weight/body weight, LVEDd, LVESd | hUCB-MSCs reduced CVF, cytoplasmic vacuolisation and apoptotic nuclei and increased CD31+ vessels and αSMA+ aterioles (IHC). hUCB-MSCs increased Bcl-2/Bax ratio (WB), IGF-1 and VEGF and reduced serum CRP (ELISA) |
| Li, 2018 | Preclinical (Male Wistar rats, 180–200 g) | Isoproterenol induced HF | Syngeneic eGFP + DAPI labelled BM-MSCs, 5 × 106 | Intramyocardial | BM-MSCs increased LVEF to 69.24% and reduced LVESd | BM-MSCs decreased CVF (IHC), upregulated HGF and downregulated Col-I and III, MMP-2, MMP-9, TNF-β (qPCR), MMP-2 and MMP-9 (WB). BM-MSCs were present in the myocardium after four weeks |
| Li, 2008 | Preclinical (Male Wistar rats, 180–200 g) | Isoproterenol induced HF | Syngeneic DAPI labelled BM-MSCs, 3 × 106 | Intramyocardial | BM-MSCs increased LVEF to 78.51% and decreased LVESd | BM-MSCs increased HGF (qPCR and WB) and decreased CVF (IHC), Col-I and III, MMP-2 and MMP-9 (qPCR), Pro MMP-2, Active MMP-2 and MMP-9 (WB) |
| Mohamed, 2015 | Preclinical (Male Wistar rats, 170–190 g) | Isoproterenol induced HF | Syngeneic PKH26 labelled BM-MSCs, 1 × 106 | Intravenous | BM-MSCs increased LVEF to 58.33% | BM-MSCs reduced cardiac fibrosis (IHC) and increased eNOS, Cx43 (WB). BM-MSCs reduced caspase 3 (WB) and TGF- β (ELISA) |
| Nagaya, 2006 | Preclinical (Male Lewis rats, 220–250 g) | NIDCM induced by autoimmune myocarditis | Syngeneic BM-MSCs, 5 × 56 | Intramyocardial | BM-MSCs increased FS% and decreased LVEDP, LVDd |
BM-MSCs increased myocardial capillary density and decreased CVF (IHC). BM-MSCs reduced MMP-2 (WB) |
| Psaltis, 2010 | Preclinical (Merino wether sheeps, 50 kg) | Doxorubicin induced NIDCM | Allogeneic GFP labelled Mesenchymal progenitor cells (MPCs), 1 × 109 ± 5 × 106 | Trans-endocardial | MPCs increased LVEF to 39.2% | MPC treatment reduced CVF and increased the density of karyokinetic cardiomyocytes and myocardial arterioles (IHC) |
| Yang, 2013 | Preclinical (Female Wistar rats, 210–240 g) | Adriamycin induced NIDCM | Syngeneic BrdU labelled BM-MSCs, 5 × 106 | One or two intravenous injections (1-day interval | Only two doses significantly increased LVEF. Two doses of BM-MSCs increased LVEF to 75.4%. BM-MSCs reduced mortality, LVESd and LVEDd, which were significantly improved by double infusion | BM-MSCs led to upregulation of VEGF (qPCR). Two injections decreased CVF (IHC) and serum BNP (ELISA). BM-MSCs improved fiber alignment (IHC) All parameters significantly improved by double infusion BrdU labelled BM-MSCs were present in the myocardium after Four weeks |
| Zhang, 2013 | Preclinical (Wistar rats, 6–7 weeks, 200–220 g) | Adriamycin induced NIDCM | Syngeneic BrdU labelled BM-MSCs, 1 × 107 | Intravenous | BM-MSCs increased LVEF ti 55.56% and decreased LVESd | BM-MSCs increased GATA-4, cTnI, Cx43 (IHC) and decreased serum BNP (ELISA) |
| Zhou, 2007 | Preclinical (New Zealand rabbits, 1.9 kg) | Adriamycin induced NIDCM | Autologous DAPI labelled BM-MSCs, 4 × 106 | Intramyocardial | No significant improvement in heart function. | BM-MSCs were present in the myocardium after two weeks and increased Bcl-2 (IHC) |
Appendix D Included studies. Abbreviations ordered according to the table; Non-ischemic dilated cardiomyopathy (NIDCM), Bone marrow mononuclear cells (BM-MNCs), Bone marrow derived mesenchymal stem cells (BM-MNCs), Adipose tissue–derived mesenchymal stem cells (AT-MSCs), Left ventricular ejection fraction (LVEF), Vascular endothelial growth factor (VEGF), Immunohistochemistry (IHC), Connexin43 (Cx43), Myocyte enhancer factor-2 (MEF2), Transcription factor GATA-4 (GATA4), Transforming growth factor beta (TGF-β), Collagen (Col), Quantitative Polymerase Chain Reaction (qPCR), Collagen volume fraction (CVF), New York heart association (NYHA), Brain natriuretic peptide (BNP), Tumor necrosis factor α (TNF-α), Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy (POSEIDON-DCM), Endothelial progenitor cell-colony forming units (EPC-CFU), Flow mediated vasodilation (FMD), Fractional shortening (FS%), Left ventricular diastolic dimension (LVDd), Left ventricular end-diastolic pressure (LVEDP), Growth Associated Protein 43 (GAP-43), Cholineacetyltransferase (ChaT), Synaptophysin (SYN), Western blotting (WB), Heart failure (HF), Human umbilical cord blood MSCs (hUCB-MSCs), Conditioned medium (CM), Leukocyte inhibitory factor (LIF), Hepatocyte growth factor (HGF), Granulocyte- macrophage colony-stimulating factor (GM-CSF), Insulin-like growth factor-1 (IGF-1), Troponin T (cTNI), Enzyme-linked immunosorbent assay (ELISA), Stromal cell-derived factor 1 alpha (SDF-1α), The Transendocardial Stem Cell Injection Delivery Effects on Neomyogenesis Study (TRIDENT), The Minnesota living with heart failure questionnaire (MLHFQ), Collagen Type III Alpha 1 Chain (Col3a1), Matrix metalloproteinase (MMP), Tissue inhibitor of metalloproteinase (TIMP), Left ventricular end-diastolic diameter (LVEDd), Angiotensin II receptor type 1 (AT1), Cytochrome P450 Family 11 Subfamily B Member 2 (CYP11B2), Extracellular signal-regulated kinase (ERK), End diastolic pressure (EDP), Left ventricle maximal pressure rise in early systole (dP/dt max), Left ventricle maximal decline of pressure in early diastole (dP/dt min), Left ventricular end-systolic diameter (LVESd), Bromodeoxyuridine (Brdu), Endothelial NOS (eNOS), Green fluorescent protein (GFP), Alpha smooth muscle actin (αSMA), B-cell lymphoma 2 (Bcl-2), Bcl-2 Associated X, Apoptosis Regulator (Bax), C-reactive protein (CRP), Tumor necrosis factor β (TNF-β), 4′,6-diamidino-2-phenylindole (DAPI), Red fluorescent cell linker (PKH26).