Introduction
Study | Pts | Cell type | Assessment method | Outcome |
---|---|---|---|---|
204 | Intracoronary BMC vs placebo | LV angiography | At 4 months LVEF increased in BMC vs placebo (mean±SD) increase, (5.5 ± 7.3% vs. 3.0 ± 6.5%; P = 0.01). At 12 months: death, recurrence of myocardial infarction, rehospitalization for heart failure significantly reduced. | |
100 | Intracoronary BMC vs control |
99mTc-SPECT; echo; MRI | No effect on global left ventricular function at 6 months and 3 years. | |
60 | Intracoronary BMC vs control | MRI | At 6 months global LVEF increase (6.7%). No effects at 18 months and 5 years. | |
Janssens et al. [107] | 67 | Intracoronary BMC vs placebo | MRI; [11C] acetate PET | At 4 months no effect on LVEF and LV volumes. Reduction of infarct volume (measured by serial contrast-enhanced MRI) was greater in BMC patients than in controls. |
TOPCARE-AMI [16] | 59 | Intracoronary BMC vs CPC | LV angiography; MRI | At 4 months LV angiography showed significant increase of LVEF (50 ± 10% to 58 ± 10%), and significant decrease of end-systolic volumes (54 ± 19 ml to 44 ± 20 ml) without differences between the two cell groups. At 12 months MRI showed reduced infarct size and absence of reactive hypertrophy. |
Meluzin et al. [108] | 60 | Intracoronary BMC (high and low doser) vs control | Echo; 99mTc-SPECT; 18F-FDG PET | LVEF improved in the group receiving the highest dose (108 cells) by 6%, 7%, and 7% at months 3, 6, and 12, respectively. |
MAGIC [8] | 97 | SMB vs placebo injected in and around the scar | Echo | No improvement in regional or global LV function at 6 months. |
Chen et al. [109] | 69 | Intracoronary BMSC (bone marrow mesenchymal stem cells) vs placebo |
18F-FDG; Echo | At 3 months LVEF significantly increased in the BMSC group (67 ± 11%) compared to controls (53 ± 8%) and the same group before implantation (49 ± 9%). No change in LVEF at 6 months versus 3 months. |
Dill T et al. [110] | 204 | Intracoronary BMC vs placebo | MRI | In the BMC group, EF increased significantly by 3.2 ± 1.3 absolute percentage points at 4 months, and this increase was sustained at 12 months (+3.4 ± 1.3 absolute percentage points vs baseline). In the placebo group, EF was unchanged (+0.6 ± 1.2 absolute percentage points, at 12 months. |
Stem cells for cardiac repair
Imaging of stem cells
Study | Species | Cell type | Detection method | Delivery | Results |
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MRI
| |||||
Kraitchman et al. [111] | swine | MSC | SPIO | Intramyocardial -percutaneous | Detection of tranplanted cells (25.8%) up to 3 weeks. |
Amado et al. [112] | swine | MSC | SPIO | Intramyocardial- percutaneous | Gradual loss of intensity of the SPIO label but retection of tranplanted cells (42.4%±15) at 8 weeks. |
Stuckey et al. [113] | rat | BMC | GFP-SPIO | Intramyocardial –direct | No improvement in LEVF. Detection of tranplanted cells up to 16 weeks confirmed by MR and immunofluorescence. |
Amsalem et al. [43] | rat | MSC | SPIO | Intramyocardial –direct | At 4 weeks after injection, most of the transplanted labelled MSCs did not survive and their iron content was engulfed by resident macrophages. Injection of labelled or unlabelled cells attenuate ventricular dilatation and dysfunction after MI. |
Ebert et al. [114] | mice | mESC | SPIO | Intramyocardial -direct | Detection up to 4 weeks by MRI. LVEF identical between the tranplanted group and control. |
Terrovitis et al. [45] | rat | hCDCrCDC | SPIO | Intramyocardial -direct | Signal void persisted after 3 weeks in both syngeneic and xenogeneic cell implantation. Immunohistochemistry identifies the iron containing cells as macrophages. |
Radionuclide
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Chin et al. [62] | swine | MSC |
111In-oxine | Intravenous | Significant lung activity that obscured the assessment of myocardial cell tracking. |
Brenner et al.[63] | rat | HPC-CD34+ |
111In-oxine | Intracavitary (left ventriculum) | Impairment of cell proliferation and differentiation induced by 111In-oxine. At 96 h only 1% of radioactivity was detected in the heart. |
Blackwood [65] | dog | BMC |
111In-tropolone | Intramyocardial -direct | Viability at day 6 after intramyocardial injection was calculated to be 75%. |
Terrovitis et a.. [82] | rat | rCDC |
18F-FDG | Intramyocardial -direct | Different retention values were observed at 1 h after injection of cells with normal condition (17.8%±7.3), arrested heart (75.8%±18.3), adenosine injection (35.4%±5.3) and adenosine plus fibrin glue (39.3%±11.6). |
Mitchell et al. [66] | dog | EPC |
111In-tropolone | Intramyocardial -percutaneous | 15 days after intramyocardial injection SPECT/CT imaging demonstrated comparable degrees of retention: 57%±15 for the subepicardial injections and 54%±26 for the subendocardial injections. |
Multimodal
| |||||
Terrovitis et al.. | rat | rCDC |
99mTc, 124I; hNIS | Intramyocardial -direct | Detection up to 6 days after injection and their presence validated by ex vivo imaging and qPCR. |
Qiao et al. [98] | rat | mESC | SPIO; HSV1-tk+ 18F-FHBG | Intramyocardial -direct | Increasing 18 F -FHBG uptake up to 4 weeks. Most of the SPIO were contained in infiltrating macrophages at week 4. Teratoma formation. Increased LVEF. Only <0.5% of the implanted cell were cardiomyocytes. |
Chapon et al. [115] | rat | rBMC | SPIO; 18F-FDG | Intramyocardial -direct | MRI detection of SPIO labelled cells grafted in the heart up to 6 weeks, confirmed by hystology. At 1 week increased 18 F-FDG uptake in BMC implanted heart vs control. No improvement of heart function. |
Higuchi et al. [99] | rat | hEPC | SPIO; NIS +124I | Intramyocardial -direct | Rapid decrease of 124I uptake after day 3. Signal not detectable at day 7. MRI signal void remained unchanged throughout the follow-up period. Histology confirmed the presence of transplanted cells on day 1 but not on day 7, when iron was contained only in resident macrophages. |
Li et al. [116] | rat | RCSC | Fluc + D-Luciferin; 18F-FDG PET; echocardiography; MRI | Intramyocardial -direct | Implanted cells detected up to 7 weeks by bioluminescence. No improvement in cardiac function assessed by 18F-FDG PET, MRI, echocardiogram and invasive hemodynamic pressure volume-analysis. |
Imaging modality | Spatial resolution (mm) | Sensitivity (mol/L) | Cell Manipulation | What to image | How to image | Advantages | Disadvantages |
---|---|---|---|---|---|---|---|
Fluorescence Imaging | FRI: 2–3 mm; FMT: 1 mm | 10−9–10−12
| Cells labeled with near-infrared probes (fluorochromes, Quantum dots, etc.) | Residence, homing, quantification (FMT) | Direct imaging; at NIR wavelenghts can image deep tissue | Multiplexed imaging | Not suitable for clinical translation; relatively low spatial resolution |
Bioluminescence Imaging | 3–5 | 10−15–10−17
| Cells transduced to express luciferase | Residence, homing, viability, differentiation, quantification | After systemic injection of D-Luciferine or Coelenterazine | Easy, high sensitivity, high-throughput, low cost; assessment of cell viability | Not suitable for clinical translation; surface imaging; relatively low spatial resolution; requires completely dark environment |
PET | 1-2 (μPET); 6–10 (clinical PET) | 10−11–10−12
| Cells loaded with 18F-FDG; 64Cu labelled compounds | Residence, homing, quantification | Direct imaging | High sensitivity, translational | Radiation; only short term cell tracking |
Cells transduced to express PET reporter genes (HSV1tk, HSV1-sr39tk ) | Residence, homing, differentiation, quantification, | After systemic injection of correspondent radiolabelled probe (18F-FHBG, 18F-FEAU, etc.) | High sensitivity, long term cell tracking; assessment viability | Radiation; need to transduce cells; potential immunogenicity | |||
SPECT | 0.5-2 (μSPECT); 7–15 (clinical SPECT) | 10−10–10−11
| Cells labelled with 99mTc-, 111In-labelled compounds | Residence, homing, quantification | Direct imaging | High sensitivity, translational; assessment viability | Radiation; only short term cell tracking |
Cells transduced to express reporter genes (hNIS ) | Residence, homing, viability, differentiation, quantification, | After systemic injection of correspondent radiolabeled probe ( 99mTc, etc.) | High sensitivity, long term cell tracking | Radiation; need to transduce cells; potential immunogenicity | |||
MRI | 0.01–0.1 (small animal); 0.5–1.5 (clinical) | 10−3–10−5
| Cells labeled with Iron Oxides; Gd or Mn chelates; perfluorocarbon (19F) | Residence, homing, migration, quantification | Direct imaging | High spatial resolution; high soft tissue contrast; functional imaging | Relatively low sensitivity; long scanning times; probe dilution upon cell proliferation; persistence of SPIO after cell death (macrophage) |
Cells transduced to express MRI reporter genes β-galactosidase, transferrin receptor, ferritin, MagA and lysine-rich proteins | Residence, homing, quantification, migration, differentiation | Direct imaging or after injection of iron oxides (transferrin receptor, ferritin) | High spatial resolution; high soft tissue contrast; functional imaging; no probe dilution; | Low sensitivity; need to transduce cells; potential immunogenicity |