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1.
[Chinese expert consensus on autologous stem cell transplantation for the treatment of heart failure]
Zhonghua yi xue za zhi. 2023;103:1-10
Abstract
Cardiovascular diseases have been the leading cause of death in both urban and rural residents. Among them, heart failure, which develops from various heart diseases to the end stage, is the main cause of death. With the development of regenerative medicine, stem cell transplantation is expected to be a potential and promising treatment for heart failure. In recent years, basic research and clinical application research related to stem cells have been vigorously developed in China, and many latest achievements and progress have been obtained. However, relevant guidance documents are still needed to standardize and scale up clinical applications of stem cell transplantation. Therefore, experts from the Tissue Repair and Regeneration Branch of the Chinese Medical Association, by referring to the latest research results, discussed the treatment of heart failure by autologous stem cell transplantation and reached the following consensus. The key technical issues related to autologous stem cell transplantation were mainly expounded, and scientific suggestions were proposed to standardize and promote the clinical research and application of stem cells.
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2.
A Systematic Review of CD34+ Stem Cell Therapy as an Innovative and Efficient Treatment for the Management of Refractory Angina
Vithani, V., Sutariya, B., Montenegro, D. M., Chukwu, M., Ehsan, P., Aburumman, R. N., Muthanna, S. I., Menon, S. R., Penumetcha, S. S.
Cureus. 2022;14(12):e32665
Abstract
Despite optimal medical treatment, many individuals suffering from severe coronary artery disease are not suitable candidates for further revascularization. Therapeutic angiogenesis has attracted continuous interest to increase myocardial perfusion. Cell therapy using autologous stem cells expressing Cluster of Differentiation 34 plus (CD34+) offers a special therapeutic choice for individuals with refractory angina, seeing as CD34+ stem cells can restore microcirculation. We searched PubMed, PubMed Central (PMC), and Google Scholar to find the relevant articles to write this systematic review about the role of CD34+ stem cell therapy in the management of refractory angina. Additionally, we provided a brief explanation of CD34+ cells and their mechanism of action. Along with the positive finding of other trials, a recent open-label, single-center intracoronary CD34+ cell therapy for the treatment of coronary endothelial dysfunction in patients with angina and nonobstructive coronary arteries (IMPROvE-CED) clinical trial published in 2022 concluded improvement in coronary blood flow, a significant reduction in daily as-needed sublingual nitroglycerin use and improvement in Canadian Cardiovascular Society (CCS) angina class were observed after autologous CD34+ cell treatment. In conclusion, refractory angina management and overall prognosis may be revolutionized once this treatment is approved.
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3.
Effects of stem cells on non-ischemic cardiomyopathy: a systematic review and meta-analysis of randomized controlled trials
Xia, L., Zeng, L., Pan, J., Ding, Y.
Cytotherapy. 2020
Abstract
BACKGROUND AIMS To assess the impacts of stem cell therapy on clinical outcomes in patients with non-ischemic cardiomyopathy (NICM). The effect of stem cell therapy on prognosis is unclear and controversial. METHODS The authors performed a systematic review and meta-analysis of the effects of autologous stem cell transplantation in patients with NICM on a composite outcome of all-cause mortality and heart transplantation, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), New York Heart Association (NYHA) classification, 6-minute walk test (6-MWT) distance and serum brain natriuretic peptide (BNP) level, considering studies published before March 19, 2020. RESULTS Twelve trials with 623 subjects met inclusion criteria. Compared with the control group, stem cell therapy improved LVEF (weighted mean difference [WMD], 4.08%, 95% confidence interval [CI], 1.93-6.23, P = 0.0002) and 6-MWT distance (WMD, 101.49 m, 95% CI, 45.62-157.35, P = 0.0004) and reduced BNP level (-294.94 pg/mL, 95% CI, -383.97 to -205.90, P < 0.00001) and NYHA classification (-0.70, 95% CI, -0.98 to -0.43, P < 0.00001). However, LVEDD showed no significant difference between the two groups (WMD, -0.09 cm, 95% CI, -0.23 to 0.06, P = 0.25). In 10 studies (535 subjects) employing the intracoronary route for cell delivery, mortality and heart transplantation were decreased (risk ratio [RR], 0.73, 95% CI, 0.52-1.00, P = 0.05). Furthermore, in four studies (248 subjects) with peripheral CD34+ cells, either all-cause mortality (RR, 0.44, 95% CI, 0.23-0.86, P = 0.02) or mortality and heart transplantation (RR, 0.45, 95% CI, 0.27-0.77, P = 0.003) improved in the treatment group compared with the control. The trial sequential analysis suggested the information size of LVEF, 6-WMT and BNP has been adequate for evidencing the benefits of stem cells on NICM. However, to determine the potential survival benefit, more clinical data are required to make the statistical significance in meta-analysis more conclusive. CONCLUSIONS This meta-analysis demonstrates that stem cell therapy may improve survival, exercise capacity and cardiac ejection fraction in NICM, which suggests that stem cells are a promising option for NICM treatment.
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4.
Stem cell transplantation for ischemic stroke
Boncoraglio, G. B., Ranieri, M., Bersano, A., Parati, E. A., Del Giovane, C.
The Cochrane database of systematic reviews. 2019;5:Cd007231
Abstract
BACKGROUND Stroke is a leading cause of morbidity and mortality worldwide, with very large healthcare and social costs, and a strong demand for alternative therapeutic approaches. Preclinical studies have shown that stem cells transplanted into the brain can lead to functional improvement. However, to date, evidence for the benefits of stem cell transplantation in people with ischemic stroke is lacking. This is the first update of the Cochrane review published in 2010. OBJECTIVES To assess the efficacy and safety of stem cell transplantation compared with control in people with ischemic stroke. SEARCH METHODS We searched the Cochrane Stroke Group Trials Register (last searched August 2018), CENTRAL (last searched August 2018), MEDLINE (1966 to August 2018), Embase (1980 to August 2018), and BIOSIS (1926 to August 2018). We handsearched potentially relevant conference proceedings, screened reference lists, and searched ongoing trials and research registers (last searched August 2018). We also contacted individuals active in the field and stem cell manufacturers (last contacted August 2018). SELECTION CRITERIA We included randomized controlled trials (RCTs) that recruited people with ischemic stroke, in any phase of the disease (acute, subacute or chronic), and an ischemic lesion confirmed by computerized tomography or magnetic resonance imaging scan. We included all types of stem cell transplantation, regardless of cell source (autograft, allograft, or xenograft; embryonic, fetal, or adult; from brain or other tissues), route of cell administration (systemic or local), and dosage. The primary outcome was efficacy (assessed as neurologic impairment or functional outcome) at longer term follow-up (minimum six months). Secondary outcomes included post-procedure safety outcomes (death, worsening of neurological deficit, infections, and neoplastic transformation). DATA COLLECTION AND ANALYSIS Two review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, and extracted data. If needed, we contacted study authors for additional information. We performed random effects meta-analyses when two or more RCTs were available for any outcome. We assessed the certainty of the evidence by using the GRADE approach. MAIN RESULTS In this updated review, we included seven completed RCTs with 401 participants. All tested adult human non-neural stem cells; cells were transplanted during the acute, subacute, or chronic phase of ischemic stroke; administered intravenously, intra-arterially, intracerebrally, or into the lumbar subarachnoid space. Follow-up ranged from six months to seven years. Efficacy outcomes were measured with the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), or Barthel Index (BI). Safety outcomes included case fatality, and were measured at the end of the trial.Overall, stem cell transplantation was associated with a better clinical outcome when measured with the NIHSS (mean difference [MD] -1.49, 95% confidence interval [CI] -2.65 to -0.33; five studies, 319 participants; low-certainty evidence), but not with the mRS (MD -0.42, 95% CI -0.86 to 0.02; six studies, 371 participants; very low-certainty evidence), or the BI (MD 14.09, 95% CI -1.94 to 30.13; three studies, 170 participants; very low-certainty evidence). The studies in favor of stem cell transplantation had, on average, a higher risk of bias, and a sample size of 32 or fewer participants.No significant safety concerns associated with stem cell transplantation were raised with respect to death (risk ratio [RR] 0.66, 95% CI 0.39 to 1.14; six studies, participants; low-certainty evidence).We were not able to perform the sensitivity analysis according to the quality of studies, because all of them were at high risk of bias. AUTHORS' CONCLUSIONS Overall, in participants with ischemic stroke, stem cell transplantation was associated with a reduced neurological impairment, but not with a better functional outcome. No obvious safety concerns were raised. However, these conclusions came mostly from small RCTs with high risk of bias, and the certainty of the evidence ranged from low to very low. More well-designed trials are needed.
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5.
Efficacy and safety of stem cell therapy in patients with dilated cardiomyopathy: a systematic appraisal and meta-analysis
Rong, S. L., Wang, Z. K., Zhou, X. D., Wang, X. L., Yang, Z. M., Li, B.
Journal of translational medicine. 2019;17(1):221
Abstract
BACKGROUND The clinical significance of stem cell therapy in the treatment of dilated cardiomyopathy remains unclear. This systemic appraisal and meta-analysis aimed to assess the efficacy and safety of stem cell therapy in patients with dilated cardiomyopathy. After searching the PubMed, Embase, and Cochrane library databases until November 2017, we conducted a meta-analysis to evaluate the efficacy and safety of stem cell therapy in patients with dilated cardiomyopathy. METHODS The weighted mean difference (WMD), standard mean difference (SMD), relative risk (RR), and 95% confidence interval (CI) were summarized in this meta-analysis. Both fixed effects and random effects models were used to combine the data. Sensitivity analyses were conducted to evaluate the impact of an individual dataset on the pooled results. RESULTS A total of eight randomized controlled trials, which involved 531 participants, met the inclusion criteria in this systematic appraisal and meta-analysis. Our meta-analysis showed that stem cell therapy improves left ventricular ejection fraction (SMD = 1.09, 95% CI 0.29 to 1.90, I(2) = 92%) and reduces left ventricular end-systolic volume (SMD = - 0.36, 95% CI - 0.61 to - 0.10, I(2) = 20.5%) and left ventricular end-diastolic chamber size (SMD = - 0.48, 95% CI - 0.89 to - 0.07, I(2) = 64.8%) in patients with dilated cardiomyopathy. However, stem cell therapy has no effect on mortality (RR = 0.72, 95% CI 0.50 to 1.02, I(2) = 30.2%) and 6-min-walk test (WMD = 51.52, 95% CI - 24.52 to 127.55, I(2) = 94.8%). CONCLUSIONS This meta-analysis suggests that stem cell therapy improves left ventricular ejection fraction and reduces left ventricular end-systolic volume and left ventricular end-diastolic chamber size in patients with dilated cardiomyopathy. However, future well-designed large studies might be necessary to clarify the effect of stem cell therapy in patients with dilated cardiomyopathy.
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6.
Effect of stem cell transplantation on patients with ischemic heart failure: a systematic review and meta-analysis of randomized controlled trials
Wang, Y., Xu, F., Ma, J., Shi, J., Chen, S., Liu, Z., Liu, J.
Stem cell research & therapy. 2019;10(1):125
Abstract
Stem cell transplantation (SCT) has become a promising way to treat ischemic heart failure (IHF). We performed a large-scale meta-analysis of randomized clinical trials to investigate the efficacy and safety of SCT in IHF patients. Randomized controlled trials (RCTs) involving stem cell transplantation for the treatment of IHF were identified by searching the PubMed, EMBASE, SpringerLink, Web of Science, and Cochrane Systematic Review databases as well as from reviews and the reference lists of relevant articles. Fourteen eligible randomized controlled trials were included in this study, for a total of 669 IHF patients, of which 380 patients were treated with SCT. The weighted mean difference (WMD) was calculated for changes in the New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), left ventricular end-diastolic and end-systolic volumes (LVEDV and LVESV), and Canadian Cardiovascular Society (CCS) angina grade using a fixed effects model, while relative risk (RR) was used for mortality. Compared with the control group, SCT significantly lowered the NYHA class (MD = - 0.73, 95% CI - 1.32 to - 0.14, P < 0.05), LVESV (MD = - 14.80, 95% CI - 20.88 to - 8.73, P < 0.05), and CCS grade (MD = - 0.81, 95% CI - 1.45 to - 0.17, P < 0.05). Additionally, SCT increased LVEF (MD = 6.55, 95% CI 5.93 to 7.16, P < 0.05). However, LVEDV (MD = - 0.33, 95% CI - 1.09 to 0.44, P > 0.05) and mortality (RR = 0.86, 95% CI 0.45 to 1.66, P > 0.05) did not differ between the two groups. This meta-analysis suggests that SCT may contribute to the improvement of LVEF, as well as the reduction of the NYHA class, CCS grade, and LVESV. In addition, SCT does not affect mortality.
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7.
Stem cell therapy for treatment of thromboangiitis obliterans (Buerger's disease)
Cacione, D. G., do Carmo Novaes, F., Moreno, D. H.
The Cochrane database of systematic reviews. 2018;10:Cd012794
Abstract
BACKGROUND Thromboangiitis obliterans, also known as Buerger's disease, is a non-atherosclerotic, segmental inflammatory pathology that most commonly affects the small- and medium-sized arteries, veins, and nerves in the upper and lower extremities. The etiology is unknown, but involves hereditary susceptibility, tobacco exposure, immune and coagulation responses. In many cases, there is no possibility of revascularization to improve the condition. Stem cell therapy is an option for patients with severe complications, such as ischemic ulcers or rest pain. OBJECTIVES To assess the effectiveness and safety of stem cell therapy in individuals with thromboangiitis obliterans (Buerger's disease). SEARCH METHODS The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and AMED databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 17 October 2017. The review authors searched the European grey literature OpenGrey Database, screened reference lists of relevant studies and contacted study authors. SELECTION CRITERIA Randomized controlled trials (RCTs) or quasi-RCTs of stem cell therapy in thromboangiitis obliterans (Buerger's disease). DATA COLLECTION AND ANALYSIS The review authors (DC, DM, FN) independently assessed the studies, extracted data and performed data analysis. MAIN RESULTS We only included one RCT (18 participants with thromboangiitis obliterans) comparing the implantation of stem cell derived from bone marrow with placebo and standard wound dressing care in this review. We identified no studies that compared stem cell therapy (bone marrow source) versus stem cell therapy (umbilical cord source), stem cell therapy (any source) versus pharmacological treatment and stem cell therapy (any source) versus sympathectomy. Ulcer healing was assessed in the form of ulcer size. The mean ulcer area decreased more in the stem cell implantation group: from 5.04 cm(2) (standard deviation (SD) 0.70) to 1.48 cm(2) (SD 0.56) compared with the control group: mean ulcer size area decreased from 4.68 cm(2) (SD 0.62) to 3.59 cm(2) (SD 0.14); mean difference (MD) -2.11 cm(2), 95% confidence interval (CI) -2.49 to -1.73; 1 study, 18 participants; very low-quality evidence. Pain-free walking distance showed more of an improvement in the stem cell implantation group: from mean of 38.33 meters (SD 17.68) to 284.44 meters (SD 212.12) compared with the control group: mean walking distance increased from 35.66 meters (SD 19.79) to 78.22 meters (SD 35.35); MD 206.22 meters, 95% CI 65.73 to 346.71; 1 study; 18 participants; very low-quality evidence.Outcomes such as rate of amputation, pain, amputation-free survival and adverse effects were not assessed.The quality of evidence was classified as very low, with only one study, small numbers of participants, high risk of bias in many domains and missing information regarding tobacco exposure status. AUTHORS' CONCLUSIONS Very low-quality evidence suggests there may be an effect of the use of bone marrow-derived stem cells in the healing of ulcers and improvement in the pain-free walking distance in patients with Buerger's disease. High-quality trials assessing the effectiveness of stem cell therapy for treatment of patients with thromboangiitis obliterans (Buerger's disease) are needed.
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8.
Intramyocardial autologous CD34+ cell therapy for refractory angina: A meta-analysis of randomized controlled trials
Velagapudi, P., Turagam, M., Kolte, D., Khera, S., Hyder, O., Gordon, P., Aronow, H. D., Leopold, J., Abbott, J. D.
Cardiovascular revascularization medicine : including molecular interventions. 2018
Abstract
BACKGROUND Previous studies have demonstrated that intramyocardial human CD34+ cells may relieve symptoms and improve clinical outcomes in chronic refractory angina unresponsive to optimal medical therapy or not amenable to revascularization. METHODS We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the impact of human CD34+ cells compared with placebo in chronic refractory angina. Primary efficacy outcomes in our analysis were angina frequency and exercise time. Primary safety outcomes included major adverse cardiovascular events such as myocardial infarction (MI), stroke and death. RESULTS Three eligible randomized trials including 269 patients (placebo=90, CD34+=179) were included. Dose of auto-CD34+ cells ranged from 5x10(4) to 5x10(5)cells/kg. Follow-up ranged from 6 to 24months. In a pooled analysis, administration of CD34+ cells decreased the risk of all-cause mortality [OR 0.24, 95% CI (0.08-0.73), p=0.01], reduced angina frequency [mean difference -2.91, 95% CI (-4.57 to -1.25), p=0.0006] and improved exercise time [mean difference 58.62s, 95% CI (21.19 to 96.06), p=0.02] compared with control group. However, there was no significant difference in the risk of myocardial infarction (MI) and stroke between groups. CONCLUSION In a meta-analysis, intra-myocardial CD34+ cell therapy was superior to placebo in improving risk of all - cause mortality, angina frequency with an increase in exercise time, without a significant increase in adverse events. This analysis supports further trials of CD34+ cell therapy for ischemic heart disease.
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Effects of Repetitive Transendocardial CD34(+) Cell Transplantation in Patients with Non-Ischemic Dilated Cardiomyopathy
Vrtovec, B., Poglajen, G., Sever, M., Zemljic, G., Frljak, S., Cerar, A., Cukjati, M., Jaklic, M., Cernelc, P., Haddad, F., et al
Circulation research. 2018
Abstract
Rationale: Preclinical data in heart failure models suggest that repetitive stem cell therapy may be superior to single-dose cell administration. Objective: We investigated whether repetitive administration of CD34(+) cells is superior to single dose administration in patients with non-ischemic dilated cardiomyopathy (DCM). Methods and Results: Of 66 patients with DCM, NYHA functional class III, and left ventricular ejection fraction (LVEF)< 40% enrolled in the study, 60 were randomly allocated to repetitive cell therapy (Group A, N=30), or single cell therapy (Group B, N=30). Patients received granulocyte-colony stimulating factor (G-CSF) for 5 days and 80 million CD34(+) cells were collected by apheresis and injected transendocardially. In Group A, cell therapy was repeated at 6 months. All patients were followed for 1 year, and the primary end-point was the difference in change in LVEF between the groups. At baseline, the groups did not differ in age, sex, LVEF, NT-proBNP, or 6-minute walk test distance. When directly comparing groups A and B at 1 year, there was no significant difference in change in LVEF (from 32.2+/-9.3% to 41.2+/-6.5% in Group A and from 30.0+/-7.0% to 37.9+/-5.3% in Group B, P=0.40). From baseline to 6 months, both groups improved in LVEF (+6.9+/-3.3% in Group A, P=0.001 and +7.1+/-3.5% in Group B, P=0.001), NT-proBNP (-578+/-211 pg/ml, P=0.02 and -633+/-305 pg/ml, P=0.01) and 6MWT (+87+/-21 m, P=0.03 and +92+/-25 m, P=0.02). In contrast, we observed no significant changes between 6 months and 1 year (LVEF: +2.1+/-2.3% in Group A, P=0.19 and +0.8+/-3.1% in Group B, P=0.56; NT-proBNP: -215+/-125 pg/ml, P=0.26 and -33+/-205 pg/ml, P=0.77; 6MWT: +27+/-11 m, P=0.2 and +12+/-18 m, P=0.42). Conclusions: In patients with DCM, repetitive CD34(+) cell administration does not appear to be associated with superior improvements in LVEF, NT-proBNP, or 6MWT when compared to single dose cell therapy. Clinical Trial: NCT02248532.
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10.
PreSERVE-AMI: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Intracoronary Administration of Autologous CD34+ Cells in Patients With Left Ventricular Dysfunction Post STEMI
Quyyumi, A. A., Vasquez, A., Kereiakes, D. J., Klapholz, M., Schaer, G. L., Abdel-Latif, A., Frohwein, S., Henry, T. D., Schatz, R. A., Dib, N., et al
Circulation Research. 2017;120(2):324-331
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Abstract
RATIONALE Despite direct immediate intervention and therapy, ST-segment-elevation myocardial infarction (STEMI) victims remain at risk for infarct expansion, heart failure, reinfarction, repeat revascularization, and death. OBJECTIVE To evaluate the safety and bioactivity of autologous CD34+ cell (CLBS10) intracoronary infusion in patients with left ventricular dysfunction post STEMI. METHODS AND RESULTS Patients who underwent successful stenting for STEMI and had left ventricular dysfunction (ejection fraction<48%) >4 days poststent were eligible for enrollment. Subjects (N=161) underwent mini bone marrow harvest and were randomized 1:1 to receive (1) autologous CD34+ cells (minimum 10 mol/L+/-20% cells; N=78) or (2) diluent alone (N=83), via intracoronary infusion. The primary safety end point was adverse events, serious adverse events, and major adverse cardiac event. The primary efficacy end point was change in resting myocardial perfusion over 6 months. No differences in myocardial perfusion or adverse events were observed between the control and treatment groups, although increased perfusion was observed within each group from baseline to 6 months (P<0.001). In secondary analyses, when adjusted for time of ischemia, a consistently favorable cell dose-dependent effect was observed in the change in left ventricular ejection fraction and infarct size, and the duration of time subjects was alive and out of hospital (P=0.05). At 1 year, 3.6% (N=3) and 0% deaths were observed in the control and treatment group, respectively. CONCLUSIONS This PreSERVE-AMI (Phase 2, randomized, double-blind, placebo-controlled trial) represents the largest study of cell-based therapy for STEMI completed in the United States and provides evidence supporting safety and potential efficacy in patients with left ventricular dysfunction post STEMI who are at risk for death and major morbidity. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01495364. Copyright © 2016 American Heart Association, Inc.