Application and Progress of Combined Mesenchymal Stem Cell Transplantation in the Treatment of Ischemic Cardiomyopathy.

Treatment of ischemic cardiomyopathy caused by myocardial infarction (MI) using mesenchymal stem cell (MSC) transplantation is a widely researched field, with promising clinical application. However, the low survival rate of transplanted cells has a severe impact on treatment outcome. Currently, research is focused on investigating the strategy of combining genetic engineering, tissue engineering materials, and drug/hypoxia preconditioning to improve ischemic cardiomyopathy treatment outcome using MSC transplantation treatment (MSCTT). This review discusses the application and progress of these techniques.

Voxel-based analysis of fractional anisotropy in post-stroke apathy.

OBJECTIVE: To explore the structural basis of post-stroke apathy by using voxel-based analysis (VBA) of fractional anisotropy (FA) maps. METHODS: We enrolled 54 consecutive patients with ischemic stroke during convalescence, and divided them into apathy (n = 31) and non-apathy (n = 23) groups. We obtained magnetic resonance images of their brains, including T1, T2 and DTI sequences. Age, sex, education level, Hamilton Depression Scale (HAMD) scores, Mini-Mental State Examination (MMSE) scores, National Institutes of Health Stroke Scale (NIHSS) scores, and infarct locations for the two groups were compared. Finally, to investigate the structural basis of post-stroke apathy, VBA of FA maps was performed in which we included the variables that a univariate analysis determined had P-values less than 0.20 as covariates. RESULTS: HAMD (P = 0.01) and MMSE (P<0.01) scores differed significantly between the apathy and non-apathy groups. After controlling for age, education level, HAMD scores, and MMSE scores, significant FA reduction was detected in four clusters with peak voxels at the genu of the corpus callosum (X = -16, Y = 30, Z = 8), left anterior corona radiata (-22, 30, 10), splenium of the corpus callosum (-24, -56, 18), and right inferior frontal gyrus white matter (52, 24, 18), after family-wise error correction for multiple comparisons. CONCLUSIONS: Post-stroke apathy is related to depression and cognitive decline. Damage to the genu of the corpus callosum, left anterior corona radiata, splenium of the corpus callosum, and white matter in the right inferior frontal gyrus may lead to apathy after ischemic stroke.

In vivo magnetic resonance imaging tracking of transplanted superparamagnetic iron oxide-labeled bone marrow mesenchymal stem cells in rats with myocardial infarction.

Superparamagnetic iron oxide (SPIO) nanoparticles generate superparamagnetism, thereby resulting in an inhomogeneous local magnetic field, which shortens the T2 value on magnetic resonance imaging (MRI). The purpose of the present study was to use MRI to track bone marrow mesenchymal stem cells (BMSCs) labeled with SPIO in a rat model of myocardial infarction. The BMSCs were isolated from rats and labeled with SPIO. The anterior descending branch of the coronary artery was ligated under anesthesia. Two weeks later, the rats received, at random, 5 x 10(7) SPIO-labeled BMSCs, 5 x 10(7) unlabeled BMSCs or a vehicle (100 µl phosphate-buffered saline) via direct injection into the ischemic area (20 animals/group). MRI was used to track the SPIO­labeled BMSCs and the rats were then sacrificed to verify the presence of BMSCs using immunohistochemistry with an anti-CD90 antibody. The procedure labeled 99% of the BMSCs with SPIO, which exhibited low-intensity signals on T2 and T2* MRI imaging. At 24 h post-BMSC transplantation, low-intensity MRI signals were detected on the T2 and T2* sequences at the infarction margins. After 3 weeks following transplantation, low-intensity signals started to appear within the infarcted area; however, the signal intensity subsequently decreased and became indistinct. Immunohistochemistry revealed that the SPIO-labeled BMSCs migrated from the margin into the infarcted region. In conclusion, the BMSCs were readily labeled with SPIO and in vivo and MRI tracking demonstrated that the SPIO-labeled BMSCs established and grew in the infarcted myocardium.

Factors related to executive dysfunction after acute infarct.

AIM: The aim of this study was to investigate the association of infarct location with post-stroke executive dysfunction. METHODS: One hundred seventy-seven patients hospitalized with acute infarction were enrolled. General information and NIHSS score at admission were recorded. The infarct site was recorded from magnetic resonance T2-W1 and FLAIR images, and the extent of white matter disease was assessed using the Fazekas score. Seven days after symptoms, executive function was assessed using the validated Chinese version of Mattis Dementia Rating Scale (MDRS) Initiation/Perseveration (I/P) [MDRS I/P]. RESULTS: The average MDRS I/P score of the 177 infarction patients was 24.16 ± 5.21, considerably lower than the average score (32.7 ± 3.1) of a control group of normal individuals. Patients with infarcts in the corona radiata or basal ganglia had significantly lower MDRS I/P scores that those without infarcts at these locations. The number of infarcts in the basal ganglia was also significantly associated with low MDRS I/P scores. Male gender and low NIHSS score were significantly associated with low MDRS I/P score, and high-density lipoprotein cholesterol was significantly associated with high MDRS I/P score. The number of infarcts in areas other than the basal ganglia as well as corona radiata and the extent of white matter disease had no influence on this score. CONCLUSIONS: The number of infarcts in the basal ganglia corona radiata, low NIHSS score, and male gender are significantly and independently related to poor executive function (that is, low MDRS I/P score) after acute infarct.

Cell transplantation into ischemic myocardium using mesenchymal stem cells transfected by vascular endothelial growth factor.

AIMS: To investigate the effects of mesenchymal stem cells (MSCs) transplantation combining with vascular endothelial growth factor (VEGF) gene therapy on myocardium rebuilding, angiogenesis, and heart function improvement in rats with myocardial infarction. METHODS: SD rat MSCs were isolated, cultured in vitro, labeled with BrdU and transfected by Ad.VEGF gene. Four weeks after left anterior descending artery was ligated to create rat myocardial infarction, cardiac function was examined with echocardiography. Rats were randomly divided into four groups (n = 10 in each group): Group I: MSCs/Ad.VEGF implantation; Group II: MSCs implantation; Group III: Ad.VEGF injection; Group IV: Control. MSCs differentiation was observed 4 weeks after transplantation. Immunohistochemistry and angiogenesis were observed. Echocardiography was performed to detect the effects on heart function. RESULTS: MSCs labeled with BrdU could be identified in host hearts in group I and II, most of them positively stained with cTnT antibody. Echocardiography indicated that the improvement of the LVEF value in group I was more significant than that in the other three groups (P < 0.01, respectively). Some cells were incorporated into the coronary capillaries in the infarcted region. The capillary density in group I was higher than that in the other three groups (P < 0.01, respectively). CONCLUSION: MSCs implantation combining with VEGF gene therapy can obviously repair damaged myocardium and enhance the angiogenesis in ischemic heart tissue.

Inhibition of apoptosis by knockdown of caspase-3 with siRNA in rat bone marrow mesenchymal stem cells.

Transplantation of bone marrow mesenchymal stem cells is a promising new strategy for the repair of infarcted cardiac tissue. However, the majority of transplanted bone marrow mesenchymal stem cells (BMSCs) die soon after transplantation, due in part to oxidative stress in the ischemic region. Oxidative stress is known to induce apoptosis through the activation of caspase-3. The aim of this study is to determine whether small interfering RNA targeting caspase-3 can inhibit the apoptosis of rat BMSCs in vitro. Caspase-3 siRNA expression vectors were prepared and transfected into rat BMSCs in the presence of liposomes. Western blot assay and real-time polymerase chain reaction (RT-PCR) were performed to detect caspase-3 expression. A retrovirus packaging system was employed to package 293FT cells producing caspase-3 siRNA virus, which were transfected into rat BMSCs. Those stably expressing caspase-3 siRNA were screened by Western blot assay and RT-PCR to determine caspase-3 expression levels. Stable transfection of caspase-3 siRNA significantly decreased caspase-3 protein (0.26 ± 0.001 vs. 0.42 ± 0.004, P < 0.05) and mRNA expression (0.19 ± 0.002 vs. 1, P < 0.05) in BMSCs compared to non-transfected BMSCs. Cells were incubated in H2O2 to induce apoptosis, which was detected by TUNEL staining, and BMSC morphology was not altered by either transient or stable transfection of caspase-3 siRNA. H2O2-induced apoptosis of BMSCs stably transfected with caspase-3 siRNA was dramatically reduced compared to that of normal BMSCs (11.0 ± 3.2 vs. 25.8 ± 4.2, P < 0.05). Caspase-3 knockdown BMSCs are thus more resistant to apoptosis than normal BMSCs, potentially increasing their survival rates under conditions that cause oxidative stress.

Predictors of early post ischemic stroke apathy and depression: a cross-sectional study.

BACKGROUND: Apathy and depression are important neuropsychiatric disorders that can occur after a stroke but the etiology and risk factors are not well understood. The purpose of this study was to identify risk factors for apathy and depression following a stroke. METHODS: Patients with an acute stroke who met the inclusion criteria were recruited from our hospital, and general information was recorded from patient charts. The Apathy Evaluation Scale, Clinician Version (AES-C) was used to evaluate these patients within 2 weeks after the stroke. The Montreal Cognitive Assessment (MoCA), mini-mental state examination (MMSE), Hamilton Depression Scale (HAMD), Mattis Dementia Rating Scale Initiation/Perseveration subset (MDRS I/P), Frontal Assessment Battery (FAB) and Stroop Color-Word Association Test were employed to evaluate emotion, cognitive function and executive function. The patients were divided into two groups: the apathy group and the non-apathy group. We also divided the patients into two groups based on whether or not they had post-stroke depression. The clinical characteristics and scores on the MoCA, MMSE, HAMD and MDRS I/P were compared between the apathy and non-apathy groups as well as between patients with and without depression. Logistic regression analysis was performed to identify risk factors for apathy and depression following a stroke. RESULTS: A total of 75 patients with acute stroke were recruited. Of these, 25 (33.3%) developed apathy and 12 (16%) developed depression. Multivariate logistic regression analysis indicated that a history of cerebrovascular disease (OR: 6.45, 95% CI: 1.48-28.05, P = 0.013), low HbA1c (OR: 0.31, 95% CI: 0.12-0.81, P = 0.017) and a low MDRS I/P score (OR: 0.84, 95% CI: 0.74, 0.96, P = 0.010) were risk factors for post-stroke apathy. Additionally, multivariate logistic regression indicated that a low MDRS I/P (OR: 0.85, 95% CI: 0.75, 0.97, P = 0.015) was associated with post-stroke depression. CONCLUSIONS: Three risk factors for post-stroke apathy were identified as a history of cerebrovascular disease, low HbA1c and lower MDRS I/P scores. A low MDRS I/P score was also identified as a risk factor for post-stroke depression. These results may be useful to clinicians in recognizing and treating apathy and depression in patients after a stroke.

Patient-specific decision-making for warfarin therapy in nonvalvular atrial fibrillation: how will screening with genetics and imaging help?

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) accounts for a majority of long-term morbidity and mortality associated with bleeding while on warfarin. Both ICH and warfarin-related ICH appear to have a genetic component. Furthermore, advanced neuroimaging using MRI can now identify individuals at increased risk of ICH. We explore whether screening strategies that include genetic profiling and neuroimaging might improve the safety of chronic anticoagulation for atrial fibrillation by identifying individuals from whom warfarin should be withheld. METHODS: We used a Markov state transition decision model. Effectiveness was measured in quality-adjusted life-years. Data sources included the English language literature using MEDLINE searches and bibliographies from selected articles along with empirical data from our institutions. The base case was a 69-year-old man with newly diagnosed nonvalvular atrial fibrillation. RESULTS: For patients at average risk for thromboembolic events and known to possess a hypothetical genetic profile increasing risk for warfarin ICH, anticoagulation remains the preferred strategy until the relative hazard of ICH exceeds 23.8. Genetic profiling would be favored for patients at low risk of thromboembolism (1.5% per year) if the hypothetical gene variant(s) conferred a relative risk of ICH >4.1. Screening strategies in which patients underwent genotyping and MRI before anticoagulation did not improve aggregate patient outcomes unless the predictive power of MRI exceeded current best guess estimates and patients were at low to moderate risk of thromboembolism. CONCLUSIONS: Currently identified genetic markers of bleeding risk do not confer a risk of ICH sufficiently high to warrant routine genetic testing for patients at average risk of thromboembolism. Even if patients undergo screening with MRI as well as genotyping, currently available data on the role of MRI on risk of ICH and warfarin ICH do not support use of these tests for withholding anticoagulation in patients with atrial fibrillation.

Risk vs benefit of anti-thrombotic therapy in ischaemic stroke patients with cerebral microbleeds.

BACKGROUND: Retrospective studies suggested that cerebral microbleeds (MB) on magnetic resonance images (MRI) increase risk of intracerebral haemorrhage (ICH). OBJECTIVE: To compare the benefit of anti-thrombotic agents in stroke prevention (absolute risk reduction 2.49 -6 %) versus risk of ICH in ischaemic stroke patients with MB. MATERIALS AND METHODS: We prospectively studied patients admitted consecutively for acute ischaemic stroke between 1999 and 2004. MB on MRI were documented. Primary end points were subsequent ICH, recurrent cerebral infarct (CI) and mortality. RESULTS: A total of 908 patients were recruited. MB were identified in 252 (27.8 %) patients. Mean follow-up period was 26.6 +/- 15.4 months. Risk of subsequent ICH increased significantly with quantity of MB: 0.6 % (no MB), 1.9 % (1 MB), 4.6 % (2-4 MB) and 7.6 % (>or= 5 MB) (p < 0.001). There was also a significant increase in mortality from ICH: 0.6 %, 0.9 %, 1.5 % and 3.8 % respectively (p = 0.054). Rate of recurrent CI was 9.6 %, 5.6 %, 21.5 % and 15.2 % respectively (p = 0.226). Mortality from CI and myocardial infarction did not increased with quantity of MB. Survival analyses showed that age, presence of MB, mixed cortical-subcortical distribution of MB were independent predictors of subsequent ICH. CONCLUSION: Risk and mortality of ICH increased with quantity of MB. As tendency to recurrent CI exceed that of ICH, anti-thrombotic agents are still warranted. However, in patients with >or= 5 MB, the high risk and mortality of ICH seem to outweigh the modest benefit of antithrombotic agents. Extra precautions should be taken to minimize risk of ICH. Further studies in patients on Coumadin and assessment of functional outcome are warranted to support these preliminary findings.