| Obiective:Bone morrow mesenchymal stem cells (BM-MSCs) have been one of the optimal candidate cells for acute myocardial infarction (AMI) in recent years, however, the mechanism of MSCs transplantation in curing ischemic heart disease has not yet been fully. We proposed, MSCs transplantation improves cardiac function not only by differentiation and angiogenesis of MSCs, but also improve the metabolism of cardiocytes energy substrate, and then improve myocardial contraction. In this study, we will in vivo observe the changes of myocardial glucose metabolism, myocardial perfusion and cardiac function after MSCs transplantation in swine with AMI by means of cell biology and molecular imaging methods including positron emission tomography-computer tomography (PET-CT), single-photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI), in the purpose of evaluating the effect and mechanism of MSCs transplantation treating ischemic heart disease.Method:Twenty-four Chinese mini-swine were randomized into2groups of MSCs transplantation group (MSCs group; n=12) and Control group (n=12). Myocardial infarction was induced in swine hearts by occlusion of the left anterior descending artery (LAD). Thirty minutes later, the MSCs group received autologous BM-MSCs transplantation through intramyocardial injection into the peri-infarcted areas and Control group were subjected to cell culture medium in the same way. After1week and4weeks, myocardial glucose metabolism, myocardial perfusion and cardiac function were evaluated in the two groups through PET-CT, SPECT and MRI. On the end point (the4th week), H&E stain and Masson's Trichrome stain were performed to observe the extent of infarction area, inflammatory cells infiltration and myocardial fibrosis.Results:As evaluated by PET, on the baseline, the minimum FDG mean signal intensity (MSI) in MSCs group was below Control group (22.10±3.18vs.35.70±3.02, P<0.05), and the summed MSI was below Control group (1013.50±29.37vs.1084.00±21.15, P <0.05). Compared to the1st week, the minimum MSI in MSCs group was increased obviously (34.00±4.25vs.22.10±3.18, P<0.01) on the4th week, and also the summed MSI (1075.50±28.30vs.1013.50±29.37, P<0.01); summed rest score (SRS) and SRS%were decreased on the4th week compared to the1st week (20.20±2.24vs.23.80±1.58, P<0.05;29.80±3.31vs.35.10±2.34, P<0.05); the summed MSI in left ventricular infarction area (in area MSI below70) and average MSI were also increased (384.60±37.13vs.323.60±18.99, P<0.01;56.25±3.54vs.48.14±2.71, P<0.01); the metabolism defect area, defect extent and TPD the4th week were lower than those was on the1st week, but there were no significant differences (27.20±4.06vs.28.90±2.48;37.70±3.79vs.42.40±2.46;31.70±3.52vs.36.00±2.57; P>0.05). However, in the Control group, the variables mentioned above had no statistics differences in the endpoint than in the baseline (all P<0.05). The differences of minimum MSI between1st week and4th week in the MSCs group significantly high than the Control group (11.90±2.93vs.1.70±2.00, P<0.05), and also the differences of summed MSI between the two groups (85.80±19.50vs.1.10±17.09, P<0.01). Only6swine in the MSCs group and5swine in the Control group evaluated myocardial perfusion by SPECT. On the baseline, the perfusion variables had no significant differences between the two groups (P>0.05), and there were no differences in variables reflecting myocardial perfusion and defect area between baseline and endpoint in the two groups (P>0.05). As evaluated by MRI, the cardiac functional parameters had no significant differences in the two groups on the baseline. In the MSCs groups, left ventricular ejection fraction (LVEF) was increased significantly (54.41±2.62vs.47.54±2.43, P<0.01) and end-systolic volume (ESV) was significantly reduced (22.85±1.91vs.27.07±1.67, P<0.01) on the4th week compared to the1st week; stroke volume (SV) and cardiac output (CO) in the4th week also increased significantly (29.35±1.84vs.26.52±1.46, P<0.05;2.23±0.14vs.1.96±0.13, P<0.05). In the Control group, there were no significant differences in the cardiac functional parameters on the baseline and endpoint(P>0.05).Conclusion:Four weeks after MSCs transplantation for curing AMI, cardiac function and myocardial glucose metabolism improved significantly; however, obvious myocardial perfusion improvement was not seen. It is speculated that the cardiac improvement is associated with the enhancement of myocardial glucose metabolism. Objective:The mechanism of stem cells transplantation in curing ischemic heart diseases has not been clarified. The aim of this study is to investigate the effect and mechanism of bone marrow mesenchymal stem cells (BM-MSCs) transplantation in acute myocardial infarction (AMI) by means of detecting glucose metabolism in global left ventricular myocardium and regional myocardium, combined with assessment of cardiac function, and also to study the changes of glucose transporters, glucose metabolism-related enzymes and the signal transduction pathway which may participate in the MSCs paracrine process.Methods:Thirty-two Chinese mini-swine were randomized into3groups of MSCs transplantation1-week group (MSCs-lw group; n=8), MSCs transplantation4-week group (MSCs-4w group; n=12) and Control group (n=12). BM-MSCs were separated and cultured for3-4weeks and then myocardial infarction was induced in swine hearts by occlusion of the left anterior descending artery (LAD). Thirty minutes later, the MSCs groups (MSCs-lw group and MSCs-4w group) received autologous MSCs (2×107,2ml) transplantation through intramyocardial injection into the peri-infarcted areas and Control group were subjected to cell culture medium in the same way. Positron emission tomography-computer tomography (PET-CT) and magnetic resonance imaging (MRI) were performed on the1st week and4th week. The swine were killed on the endpoints (1st week or4th week), and the gene expression of glucose transporters (GLUT1, GLUT4), glucose metabolism-related enzymes (PFK, GAPDH) and the proteins in mTOR signal transduction pathway in MSCs injection area were measured by real-time polymerase chain reaction (PCR).Results:As shown by PET-CT, all the variables had no differences in the MSCs-lw group and MSCs-4w group on the baseline. The minimum FDG mean signal intensity (MSI) in MSCs-4w group was below Control-4w group (22.10±3.18vs.35.70±3.02, P <0.05), and the summed MSI was below Control-4w group (1013.50±29.37vs.1084.00±21.15, P<0.05). Compared to the1st week, the minimum MSI in MSCs-4w group was increased obviously (34.00±4.25vs.22.10±3.18, P<0.01) on the4th week, and also the summed MSI (1075.50±28.30vs.1013.50±29.37, P<0.01); summed rest score (SRS) and SRS%were decreased on the4th week compared to the1st week (20.20±2.24vs.23.80±1.58, P<0.05;29.80±3.31vs.35.10±2.34, P<0.05); the summed MSI in left ventricular infarction area (in area MSI below70) and average MSI were also increased (384.60±37.13vs.323.60±18.99, P<0.01;56.25±3.54vs.48.14±2.71, P <0.01). However, in the Control-4w group, the variables mentioned above had no statistics differences in the endpoint than in the baseline (all P<0.05). Metabolic evaluation in regional left ventricular showed that MSI increased in these segments on the4th week compared to the1st week:apical-anterior segment (32.00±5.35vs.44.10±5.90, P<0.05), mid-anterior segment (57.40±4.00vs.65.30±4.66, P<0.05), apical-septal segment (52.00±2.55vs.61.60±2.67, P<0.05) and mid-anteroseptal segment (62.80±2.85vs.69.50±2.17, P<0.05), and MSI in other segments didn't increase significantly (P>0.05). However, there were no differences in MSI between the1st week and4th week in the Control-4w group. As evaluated by MRI, the cardiac functional parameters had no significant differences in the three groups on the baseline (P>0.05). In the MSCs-4w group, left ventricular ejection fraction (LVEF) was increased significantly (54.41±2.62vs.47.54±2.43, P<0.01) and end-systolic volume (ESV) was significantly reduced (22.85±1.91vs.27.07±1.67, P<0.01) on the4th week compared to the1st week; stroke volume (SV) and cardiac output (CO) in the4th week also increased significantly (29.35±1.84vs.26.52±1.46, P<0.05;2.23±0.14vs.1.96±0.13, P<0.05). In the Control-4w group, there were no significant differences in the cardiac functional parameters on the baseline and endpoint (P>0.05). In the MSCs-4w group, real-time PCR analysis showed positive up-regulation of GLUT1, GLUT4, PFK, GAPDH and p70s6k (a downstream protein in mTOR signal transduction pathway) compared to the Control-4w group and the MSCs-lw group (all P<0.05).Contusion:Intramyocardial injection of MSCs after AMI could improve cardiocytes glucose metabolism and improve cardiac function. The gene expression of glucose transporters (GLUT1, GLUT4), glucose metabolism-related enzymes (PFK, GAPDH) and p70s6k in MSCs injection area are up-regulated on the4th week after MSCs transplantation. It indicates that MSCs may active mTOR signal transduction pathway through paracrine effect to promote myocardial glucose metabolism and cardiocytes growth and then give rise to improved myocardial contraction and enhanced cardiac function. Objective:Gated single photon emission computed tomography (SPECT) myocardial perfusion imaging has proven to be invaluable not only in assessing myocardial perfusion, but also in providing functional and volumetric information. The aim was to investigate the value of rest gated-SPECT myocardial perfusion imaging for predicting cardiac death in patients with chronic heart failure (CHF).Methods:Seventy-three consecutive hospitalized patients (50.7±16.5years,60men) with defined diagnosis of CHF (25ischemic CHF and48non-ischemic CHF) and echocardiography left ventricular ejection fraction (LVEF)<40%, who underwent rest99mTc-MIBI gated SPECT myocardial perfusion imaging, were followed up for18.6±8.5months (range,1.1-30.0months). Only cardiac death during follow-up served as the endpoint. Cox proportional hazard regression analysis was applied to determine independent predictors of cardiac death and Kaplan-Meier method was applied to estimate the probability of survival with CHF.Results:During the follow-up period,14(19.2%) cardiac deaths occurred in the73patients. Univariate Cox analysis showed that body mass index (BMI,23.3±4.1Kg/m2, P<0.05), brain natriuretic peptide (BNP, P<0.05), gated-LVEF (20.8%±7.9%, P <0.05), summed motion score (P<0.05), summed rest score (SRS, P<0.05) and defect extent (P<0.05) were significant predictors. When the above predictors were applied to multivariate Cox analysis, BMI (P<0.05, Hazard Ratio=0.85) and SRS (P<0.05, Hazard Ratio=1.05) showed predictive values for future cardiac death. The optimal threshold of BMI was25Kg/m2, the difference of cumulative survival between patients with BMI<25Kg/m2and those with BMI≥25Kg/m2was significant (P<0.05) and patients with BMI<25Kg/m2had lower survival. The optimal threshold of SRS was set as11, the difference of cumulative survival between patients with SRS≤1and those with SRS>11was significant (P<0.01), and patients with SRS>11had lower survival. The patients with BMI<25Kg/m and SRS>11simultaneously had the lowest survival in the73patients with CHF (P<0.001).Conclusions:The present study indicates that the rest gated SPECT myocardial perfusion imaging gives prognostic information in patients with CHF. Both BMI and SRS are predictors for future occurrence of cardiac death, and patients with BMI<25Kg/m2and SRS>11simultaneously should be treated and cared for intensively.
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