| Chronic ischemic heart disease remains a major cause of morbidity andmortality. Despite significant advances in medical therapy and interventionaltherapies such as coronary artery bypass grafting and percutaneous coronaryintervention, no therapies are currently available to restore dead myocardium.Recent experimental studies and clinical trials suggested stem cells mightcontribute to the regeneration of infarct myocardium and enhanceneovascularization of ischemic myocardium.Granulocyte colony-stimulating factor (G-CSF), a hematopoietic cytokine,induces the mobilization of hematopoietic stem cells and endothelial progenitorcells (EPC) from bone marrow into the peripheral bolld circulation. Recently,several groups have reported that G-CSF prevents left ventricular remodelingafter acute myocardial infarction. However, few studies focus on the effects ofchronic ischemia myocardium.Therefore, in the present study, we examined whether G-CSF treatment iseffective on chronic myocardial ischemia in swine and investigated themechamism of beneficial effects of G-CSF.Partâ… Experimental study on animal model ofchronic myocardial ischemiaOBJECTIVES: To develop a swine model of chronic myocardial ischemia withAmeroid. constrictor implantation.METHODS: A thoracotomy and limited pericardiectomy were performed in 21mini-pigs. They were randomly assigned into three groups: 1) control group(sham-operated) (n=7), with no constrictor implanted; 2) Four-week group(n=7), with Ameroid. constrictor implanted and sacrificed four weeks afteroperation; 3) Eight-week group (n=7), with Ameroid. constrictor implanted andsacrificed eight weeks after operation. An Ameroid constrictor with internaldiameter of 1.5 2.5mm was placed in the proximal portion of leftcircumflex(LCX). Prior to the operation and being sacrificed, all animalsunderwent electrocaridogram, coronary angiography, left ventriculography, echocardiography, 99mTc-SPECT and cardiac blood pool imaging andfirst-pass delayed cardiac magnetic resonance imaging (CMR) to evaluatethe degree of stenosis and myocardial dysfunction.RESULTS: Total and subtotal stenosis of the left circumflex branch of coronaryartery were observed in 11 swines with Ameriod constrictor. At four weeks, asignificant decrease was found in Left ventricular ejection fraction (LVEF) from73.4±2.3ï¼…to 55.0+9.8ï¼…(p＜0.001), with the absolute change of LVEF17.9±2.3ï¼…from baseline according to angiography. LVEF decreased by24.4±3.1ï¼…in eight-week group, compared to 0.3±0.4ï¼…in control group and17.9±6.8ï¼…in four-week group, (both p＜0.001). The data fromechocardiography indicated an apparent rise in the left ventricular end-diatolicdiameter (LVEDd) and left ventricular end-systolic diameter (LVESd) at fourweek following the operation, accompanying the significant attenuated the wallmotion of the LCX distributing territory, the myocardial perfusion defect areaincreased to 12.8±2.6ï¼…at four weeks and 17.5±4.0ï¼…at eight weeks, withcorresponding increase in the same territory in regard to myocardial infarctsize. And the myocardium apoptosis and fibrosis were significantly moreapparent in the swine with constictor implanted than in control group.CONCLUSION: This is a useful model of chronic myocardial ischemic that isreproducible and applicable to clarification of therapeutic interventions forchronic myocardial ischemiaPartâ…¡Cardioprotective Effect of Granulocyte Colony-StimulatingFactor in Swine with Chronic Myocardial IschemiaChapterâ… Efficacy of G-CSF Treatment with various dosage on cardiac functionand ventricular remodeling in Swine with Chronic Myocardial IschemiaOBJECTIVES: The aim of this study was to investigate the effect ofgranulocyte colony-stimulating factor (G-CSF) on chronic myocardial ischemia in swine.METHODS: Twenty-four swine underwent placement of ameriod constrictor onleft circumflex coronary artery. The presence of myocardial ischemia wasverified at four weeks after the operation, after the presence of myocardialischemia at four weeks, all the animals were randomly assigned into fourgroups: 1) administration of vehicle (control group, n=6), 2) administration oflow dosage G-CSF(2.5μg/kg/d) for five days (LOW group, n=6), 3)administration of routine dosage G-CSF(5μg/kg/d) for five days (MID group,n=6), and 4) administration of high dosage G-CSF(10μg/kg/d) for five days(HIGH group, n=6). Measurements were obtained pre-administration and at 4weeks post administration, including coronary angiogram, routineechocardiography, cardiac MRI, 99mTc-SPECT and18F-FDG-SPECT/99mTc-SPECT (DISA-SPECT). Global heart function such asleft ventricular end-diatolic diameter (LVEDd), left ventricular end-systolicdiameter ((LVESd) and left ventricular ejection fraction (LVEF), segmental wallmotion score, myocardial perfusion, myocardial viability and myocardial infarctarea were evaluated.RESULTS: At eight weeks, G-CSF treatment with routine dosage exerted afavorable influence on left ventricular dilation and dysfunction according toEchocardiography and MRI, and SPECT revealed that G-CSF couldameliorate the regional contractility of chronic myocardial ischemia andpreserve myocardial viability, meanwhile Myocardial infarct size on MRI wasalso reduced after G-CSF treatment. Furthermore, G-CSF treatment wasassociated with a significant reduction in infarct size, collagen expression andmyocardial apoptosis. There were less infarcted myocardium, collagen I andapoptotic cells at the ischemic region of the heart of the G-CSF group thancontrol group. Among the three groups of different dosage G-CSF treatment,5μg/kg/d G-CSF was identified as optimal dose in term of cardioprotectiveeffect.CONCLUSIONS: Our result suggested that 5μ/kg/d G-CSF could contributeto the improvement of cardiac function of chronic myocardial ischemia,probably via a mechanism involving in reduction of cardiac fibrosis andapoptosis Chapterâ…¡Prophylactic Efficacy of G-CSF Treatment on cardiac function andventricular remodeling in Swine with Chronic Myocardial IschemiaOBJECTIVES: The aim of this study was to investigate the prophylactic effectof granulocyte colony-stimulating factor (G-CSF) on chronic myocardialischemia in swine.METHODS: Twelve swine underwent placement of amefiod constrictor on leftcircumflex coronary artery. The presence of myocardial ischemia was verifiedrightly after the operation, and the animals were randomly assigned into twogroups: 1) administration of vehicle (control group, n=6) and 2) administrationof low dosage G-CSF(5μg/kg/d) for five days (LOW group, n=6) three hoursafter operation. Measurements were obtained pre-administration and at 4weeks post administration, including coronary angiogram, 99mTc-SPECT,18F-FDG-SPECT/99mTc-SPECT(DISA-SPECT) and cardiac MRI. Global heartfunction such as left ventricular end-diatolic volume (LVEDV), left ventricularend-systolic volume ((LVSDV) and left ventricular ejection fraction (LVEF),myocardial perfusion, myocardial viability and myocardial infarct area wereevaluated.RESULTS: All animals were alive before sacrificed. Prophylactic treatmentwith G-CSF of 5μg/kg/d could prolong the time of coronary stenosis andattenuate the extent of stenosis. SPECT data revealed that the LVEF in G-CSFgroup was less than that in the control (61.0±3.5ï¼…vs 55.6±1.6ï¼…, p＜0.01)four weeks after operation. Meanwhile the absolute decreae of LVEF in G-CSFgroup was less than that in the control group(12.2±3.8ï¼…vs 18.8±2.3ï¼…,p＜0.01) by MRI detecting. In addition, LVEDV and LVESV increased in bothgroups. Compared with the control group, LVESV was much less in G-CSFtreatment while no significant differece was found in the two groups.Myocardial infarct size and myocardial perfusion defect size was also less inG-CSF group than that in the control detected by MRI and SPECT. CONCLUSIONS: These findings suggested that prophylactic GoCSF treatmentcould attenuate the progress of chronic myocardial ischemia and the extent ofcoronary stenosis.Chapterâ…¢Intracoronary Injection of G-CSF Ameliorates the Progression of LeftVentricular Remodeling in Swine with Chronic Myocardial IschemiaOBJECTIVES: The aim of this study was to investigate whether intracoronaryinjection of granulocyte colony-stimulating factor (G-CSF) was safe andfeasible for chronic myocardial ischemia in swine.METHODS: Eighteen swine underwent placement of amedod constrictor onleft circumflex coronary artery. The presence of myocardial ischemia wasverified at four weeks after the operation, and the animals were randomlyassigned into three groups: 1) administration of vehicle (control group, n=6), 2)hypodermic injection of G-CSF(5μg/kg/d) for five days (IH group, n=6), and 3)intracoronay injection of a bonus G-CSF (60μg/kg) (IC group, n=6).Measurements were obtained pre-administration and at 4 weeks postadministration, including coronary angiogram, cardiac MRI 99mTc-SPECT and18F-FDG-SPECT/99mTc-SPECT(DISA-SPECT). Global heart function such asleft ventricular end-diatolic volume (LVEDV), left ventricular end-systolicvolume ((LVSDV) and left ventricular ejection fraction (LVEF), myocardialperfusion, myocardial viability and myocardial infarct area were evaluated.RESULTS: MRI data showed that the G-CSF treatment in both methodsprevented left ventricular dilation and dysfunction at eight weeks after theoperation. SPECT revealed that G-CSF ameliorated the regional contractilityof chronic myocardial ischemia and increase myocardial viability. Myocardialinfarct size was also decrease after G-CSF treatment detected by MRI. Nosignificant difference was found between SC group and IC group. Intracoronayinjection of G-CSF did not lead to angiogenesis in other tissues. CONCLUSIONS: These findings suggested that intracoronay injection ofG-CSF was safe and feasible as same as hypodermic injection of G-CSF.Chapterâ…£The mechanism of G-CSF treatment for Swine withChronic Myocardial IschemiaOBJECTIVES: The aim of this study was to investigate the machanism oftherapeutic efficacy of different dosage granulocyte colony-stimulating factor(G-CSF) treatment on cardiac function in swine with chronic myocardialischemia.METHODS: Twenty-four swine underwent placement of ameriod constrictor onleft circumflex coronary artery. The presence of myocardial ischemia wasverified at four weeks after the operation, and the animals were randomlyassigned into four groups: 1) administration of vehicle (control group, n=6), 2)administration of low dosage G-CSF(2.5μg/kg/d) for five days (LOW group,n=6), 3) administration of routine dosage G-CSF(5μg/kg/d) for five days (MIDgroup, n=6), and 4) administration of high dosage G-CSF(10μg/kg/d) for fivedays (HIGH group, n=6). Serum was collected at the designed timepoints forELISA test. Four weeks after the injection, all animals were sacrificed. Thevessel and myocardium distributed by LCX were stored in liquid nitrogen untilmeasured.RESULTS: There were more vessels and less apopototic cells at the ischemicregion of the heart of the MID and HIGH G-CSF group than control group andLOW group. It was showed that the level of protein and mRNA of vWF, VEGFand MCP-1 was significantly up-regulation in the ischemic myocardium inthese two groups. Moreover, Aktl was more strongly activated in the heart ofthe MID and HIGH G-CSF group than control group. On the other hand,hsCRP, TNF-alpha and S-100 was also elevated after high dosage G-CSF treatment, which may be related to artherosclerosis aggravation.CONCLUSIONS: These findings suggested that G-CSF improves cardiacfunction of chronic myocardial ischemia through decreases in fibrosis andapoptotic death in the ischemic region. The other side effect of G-CSF on theheart was to aggravate inflammation and artherosclerosis, which attenuatedthe cardiaoprotective effect of G-CSF in high dosages. |
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