Abstract 1096: Cytokine Enhancement with Hgf Or Vegf in the Infarct Border Zone is Key to Attenuating the Negative Remodelling after Myocardial Infarction
Sonja SchrepferT. DeuseChristoph PeterWilliam SteinTimothy C. DoyleWolfram H. ZimmermannThomas EschenhagenMarc PelletierJoseph C. WuRobert C. Robbins
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Adult mesenchymal stem cell (MSC)-based treatment strategies have been proposed to alleviate the consequences of myocardial infarction (MI). The cytokine release of ischemic myocardium was investigated in vivo after LAD ligations in mice and in vitro in cultured cardiomyocytes. Of all cytokines that were at least 5-fold upregulated during ischemia, only HGF and VEGF proved to promote MSC proliferation, and chemotaxis in vitro. Homing of intranenously (IV) injected MSCs (0.5×106 per animal) into the infarct border zone after LAD ligation was inefficient (1±0.5 cells/HPF). Cytokine enhancement (CE) of HGF or VEGF by intramyocardial injection at the time of MI significantly facilitated MSC homing (11±4 cells/HPF and 7±4 cells/HPF, respectively; p=0.001). To our knowledge, this is the first study monitoring cardiac geometry and function over a long-term period of 6 months. using ECG-triggered contrast Micro-CT. It revealed that the progressive decrease in EF over time (to 19±1%) could be attenuated by CE with HGF (29±6%; p=0.003) or VEGF (28±4%; p=0.004) and subsequent IV MSC injection. However, LVEFs of animals treated with CE with HGF or VEGF only, but received no MSC injection, were similar to those groups that also received IV MSCs (p=0.127 and p=0.54, respectively). Best results were finally achieved by prolonged presence of HGF or VEGF, achieved by intramyocardial injection of MSCs stably transfected to produce HGF or VEGF and firefly luciferase into the infarct border zone. Duration of cytokine release was estimated by monitoring MSC survival using in vivo bioluminescence imaging (BLI). BLI signals were detectable for 10 days in contrast to the rapid fate of the cytokines after single dose administration in the CE group, resulting in preserved LVEFs at 6 months This study highlights the beneficial effect of HGF and VEGF to attenuate the negative LV remodelling after MI and diminishes the role of the MSCs to a pure delivery system for paracrine effects.Keywords:
Homing (biology)
Border zone
Rabbits and rats are becoming popular models for in vitro as well as in situ studies of myocardial infarction. In the present analysis we evaluated the results of several of our completed investigations and tested whether blood-free perfusate, anesthesia, or risk zone size affects infarction in these species. In addition, the influence of the method used for determining infarct size (histology or histochemistry) was examined in rabbits. All hearts experienced 30 min of regional ischemia followed by either 2-3 h of reperfusion in animals in which infarct size was assessed by staining with triphenyltetrazolium chloride or 72 h in those in which histological methods were used to measure infarct size. Eighteen rabbit and seven rat hearts perfused with Krebs buffer, seventeen open-chest rabbits, eight rats anesthetized with pentobarbital, and ten conscious rabbits were studied. Risk zone size measured with fluorescent particles was plotted against infarct size. Infarct size was linearly correlated with risk zone size and did not differ among models for each species. In rat hearts the regression line passed through the origin so that zero infarction occurred with zero risk zone size. However, in the rabbit heart there was no apparent infarction for risk zone sizes < 0.3 cm3. Although the relationship between risk zone and infarction was found to be remarkably independent of the model chosen, the nonzero intercept for the rabbit heart can be an important, previously unrecognized source of experimental variability when infarct size is expressed as a percentage of the risk zone.
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Surface isopotential maps were recorded immediately before and 1 week after production of myocardial infarctions in 15 dogs. Difference maps were made by subtracting pre-infarction maps from time-equivalent post-infarction maps, and the electrophysiological basis of the difference maps was examined. The dogs were classified into 4 groups according to the location and extent of the infarction. Difference maps of these groups displayed an area with significant surface potential defects due to infarction. These changes were observed during specific phases of ventricular activation and in specific portions of the chest surface, depending on the location and extent of the infarction. These findings were well accounted for by the hypothesis that difference maps reflect the loss of activation fronts as a result of the infarction.
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The present study was attempted in order to investigate the effectiveness of propranolol in limiting of myocardial infarct size following ligation of the left coronary artery in Wistar rats. The non-infarcted ischemic zone, the border zone, was significantly larger in the rats sacrificed 3 hours after the ligation (25.6±4.9% LV) than in those sacrificed 6 hours after ligation (10.7±6.6%LV). No border zone was demonstrated when the rats were sacrificed 12 hours after the ligation. Nor were any differences in the size of the area at risk found among the above 3 groups. The size of the infarcted area was significantly smaller than in the control group (46. 0±5.5%LV) when propranolol was administered intraperitoneally before (25.3±4.6%LV), immediately after (35.0±4.1%LV) or 3 hours after ligation (36.6±4.7%LV). However, propranolol could not reduce infarct size when administered 6 hours (44.1±8.5%LV) or 12 hours (46.2±3.6%LV) after ligation of the coronary artery.The present study clearly demonstrates the presence of a non-infarcted ischemic zone, a border zone, until at least 6 hours after the ligation of the coronary artery and reduction of the infarcted area by propranolol when administered until at least 3 hours after the ligation. Thus, the author postulated the usefulness of beta-blocking agents in the early phase of acute myocardial infarction.
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Non‐refused areas of infarcted hearts are commonly thought to be severely hypoxic. However, the actual PO2 levels in the infarct area are not well known. This is critical for finding the best time and place of stem cells injection used in myocardial repair. We used electron paramagnetic resonance (EPR) and lithium phthalocyanine (LiPc) crystals as probes to measure PO2 in hearts at 1, 3, 5 and 7 days of permanent left anterior descending coronary artery (LAD) ligation in C57BL/6 mice (n=23). Immediately after LAD ligation, myocardial PO2 decreased from 20 mmHg to ∼0.8 mmHg, while at border zone remained significantly higher at ∼14 mmHg (P<0.01). Surprisingly, PO2 at infarct area started to increase after 3‐day and remained stable at ∼ 40mmHg after 5 days. At border zone, PO2 increased to ∼40mmHg after 1‐day ligation. About 40% of mice with infarction died of left ventricular rupture that occurred on average at 4.4±0.8 days, similar to control mice without LiPc injection (n=40). However, the pattern of PO2 was indistinguishable between ventricular ruptured and surviving mice up to the 4th day. To our knowledge, this is the first documentation of spontaneous reoxygenation of infarct area after LAD ligation in mice. This suggests that an optimal time for stem cell injection in the infarct zone‐based on myocardial oxygenation‐would be 3∼4 days after onset of ischemia, while the border zone is a preferable site at earlier times.
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Objective:To detect the tissue intensity features of regional wall abnormalities in dogs with acute myocardial infarction during diastolic period,and the results from this study provide experimental foundation for tissue intensity cure(TIC) in estimating the regional left ventricular diastolic function of acute myocardial infarction.Methods:Twelve dogs ligated left anterior descending coronary artery(LADCA) were performed at apical two-chamber view by doppler tissue imaging in pre-ligation and post-ligation 4 hours.Tissue intensity of LV segments was analyzed by tissue intensity curves synchronously.Results:Pre-ligation TIC showed increasing negative value from base to apex during the whole relaxation period;in post-ligation 4 hours,this law disappeared and the negative value of dB in infarction segments was bigger than that of pre-ligation.During ventricular filling phase post-ligation the value of dB of infarction segment was bigger than pre-ligation and non-infarction segment(P0.01).Conclusion:The dB value of myocardial tissue increases during acute myocardial infarction(AMI).The infarction and normal myocardium can be distinguished and assessed by quantitatively analyzing the change of tissue intensity.And TIC is very useful for clinical diagnosing acute myocardial infarction and positioning the segment of infarction.
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Objective To study the clinical Features and the crisis factors.Methods We selected the patients with cortical border-zone infarction,internal border-zone infarction and combined border-zone infarction.The digital subtraction angiography and MRI were studied.Results There were no difference in clinical characteristics among the three groups.80% patients with cortical border-zone infarction had serious vascular stenosis,patients with internal border-zone infarction had serious vascular stenosis.patients with combined border-zone infarction had serious vascular stenosis.Conclusion The cerebral border-zone infarction is associated with serious vascular stenosis,hypotension is important crisis factor.
Border zone
Digital subtraction angiography
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Objective To evaluate the changes of MRI signs during the myocardial infarction.Methods Left anterior descending (LAD) and Left cricumflex (LCx) coronary artery were ligated simultaneously in rabbits.Before the operation,at 30 minutes,1 hour,2 hours,4 hours,8 hours,1 day,3 days,1 week,2 weeks,and 4 weeks after ligation,imagings on T1,PD,T2,enhancement,cine-MRI were obtained respectively,to measure the intensity and thickness in different regions of left ventricular wall.Results At 30 minutes after ligation,the ischemic local wall of left ventricle became thinner,more in contractile phase,and became worse gradually.At 1 hour after ligation,hyperintensity on PDWI and T2WI in region of infarction was found,and became higher gradually,then the signal descended in 1 week after ligation,hypointensity in 4 weeks; hypointensity on T1WI was found in 4 weeks in region of infarction; In acute myocardial infarction,normal myocardium was enhanced in 5 minutes after injection, ring enhancement could be found in the marginal region of infarction in 15-20 minutes,centre of infarction was enhanced in 30 minutes.Conclusion MRI can find the myocardial ischemia of large area at early stage and can comfirm the stages of myocardial infarction.
Circumflex
Left coronary artery
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Results are described on the effect of limitation of the infarction zone on the course of IHD during the first year of observation in 320 patients with a history of myocardial infarction (MI). The clinical course of the disease and changes of tolerance of physical load were studied in two groups of patients. In one of the groups limitation of the infarction zone was realized during the first ten days. It was found that limitation of the infarction zone is of importance only in the acute period of MI reducing the frequency of fibrillations and lethal outcomes. Limitation of the infarction zone did not effect the course of IHD during the first postinfarction period. Infarction in the involved zone showed no increases in frequency.
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Objective To explore the clinical features and pathogenesis of cerebral border-zone infarction.Methods We reviewed 1023 consecutive patients with ischemic stroke.The patients with cortical border-zone infarction (CBI),inter- nal border-zone infarction (IBI) and combined broder-zone infarction were selected based on the neuroradiological template. The clinical features and pathogenesis were compared among three groups.Results We identified 124 (12.1%) patients. There was no difference in clinical characteristics among three groups (P＞0.05).The incidence of internal border-zone in- farction was significantly higher than cortical border-zone infarction and combined border-zone infarction (9.0%:1.9%: 1.2% P＜0.001).Among 95 patients who received cerebral vascular digital subtraction angiography (DSA),75% (9/12) patients with cortical border-zone infarction had serious vascular stenosis (stenosis＞50%),60.7% (33/84) patients with internal border-zone infarction had serious vascular stenosis.9 patients with combined border-zone infarction had serious vas- cular stenosis.Conclusion The cerebral border-zone infarction is associated with serious vascular stenosis.
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Pathogenesis
Digital subtraction angiography
Stroke
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The experiments on white rats with induced myocardial infarction have studied the influence of dalargin on the infarction size and peri-infarction zone ultrastructure. 24 hours later the decrease in the infarction zone size was detected in rats who had received dalargin in a dose of 50 and 100 micrograms/kg. In the peri-infarction zone the increase in glycogen quantity, the lower degree of lipid infiltration, the increase in mitochondrial number and mitochondrial energy effectiveness coefficient were noted, as compared to control animals. Sarcolemma of cardiomyocytes from the peri-infarction zone in rats on dalargin was impermeable for colloidal lanthanum. The decrease in the infarction size under the effect of dalargin is explained by its influence on the survival of cardiomyocytes in the peri-infarction zone.
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Border zone
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