| PART ONETreatment of Chronic Ischemic Myocardium with Adenovirus-mediated Hepatocyte Growth Factor Gene Transfer in MinipigsBackgrounds: Hepatocyte growth factor (HGF) is one of the major angiogenic factors. Overexpression of HGF gene by myocardiocytes can promote formation of collateral circulation and alleviate myocardial ischemia. This present study established a minipig model of chronical ischemic myocardium and evaluated the effect of previously adenovirus carrying HGF gene (Ad-HGF) on improvement of the cardiac function of chronic ischemic myocardium and on formation of collateral circulation in myocardium, in order to provide basis for clinical application.Methods: A total of 18 minipigs were allotted randomly into 3 groups: control group (n=5), model group (n=5) and Ad-HGF group (n=8). For minipigs of the control group, two thoracotomic operations were performed at an interval of 3 weeks, whereas in those of the other two groups, besides two such operations, an Ameroid constrictor was placed around the proximal of left circomflex branch (LCX) of every pig during the first operation, and at the second operation, 1 ml of sterile saline for the minipigs of the model group or of Ad-HGF (1×10~9pfu or 4×10~9pfu) for those of two Ad-HGF group was injected directly into the heart muscles in the transitional zone between the ischemic zone, in which the blood was supplied by the LCX, and the non-ischemic zone not supplied by LCX. The injection was applied randomly to 10 points each animal before closing the thoracic cavity. SPECT imaging, coronary artery angiography, cardiac sonography were carried out twice both immediately before and 4 weeks after the second operation to observe myocardial perfusion, formation of collateral blood microvessels and change of cardiac function. At the end of clinical observation period, i.e., 4 weeks after the second operation, the heart was removed in order to evaluate the myocardial ischemic area and the amount of microvessels formed at the border of the infarct area by a special staining and immunohistochemistry, respectively.Results: The results showed that myocardial perfusion was remarkably improved in the Ad-HGF group after injection of Ad-HGF as compared with both that of the same group before the injection and that of the model group after saline injection. The density of newly formed blood vessels was higher and the number of collateral blood vessels was greater in the Ad-HGF group than those of the model group at 4 weeks after the second operation. The area of myocardial ischemia reduced evidently and the ejection fraction of the left heart improved significantly in the Ad-HGF group after treatment.Conclusion: Ad-HGF used in gene therapy of chronic ischemic heart disease via direct injection into heart muscle can enhance formation of collateral blood vessels, improve myocardial perfusion, and reinforce motility function of the heart. This approach could become a novel modality in treatment of chronic ischemic myocardium.PART TWOShort-Term Safety and Curative Effect of Genetherapy with Recombinant Adenoviral Hepatocyte Growth Factor (Ad-HGF) on Ischemic Cardiac DiseaseObjective: The purpose of this study was to observe the safety and curative effect of Ad-HGF i.m. on the pathological changes of coronary arteria with diffuse pathological changes of small blood vessels.Methods: 18 patients suffered from coronary heart disease(CHD) were randomly divided into small-, middle- and large- dose group, directly received 5×10~8, 1.5×10~9 and 5×10~9 pfu of Ad-HGF, respectively, and the direct multipoint injection of different doses of Ad-HGF into myocardia while coronary artery bypass is not suitable. At 2 weeks before and 1,3 and 5 weeks after this therapy, the changes of vital symptoms, blood and urea routine analyses, hepatonephric function, assays of hepatofunctions(so-called "two and half of pairs") for type B hepatitis, antibodies of type C hepatitis,α-fetoprotein(α-FP, AFP), carcinoembryonic antigen(CEA), HIV antibodies, adenovirus antibody, serum HGF level, ECG, chest X-ray film, abdominal ultrasonography, ophthalmoscopy of eye grounds, and cardiac transfusion at 5 weeks before and after the treatment should be examined by SPECT.Results: Only the count of leukocyte out of various indexes examined within 5 weeks abnormally increased and other indexes were in the normal limits, no regular changes were observed. The physical signs have been normal before and after the treatment. The changes of EF value before and after the treatment in 18 cases were positively correlated with HGF doses, and the correlation coefficient was 0.721(p<0.01); the changes of LVEDV value before and after the treatment were negatively correlated with HGF doses, and the correlation coefficient was -0.51(p<0.01).SPECT showed that the myocardial transfusions were improved in 3 cases of the small dose group, 5 cases of the middle dose group, and in the non-bypass area of large dose group. The improvement of myocardial transfusion in the ischemic area was positively and significantly correlated with the doses of Ad-HGF, and the correlation coefficient was 0.49(p<0.05).Conclusions: The results of preliminary clinical trial indicated that the direct injection of Ad-HGF was not suitable for the coronary bypass area, no side-effect occurred without the need of trial termination recently. The middle and large doses of Ad-HGF could promote the improvement of myocardial transfusion with the dose-effect relationship.
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