Myocardial Regeneration Therapy for Heart Failure

Abstract

Background — We hypothesized that transfection of the gene for human hepatocyte growth factor (hHGF) combined with cellular cardiomyoplasty might regenerate the impaired myocardium. Methods and Results — We used a ligation model of proximal left anterior descending coronary artery (LAD) of Lewis rats. Two weeks after LAD ligation, 3 different treatments were conducted: (1) neonatal rat cardiomyocytes group (10 6 cells, T group, n=11), (2) HVJ-liposomes bearing the hHGF gene group (H group, n=10), and (3) combined (T-H group, n=10). The injection site was the scar area of myocardial infarction. For control, culture medium was injected (C group, n=13). Echocardiography demonstrated that cardiac performance was significantly ameliorated in the T-H group 4 and 8 weeks after injection. Contrast echocardiography also showed a marked increase in myocardial perfusion in the T-H group but not in the other groups. In the T-H group, neovascularization and a marked reduction of fibrosis were observed histologically. In an immunohistochemical study, strong staining for β 1 -integrin, α-, and β-dystroglycan were found principally in the basement membrane of myocytes in the T-H group 8 weeks after transplantation, although there was weak immunoreactivity in the T group. Conclusions — hHGF gene transfection enhanced the cellular cardiomyoplasty possibly by stimulating angiogenesis, restoring the impaired ECM, and promoting the integration of the dissociated grafted myocytes. The combined effects might have lead to the improved cardiac performance. Thus, combined therapy may be a promising strategy for the treatment of heart failure caused by myocardial infarction.

Long-term effects of hepatocyte growth factor gene therapy in rat myocardial infarct model

“…Typically, transgene expression levels after adenovirus-mediated transfer are transient, lasting only 4--6 weeks. 27,28 This raises the possibility that the functional recovery in the study of Miyagawa et al 26 and our study became less prominent late after gene transfer, whereas that in other positive studies was prominent early after gene transfer, probably because the antiapoptotic and antifibrotic effects of HGF gene therapy on ventricular remodeling and dysfunction may be transient and be lost after HGF expression ceases.…”

“…In the previous studies, 5--8,10--13,15--17 the positive functional recovery was observed at 2--6 weeks after HGF gene transfer, whereas we repeated the measurement of LV function at a relatively long-term time point of 10 weeks after the gene transfer. Although we could not perform cine MRI at three different time points because of its limited availability, Miyagawa et al 26 measured LVEF and percentage fractional shortening by echocardiography 3 times up to 8 weeks and, interestingly, reported slight improvement in the functional parameters at 4 weeks and their return to baseline levels at 8 weeks in the HGFtreated group. Typically, transgene expression levels after adenovirus-mediated transfer are transient, lasting only 4--6 weeks.…”

“…Among the 13 articles mentioned above, 11 studies reported some functional recovery after the therapy. 5--8,10--13,15--17 Only Miyagawa et al 26 reported that LV function was not improved in myocardial infarction rats treated with the HGF gene alone; however, it improved in myocardial infarction rats treated with a combination of the HGF gene and neonatal cardiomyocytes. Some investigators attempted to explain this discrepancy to be a result of too late initiation of the therapy in the study of Miyagawa et al 26 because at 2 weeks after myocardial infarction, the infarct had already begun to change into a scar, although this possible explanation does not seem to match the positive observation in their HGF gene and stem cell combination group.…”

“…5--8,10--13,15--17 Only Miyagawa et al 26 reported that LV function was not improved in myocardial infarction rats treated with the HGF gene alone; however, it improved in myocardial infarction rats treated with a combination of the HGF gene and neonatal cardiomyocytes. Some investigators attempted to explain this discrepancy to be a result of too late initiation of the therapy in the study of Miyagawa et al 26 because at 2 weeks after myocardial infarction, the infarct had already begun to change into a scar, although this possible explanation does not seem to match the positive observation in their HGF gene and stem cell combination group. 4,7 In the present study, we did not find statistically significant differences in LVEF and EDV between the treatment and control groups despite HGF gene therapy being initiated immediately after coronary ligation.…”

Postinfarction Treatment With an Adenoviral Vector Expressing Hepatocyte Growth Factor Relieves Chronic Left Ventricular Remodeling and Dysfunction in Mice

“…Moreover, in clinical settings, preinfarction treatments are not practical. Recently, Miyagawa et al 12 injected hemagglutinating virus of Japan (HVJ)-liposomes bearing the human HGF gene directly into the postinfarction rat heart but found no beneficial effects on ventricular remodeling or dysfunction. They started the therapy 2 weeks after MI, which we assume may have been too late to be effective.…”