Effect Of Hepatocyte Growth Factor On Left Ventricular Remodeling Caused By Acute Myocardial Infarction In Canine

Objectives To investigate the effect of hepatocyte growth factor (HGF) on left ventricular (LV) remodeling caused by acute myocardial infarction in canine.Methods Endofree pc-DNA3-HGF was harvested through the modified alkaline lysis procedure. We used a ligation model of proximal left anterior descending coronary artery (LAD) of 13 hybrid canines. These animals were randomized into 2 groups: HGF-group (n=6) and control group (n=6). Canines in HGF-group were injected pc-DNA3-HGF lml (about 300ug) at the margin of infarcted myocardial and another group were injected equal volume saline. Cardiac function and left ventricular remodeling data were measured through echocardiography after 1, 4, 8 weeks of ligation. All animals were put to death at 8 weeks after ligation and the heart was taken out. LV myocardium specimens were obtained and stained with hematoxylin and eosin for histological examination, with picrosirius red staining to assess the collagen content, immunostaining for the Factor VIII-related antigen to count capillary density, TUNEL staining to detect cell apoptosis.Results(1) Compared with control group, left ventricular eject fraction (LVEF) in HGF-group increased after 4 weeks of ligation (P<0.05);LVEF significantly improved and left ventricular end-systolic volume (LVESV) decreased after 8 weeks of ligation (P<0.05). In HGF-group, LVEF improved gradually from 1 week to 8 weeks after ligation, conversely, LVESV reduced.(2) In control group, posterior left ventricular wall thickness got more lower than HGF-group (P<0.05). After 4 and 8 weeks of ligation tissue synchronizationimaging (TSI) indicated that Ts value of anterior septal midsegments was significantly shorter in HGF-group when compared with control group (P<0.05). After 8 weeks of ligation, Ts-SD, Ts max-min prolonged in control group than HGF-group (P<0.05). Lowered left atrial area, mitral reflux area and the ratio (mitral reflux area/ left atrial area) were observed in HGF-group than control group (P>0.05). And control group had higher heart and left ventricular weight (P>0.05).(3) In HGF-group, neovascularization and fewer scars was observed histologically. Control group had obvious cicatrisation.(4) Picrosirius red staining indicated higher type III collagen volume and lower I /III ratio value compared in HGF-group than control group (P<0.05).(5) Compared with control group, HGF-group showed higher capillary density in margin of infarcted area by Factor VDI-related immunohistochemistry staining (P<0.01). To be interested, more capillaries were seen in non-infarcted area in HGF-group (P=0.05).(6) TUNEL staining detected less apoptotic cells in margin of infarcted area in HGF-group.Conclusions HGF gene improved cardiac function, LV remodeling and LV systolic asynchrony after acute myocardial infarction. The mechanisms include: firstly, HGF inhibit collagen deposition, especially type I collagen, decrease myocardial stiffness, improve LV remodeling and cardiac performance. Secondly, HGF diminish cardiocyte apoptosis, increase alive cadiocyte population, slow down the process of left ventricular remodeling. Thirdly, by inducing angiogenesis, HGF promote vascular endothelial cell proliferation, reduce myocardiolysis, and strengthen myocardial contractility.