Treatment Of Myocardial Infarction Using Transmyocardial Jet Revascularization With Hydrogel Scaffolds Filling Channels In Canines

Background and Objective:Transmyocardial revascularization(TMR) is a process in which channels are created into ischemic myocardium by either laser or mechanical means to enhance myocardial perfusion by directly supplying tissue with endoventricular oxygenated blood or angiogenesis. Transmyocardial laser revascularization(TMLR) is a supplementary treatment for patients with refractory angina pectoris and severe end-stage coronary artery disease who are not amenable to conventional revascularization. TMLR could improve the symptoms of angina, exercise tolerance, myocardial perfusion and function. However, disadvantages such as the occlusion of laser transmyocardial channels and the heat injury to surrounding myocardium limited its application. Similarly, the channels made by needles or drills were occluded too.Therefore we devised a new treatment strategy-transmyocardial jet revascularization (TMJR) . This new method could avoid laser caused heat injury during TMLR and avoid injury of needles or drills inserting the beating heart during TMR with needles or drills. And at the same time of TMJR, the hydrogel scaffold could been delivered into the channels made by TMJR. The hydrogel scaffold in channels could support the channels for a time and the channels may be retained, endothelialization and vascularization. Therefore, we investigated the transmyocardial channels changes after TMJR with different hydrogel scaffolds filling the channels and histocompatibility of different hydrogel scaffolds in canine nomal myocardium; And we investigated the effect of TMJR with hydrogel scaffold on transmyocardial channel patency , myocardial angiogenesis, ventricular remodeling and hemodynamic function after MI in a canine model.Methods:1. Transmyocardial jet revascularization with different hydrogel scaffolds filling the channels in canine nomal heartsTwelve canines were randomly divided into three groups(n=4):①Agarose hydrogel group (AH group);②Fibrin glue group (GF group);③Chitosan hydrogel group (CH group).Transmyocardial revascularization in different groups was performed with needle-free systems jeting out different hydrogels. Myocadium including channels in three groups were obtained at 2,4,6 weeks for hematoxylin-eosin (HE) staining and Masson's trichrome staining to observe①the degradation and histocompatibility of the three hydrogels in myocardium;②whether the channels in three groups could keep patency;③fibrosis inside and around the transmyocardial channels in three groups.2. Transmyocardial jet revascularization with chitosan hydrogel filling the channels in canine infarcted hearts32 canines were randomly divided into four groups(n=8): myocardial infarction group(MI group), nomal saline group (NS group), chitosan hydrogel group (CH group), and chitosan incorporating grow factors group(CH+GF group).Myocardial infarction was induced in canines by ligating the left anterior descending coronary artery. In MI group, myocardial infarction was made. And in NS group, CH group and CH+GF group, transmyocardial revascularization was performed at the ischemia and infarcted myocardium after myocardial infarction with needle-free systems. The transmyocardial channels in NS group were filled with nomal saline, the channels in CH group with chitosan, and the channels in CH+GF group with Chitosan incorporating vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).After 6 weeks, the animals underwent hemodynamic analysis. The patency of channels and the endothelialization of channels were observed from hematoxylin-eosin (HE) staining and immunohistochemistry. Fibrosis inside and around the transmyocardial channels was assessed by Masson's trichrome staining. The expression of von Willebrand factor(VWF ) and a-smooth muscle actin (a-SMA) in ischemic myocardium were detected by immunohistochemistry and the density of microvascular , small blood vessels and arterioles were messured. The infarct size, the left and right ventricular weight index were recorded. In addition, the collagen volume fraction of type-Ⅰand type-Ⅲcollagen and theⅠ/Ⅲratio in myocardium were recorded.Results:1. Transmyocardial jet revascularization with different hydrogel scaffolds filling the channels in canine nomal hearts①Agarose hydrogel had bad biodegradation and histocompatibility, making the collagen fibers proliferation of the surrounding tissue and making the channels occluded.②Fibrin glue had good biodegradation and histocompatibility,while the mechanical strength was weak and the channels were almost occluded after the degradation of fibrin glue.③Chitosan hydrogel had excellent biodegradation, histocompatibility and mechanical strength. The channels were open and endothelialization after it degraded. Little fibrosis inside and around the transmyocardial channels was observed.2. Transmyocardial jet revascularization with chitosan hydrogel filling the channels in canine infarcted hearts①After 6 weeks of TMJR, HE staining and immunohistochemistry showed that the channels in NS group were occluded and the channels in CH group and CH+GF group could keep patency. Luminal endothelization was more obvious in CH+GF group.②Masson's trichrome staining showed thar the channels in NS group were filled with collagen fibers. However in CH and CH+GF group, the channels were open with less collagen fibers.③The small blood vessels in NS group, CH group and CH+GF group increased significantly compared with the MI group (P<0.05); the small blood vessels in CH group and CH+GF group increased significantly compared with the NS group (P<0.05),especially in CH+GF group; the arterioles in CH+GF group increased significantly compared with the MI group and NS group (P<0.05).④Compared with MI group, the collagen volume of type-Ⅰcollagen in CH group decreased significantly(P<0.05); the collagen volume of type-Ⅲcollagen in CH+GF group increased significantly Compared with MI group, NS group and CH group (P<0.05). And theⅠ/Ⅲratio in CH group and CH+GF group were lower than MI group and NS group (P<0.05).⑤Some of the hemodynamic parameters in CH group and CH+GF group were significantly improved compared with MI group(P<0.05).Conclusions:1. Transmyocardial jet revascularization with different hydrogel scaffolds filling the channels is feasible;2. Agarose hydrogel and fibrin glue are not suitable as a channels filler of transmyocardial revascularization. However TMJR with the chitosan hydrogel filling the channels could keep the channels patency.3. TMJR with the chitosan hydrogel filling the channels could keep the channels patency and endothelialization in canine infarcted hearts, enhance angiogenesis, improve ventricular remodeling and hemodynamic function.