| Objective:Coronary artery disease remains the leading cause of morbidity and mortality in the world. Approximately 12% of patients with coronary artery disease, because of unfavorable characteristics such as diffuse coronary atherosclerosis, small distal vessels or lack of suitable bridge vessels, are not amenable to coronary artery bypass grafting or percutaneous coronary intervention. Recently, we have developed a novel method:transmyocardial drilling revascularization combined with heparinized basic fibroblast growth factor (bFGF)-incorporating stent implantation. In previous studies, the feasibility of this method has been confirmed. The objective of this study is to investigate the effects of the method against ischemic myocardial injury.Methods:The miniswine model of acute myocardial ischemia was used in present study. The animals were divided into control group (without any treatment) and treatment group. In treatment group, two channels with 3.5 mm in diameter were established in ischemic region, followed by implantation of two stents.(1) Myocardial remodeling and left ventricular function related parameters were determined by MRI scan and physiological recorder.(2) Myocardial fibrosis, cell apoptosis, proliferation and differentiation of cardiac stem cell were evaluated by RT-PCR and immunohistochemical analysis to explore the underlying mechanisms.(3) The effective radius of every channel was determined at cell level, to provide a guide for selection of pitch of channelsResults:(1) Six weeks after operation, left ventricular end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV) were significantly decreased (P<0.05), the wall thick of ischemic region increased significantly (P<0.001), LV ejection fraction (LVEF) was significantly promoted (P<0.001), and the maximum velocity of LV contraction (dP/dtmax) and the maximum velocity of LV diastole (dP/dtmin) were significantly improved (P<0.001) in treatment group, compared with control group.(2) Six weeks after therapy, there was up-regulative expressions of vascular endothelial growth factor (VEGF), von Willebrand Factor (vWF), transforming growth factor-β3 (TGF-β3), Interleukin-1β(IL-1β), stromal cell-derived factor-1 (SDF-1) and CXC chemokine receptor 4 (CXCR4) mRNA in treatment group (P<0.05), compared with control group. vWF staining analysis showed an enhanced angiogenesis in treatment group relative to control group (P<0.001). It was demonstrated by TUNEL that cell opoptosis was significantly inhibited in treatment group compared with control group (P<0.001). Quantitative analysis of 5-bromo-2-deoxyuridine (BrdU) stained positive region revealed more neonatal myocytes in treatment group than the control (P<0.001). There were similar results in c-kit staining analysis (P<0.001). Masson trichrome staining analysis demonstrated that myocardial viability was significantly improved in treatment group compared with control group (P<0.001).(3) There was a significant negative correlationship between the effects of transmyocardial drilling revascularization combined with stent implantation and the distance away from the center of channels. Although the effective radius of angiogenesis was more than 10 mm, the result of myocardial viability analysis was 5 mm, and cell apoptosis analysis yielded an effective radius of 7.5 mm.Conclusions:(1) Transmyocardial drilling revascularization combined with heparinized bFGF-incorporating stent implantation may reverse ventricular remodeling, and promote left ventricular function.(2) This method may attenuate myocardial fibrosis, inhibit cell apoptosis, and promote proliferation of cardiac stem cells and differentiation to myocytes, consequently provide protective effects against ischemic injury.(3) The effective radius of every channel was 5-7.5 mm, it is therefore suggested that the pitch between two channels should be 10 mm.
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