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Objective: Angiogenic therapy is emerging as a potential strategy for the treatment of ischemic heart disease but is limited by a relatively short half-life of growth factors. Fibrin glue (FG) provides a reservoir for controlled- release of growth factors. The aim of this study was to evaluate the effects of basic fibroblast growth factor (bFGF) incorporating FG on angiogenesis and cardiac performance in a canine infarct model. Methods: Acute myocardial infarction was induced by ligation of the left anterior descending coronary artery (LAD). Group I (n=6) underwent ligation of LAD alone. In Group II, transmural channels were created in the infarct area (n=6). In Group III, non-transmural channels were created to locate FG cylinders containing bFGF (n=6). Eight weeks after operation, myocardial perfusion was assessed by single photon emission computed tomography, cardiac function by echocardiography, and vascular development by immunohistochemical staining. Results: Total vascular density and the number of large vessels (internal diameter ≥50 μm) were dramatically higher in Group III than in Groups I and II at eight weeks. Only the controlled-release group exhibited an improvement in regional myocardial perfusion associated with lower defect score. Animals in Group III presented improved cardiac regional systolic and diastolic functions as well as global systolic function in comparison with the other two groups. Conclusions: Enhanced and sustained angiogenic response can be achieved by controlled-release bFGF incorporating FG within transmyocardial laser channels, thus enabling improvement in myocardial perfusion and cardiac function.

Objective To elucidate the mechanisms of combined myogenesis and angiogenesis using mesenchymal stem cells (MSCs) and basic fibroblast growth factor (bFGF), we established concentration gradient of bFGF between coronary venous blood and target myocardium by coronary venous retroperfusion along with assessing the effects of bFGF gradient on in vivo homing and differentiation of MSCs. Methods Acute myocardial infarction (AMI) was induced by ligation of left anterior descending coronary artery. (1) 12 animals were randomly divided into four groups based on the time of balloon dilation (retroperfusion time), being 0 min (n=3), 5 min (n=3), 10 min (n=3), 15 min (n=3). One week after AMI, bFGF was retrogradely perfused and bFGF concentrations of serum and myocardial tissue were measured by ELISA. The time of bFGF gradients after coronary venous retroperfusion was evaluated. (2) 12 animals were randomly divided into MSCs group (n=6) and bFGF+MSCs group (n=6) after AMI. MSCs were labelled by 49,6-diamidino-2-phenylindole (DAPI) and one week after implantation, DAPI-positive MSCs in infarcted myocardium were compared between the two groups by immunofluorescence method. (3) 12 animals were randomly divided into MSCs group (n=6) and bFGF+MSCs group (n=6) after AMI. MSCs was cultured and transfected by pLEGFP-N1 vector. 1 week after retroperfusion, EGFP-positive endothelial cells and cardiomyocytes in infarcted myocardium were compared between the two groups by immunofluorescence method. Results (1) There were statistical differences regarding bFGF concentration between coronary venous blood and infarcted myocardium at 5 min (81.13±15.07 pg/ml vs 210.66±65.09 pg/ml, p 2 vs 11.4±2.9/mm 2 , p 2 vs 8.3±2.2/mm 2 , p Conclusions Coronary venous retroperfusion was safe. A stable bFGF concentration gradient can be established in vivo between coronary venous blood and infarcted myocardium at 5 to 10 min after retroperfusion, which can promote homing of MSCs into the infarcted myocardium and differentiation.

Objective Effective cell homing to ischemic myocardium remains a practical challenge. This study evaluated the efficiency of cell delivery via coronary venous system using over-the-wire balloon in a canine model of acute myocardial infarction. Methods Acute myocardial infarction was induced by ligation of the left anterior descending (LAD) coronary artery in eight dogs (22.1±1.9 kg). Mesenchymal stem cell (MSCs) from canine bone marrow were isolated and purified by density gradient centrifugation, cultured by adhering to culture-flask and labelled with enhanced green fluorescence protein (EGFP). One week after infarction, the coronary sinus was cannulated percutaneously and an over-the wire balloon catheter advanced to the proximal portion of anterior interventricular vein (AIV) in parallel to LAD. The balloon catheter was inflated temporarily to occlude the AIV, and 1×10 7 EGFP-labelled MSCs was injected into the AIV. Animals were sacrificed at days 14 (n=4), 28 (n=4), and the hearts were excised and examined. Results Complete AIV occlusion had no impact on LAD flow parameters. No death, cardiac tamponade, ventricular arrhythmia, or other procedural complications occurred. Immunofluorescence studies showed that EGFP-positive cells localised primarily in the infarct region but none in infarct marginal or normal regions both at 14 and 28 days. Conclusion Selective regional myocardial perfusion is feasible through coronary venous system with over-the-wire balloon, targeting selected ischemic myocardium. This novel technique has potential application for effective cell transplantation.