Intramyocardial thrombin promotes angiogenesis and improves cardiac function in an experimental rabbit model of acute myocardial infarction

Objective: Thrombin has been reported to play a pivotal role in the initiation of angiogenesis by indirectly regulating and organizing a network of angiogenic molecules. On the basis of these reports, we investigated the angiogenic action of thrombin in a rabbit model of acute myocardial infarction. Methods: Arabbit model of acute myocardial infarction was established by ligation of the left anterior descending coronary branch. Subjects were then divided into 2 groups and treated with intramyocardial administration of thrombin (2500 IU; n=13) or an equal volume of normal saline (n=13). Four weeks later, animals were euthanized and histopathologic analysis, immunohistochemical staining for endothelial markers CD31 and vascular endothelial growth factor-A, and electron microscopy examination were performed on excised hearts. Electrocardiography, cardiac enzymes, and assessment of cardiac function by measuring left ventricular end-diastolic pressure and ejection fraction were recorded before and after myocardial infarction, and both left ventricular end-diastolic pressure and ejection fraction were further measured on the day of euthanasia (n=5-8 in each case). Results: Increased levels of troponin, ST elevation, and histopathologically confirmed myocardial infarction were observed in all animals. A significant increase of microvessel density at the infarct border zone, as evaluated by CD31 immunohistochemistry, was observed in the thrombin-treated group compared with the control group (30.3 +/- 12.8 vs 12.6 +/- 4.8, P-.0065). A significantly higher number of vascular endothelial growth factor-A-positive vessels at the infarct border zone was observed in the thrombin-treated animals compared with the control group (21.8 +/- 8.9 vs 5.6 +/- 4.4; P=.0009). The thrombin-treated animals showed a statistically significant reduction in left ventricular end-diastolic pressure values (6.9 +/- 1.8 mm Hg vs 12.7 +/- 2.2 mm Hg, P=.0002) and significant improvement in left ventricular ejection fraction (59.8%+/- 3.1% vs 42.2%+/- 6.14%, P=.002) on the day of euthanasia compared with the post-infarct day, reflecting significantly improved cardiac function compared with control subjects that showed no significant change. Conclusions: Intramyocardial administration of thrombin seems to promote angiogenesis and improve cardiac function of the ischemic myocardium, which may provide a new therapeutic approach in patients with myocardial ischemia.