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

A rabbit 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.