Short-term vasculoprotective effects of imatinib mesylate on intimal hyperplasia of arterial anastomosis: An experimental study using a rabbit model

Abstract

Background: Since the beginning of the 'microvascular era', the success rates of microvascular procedures have increased to more than 90% in most series. The main reason for failure, however, is the healing of microarterial anastomosis, which is dependent on the status of endothelial cells and affects the rate of arterial thrombosis. In 80% of arterial thrombosis cases, complications are primarily observed during the first 72 h after surgery. Healing of arterial anastomosis results in intimal hyperplasia in which myofibroblasts comprise the predominant cell type. Intimal hyperplasia has been described previously as an adaptive process that occurs in response to hemodynamic stress or injuries to the vascular bed. During wound healing, fibroblasts proliferate, migrate and differentiate into myofibroblasts - a process that takes one to three days. Imatinib mesylate (ST1571-Gleevec, Novartis, Germany) is a specific platelet-derived growth factor receptor blocker that has found use as an adjunct to sirolimus in cardiovascular surgery for restenosis. However, its potential utility in preventing arterial thrombosis in microvascular surgery has not been evaluated in routine plastic surgery practice.

Methods: Twenty-four randomly selected, male, white New Zealand rabbits were divided into six groups (A to F), and the femoral artery model was used for arterial anastomosis. Following anastomosis, groups A, B and C received phosphate-buffered saline orogastrically. In groups D, E and F, imatinib mesylate was administered via an orogastric tube twice per day at a dose of 10 mg/kg starting two days before arterial anastomosis. Following anastomosis, imatinib mesylate was administered for one, three and seven days, and the regression of intimal hyperplasia was recorded.

Results: In groups administered imatinib mesylate (ie, groups D, E and F), intimal hyperplasia decreased by up to 50%, which represented a statistically significant difference. Histological analysis confirmed smooth muscle cell migration from the tunica intima to media on days 3 and 7 in groups E and F.

Conclusion: The present study revealed that imatinib mesylate, which was initiated as a prophylactic, systemic pretreatment and continued for seven days, gradually decreased intimal hyperplasia at the anastomosis site.

Keywords: Imatinib mesylate; Intimal hyperplasia; Thrombosis.

Figure 1)

Patent arterial anastomosis with a minimal number of erythrocytes. Hematoxylin and eosin stain, original magnification ×40

Figure 2)

Bar graph comparing all groups with respect to intima/media thickness ratios

Figure 3)

Group C slide showing intimal hyperplasia. Hematoxylin and eosin stain, original magnification ×40. Asterisk (*) and bracket indicate thickness of intimal hyperplasia

Figure 4)

Group D slide showing intimal hyperplasia. Hematoxylin and eosin stain, original magnification indicated in lower right of each panel. Asterisk (*) and bracket indicate thickness of intimal hyperplasia

Figure 5)

Smooth muscle cell migration and vacuolization visualized on postoperative day 3 of imatinib mesylate therapy. Hematoxylin and eosin stain, original magnification indicated at lower right of each panel. Asterisk (*) and bracket indicate thickness of intimal hyperplasia

Figure 6)

Thin layer of endothelium observed on postoperative day 7 after imatinib mesylate treatment. Hematoxylin and eosin stain, original magnification ×40

Figure 7)

Erythrocytes in the tunica media of specimens from group B. Hematoxylin and eosin stain, original magnification ×40

Figure 8)

Masson’s trichrome staining of endothelial proliferation in specimens from groups D, E and F compared with the control group C. Original magnification ×40. Asterisk (*) and bracket indicate thickness of intimal hyperplasia