Effect of the P2Y12 antagonist ticagrelor on neointimal hyperplasia in a rabbit carotid anastomosis model†

Objectives: In the present study, we aimed to deterimine the dose-related effects of ticagrelor, the first reversible inhibitor of the P2Y12 receptor, found in smooth muscle cells as well as platelets, during neointimal hyperplasia in a rabbit carotid anastomosis model.

Methods: This study was an experimental, prospective, randomized controlled study including 20 New Zealand white female rabbits (6-months old; weighing 2300 ± 300 g). Under general anaesthesia, the rabbits underwent transection of the right carotid artery and subsequent anastomosis of both ends. The study animals were divided into the following 4 groups: T1 (ticagrelor 5 mg/kg, orally, daily), T2 (ticagrelor 10 mg/kg, orally, daily), T3 (ticagrelor 20 mg/kg, orally, daily) and control (no ticagrelor treatment). The single oral doses were administered in phosphate-buffered saline. The control group received sterile phosphate-buffered saline (2 ml/kg/day, orally) for 3 weeks postoperatively. At the end of the study, the animals were killed, and the anastomosed segment of the right carotid artery and part of the left carotid artery were excised from each animal. Antibodies against transforming growth factor-β were used in staining of arterial sections, which was followed by histomorphological and immunohistochemical studies.

Results: The median intimal thickness (2.0 ± 0.14 µm left vs 73.4 ± 35.8 µm anastomosed right arteries; P <0.05), the median medial thickness (70.8 ± 5.6 µm left vs 92.3 ± 4.5 µm anastomosed right arteries; P <0.05) and the index ratio of intimal thickness to medial thickness (0.03 ± 0.00 left vs 0.8 ± 0.35 anastomosed control right arteries; P <0.05) increased significantly in the anastomosed right arteries compared with the left carotid arteries in the control group. In the treatment groups, the intimal thickness (73.4 ± 35.8 µm in control group vs T1 32.7 ± 19;1 µm, T2 1.9 ± 0.09 µm and T3 2.2 ± 0.5 µm; P = 0.047, P = 0.009 and P = 0.009, respectively), carotid artery intima/media ratio (0.8 ± 0.35 in control group vs T1 0.4 ± 0.2, T2 0.03 ± 0.01 and T3 0.03 ± 0.01 in ticagrelor groups; P = 0.028, P = 0.009 and P = 0.009, respectively) and medial thickness (92.3 ± 4.5 µm in control group vs T2 65.6 ± 7.1 and T3 66.1 ± 7.6 µm; P = 0.009 and P = 0.009, respectively) decreased significantly in the anastomosed right arteries.

Conclusions: This study indicates that effective doses (10 and 20 mg/kg, daily) of the antiplatelet agent ticagrelor in a rabbit model may be beneficial in prevention of intimal hyperplasia. Restenosis due to intimal hyperplasia has been high. Ticagrelor has also been linked to inhibition of smooth muscle cell proliferation and, hence, reduced intimal hyperplasia.