title: Effect of the P2Y12 antagonist ticagrelor on neointimal hyperplasia in a rabbit carotid anastomosis model†.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Cardiovascular Surgery, Bursa Yuksek Ihtisas Education and Research Hospital, Bursa, Turkey drsuleyman1@hotmail.com.
authors.forename: Süleyman
authors.initials: S
authors.lastname: Sürer
authors.affiliation: Department of Cardiovascular Surgery, Bursa Yuksek Ihtisas Education and Research Hospital, Bursa, Turkey.
authors.forename: Faruk
authors.initials: F
authors.lastname: Toktas
authors.affiliation: Department of Cardiovascular Surgery, Bursa Yuksek Ihtisas Education and Research Hospital, Bursa, Turkey.
authors.forename: Derih
authors.initials: D
authors.lastname: Ay
authors.affiliation: Department of Cardiovascular Surgery, Bursa Yuksek Ihtisas Education and Research Hospital, Bursa, Turkey.
authors.forename: Cuneyt
authors.initials: C
authors.lastname: Eris
authors.affiliation: Department of Cardiovascular Surgery, Bursa Yuksek Ihtisas Education and Research Hospital, Bursa, Turkey.
authors.forename: Senol
authors.initials: S
authors.lastname: Yavuz
authors.affiliation: Department of Cardiovascular Surgery, Bursa Yuksek Ihtisas Education and Research Hospital, Bursa, Turkey.
authors.forename: Tamer
authors.initials: T
authors.lastname: Turk
authors.affiliation: Department of Cardiovascular Surgery, Bursa Yuksek Ihtisas Education and Research Hospital, Bursa, Turkey.
authors.forename: Ahmet Hakan
authors.initials: AH
authors.lastname: Vural
authors.affiliation: Department of Cardiovascular Surgery, Bursa Yuksek Ihtisas Education and Research Hospital, Bursa, Turkey.
authors.forename: Mehmet Tugrul
authors.initials: MT
authors.lastname: Goncu
authors.affiliation: Faculty of Veterinary Medicine, Uludag University, Bursa, Turkey.
authors.forename: Nihal Yasar
authors.initials: NY
authors.lastname: Gul
authors.affiliation: Department of Pathology, Faculty of Medicine, Uludag University, Bursa, Turkey.
authors.forename: Ulviye
authors.initials: U
authors.lastname: Yalcınkaya
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000714:Anastomosis, Surgical; D000818:Animals; D001706:Biopsy; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D016893:Carotid Stenosis / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006965:Hyperplasia; D007150:Immunohistochemistry; D058426:Neointima; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D011817:Rabbits; D058925:Receptors, Purinergic P2Y12 / Q000187:drug effects* / Q000378:metabolism; D012008:Recurrence; D000077486:Ticagrelor; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D016212:Transforming Growth Factor beta; D000077486:Ticagrelor; D000241:Adenosine
keywords: Carotid artery; Intimal hyperplasia; Rabbit model; Ticagrelor