Abstract 12530: Sustained P2Y12 Receptor Inhibition is Required to Effectively Inhibit Neointima Formation in a Murine Vascular Injury Model
Background: Inhibiting or genetically knocking out platelet P2Y12 receptors inhibits the initial platelet response that subsequently drives neointima formation following vascular injury and consequently this receptor is a potential target for preventing in-stent restenosis. Ticagrelor is an oral, reversibly-binding P2Y12 inhibitor. We used the reversible properties of ticagrelor to assess the time course of P2Y12 inhibition required to inhibit neointima formation.
Methods: Dose-ranging studies were conducted in C57BL/6 mice treated with ticagrelor 10–100 mg/kg, assessing platelet aggregation and P-selectin expression over 24 hours. Subsequently neointima formation was assessed 28 days following injury of the right carotid artery of anaesthetised C57BL/6 mice with 10% w/v FeCl3. Mice were given either vehicle before and 4h and 24h after injury (control) or ticagrelor (100 mg/kg) at the following time points: (1) before injury only; (2) both before and 4 hours after injury; and (3) 4h and 24 h after but not before injury. Intima:media ratio and neointima area were calculated using NIS-Elements software.
Results: Ticagrelor effectively inhibited platelet aggregation and P-selectin expression in a dose-dependent and reversible manner with a short half-life, such that most of the effects of a single dose of ticagrelor 100 mg/kg had resolved by 24h post dose. Neointima formation was markedly reduced in mice treated with ticagrelor both before and 4 hours after injury (neointima area: control 39,921 ± 22,749 μm2 vs. ticagrelor 3,705 ± 2,600 μm2; p<0.01), whilst administration of ticagrelor either before injury only or post injury only (4 and 24 hours) was ineffective (Figure A-B).
Conclusions: High-level P2Y12 receptor inhibition by ticagrelor both at the time of vascular injury and sustained after injury is necessary for effective prevention of subsequent neointima formation.
- © 2010 by American Heart Association, Inc.