Abstract 1034: Targeted Inhibition of the Serotonin 5-HT2A Receptor Improves Coronary Patency in an In Vivo Model of Recurrent Thrombosis
Background: Current therapies aimed at attenuating platelet-mediated thrombosis target either cyclooxygenase 1, the GPIIb/IIIa receptor, or the ADP P2Y12 receptor. Our aim was to investigate an alternative approach: using an in vivo canine model mimicking unstable angina, we assessed whether targeted inhibition of the serotonin 5-HT2A receptor – initiated either in a prophylactic manner or in the setting of ongoing, recurrent thrombosis – would improve coronary patency.
Methods: Anesthetized open-chest dogs were randomized to receive: (i) a novel and selective small-molecule 5-HT2A receptor inhibitor (APD791; Arena Pharmaceuticals: 0.07 mg/kg bolus + 1.16 μg/kg/min infusion); or (ii) placebo. Fifteen min later, recurrent thrombosis was triggered by coronary artery injury + stenosis. Coronary blood flow and hemodynamics (heart rate, arterial pressure) were monitored throughout a subsequent 3-h observation period. Primary endpoints were: (i) area of the flow-time profile (index of coronary patency, expressed as % of baseline flow); (ii) duration (in min) of total thrombotic occlusion (flow=0); and (iii) molecular markers of platelet activation (assessed by flow cytometry and normalized to baseline values). In supplemental post-hoc experiments, the same model was utilized; however, APD791 (bolus + infusion) was begun at 1 hour after the onset of recurrent thrombosis.
Results: The placebo-control group was characterized by platelet activation (surface P-selectin increased to 190±27% of baseline) and poor coronary patency (flow-time area = 28±3%; zero flow duration = 57±15 min). Prophylactic treatment with APD791 had no significant effect on hemodynamics, but attenuated platelet activation and recurrent thrombosis: platelet surface P-selectin was reduced to 115±10%* of baseline, flow-time area was increased to 58±3%**, and zero flow duration reduced to 1±1 min** (*p<.05; **p<.01 vs. controls). Moreover, the efficacy of APD791 may be maintained when given after injury + stenosis: flow-time area before vs. after APD791 treatment was 25±1% vs. 57±7%.
Conclusion: 5-HT2A receptor inhibition with APD791, even when initiated after the onset of recurrent thrombosis, improves coronary patency in an in vivo canine model.