Abstract 9819: Elevated Plasma Serotonin and Endothelin-1 in Coronary Artery Disease Patients: A Potential for Novel Pharmacotherapeutic Targets?

Abstract

Background: High on-treatment platelet reactivity (HTPR) was reported in patients with coronary artery disease (CAD) on dual antiplatelet therapy with aspirin and clopidogrel, particularly in diabetic patients. We sought to investigate the potential for targeting platelet and endothelium-derived vasoactive substances (such as thromboxane A 2 [TXA 2 ], serotonin [5-HT], and endothelin-1 [ET-1]) released upon platelet activation to complement current antiplatelet therapy without increasing the risk of bleeding. Methods: Three groups of subjects were recruited: a) 20 diabetic patients with known CAD (DM), b) 24 non-diabetic patients with known CAD (ND) and c) 27 healthy subjects without diabetes or CAD (CTL). Subject groups were compared to each other with respect to plasma and platelet concentrations of various vasoactive substances measured by ELISA and to platelet reactivity measured by light transmission aggregometry (LTA) and VerifyNow ® . Results: Significantly higher ET-1 (CTL: 0.372 0.1 pg/mL; ND: 0.564 ± 0.2 pg/mL, P<0.005 vs. CTL; DM: 0.961 ± 0.2 pg/mL, P<0.02 vs. CTL) and 5-HT (CTL: 600.5 ± 52.5 ng/mL; ND: 679.6 ± 68.7 ng/mL, P<0.05 vs. CTL; DM: 729.7 ± 81.8 pg/mL, P<0.02 vs. CTL) plasma concentrations were found in CAD patients, with a more pronounced increase in the DM group. Platelet 5-HT was lower in the DM group (335.8 ± 71 ng/10 9 platelets) compared to both CTL subjects (447.1 ± 88.5 ng/10 9 platelets) and ND patients (374.6 ± 58.8 ng/10 9 platelets), which may be due to increased platelet activation and release. Plasma TXB 2 concentrations were higher in the DM group (557.4 ± 172.4 pg/mL) compared to the ND group (350.7 ± 42.4 pg/mL), which indicates higher platelet reactivity in DM patients despite the regular use of ASA. Platelet function tests such as VerifyNow ® (ASA) and LTA (AA 1.6 mM) showed higher HTPR in DM patients (VerifyNow ® : 445 ± 29.1 ARU; LTA: 16.78 ± 3.9% aggregation) compared to ND patients (VerifyNow®: 419.1 ± 13.4 ARU; LTA: 3.76 ± 0.8% aggregation). Conclusion: This study identifies ET-1 and 5-HT as new potential pharmacological targets in the platelet activation pathway for management of HTPR in CAD patients to reduce the risk of incidence and recurrence of ischemic events.