Impaired adenylate cyclase signaling in acute myocardial ischemia: Impact on effectiveness of P2Y12 receptor antagonists

Introduction: P2Y(12) receptor antagonists reduce risk of thrombotic complications after stent implantation but increase bleeding risk. Activation of P2Y(12) receptors by ADP causes Gi-protein-mediated inhibition of adenylate cyclase (AC), thus limiting platelet response to anti-aggregatory effect of prostacyclin (PGI(2)). However, P2Y(12) blockade reverses this ADP-induced suppression of the platelet PGI(2)/AC signaling pathway. We previously demonstrated that impairment of this pathway predicts poor response to clopidogrel. Objectives: To identify clinical correlates of variability in PGI(2)/AC signaling, and to assess the impact of such variability on individual responses to the direct P2Y(12) receptor antagonists ticagrelor (in vivo) and 2-methyl-thioadenosine-monophosphate (2MeSAMP) (in vitro). Patients/Methods: We compared the inhibitory effects of prostaglandin E-1 (PGE(1)) and the PGI(2) analog Iloprost (Ilt) on platelet aggregation in whole blood samples from healthy control subjects (n = 17), and patients with stable angina pectoris (SAP; n = 35) or acute coronary syndromes (ACS; n = 23), with or without associated diabetes/hyperglycemia. Results: Compared to control subjects, patients with ACS and - to a lesser extent - those with SAP, exhibited impaired responses to PGE(1), accentuated in the presence of hyperglycemia. Efficacy of ticagrelor treatment, measured as change in platelet reactivity index, was directly related to pre-treatment PGE(1) response, both at univariate and multivariate analysis. There was a strong correlation between extent of inhibition of platelet aggregation, whether by PGE(1) or Ilt, and the anti-aggregatory effect of 2MeSAMP in vitro. Conclusions: The integrity of PGI(2)/AC signaling, which is impaired in the presence of ACS and hyperglycemia, predetermines the anti-aggregatory efficiency of P2Y(12) receptor antagonists.