Impaired adenylate cyclase signaling in acute myocardial ischemia: Impact on effectiveness of P2Y 12 receptor antagonists

• Published in: Thrombosis research Vol. 181; p. 92
• Main Authors: Imam, H, Nguyen, T H, De Caterina, R, Nooney, V B, Chong, C-R, Horowitz, J D, Chirkov, Y Y
• Format: Journal Article
• Language: English
• Published: United States 01.09.2019
• Subjects: Acute Coronary Syndrome - blood; Acute Coronary Syndrome - drug therapy; Acute Coronary Syndrome - pathology; Adenylyl Cyclases - metabolism; Aged; Female; Humans; Male; Middle Aged; Platelet Aggregation - drug effects; Purinergic P2Y Receptor Antagonists - pharmacology; Purinergic P2Y Receptor Antagonists - therapeutic use; Signal Transduction; Adenylate cyclase; Diabetes mellitus; Platelet aggregation; Acute coronary syndrome; Ticagrelor
• ISSN: 1879-2472

P2Y receptor antagonists reduce risk of thrombotic complications after stent implantation but increase bleeding risk. Activation of P2Y receptors by ADP causes Gi-protein-mediated inhibition of adenylate cyclase (AC), thus limiting platelet response to anti-aggregatory effect of prostacyclin (PGI ). However, P2Y blockade reverses this ADP-induced suppression of the platelet PGI /AC signaling pathway. We previously demonstrated that impairment of this pathway predicts poor response to clopidogrel. To identify clinical correlates of variability in PGI /AC signaling, and to assess the impact of such variability on individual responses to the direct P2Y receptor antagonists ticagrelor (in vivo) and 2-methyl-thioadenosine-monophosphate (2MeSAMP) (in vitro). We compared the inhibitory effects of prostaglandin E (PGE ) and the PGI 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. Compared to control subjects, patients with ACS and - to a lesser extent - those with SAP, exhibited impaired responses to PGE , accentuated in the presence of hyperglycemia. Efficacy of ticagrelor treatment, measured as change in platelet reactivity index, was directly related to pre-treatment PGE response, both at univariate and multivariate analysis. There was a strong correlation between extent of inhibition of platelet aggregation, whether by PGE or Ilt, and the anti-aggregatory effect of 2MeSAMP in vitro. The integrity of PGI /AC signaling, which is impaired in the presence of ACS and hyperglycemia, predetermines the anti-aggregatory efficiency of P2Y receptor antagonists.