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

INTRODUCTION: P2Y12 receptor antagonists reduce risk of thrombotic complications after stent implantation but increase bleeding risk. Activation of P2Y12 receptors by ADP causes Gi-protein-mediated inhibition of adenylate cyclase (AC), thus limiting platelet response to anti-aggregatory effect of prostacyclin (PGI2). However, P2Y12 blockade reverses this ADP-induced suppression of the platelet PGI2/AC signaling pathway. We previously demonstrated that impairment of this pathway predicts poor response to clopidogrel. OBJECTIVES: To identify clinical correlates of variability in PGI2/AC signaling, and to assess the impact of such variability on individual responses to the direct P2Y12 receptor antagonists ticagrelor (in vivo) and 2-methyl-thioadenosine-monophosphate (2MeSAMP) (in vitro). PATIENTS/METHODS: We compared the inhibitory effects of prostaglandin E1 (PGE1) and the PGI2 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 PGE1, accentuated in the presence of hyperglycemia. Efficacy of ticagrelor treatment, measured as change in platelet reactivity index, was directly related to pre-treatment PGE1 response, both at univariate and multivariate analysis. There was a strong correlation between extent of inhibition of platelet aggregation, whether by PGE1 or Ilt, and the anti-aggregatory effect of 2MeSAMP in vitro. CONCLUSIONS: The integrity of PGI2/AC signaling, which is impaired in the presence of ACS and hyperglycemia, predetermines the anti-aggregatory efficiency of P2Y12 receptor antagonists.

Post receptor determinants of acute platelet response to clopidogrel in patients with symptomatic myocardial ischemia.

BACKGROUND: Clopidogrel resistance is more common in patients with loss-of-function CYP2C19 genotypes. Since adenylate cyclase (AC) and soluble guanylate cyclase (sGC) pathways are variably impaired in patients with ischaemic heart disease, we tested the relevance of these determinants in patients undergoing acute loading with clopidogrel (600 mg) prior to non-emergent coronary stenting. METHODS: Inhibitory effects of prostaglandin E1 (PGE1, an AC activator) and sodium nitroprusside (NP, a sGC activator) on platelet aggregation were determined at baseline and compared with platelet responses to clopidogrel (4 h after administration) assessed as ∆ADP, and Platelet Reactivity Index (∆PRI). Data were analysed according to CYP2C19 genotype. RESULTS: In patients without loss of function mutations (n=18), ∆ADP but not ∆PRI, was directly correlated with baseline PGE1 responsiveness (rs=0.62, p=0.005)). NP responsiveness did not predict ∆ADP. However there was no relationship between clopidogrel responses and either PGE1 or NP responsiveness in patients with loss of function mutations. Multivariate correlates of clopidogrel response were both the genotype status (ß=-0.609, p<0.001) and the baseline response to PGE1 (ß=0.303, p=0.03). CONCLUSIONS: While genetically impaired bio-activation markedly limits acute (4 h) clopidogrel response, impaired AC signalling provides an additional cause for clopidogrel resistance.

Clopidogrel "resistance": pre- vs post-receptor determinants.

The clinical efficacy of the P2Y12 receptor antagonist clopidogrel as an agent to prevent thrombotic events predominantly reflects its anti-aggregatory effects. Stent thrombosis in particular is more likely to occur in patients in whom clopidogrel effect is limited. "Resistance" to clopidogrel in general should theoretically arise either because of a reduction in plasma concentration of the active metabolite and/or of the downstream intracellular biochemical changes underlying antiplatelet effects. We therefore postulate that "resistance" to clopidogrel arises via a combination of pharmacogenetic, pharmacokinetic and intracellular biochemical mechanisms. Considerable attention has been so far directed to the finding that stent thrombosis occurs more frequently in patients with loss-of-function mutations of CYP2C19, thus limiting clopidogrel bioactivation. Furthermore, a number of drug-drug interactions may marginally impair responsiveness to clopidogrel, largely via impairment of bioactivation. However, population data also suggest that clopidogrel "resistance" occurs more frequently in patients with acute coronary syndromes than in normal subjects, and that "resistance" is particularly common in obese subjects and with diabetes. Here we critically review available literature and speculate on the possibility that non-genetic causes of clopidogrel "resistance" may arise from impairments of the intracellular signaling cascade initiated by P2Y12 receptor inhibition. In such cases, "resistance" to clopidogrel may also theoretically occur with other P2Y12 receptor antagonists, irrespective of the need for bioactivation. Delineation of this non-genetic component of "resistance" to P2Y12 inhibitors may facilitate the development of optimal therapeutic strategies for high-risk cardiovascular patients.