Modulation of Circulating MicroRNAs Levels during the Switch from Clopidogrel to Ticagrelor

Abstract

Background. Circulating microRNAs are appealing biomarkers to monitor several processes underlying cardiovascular diseases. Platelets are a major source for circulating microRNAs. Interestingly, the levels of specific microRNAs were reported to correlate with the level of platelet activation. The aim of the present study was to test whether the treatment with the novel antiplatelet agent, ticagrelor, is associated with modulation in the levels of key platelet-derived microRNAs. Methods and Results. Patients were randomly selected from those participating in the SHIFT-OVER study, in which we had previously evaluated the effect of the therapeutic switch from clopidogrel to ticagrelor on platelet aggregation. Circulating levels of selected microRNAs were measured before and after the therapeutic switch from a dual antiplatelet therapy including acetylsalicylic acid (ASA) and clopidogrel to the more potent ticagrelor. Interestingly, the circulating levels of miR-126 (p = 0.030), miR-223 (p = 0.044), and miR-150 (p = 0.048) were significantly reduced, while the levels of miR-96 were increased (p = 0.038). No substantial differences were observed for the remaining microRNAs. Conclusions. Switching from a dual antiplatelet treatment with clopidogrel to ticagrelor is associated with significant modulation in the circulating levels of specific microRNAs. If confirmed in larger, independent cohorts, our results pave the way for the use of circulating microRNAs as biomarkers of platelets activity in response to specific pharmacological treatments.

Course of platelet miRNAs after cessation of P2Y12 antagonists

“…As illustrated in Figure 1, cessation of clopidogrel, prasugrel and ticagrelor led to a significant increase in ADP-mediated platelet aggregation measured by MEA, as one would expect. 22 Furthermore, Willeit and colleagues showed that the administration of a loading dose of prasugrel alters the expression of miRNA-126, -150, -191, -223 and -24 in healthy volunteers and patients with symptomatic carotid atherosclerosis. This is against our expectations based on previous studies: Carino et al found a significant reduction in miRNA-126, -223 and -150 after switching from clopidogrel to prasugrel in 16 patients with acute coronary syndrome and an increase in the levels of miRNA-96.…”

“…13,22 Moreover, our patients were followed for 6 months at 4 different time points and the investigated miRNA were predefined at the beginning of the study. All patients received optimal contemporary concomitant pharmacological treatment and last generation drug-eluting stents and, therefore, represent a relevant, well-treated cohort of stable CAD patients.…”

“…This is against our expectations based on previous studies: Carino et al found a significant reduction in miRNA-126, -223 and -150 after switching from clopidogrel to prasugrel in 16 patients with acute coronary syndrome and an increase in the levels of miRNA-96. 22 Furthermore, Willeit and colleagues showed that the administration of a loading dose of prasugrel alters the expression of miRNA-126, -150, -191, -223 and -24 in healthy volunteers and patients with symptomatic carotid atherosclerosis. 8 This discrepancy may be explained by the long-term intake of DAPT in our cohort, which might have caused chronic adaption at the level of RNA transcription.…”

“…Although only a relatively small study of 62 patients, our patient cohort is larger than previous studies. 13,22 Moreover, our patients were followed for 6 months at 4 different time points and the investigated miRNA were predefined at the beginning of the study. Cessation of P2Y 12 -inhibitor therapy increased ADP-mediated platelet aggregation, as expected, but did not significantly change plasma levels of miRNA-223, miRNA-150, miRNA-21 and miRNA-126.…”

Transcoronary concentration gradients of circulating microRNAs in heart failure

“…5 In fact, several studies reported an association between circulating levels of specific miRNAs and cardiovascular diseases, including acute myocardial infarction, 5,6 myocarditis, 7 takotsubo syndrome, 8 acute and chronic HF, 9 stable coronary artery disease, 10,11 in-stent restenosis, 3,11,12 type 2 diabetes, 13 or in association with different levels of platelet activity. 14 Importantly, since specific miRNAs are differentially expressed in different cell types, circulating levels of specific miRNAs might reflect different biological alterations, which could provide useful hints to the underlying aetiopathogenesis. 15 In this context, we evaluated the transcoronary expression gradients of selected circulating miRNAs in HF patients, to investigate whether a specific release from the heart could be found for different aetiologies underlying HF.…”