Association of plasma miR-223 and platelet reactivity in patients with coronary artery disease on dual antiplatelet therapy: A preliminary report

Abstract

Decreased plasma levels of microRNA-223 (miR-223), predominantly of platelet origin, were proposed as a surrogate marker of efficacy of antiplatelet therapy. However, higher on-treatment platelet reactivity was associated with lower plasma miR-223 in patients with coronary artery disease (CAD) on dual antiplatelet therapy (DAPT) including clopidogrel and aspirin. Our aim was to compare plasma miR-223 and platelet reactivity in CAD patients on DAPT with newer P2Y12 antagonists vs. clopidogrel. We studied 21 men with CAD admitted to our centre owing to a non-ST-elevation acute coronary syndrome, and with an uncomplicated hospital course. From the day of admission, the patients were receiving either clopidogrel (n = 11) or prasugrel/ticagrelor (n = 10) in addition to aspirin. Before discharge, miR-223 expression in plasma was estimated by quantitative polymerase chain reaction using the comparative Ct method relative to miR-16 as an endogenous control. Multiple electrode aggregometry was used to assess platelet aggregation in response to adenosine diphosphate (ADP). ADP-induced platelet reactivity was decreased in the patients treated with prasugrel or ticagrelor compared with those on clopidogrel (mean ± SD: 139 ± 71 vs. 313 ± 162 arbitrary units [AU]*min, p = 0.006), due to a more potent antiplatelet activity of the novel P2Y12 antagonists. Consequently, six out of seven patients in the lower tertile of the ADP-induced platelet aggregation were treated with the newer P2Y12 blockers, whereas six out of seven patients in the upper tertile were on clopidogrel. Plasma miR-223 was elevated with decreasing platelet reactivity (Spearman's rho = -0.52; p = 0.015 for trend), being significantly higher in the lower tertile of the ADP-induced platelet aggregation (median [range]: 1.06 [0.25-2.31]) vs. the upper tertile (0.20 [0.13-2.30]) (p = 0.04). In conclusion, our preliminary results argue against the notion of low plasma miR-223 as a marker of platelet responsiveness to DAPT. On the contrary, more potent platelet inhibition associated mainly with newer P2Y12 antagonists appears to coincide with higher miR-223 relative to the subjects with attenuated responsiveness to DAPT.

miRNA-15a/16: As Tumor Suppressors and More

“…Because studies showed that circulating miRNAs often bind to carrier proteins or are wrapped in exosomes, they may be better protected from RNase and serve as better endogenous controls. miR-16 has been used in a variety of studies, such as studies on gastric cancer [45], adrenocortical tumors [46] and coronary artery disease [47].…”

Gene Expression Signatures and the Spectrum of Coronary Artery Disease

“…Notably, one analysis showed that when patients treated with antiplatelet therapy were dichotomized according to a platelet response assay, miRNA-223 levels were significantly lower in patients in the Blow response^group compared to those with a Bnormal response,^a difference which was independent of other variables including CYP2C19 loss-of-function genotypes [78]. In addition, miRNA-223 was found to be further decreased in patients treated with the more potent P2Y12 inhibitors, prasugrel and ticagrelor, when compared to clopidogrel [80], which may be a surrogate for the differences in treatment effects seen between these drugs in randomized control trials [81].…”

MicroRNAs for Restenosis and Thrombosis After Vascular Injury

“…[38][39][40] In addition, some miRNAs are closely related to platelet function, their responsiveness to antiplatelet treatment, and, hence, to stent thrombosis. 94 Therefore, this represents an active area of research as discussed in the next paragraphs.…”

“…[116][117][118] The large clinical potential of platelet-derived miRNAs is well exemplified by the evidence that low plasma levels of miR-223 are a reliable marker of platelet responsiveness to antiplatelet therapy, a key issue in stent thrombosis. 94 Besides circulating platelet-derived miRNAs, these molecules can be also easily measured from platelet pellets. Interestingly, elevated levels of miR-340 and miR-624 were found in platelets from young patients with early development of coronary artery disease as compared with healthy controls.…”