Pleiotropic effects of ticagrelor on microRNA expression in acute coronary syndrome on long term follow up
Authors: Grimaldi M.C , Canonico F , Larosa G , Cappannoli L , Maino A , Mandolini C , Copponi G , Liuzzo G , Crea F , Biasucci L.M 
Published: November 2020

Abstract

Background
PLATO study showed that Ticagrelor (Ti) significantly reduced the rate of death from vascular causes, myocardial infarction or stroke without a significant increase of major bleeding vs Clopidogrel (Cl). Previous studies demonstrated the stronger direct anti-platelet effect of Ti versus Cl. Few data exist about the indirect anti-platelet properties and pleiotropic effects, eventually involved in the positive effect of Ti on acute coronary syndrome (ACS) outcome.

Aim
As Ti has multiple pleiotropic effects, we sought to assess whether the different outcome of Ti versus Cl in NSTE-ACS patients could be explained, at least in part, by different modulation of circulating microRNA (miRNA). The primary endpoint was to characterize the effect of the two different P2Y12 inhibitors on miRNA expression. Secondary endpoint was to correlate miRNA profile to clinical outcome.

Methods
Thirty-one patients with a diagnosis of NSTE-ACS were enrolled in this study. Patients were randomized for Ti or Cl assumption before undergoing PCI. Clinical characteristics were homologues between Ti and Cl groups. Blood samples were drawn at different time point (T0, T1 and T2) to test miRNA modulation and stability (T0, at baseline; T1, three hours after drug administration; T2, twenty-four hours after coronarography). Plasma RNA was extracted and pooled for microarray PCR based panel of ninety miRNA analysis. MiRNA expression was normalized on the global mean of each patient. Levels of circulating miRNAs were compared using statistical tests, assuming significance at P&lt;0,05.

Results
A panel of seven circulating miRNAs associated with atherosclerosis, thrombosis and inflammation were selected for validation (miR-652-3p; miR-26-5p; miR-25-3p; miR-let7c; miR-155-5p; miR-222-3p; miR-223-3p). Microarray analysis showed an opposite modulation of most miRNAs at T0, T1 and T2 in patients with Cl or Ti treatment. In particular, Cl group showed an upregulation of most miRNAs, while Ti administration caused their down-regulation. Of the seven miRNA selected for validation, miR-652-3p, expression at T1 showed a significantly modulation in patients in Cl treatment compared to Ti (T1 Cl 2,637±1,092, T1 Ti 0,660±0,171; p=0.03). MiRNA-652-3p has a validated pro-atherogenic role. On five-years follow, an higher rate (40%) of cardiovascular events (new ACS, recurrent ischemia and stent thrombosis) was reported in the Cl group compare to Ti. Indeed, no one death or bleeding occurred.

Conclusion
This data suggest that Ti has a protective role down-regulating pro-atherogenic and pro-thrombotic miRNAs (miR-652-3p, miR-let7c, miR-223-3p, miR-155-5p) and promoting the expression of anti-atherogenic miRNAs (miR-25-3p) when compared to Cl. This may contribute to explain the positive effect on clinical outcome of Ti. Although the small number of patients, this pilot study gives another evidence about the multiple positive pleiotropic effect of Ti.
Figure 1. miRNA 652-3p expression

Funding Acknowledgement
Type of funding source: None