Differential miRNAs in acute spontaneous coronary artery dissection: Pathophysiological insights from a potential biomarker

Abstract

Background Spontaneous Coronary Artery Dissection (SCAD) is an important cause of acute coronary syndromes, particularly in young to middle-aged women. Differentiating acute SCAD from coronary atherothrombosis remains a major clinical challenge. Methods A case-control study was used to explore the usefulness of circulating miRNAs to discriminate both clinical entities. The profile of miRNAs was evaluated using an unbiased human RT-PCR platform and confirmed using individual primers. miRNAs were evaluated in plasma samples from acute SCAD and atherothrombotic acute myocardial infarction (AT-AMI) from two independent cohorts; discovery cohort (SCAD n = 15, AT-AMI n = 15), and validation cohort (SCAD n = 11, AT-AMI n = 41) with 9 healthy control subjects. Plasma levels of IL-8, TGFB1, TGBR1, Endothelin-1 and MMP2 were analysed by ELISA assays. Findings From 15 differentially expressed miRNAs detected in cohort 1, we confirmed in cohort 2 the differential expression of 4 miRNAs: miR-let-7f-5p, miR-146a-5p, miR-151a-3p and miR-223-5p, whose expression was higher in SCAD compared to AT-AMI. The combined expression of these 4 miRNAs showed the best predictive value to distinguish between both entities (AUC: 0.879, 95% CI 0.72–1.0) compared to individual miRNAs. Functional profiling of target genes identified an association with blood vessel biology, TGF-beta pathway and cytoskeletal traction force. ELISA assays showed high plasma levels of IL-8, TGFB1, TGFBR1, Endothelin-1 and MMP2 in SCAD patients compared to AT-AMI. Interpretation We present a novel signature of plasma miRNAs in patients with SCAD. miR-let-7f-5p, miR-146a-5p, miR-151a-3p and miR-223-5p discriminate SCAD from AT-AMI patients and also shed light on the pathological mechanisms underlying this condition. Funding Spanish Ministry of Economy and Competitiveness (MINECO): Plan Nacional de Salud SAF2017-82886-R, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV). Fundación BBVA a equipos de Investigación Científica 2018 and from Caixa Banking Foundation under the project code HR17-00016 to F.S.M. Instituto de Salud Carlos III (AES 2019): PI19/00565 to F.R, PI19/00545 to P.M. CAM (S2017/BMD-3671-INFLAMUNE-CM) from Comunidad de Madrid to FSM and PM. The UK SCAD study was supported by BeatSCAD, the British Heart Foundation (BHF) PG/13/96/30608 the NIHR rare disease translational collaboration and the Leicester NIHR Biomedical Research Centre.

Impaired regulation of MMP2/16–MLCK3 by miR-146a-5p increased susceptibility to myocardial ischaemic injury in aging mice

“…There are studies demonstrated that the serum level of miR-146a-5p was elevated in patients with acute coronary syndrome (ACS) compared with healthy control subjects. 30 , 31 The spontaneous coronary artery dissection (SCAD), an important cause of ACS, caused a higher increase of miR-146a-5p than atherothrombotic acute myocardial infarction (AT-AMI) did. 31 Interestingly, the plasma level of MMP2 in SCAD patients was higher than that in AT-AMI, 31 suggesting a possible link between miR-146a-5p and MMP2 in SCAD.…”

“… 30 , 31 The spontaneous coronary artery dissection (SCAD), an important cause of ACS, caused a higher increase of miR-146a-5p than atherothrombotic acute myocardial infarction (AT-AMI) did. 31 Interestingly, the plasma level of MMP2 in SCAD patients was higher than that in AT-AMI, 31 suggesting a possible link between miR-146a-5p and MMP2 in SCAD. Furthermore, the exposure to PM2.5 could also increase miR-146a-5p expression in ST elevated MI (STEMI) patients.…”

Association between Exosomal miRNAs and Coronary Artery Disease by Next-Generation Sequencing

“…Many biological processes, such as cell proliferation, differentiation, and apoptosis, are reported to be regulated by miRNAs [ 16 ]. Thus, miRNAs are considered to play an important role in intercellular communication with relevant roles in various physiological and pathological processes [ 17 ].…”

Not all myocardial infarctions are created equal: The potential of circulating microRNAs to discern coronary artery dissection

“…In this article of EBioMedicine, Lozano-Prieto and colleagues report on the diagnostic power of circulating microRNAs for this purpose [4]. MicroRNAs are endogenous short non-coding RNAs with a major influence in the pathogenesis of cardiovascular diseases [5,6].…”