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Transcoronary gradients of vascular miRNAs and coronary atherosclerotic plaque characteristics. AIMS: Circulating microRNAs (miRs) may reflect pathophysiologically relevant processes in the atherosclerotically diseased coronary arterial wall. Given the unmet medical need to identify patients with an unstable plaque phenotype, we determined the relation of circulating atherosclerosis-regulatory miRs with plaque phenotypes. METHODS AND RESULTS: We assessed coronary atherosclerotic plaque burden and phenotype by optical coherence tomography in 52 patients and measured the levels of circulating miRs across the transcoronary gradient. The overall plaque load was significantly correlated with transcoronary concentration gradients of miR-126-3p (P = 0.04), miR-145-5p (P = 0.01), miR-155-5p (P < 0.01), and miR-29b-3p (P = 0.02), but not with other miRs such as miR-92a-3p. In patients with a high extent of vulnerable plaques as assessed by the presence of thin-cap fibroatheromas (TCFAs), significantly higher transcoronary gradients were observed, particularly for miR-126-3p, miR-126-5p, and miR-145-5p (all P < 0.02). Transcoronary gradients of miR-126-3p (P < 0.01), miR-126-5p (P < 0.01), miR-145-5p (P = 0.01), miR-29b-3p (P = 0.03), and miR-155-5p (P = 0.02) demonstrated a significant discriminatory power to predict the presence of TCFAs (AUC > 0.7 for all). Moreover, aortic and venous coronary sinus levels of miR-29b-3p were inversely correlated with plaque fibrosis, a finding that is consistent with the anti-fibrotic activity of miR-29b-3p. CONCLUSION: The overall plaque burden and plaque phenotypes are associated with changes in the kinetics of miR-concentrations across the transcoronary passage. Transcoronary gradients of the anti-atherosclerotic miR-126-3p and miR-145-5p correlated with the extent of TCFAs, suggesting that instable plaques may affect the local uptake or degradation of these miRs.