Circulatinng high-mobility group box 1 levels are associated with presence of thin-cap fibroatheroma in coronary culprit lesion determined by optical coherence tomography

Abstract

Purpose: Biomarkers predicting the presence of Thin-Cap Fibroatheroma (TCFA), the primary type of vulnerable plaque, have not been established. Recently, High-Mobility Group Box 1 (HMGB1), a damage-associated molecular pattern molecule derived from necrotic cells and activated macrophages, has been shown to contribute to the progression of atherosclerosis. The aim of this study was to assess whether circulating serum HMGB1 can predict the presence of TCFA as determined by Optical Coherence Tomography (OCT). Methods: Forty-eight patients (69±9 years, 39 males) with 40 stable and 8 unstable angina pectoris were enrolled. Culprit lesion morphology was assessed by OCT and Intravascular Ultrasound (IVUS) before Percutaneous Coronary Intervention (PCI). By OCT, the TCFA was defined as a plaque with lipid contents in >90° and with thinnest part of the fibrous cap measuring <65μm. Cross-sectional vessel, lumen, plaque area, and remodeling index were measured using IVUS. Circulating serum levels of HMGB1 and high sensitive C-Reactive Protein (hsCRP) were measured before PCI and compared with plaque characteristics. Serum HMGB1 levels were categorized into low (lowest tertile), intermediate (middle tertile), and high (highest tertile) groups. Results: Nineteen patients with TCFA and 29 patients without TCFA were identified. Levels of HMGB1 were significantly higher in patients with TCFA than those without TCFA (9.64±5.52 vs. 5.95±3.68 ng/mL; p = 0.008). There were no significant differences in hsCRP levels between patients with and without TCFA. Levels of HMGB1, but not hsCRP, correlated inversely with fibrous cap thickness (r = -0.30, p = 0.04) and positively with remodeling index (r = 0.45, p = 0.001). The frequency of TCFA was 13, 50, and 56% in low, intermediate, and high HMGB1 group, respectively (p = 0.024). Multivariate logistic regression analysis showed that HMGB1 level was the independent factor associated with TCFA existence (odds ratio, 1.19; 95% confidence interval, 1.02 to 1.40; p = 0.032). The area under the receiver-operating characteristics curve for HMGB1 level for prediction of TCFA was 0.73 (p = 0.008). The optimal cut-off value of HMGB1 for predicting TCFA was 6.40 ng/mL (sensitivity 74%, specificity 62%). Conclusions: Higher serum HMGB1 level was associated with the presence of TCFA, thinner fibrous cap thickness, and greater remodeling index at coronary culprit lesions. These findings suggest that circulating HMGB1 may be a useful marker reflecting the plaque vulnerability.