HMGB1 is associated with atherosclerotic plaque composition and burden in patients with stable coronary artery disease.

OBJECTIVES: The role of inflammation in atherosclerosis is widely appreciated. High mobility group box 1 (HMGB1), an injury-associated molecular pattern molecule acting as a mediator of inflammation, has recently been implicated in the development of atherosclerosis. In this study, we sought to investigate the association of plasma HMGB1 with coronary plaque composition in patients with suspected or known coronary artery disease (CAD). DESIGN: HMGB1, high sensitive troponin T (hsTnT) and high sensitive C-reactive protein (hsCRP) were determined in 152 consecutive patients with suspected or known stable CAD who underwent clinically indicated 256-slice coronary computed tomography angiography (CCTA). Using CCTA, we assessed 1) coronary calcification, 2) non-calcified plaque burden and 3) the presence of vascular remodeling in areas of non-calcified plaques. RESULTS: Using univariate analysis, hsCRP, hsTnT and HMGB1 as well as age, and atherogenic risk factors were associated with non-calcified plaque burden (r = 0.21, p = 0.009; r = 0.48, p<0.001 and r = 0.34, p<0.001, respectively). By multivariate analysis, hsTnT and HMGB1 remained independent predictors of the non-calcified plaque burden (r = 0.48, p<0.01 and r = 0.34, p<0.001, respectively), whereas a non-significant trend was noticed for hs-CRP (r = 0.21, p = 0.07). By combining hsTnT and HMGB1, a high positive predictive value for the presence of non-calcified and remodeled plaque (96% and 77%, respectively) was noted in patients within the upper tertiles for both biomarkers, which surpassed the positive predictive value of each marker separately. CONCLUSIONS: In addition to hs-TnT, a well-established cardiovascular risk marker, HMGB1 is independently associated with non-calcified plaque burden in patients with stable CAD, while the predictive value of hs-CRP is lower. Complementary value was observed for hs-TnT and HMGB1 for the prediction of complex coronary plaque

Classifying patients by plaque composition, a trend was observed for higher hs-CRP values in patients with non-calcified plaque without however, reaching statistical significance (a).

<p>HsTnT and HMGB1 values on the other hand, increased with increasing plaque presence and complexity, yielding higher values in patients with non-calcified plaque versus purely calcified or no plaques and the highest values in subjects with remodeled non-calcified plaque (b and c).</p

Expression of HMGB1 in lesional macrophages could promote vascular inflammation and ultimately cause plaque remodeling.

<p>Such remodeled, rupture-prone plaques may then cause chronic sub-clinical embolization of athero-thrombotic debris, which then results (i) in myocardial micro-necrosis, as reflected by the concomitantly increased hs-TnT values in the same patient subgroups and (ii) in further release of HMGB1 by ‘stressed’ cardiomyocytes. Increased HMBG1 expression would then elicit further pro-inflammatory response, again contributing to vascular remodeling processing, thus possibly being part of a vicious circle, which encompasses both chronic plaque inflammation and myocardial micronecrosis.</p

Weak correlations were observed between calcium scoring with hs-CRP, hs-TnT and HMGB1 (a, c and f).

<p>A weak correlation was also noted between hs-CRP and non-calcified plaque burden (b), while stronger correlations were observed between the latter with hs-TnT and HMGB1 (d and f).</p

Demographic and cardiac CT data.

<p>Data presented as number of patients or as mean±standard deviation.</p

Uni- and multivariable logistic regression analysis for the prediction plaque composition (no plaque and only calcified versus non-calcified plaque with or without vascular remodeling).

<p>HR indicates risk ratios and CI the corresponding 95% confidence intervals.</p

Calcium scoring, non-calcified plaque volume and plaque composition by hsTnT and HMBG1 tertiles.

*<p>p<0.05 versus mid and lower tertiles;</p>†<p>p<0.05 versus lower tertiles.</p