Association between plaque vulnerability and neutrophil extracellular traps (NETs) levels: The Plaque At RISK study

Abstract

Carotid atherosclerotic plaque rupture and its sequelae are among the leading causes of acute ischemic stroke. The risk of rupture and subsequent thrombosis is, among others, determined by vulnerable plaque characteristics and linked to activation of the immune system, in which neutrophil extracellular traps (NETs) potentially play a role. The aim of this study was to investigate how plaque vulnerability is associated with NETs levels. We included 182 patients from the Plaque At RISK (PARISK) study in whom carotid imaging was performed to measure plaque ulceration, fibrous cap integrity, intraplaque hemorrhage, lipid-rich necrotic core, calcifications and plaque volume. Principal component analysis generated a 'vulnerability index' comprising all plaque characteristics. Levels of the NETs marker myeloperoxidase-DNA complex were measured in patient plasma. The association between the vulnerability index and low or high NETs levels (dependent variable) was assessed by logistic regression. No significant association between the vulnerability index and NETs levels was detected in the total population (odds ratio 1.28, 95% confidence interval 0.90-1.83, p = 0.18). However, in the subgroup of patients naive to statins or antithrombotic medication prior to the index event, this association was statistically significant (odds ratio 2.08, 95% confidence interval 1.04-4.17, p = 0.04). Further analyses revealed that this positive association was mainly driven by intraplaque hemorrhage, lipid-rich necrotic core and ulceration. In conclusion, plaque vulnerability is positively associated with plasma levels of NETs, but only in patients naive to statins or antithrombotic medication prior to the index event.

Fig 1. Association between plaque characteristics and MPO-DNA levels in subgroups stratified by medication use prior to the index event.

Logistic regression with two categories of MPO-DNA as dependent variable (high vs low) and plaque characteristics as independent variables, adjusted for age, sex and time between index event and blood sampling. Odds ratios with 95% confidence intervals are reported for the two subgroups. Odds ratio for plaque volumes is presented for 1000 mm³. *indicates p-value below 0.05. IPH, intraplaque hemorrhage; LRNC, lipid-rich necrotic core.