Emerging role of inflammatory pathways on coronary atherosclerotic risk in patients with chronic coronary syndromes under current treatment

Abstract Background Progressive reduction in low-density lipoprotein cholesterol (LDL-C) levels achieved over the last few decades decreased the risk of cardiovascular (CV) events in patients with chronic coronary syndromes (CCS). Nevertheless, some of these patients continue to experience a high residual risk (RR) of events. Several inflammatory pathways may contribute to coronary plaque destabilization and evolution associated with CV events. New evidence is required to understand which are the critical inflammatory factors which are associated with high risk coronary atherosclerotic patterns persisting despite current treatment. Purpose Aim of this study was to explore the associations between plasma inflammatory profiles and the Leiden risk score, incorporating coronary stenosis severity, plaque location, extent and composition, assessed by computerized tomography coronary angiography (CTA) and predicting worse prognosis in patients with CCS. Markers of inflammasome pathway, monocyte activation, senescence, endothelial activation, vascular remodeling and adipose tissue dysfunction were investigated. Methods Among the 561 patients with CCS enrolled in the HURRICANE study (Health improvement by Understanding RR In CAd and NEw targets for treatment), 398 patients (65±10yrs, 68% males) with high quality CTA and fully characterized by classical risk factors, emergent cardiometabolic risk conditions and molecular inflammatory profiles, determined using a multiplexing platform, were selected. CTA exams were visually and semi-quantitatively analysed according to CAD-RADS2 classification and the Leiden Risk Score was computed. A Leiden Risk Score 5 was used in multivariate analysis to define an increased CV risk. Severity and extension of disease were described using categories of CAD-RADS2 scores: 1. Absent (CAD-RADS2=0), Non Obstructive (CAD-RADS2=1-2) and Obstructive disease (CAD-RADS2=3-5); 2. Absent (P=0), Less Extensive (P1-2) and More Extensive disease (P3-4). Results A higher Leiden risk score was present in 60% of patients. Among inflammatory mediators, IL-10, IL-8 and GDF-15 were the only independent predictors of a higher Leiden risk score at multivariate logistic analysis, after adjustment for LDL-C, statin therapy, and CV risk factors (Fig 1). The IL-8/IL-10 ratio was significantly increased in patients with any CAD (Non Obstructive and Obstructive) and in patients with a more extensive disease (Fig 2A). GDF-15 levels showed a significant trend to increase from patients without CAD to those in increasing severity and extension classes (Fig 2B). Conclusions Circulating levels of molecules involved in monocyte activation (IL-8 and IL-10) and senescence (GDF-15) are predictors of higher CTA coronary atherosclerosis risk scores in patients with CCS. These findings provide novel evidence on critical inflammatory pathways as potential therapeutic targets in patients with persisting high risk coronary disease despite current treatment.Predictors of higher Leiden risk score Inflammatory markers and CAD-RADS scores