Abstract
Background: Inflammation plays a crucial role in adverse outcomes of coronary artery disease. NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome activates 2 classical pathways: interleukin-1β (IL-1β)/IL-6/high-sensitivity C-reactive protein (hsCRP) and IL-18/IL-6/hsCRP. However, the predictive value of pathway-related biomarkers, particularly their combinations, remains to be systematically evaluated. Objectives: The authors aimed to explore the predictive value of individual and combined biomarkers from 2 pathways for long-term cardiovascular risk in patients with multivessel disease (MVD). Methods: From a prospective, multicenter cohort, 1,058 consecutive patients with MVD were enrolled. The primary endpoint was major adverse cardiac and cerebrovascular event (MACCE-4P), a composite of all-cause death, myocardial infarction, revascularization, and stroke. Results: During a median 2-year follow-up (IQR: 2.0-2.1 years), 130/1,058 (12.3%) MACCE-4P occurred. After multivariable adjustment, higher levels of IL-1β (HR: 1.63; 95% CI: 1.15-2.32), IL-6 (1.72, 1.20-2.46), and hsCRP (1.59, 1.09-2.30) were associated with increased MACCE-4P risk, whereas IL-18 was not. For combined analysis, any 2-biomarker combination from either the IL-1β/IL-6/hsCRP or IL-18/IL-6/hsCRP pathway significantly predicted higher MACCE-4P risk (HR range: 1.84-2.19), with further risk elevation observed for the 3-biomarker combinations (HR: 3.09; 95% CI: 1.80-5.31 for IL-1β pathway; HR: 2.26; 95% CI: 1.24-4.14 for IL-18 pathway). The 4-biomarker combination (IL-1β+IL-6+IL-18+hsCRP) also predicted significantly higher MACCE-4P risk (HR: 2.64; 95% CI: 1.36-5.14). Notably, 3-/4-combined biomarkers demonstrated significant incremental predictive value over single biomarkers. Conclusions: In patients with MVD, combined assessment of NLRP3-associated inflammatory biomarkers offers significant incremental predictive value beyond individual biomarkers. These findings highlight the importance of integrating multiple inflammatory biomarkers to better identify patients with residual inflammatory risk.