Abstract 12588: Inflammatory Pathways and High-Risk Coronary Plaque in Obstructive Coronary Artery Disease in The PROMISE Clinical Trial

Abstract

Introduction: Two-thirds of CV events occur in patients without oCAD; vulnerable plaque (VP) has been implicated in its pathobiology. Inflammation plays a role in atherosclerosis, but the relationships between its pathways and related biomarkers in VP have not been comprehensively evaluated. Methods: The PROMISE trial randomized 10,003 patients with stable outpatient chest pain to CTA for coronary imaging vs standard of care. In this substudy, we measured 92 inflammatory proteins using the Olink platform in 1788 PROMISE participants with core-lab interpreted CTA and biospecimens. Principal component analysis (PCA) was used for dimensionality reduction and protein PCA factors were tested for association with a high-risk composite (HRC) phenotype (composed of: oCAD, CAC>400, VP features and/or Leaman score>5). Significant PCA protein factors (FDR q < 0.05) were tested with individual HRC features. Results: The cohort was 53% female, had a mean age of 60, and 58% had a HRC phenotype. Of 12 PCA factors, three were significantly negatively associated and one was positively associated with HRC (Figure) including factors related to T-cell dependent responses (factor 6, p<0.0001); cytokines (factor 9, p=0.005); chemokines (factor 5, p=0.01); and IFN-gamma related proteins (factor 3, p=0.04). Only factor 9 was associated with VP (OR: 1.14, 95% CI [1.002-1.28], p=0.04), but attenuated in multivariate models. For individual proteins: SCF, TRANCE, TWEAK, TRAIL and IL8 (OR 0.58-1.27, p=0.001 to <0.001) were most significant, and all but IL8 were negatively associated with HRC. Conclusion: Leveraging a trial of individuals with stable chest pain and coronary CTA, we identified a range of inflammatory proteins and related pathways associated with HRC. These results implicate TNF-receptor binding (TRAIL, TRANCE) and cytokine pathways in high risk coronary atherosclerosis and highlight biomarkers with potential clinical utility for identifying high risk individuals.