CRP reveals an inflammatory, non-calcified coronary endotype in SMuRF-less individuals and enables efficient two-stage screening for subclinical atherosclerosis

Background A substantial fraction of individuals with coronary atherosclerosis lack standard modifiable risk factors (SMuRFs). In this understudied group, inflammatory pathways may predominate, yet simple biomarkers that reveal early disease are lacking. Purpose To determine whether C-reactive protein (CRP) identifies subclinical coronary atherosclerosis, particularly in SMuRF-less individuals, and whether CRP can support efficient two-stage CTCA screening. Methods Adults undergoing coronary CT angiography (CTCA) with CRP measurement were assessed for clinically actionable atherosclerosis and plaque phenotype using AI-derived metrics. CRP was analysed continuously and categorically. Multivariable and Bayesian logistic models estimated adjusted and counterfactual effects. Interactions with SMuRF status and sex were examined. Screening strategies were evaluated by comparing universal CTCA with CRP-guided pathways. Results In SMuRF-less individuals, CRP ≥3 mg/L was strongly associated with clinically actionable disease (adjusted OR 2.63, p<0.05). CRP correlated with total, non-calcified, fibro-fatty and low-attenuation plaque (ρ 0.23–0.26, all p<0.001), with effects most pronounced in SMuRF-less men. In participants with minimal coronary calcification (<10 mm³), elevated CRP remained associated with early fibrous, fibro-fatty and low-attenuation plaque, indicating a specific link with non-calcified, biologically active atheroma. Bayesian models confirmed higher risk with CRP ≥3 mg/L (posterior OR 1.48, 95% CrI 1.00–2.14). Patient-level counterfactual analysis demonstrated median absolute risk differences of +3.5% (IQR 1.3–6.7%), with peaks >10% in older women and middle-aged men, highlighting a distinct inflammatory endotype. CRP-guided screening maintained≥80% sensitivity while reducing CTCA utilisation by up to 37% in SMuRF-negative individuals. Decision-curve analysis showed consistently greater net benefit for CRP-based two-stage strategies compared with universal or no scanning. Conclusions CRP identifies a biologically distinct, inflammation-driven coronary endotype in SMuRF-less individuals, characterised by non-calcified and low-attenuation plaque. This translates directly into practical screening value: a simple CRP-first pathway substantially improves CTCA efficiency while maintaining diagnostic yield. CRP may therefore represent a scalable tool for precision prevention in populations overlooked by traditional risk models. Figure 1 – Association of CRP with different plaque morphology Figure 2. Top Panel - Predicted probability of CAD (CACS ≥100) by age and CRP category, stratified by sex. Bottom Panel - CRP effects on CAD risk (counterfactual analysis).Figure 2Figure 1