Coronary inflammation predicts cardiovascular risk in the absence of standard modifiable risk factors (SMuRFs): the ORFAN study

Background Standard modifiable cardiovascular (CV) risk factors (SMuRFs), including diabetes, hypertension, hyperlipidaemia, smoking and obesity, form the cornerstone of contemporary CV risk prediction. However, a substantial proportion of patients experience coronary events in the absence of these risk factors, highlighting limitations of traditional risk stratification. Coronary inflammation is a key driver of atherosclerosis and plaque instability and may represent a mechanistic pathway underlying this residual risk in patients without SMuRFs. Purpose To explore the prognostic value of coronary inflammation, quantified by the perivascular fat attenuation index (FAI) Score measured using coronary CT angiography (CCTA), in individuals without SMuRFs. Methods This multicentre longitudinal cohort study included 73,689 consecutive patients undergoing clinically indicated CCTA, enrolled in the Oxford Risk Factors and Non-invasive imaging (ORFAN) study. Patients were stratified according to SMuRF burden (0 to ≥3). Coronary inflammation was quantified using mean FAI Score (a CCTA-derived biomarker of coronary inflammation). Major adverse cardiovascular events (MACE) were defined as myocardial infarction (MI), new heart failure, or CV death. Cox proportional hazards models were fitted to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for clinical outcomes. The prognostic value of mean FAI Scores (the mean of the FAI Scores in all three coronary arteries) was evaluated in SMuRFless and SMuRF-positive individuals. Results Over a median follow-up of 6.6 years (IQR 5.1-9.1), patients without SMuRFs [n=13,294 (18%)] accounted for 722 (8.9%) of the 8,125 total MACE events and 191 (7.8%) of the total 2,454 CV deaths. Increased mean FAI Scores were predictive of CV mortality (HR 12.6, 95% CI (7.2-21.9), p<0.001) [A] and MACE (HR 4.4, 95% CI (3.5-5.5), p<0.001) [B] comparing the mean FAI Score in the 90th centile versus bottom quartile for patients without SMuRFs. The association between mean FAI Score and CV death, MI, and ischaemic stroke was strongest in SMuRFless individuals compared to those with SMuRFs[C]. For each standard deviation increase in mean FAI Score, the HR was 1.42, 95% CI (1.34–1.50) for CV death, 1.16, 95% CI (1.05–1.26) for MI, and 1.27, 95% CI (1.16–1.39) for ischaemic stroke [D]. The strength of these associations was progressively attenuated with increasing SMuRF burden even after adjustment for CAD severity, suggesting that coronary inflammation plays a proportionally greater role in risk among SMuRFless individuals. Conclusions Coronary inflammation, quantified by FAI Score, provides independent prognostic information in patients without SMuRFs. These findings highlight the limitations of SMuRF-based risk assessment and support further evaluation of imaging biomarkers of vascular inflammation to enable more precise CV risk stratification and earlier preventive intervention.Picture 1