CCTA-Based Assessment of Coronary Calcium Burden, Inflammatory and Metabolic Biomarkers, and 3-Year Outcomes in Patients with Type 2 Diabetes Mellitus and Stable Ischemic Heart Disease

Background: Coronary artery calcification (CAC) is common in patients with type 2 diabetes mellitus (T2DM) and stable ischemic heart disease (IHD). However, the associations of coronary calcium burden with inflammatory and metabolic biomarker profiles and subsequent clinical outcomes within this population remain incompletely characterized. Objective: To examine the associations of coronary CT angiography (CCTA)-based coronary calcium burden with inflammatory and metabolic biomarkers and 3-year clinical outcomes in patients with T2DM and stable IHD. Methods: In this retrospective observational study using routinely collected electronic medical record and CCTA data from a single tertiary hospital in Suzhou, China, we analyzed 3991 patients with T2DM and stable IHD who underwent CCTA between January 2016 and December 2022. Patients were stratified by coronary artery calcium score (CACS) as mild (>0-100), moderate (101-400), and severe (>400). Circulating interleukins (IL-1β, IL-6, IL-10, IL-35), TNF-α, TGF-β, and trimethylamine N-oxide (TMAO) were measured at baseline. The primary endpoint was 3-year major adverse cardiovascular and cerebrovascular events (MACCE). Results: Higher CACS correlated with increased IL-1β and TMAO and decreased IL-10 and IL-35. Over three years, MACCE occurred in 2.9%, 20.1%, and 18.9% of the mild, moderate, and severe groups (P<0.001). In the fully adjusted Cox model, higher ln(CACS + 1) and higher IL-1β levels were independently associated with increased 3-year MACCE risk, whereas higher IL-35 levels were inversely associated with MACCE. Addition of ln(CACS + 1) to the clinical model improved the C-index from 0.704 to 0.750, and the subsequent addition of IL-1β and IL-35 further increased the C-index to 0.766. Conclusion: CACS provided substantial incremental prognostic information beyond clinical variables, whereas IL-1β and IL-35 provided a further modest but statistically significant improvement in model discrimination. IL-35 should be regarded as an emerging, hypothesis-generating candidate biomarker rather than an established anti-calcific mediator. These observational findings do not establish causal mechanisms, and the prognostic utility of the combined imaging-biomarker model requires external validation before clinical implementation.