Intra-Coronary Imaging and Transcriptomics of Calcified Nodules Before And After Intensive Lipid-Lowering Therapy: A YELLOW III Substudy

Background and Aims Calcified nodules (CNs) contribute to 3-5% of acute coronary syndromes (ACS). Identifying peri-calcific lipid-rich areas is challenging with conventional imaging but feasible using near-infrared spectroscopy (NIRS). This YELLOW III substudy investigated the impact of maximal lipid-lowering on CN morphology and lipid content over 26 weeks. Methods Patients with stable CAD and lipid-rich, non-obstructive plaques (lipid arc >90°, FCT <120 µm on OCT) received Evolocumab (140 mg biweekly) plus maximally tolerated statins. Lesions were evaluated at baseline and 26 weeks using combined NIRS-IVUS and OCT. Exploratory endpoints were the maximum 4 mm lipid core burden index (LCBI) in segments containing CNs (maxLCBI4mm-CN) and morphological changes in CN. Linear mixed-effects models were used to evaluate temporal changes and group interactions. Peripheral blood mononuclear cell (PBMC) transcriptomics were analyzed. Results Among 110 patients, 43 (39.1%) had CNs. A total of 73 paired CNs were analyzed for morphology, of which 65 CNs were≥4mm. CNs with lipid signal (CNLS) demonstrated a significant reduction in maxLCBI4mm-CN from 176.8 to 113.3 (β = −63.51 ± 17.63; p < 0.001), whereas no change was observed in dense CNs (p = 0.317). Morphological parameters remained largely unchanged in both groups. A modest increase in the surrounding calcium arc was observed in CNLS (p = 0.018), while depth showed a differential change between groups (pinteraction = 0.012). Transcriptomic analysis demonstrated baseline enrichment of neutrophil degranulation pathways in CN patients, which diminished at follow-up. Conclusions Intensive lipid-lowering significantly reduces peri-calcific lipid burden without measurable short-term changes in CN morphology. The clinical implications of LCBI reduction in CNs warrant further investigation.