Intra-coronary imaging and transcriptomics of calcified nodules before and after intensive lipid-lowering therapy: a YELLOW III substudy.

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 AND

RESULTS

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 analysed. Among 110 patients, 43 (39.1%) had CNs. A total of 73 paired CNs were analysed for morphology, of which 65 CNs were ≥4 mm. 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 (p interaction = 0.012). Transcriptomic analysis demonstrated baseline enrichment of neutrophil degranulation pathways in CN patients, which diminished at follow-up.

CONCLUSION

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.

SUMMARY: Calcified nodules (CNs) are high-risk coronary features responsible for a significant portion of acute coronary syndromes, yet their response to intensive medical therapy remains poorly understood. This YELLOW III substudy utilized multi-modality intravascular imaging (NIRS-IVUS and OCT) to investigate the impact of 26 weeks of Evolocumab and maximally tolerated statins on CN morphology. In 43 patients with identified CNs, intensive lipid-lowering therapy led to a significant reduction in the maxLCBI4mmCN. Morphological parameters of CNs remained largely unchanged except for a modest increase in the surrounding calcium arc. Simultaneously, PBMC transcriptomic analysis revealed a marked attenuation of the neutrophil degranulation pathway, which was highly enriched at baseline. While the therapy successfully reduced the systemic inflammatory profile, a transition towards coagulation-related pathways at follow-up suggests a shift in the residual risk profile. These findings provide a novel mechanistic basis for using PCSK9 inhibitors to stabilize calcium-related high-risk plaques. Collectively, the data demonstrate that aggressive lipid-lowering not only modifies plaque architecture but also shifts the systemic biological environment from an inflammatory to a more stable one.