JACC Cardiovasc Imaging. 2026 Feb 24:S1936-878X(26)00052-5. doi: 10.1016/j.jcmg.2025.12.013. Online ahead of print.
ABSTRACT
BACKGROUND: Despite extensive evidence of the beneficial effects of proprotein convertase subtilisin/kexin type 9 inhibition on clinical outcomes, the mechanisms for favorable outcomes remain poorly understood.
OBJECTIVES: The authors evaluated alterations in plaque morphology using intracoronary imaging and gene expression in peripheral blood mononuclear cells after adding evolocumab to maximum statin therapy.
METHODS: A total of 110 stable coronary artery disease patients receiving maximally tolerated statin therapy were treated with evolocumab 140 mg every 2 weeks for 26 weeks. Serial optical coherence tomography, intravascular ultrasound, and near-infrared spectroscopy of nonobstructive lesions were performed in all patients at baseline and 26-week follow-up; peripheral blood mononuclear cells were isolated for bulk RNA transcriptomic sequencing. Machine learning models were used to predict baseline transcriptomic signatures of beneficial imaging response of plaque stabilization.
RESULTS: After evolocumab treatment, optical coherence tomography-verified fibrous cap thickness (FCT) increased from 70.9 ± 21.7 to 97.7 ± 31.1 μm (mean 26.8 ± 22.3 μm; P < 0.001), and maximal lipid core burden index within 4 mm (LCBI) decreased from 306.8 ± 177.6 to 213.1 ± 168.0 (mean -93.7 ± 140.5; P < 0.001). In addition, there was a significant reduction in the percentage atheroma volume (-1.38% ± 1.48%; P < 0.001) defined by intravascular ultrasound. In total, 922 up-regulated and 571 down-regulated differentially expressed genes were identified at follow-up. Among 110 patients, 88 (80%) demonstrated FCT increase >0 (FCT responders), and 86 (78%) demonstrated LCBI reduction >0 (LCBI responders). Whereas multiple canonical pathways modulating immune cell adhesion, recruitment and communication were down-regulated, those associated with mitochondrial function, cell survival, and protein synthesis were significantly up-regulated in response to evolocumab. Elastic net models with 38 genes for FCT increase (AUC = 0.97) and 71 genes for LCBI reduction (AUC = 0.86) were able to predict patient response using baseline genes with high accuracy. The transcriptomic signature of beneficial response included pathways modulating inflammation, matrix metalloproteinases, neutrophil degranulation, and oxygen exchange.
CONCLUSIONS: In stable coronary artery disease, intravascular imaging-verified beneficial changes in plaque morphology after evolocumab treatment were associated with restored mitochondrial function, suppressed inflammation, and alleviated oxidative stress. Similar studies of plaque morphology with noninvasive modalities would allow the confirmation of novel pathways of plaque stabilization in response to maximized lipid-lowering therapy in larger number of subjects.
PMID:41758107 | DOI:10.1016/j.jcmg.2025.12.013