Abstract Body (Do not enter title and authors here): Background. We recently reported that addition of PCSK9 inhibition for 26 weeks in patients receiving maximum statin therapy led to significant increase in OCT-verified minimum fibrous cap thickness (FCT) and reduction in NIRS maximum lipid-core burden over 4mm (LCBI4) suggestive of plaque stabilization. In addition to phenotypic characterization, YELLOW III evaluated changes in gene expression in peripheral blood mononuclear cells (PBMC) associated with imaging-based morphologic plaque stabilization in response to evolocumab addition to statin therapy.
Methods. 137 CAD patients were enrolled, who were scheduled for elective coronary angiography, and in addition to the culprit lesion revealed a 30-50% non-obstructive lesion with OCT-defined lipid-rich plaque. All patients received 140 mg of evolocumab for 26 weeks in addition to maximum statin treatment. PBMCs were isolated at baseline and follow-up to assess their transcriptomic profile by targeting 50M reads per sample using bulk RNA sequencing. 104 patients had imaging and transcriptomic data available at both time points. Machine learning models were used to predict baseline transcriptomic signatures of beneficial imaging response.
Results. We identified 922 upregulated and 571 downregulated transcripts at follow-up. Whereas multiple canonical pathways modulating immune cell adhesion, recruitment and communication were downregulated, those associated with mitochondrial function, cell survival and protein synthesis were upregulated after 26 weeks of evolocumab addition to maximum statin therapy (Image 1). Among 110 patients, 88(80%) patients demonstrated increased FCT (FCT responders), while 86(78%) patients had a significant reduction in LCBI4 (LCBI responders). Elastic net models with 38 genes for FCT and 71 genes for LCBI4 were able to predict patient’s response using baseline genes with high accuracy, AUC=0.97 and 0.90 respectively. Transcriptomic signature at baseline included genes associated with upregulated interleukin-10 signaling and macrophage alternative activation (IL1R2), wound healing (COL4A2, MMP9, IL1R2) and neutrophil degranulation (ABCA13, MMP9, SLPI).
Conclusions. In patients with stable CAD, beneficial changes in plaque morphology after evolocumab treatment were associated with suppressed inflammation, alleviated oxidative stress and restored mitochondrial function. Transcriptomic signature of beneficial response will facilitate development of personalized therapies for treating CAD.