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Abstract

Background: Coronary artery disease (CAD) is the leading cause of death worldwide. Current therapeutic interventions aim to inhibit the progression of established plaques to major adverse cardiovascular events, called secondary prevention. Recent clinical trials evaluated the therapeutic potential of reducing inflammation for secondary prevention. Most of these patients have already been treated with lipid-lowering drugs such as statins, which have anti-inflammatory effects. Therefore, characterizing the residual active inflammatory pathways is pivotal for designing new anti-inflammatory therapies for secondary prevention in addition to standard-of-care statin treatment. Objectives: To characterize residual inflammatory pathways enriched in established coronary plaques after statin treatment. Methods: Coronary plaques from the explanted hearts of patients with ischaemic cardiomyopathy and a history of statin treatment were pathologically characterized as pathological intimal thickening (PIT) and fibroatheroma according to the Modified American Heart Association Classification. Bulk RNA sequencing was performed to identify inflammation-related processes enriched in fibroatheroma compared to PIT. Multiplex immunostaining of therapeutic target proteins was performed on human plaque sections using the PhenoCycler system to determine the activity of a selected panel of inflammatory pathways targeted by drugs in clinical trials. Results: Differential gene expression analysis identified 38 genes enriched in fibroatheroma (n=9) compared to PIT (n=5). Gene ontology enrichment analysis showed that these genes were involved in “chondroitin sulfate/dermatan sulfate metabolism” and “chondroitin sulfate biosynthesis”. Multiplex immunostaining using the PhenoCycler system revealed high expression of interleukin 1 receptor in endothelial cells (median 78.93%) and low levels of NF-κB activity in fibroatheroma. Conclusions: Residual inflammatory pathways remain active in established coronary plaques despite statin treatment. The enrichment of chondroitin sulfate/dermatan sulfate metabolism and chondroitin sulfate biosynthesis suggests an enrichment of vascular smooth muscle cells in stable fibroatheroma. High expression of IL-1R in endothelial cells suggests that blocking IL-1 signaling using receptor antagonists such as anakinra may be a promising strategy for secondary prevention, which likely lead to few off-target effects. Identifying cellular expressions of therapeutic targets in advanced plaques can help predict therapeutic responses and guide future clinical trials.