Vulnerable atherosclerotic plaque: underlying mechanisms and novel tools for its detection

Vulnerable plaques (VP) are prone to rupture causing strokes and myocardial infarctions.

My aims are to detect subjects with VP, before they suffer symptoms and to identify clinically useful VP markers, finding new mechanisms underlying rupture.

I will:Study how plaque turnover rate is associated with VP using accelerator mass spectrometry (C14 bomb-peak dating), laser dissection and spatial transcriptomics to link it to gene expression, extracellular matrix (ECM) or plaque cell subtypeIdentify pathways in human plaques responsible for rupture leading to risk of events. “Omics” of lipids, metabolites, and ECM, histology, RNA seq and GWAS will be combined, looking for markers/therapeutic targets and how to best predict VP or events.

Mechanisms involving ECM (that emerged from the preliminary results from RNA seq/spatial transcriptomics) are studied in vitro. We just demonstrated the ruptures location and the most relevant targets for rupture are being pursued. One is MMP9, so a novel conformational selective antibody anti-MMP9 is being developed.

Immune cell interactions between carotid plaque,blood and draining lymph nodes will also be studied in relation to VP phenotype for the 1st timeEvaluate our novel non-invasive ultrasound for plaque structure (UPSA, histologically validated) by comparing with in patient MR,PET/MRI and ex vivo with synchrotron, and by testing if it can monitor plaque changes by atorvastatin, inclisiran or colchicine (randomized placebo-controlled trial)