The vulnerable atherosclerotic plaque: mechanisms of development and techniques for imaging

BAKGRUND: Vulnerable atherosclerotic plaques (VP) are prone to rupture, causing symptoms such as stroke and myocardial infarction.

MÅLSÄTTNING: My global aims are to detect subjects with VP, before they suffer symptoms and to identify clinically useful markers of VP, finding new mechanisms leading to formation or rupture of these plaques. ARBETSPLAN: In detail I will:

1. study how plaque tissue turnover rate is associated with VP using accelerator mass spectrometry (C bomb-peak dating), laser dissection to retrieve exact plaque components and spatial transcriptomics to link it to gene expression of each plaque cell subtype.

2. identify pathways in human plaques responsible for rupture and leading to risk of future events. ”Omics” of lipids, metabolites and extracellular matrix (ECM) (inc glycosaminoglycans), inflammatory/ECM markers, histology, RNA seq and GWAS will be combined, looking for biomarkers and, using machine learning, how to best predict events. How shear-stress affects gene expression in different plaque regions, leading to rupture will be explored.

3. develop further a non-invasive ultrasound-based technique (that we have previously validated with histology). Now we will compare it with pre-operative MR and ex vivo with synchrotron imaging (non-destructive, highest-resolution technique both at the Swiss Light Source and at MAX IV). Our new method can be easily used to image plaque composition, easily implemented bedside, radiation- and contrast-free clinically, as well as possibly predict events and monitor the effect of interventions on the plaque biology

BETYDELSE: The early and timely identification of patients at risk for cardiovascular events can spare lives and disability with the obvious benefits for the society. Finding new markers, as well as discovering novel mechanisms and potential therapeutic targets are important unmet clinical needs currently. Our ultrasound-based technique can be easily and immediately transferred into clinical practice, leading to improved risk stratification, better diagnosis and ultimately optimised indications for medical and surgical treatment.