Skip to main content

Carotid atherosclerosis – from molecule to man

Researchers

Professor/överläkare

Ulf Hedin

Telefon: 08-517 721 75
Enhet: Kärlkirurgi
E-post: Ulf.Hedin@ki.se

Anknuten

Silvia Aldi

Enhet: Holmdahl
E-post: silvia.aldi@ki.se

Forskarassistent

Ljubica Matic

Enhet: Kärlkirurgi
E-post: ljubica.matic@ki.se

Background

Apart from cardiac embolism, most ischemic strokes occur as a consequence to end-stage atherosclerotic disease. Atherosclerosis leads to formation of plaques in the intima of major arteries with accumulation of lipids, inflammation, fibrosis, cell death and calcification. Stable lesions are generally asymptomatic but when plaques become unstable from enhanced inflammation and proteolysis, destabilization of the fibrous cap may lead to plaque rupture, thrombosis (atherothrombosis), embolism and cerebral ischemia. More than 50% of ischemic strokes are caused by thromboembolism from extracranial vessels, as unstable plaques in the carotid bifurcation. The condition can cause transient ischemic attack (TIA), retinal symptoms (amaurosis fugax) or complete stroke. The significance of this process has been confirmed in studies demonstrating that surgery for carotid stenosis, carotid endarterectomy (CEA), in patients with symptomatic (unstable) lesions prevents stroke. Today, there are no diagnostic methods available to predict or identify plaque rupture and thus to prevent stroke from unstable atherosclerosis. Selection of patients for intervention instead rests on surrogate variables for stroke risk, such as the degree of luminal narrowing by the stenosis. In our unit, approximately 60-70 symptomatic patients undergo CEA annually, >85% within two weeks after index event (national guideline), and with an estimated efficacy of 10 prevented strokes whereas 10-15 asymptomatic patients undergo CEA with less than one prevented stroke estimated.

Work plan

This project is based on current studies utilizing an established biobank (BiKE) of plaque and plasma samples from n>800 patients treated at our clinic, which have been prospectively processed for RNA, DNA, proteomic, in situ and in vitro analyses. The biobank is combined with data of phenotypic information, transcriptomic array profiles and genome wide SNP data. The resource has progressively developed and over the years been extensively utilised to identify gene signatures in atherosclerotic plaque instability. The project is currently being expanded to include large-scale characterization of plasma- and tissue proteins as well as non-coding RNAs (miRs) of human atherosclerosis in correlation to transcriptomic profiles, ultimately aiming at detection of plausible biomarkers for unstable end-stage atherosclerosis. Through established collaborations with international and national resources (SciLife; SCAPIS; Göteborgs Universitet; Stanford; King’s College, London), we are implementing state-of-the-art proteomics (mass spectroscopy and affinity-based) of plasma- and tissue samples from patients with stable- and unstable carotid stenosis, next generation methodology for RNA expression analyses in situ, and pre-operative imaging of patients with new MRI- and ultrasound based technology with the ultimate goal of developing targeted bioimaging for the localization of unstable atherosclerotic lesions.

Aims

Through the identification of circulating signature molecules (biomarkers) for the unstable atheroma and the development of diagnostic tools for morphological characterization of unstable carotid plaques this project will improve stroke-prevention by:

  1. optimizing risk intervention
  2. improving selection of patients for stroke preventive surgery and
  3. supporting development of plaque-stabilizing drugs