An investigation into carotid atherosclerotic plaque instability

Stroke is the leading cause of death and permanent neurological disability in the developed world and a significant burden on the NHS and wider economy. A third of all strokes are caused by thrombo-embolism from unstable carotid atherosclerotic plaques. The exact pathogenesis of plaque progression and instability is unknown. The aim of this thesis was to investigate carotid plaque instability from a clinical perspective and on a molecular level. Patients with spontaneous embolisation detected during Transcranial Doppler (TCD) monitoring were significantly more likely to have recent symptoms and recurrent events than those patients without evidence of spontaneous embolisation. Features of unstable plaque histology including large lipid core, intra-plaque haemorrhage, plaque inflammation, neovascularisation and cap rupture all decreased with time since event from 0-28 days but then increased in prevalence thereafter. Ultrasound features found to be related to unstable plaques included Grayscale Median (GSM) <25 and plaque area >80mm[superscript 2]. Finally a predictive model was created to identify patients with a histologically unstable plaque using clinical and ultrasound parameters. Using whole-genome wide microarray and results validated using qRT-PCR in an independent cohort, expression of the CCL19 and CTSG genes were significantly upregulated in plaques from patients with unstable plaques graded according to 1. Clinical; 2. Ultrasound; 3. TCD microemboli and 4. Histological criteria. Using ELISA, serum concentration of CCL19 was significantly higher in patients with clinically and histologically unstable plaques (p=0.02). Immunohistochemical staining for CCL19 demonstrated positive staining in histologically and clinically unstable plaques (P=0.03) with co-localisation to CD3 positive T-cell lymphocytes. In conclusion there is further evidence that plaque instability is greatest in the hyper and acute period after symptom onset. CCL19 is significantly over-expressed in patients with clinically unstable carotid atherosclerotic plaques and warrants further investigation. Clinical and non-invasive ultrasound imaging criteria can be used to predict the patient with the unstable plaque.