The role of collagenases in atherosclerotic plaque instability
The primary aim of this thesis was to quantify the collagenase concentrations in carotid plaques and to relate them to markers to plaque instability.;Recent studies have shown that strain therapy decreases cardiovascular risk, even in patients with normal cholesterol levels. A further aim of this thesis was to observe the effects of statins on clinical and biochemical indicators of plaque instability.;Atherosclerotic plaques were collected from 159 patients undergoing carotid endarterectomy. The presence and timing of carotid territory symptoms was ascertained. Pre-operative embolisation was recorded by transcranial Doppler. Each plaque was assessed for histological features of instability. Plaque MMP and cytokine concentrations was quantified using ELISA.;Significantly higher concentrations of active MMP-8 were observed in the plaques of symptomatic patients (p=0.0002), emboli-positive patients (p=0.0037) and in those plaques demonstrating histological evidence of rupture (p=0.0036). No differences were seen in the levels of MMP-1 and MMP-13. Immunohistochemistry, in situ by hybridisation and colocalisation studies confirmed the presence of MMP-8 protein and mRNA within the plaque, which colocalised with macrophages. These data suggest that the active form of MMP-8 may be partly responsible for degradation of the collagen cap of atherosclerotic plaques. This enzyme represents an attractive target for drug therapy aimed at stabilising vulnerable plaques.;Patients on statins were less likely to have suffered symptoms in the month prior to surgery (p=0.0049) and less likely to have cerebral embolisation detected (p=0.0459). Carotid plaques retrieved from statin-taking patients, revealed significantly lower concentrations of MMP-9 (p=0.0018) and IL-6 (p=0.0005). These data suggest that statins may stabilise plaques by lowering MMP and cytokine levels, resulting in decreased embolisation and symptoms.