Atherosclerotic plaque composition and clinical outcome : A translational study in patients undergoing carotid endarterectomy

Abstract

The composition of the pathologic substrate of atherosclerosis, the atherosclerotic plaque, is not taken into account in clinical practice. Atherosclerotic plaques differ greatly in their composition, and we have learned from cross-sectional pathology studies that certain plaques may be more likely to cause clinical events such as a myocardial infarction or stroke. At present, however, plaque composition has no role in clinical decision making. The lack of clinical application is perhaps attributable to a lack of knowledge, which this thesis aims to address. We designed a large biobank containing atherosclerotic plaques obtained during vascular surgery, called Athero-Express. The unique features of this biobank are its size and clinical follow-up. During 6 years, we have included more than 1000 patients undergoing carotid endarterectomy and another 500 patients undergoing femoral endarterectomy and aneurysm surgery. The main objectives of the study were to investigate the relation between carotid plaque composition at the time of carotid endarterectomy and occurrence of restenosis and cardiovascular events during follow-up. We were able to establish that the extent of benefit of carotid endarterectomy correlates with carotid plaque composition. In patients groups who benefit most from CEA, we found an increased incidence of “vulnerable” plaques. We hypothesize that the excision of a vulnerable plaque portrays more benefit than a harmless plaque which will never cause any symptoms if it remains in place. These results suggest that pre-operative assessment of plaque characteristics with non-invasive imaging is important to obtain better outcome in patients with carotid artery stenosis, and probably also in other vascular territories. Furthermore, we identified prognostic factors in the atherosclerotic plaque. A large lipid core and marked macrophage infiltration are predictive of restenosis after carotid endarterectomy. The presence of thrombus in the carotid plaque is associated with increased incidence of cardiovascular events during 3-year follow-up. Furthermore, we were able to identify more specific targets to predict outcome. Using a proteomic approach, we identified proteins that were differentially expressed in the plaques from patients who suffered an event during the follow-up, and controls. High expression of Osteopontin was associated with a four-fold increased risk of future cardiovascular events. This predictive value of this protein was independent of clinical risk factors and exceeds biomarkers such as CRP. Testing of other protein targets identified by proteomics is ongoing and we expect to present more predictive markers in the near future. Combining multiple markers could result in even better prediction of the occurrence of future cardiovascular events. These prognostic markers can be used as intermediate outcomes of clinical trials, may be used as drug targets, and allow prediction of outcome, facilitating tailor-made treatment for each patient. In conclusion, the atherosclerotic plaque contains important prognostic information. It is essential to realize that clinical application of plaque composition can portray a major advance in treatment of advanced atherosclerotic disease. Further research on the clinical application of plaque composition, e.g. by proteomics and prospective plaque imaging studies, must be conducted and should receive high priority to improve the outcome of patients suffering from atherosclerotic disease.