The atherosclerotic plaque: risk factors and cardiovascular outcome after carotid endarterectomy

Atherosclerosis causes major invalidating and fatal events, and is a major contributing factor to the burden of cardiovascular disease, which is the number one cause of death globally. The initiation of atherosclerosis already starts in utero, but generally becomes clinically apparent during adulthood. The reason for clinical events to occur is closely associated with the underlying plaque composition. Especially for the coronary arteries, postmortem studies have revealed that atherosclerotic plaque rupture is frequently found in coronary plaques from patients who died from myocardial infarction. Also for carotid arteries symptoms including stroke and transient ischemic attack have been associated with vulnerable underlying plaque characteristics. Due to the systemic nature of atherosclerosis, and pathophysiological involvement of inflammatory responses it has been suggested that some individuals have a systemic predisposition to irregularity and rupture of atherosclerotic plaques, independent of traditional vascular risk factors. This resulted in initiation of biobanking studies, linking local atherosclerotic plaque features to patient characteristics. The Athero-Express Biobank study started in 2002 with the atherosclerotic plaque harvested during carotid endarterectomy as a starting point, followed by a three year follow up and registration of cardiovascular morbidity and mortality. This unique design facilitated cross sectional but also prospective cohort research, and served as the foundation for this thesis. The findings of the studies included in this thesis, will be discussed in this thesis

Atherosclerotic plaque vulnerability as an explanation for the increased risk of stroke in elderly undergoing carotid artery stenting

Background and Purpose-Recent randomized trials showed an increased periprocedural risk for stroke with increasing age in patients undergoing carotid artery stenting. Manipulation of atherosclerotic plaques during carotid artery stenting can result in plaque rupture with subsequent superimposed thrombus formation, embolization, and cerebrovascular events. We hypothesized that atherosclerotic plaques become more unstable with increasing age and thereby might provide insight into the age-related increased risk of cerebrovascular events during carotid artery stenting. Methods-Carotid atherosclerotic plaques were harvested from 1385 consecutive patients undergoing carotid endarterectomy between 2002 and 2010. Carotid plaques were quantitatively analyzed for macrophages, smooth muscle cells, and microvessels; and semiquantitatively analyzed for collagen, calcifications lipid cores, and intraplaque hemorrhages. Patients were divided in 4 groups by age: <60, 60 to 69, 70 to 79, and 80 years. Measures of association between age as a continuous variable and histological characteristics were also calculated. Results-Increasing age was associated with a decrease in the amount of smooth muscle cells in the carotid plaque. More plaques with large atheroma and heavy plaque calcifications were observed among elderly patients. After correction for baseline differences, risk factors, and medication use, age was independently associated with a more vulnerable carotid plaque composition. CONCLUSION-: Plaque stability decreases gradually with age. Older patients with carotid stenosis have relatively unstable plaques with low smooth muscle cell content, a high amount of large lipid cores, and more calcified plaques as compared with younger patients. The underlying vulnerable plaque composition in the elderly might be an important contributing factor to the increased risk of stroke for older patients undergoing carotid artery stenting

Endothelial insulin receptor expression in human atherosclerotic plaques: Linking micro- and macrovascular disease in diabetes?

Objective: Exogenous insulin use in patients with type 2 diabetes (DM2) has been associated with an increased risk of cardiovascular events. Through which mechanisms insulin may increase atherosclerotic plaque vulnerability is currently unclear. Because insulin has been suggested to promote angiogenesis in diabetic retinopathy and tumors, we hypothesized that insulin enhances intra-plaque angiogenesis. Methods: An in vitro model of pathological angiogenesis was used to assess the potential of insulin to enhance capillary-like tube formation of human microvascular endothelial cells (hMVEC) into a three dimensional fibrin matrix. In addition, insulin receptor expression within atherosclerotic plaques was visualized in carotid endarterectomy specimens of 20 patients with carotid artery stenosis, using immunohistochemical techniques. Furthermore, microvessel density within atherosclerotic plaques was compared between 68 DM2 patients who received insulin therapy and 97 DM2 patients who had been treated with oral glucose lowering agents only. Results: Insulin, at a concentration of 10(-8) M, increased capillary-like tube formation of hMVEC 1.7-fold (p <0.01). Within human atherosclerotic plaques, we observed a specific distribution pattern for the insulin receptor: insulin receptor expression was consistently higher on the endothelial lining of small nascent microvessels compared to more mature microvessels. There was a trend towards an increased microvessel density by 20% in atherosclerotic plaques derived from patients using insulin compared to plaques derived from patients using oral glucose lowering agents only (p = 0.05). Conclusion: Exogenous insulin use in DM2 patients may contribute to increased plaque vulnerability by stimulating local angiogenesis within atherosclerotic plaques. (C) 2012 Elsevier Ireland Ltd. All rights reserve