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Background: Atherosclerosis is an immunoinflammatory disease; however, the key factors responsible for the maintenance of immune regulation in a proinflammatory milieu are poorly understood., Methods and Results: Here, we show that milk fat globule-EGF factor 8 (Mfge8, also known as lactadherin) is expressed in normal and atherosclerotic human arteries and is involved in phagocytic clearance of apoptotic cells by peritoneal macrophages. Disruption of bone marrow-derived Mfge8 in a murine model of atherosclerosis leads to substantial accumulation of apoptotic debris both systemically and within the developing lipid lesions. The accumulation of apoptotic material is associated with a reduction in interleukin-10 in the spleen but an increase in interferon-gamma production in both the spleen and the atherosclerotic arteries. In addition, we report a dendritic cell-dependent alteration of natural regulatory T-cell function in the absence of Mfge8. These events are associated with a marked acceleration of atherosclerosis., Conclusions: Lack of Mfge8 in bone marrow-derived cells enhances the accumulation of apoptotic cell corpses in atherosclerosis and alters the protective immune response, which leads to an acceleration of plaque development.

Objectives: In this study, we evaluated the cellular origins and thrombogenic potential of microparticles., Background: Human atherosclerotic plaques contain submicron vesicles (microparticles) released during cell activation or apoptosis., Methods: Microparticles were purified from plaques and platelet-free plasma from 26 patients undergoing carotid endarterectomy. Flow cytometry analysis revealed the presence of large amounts of microparticles in plaques but not in healthy vessels., Results: Most plaque microparticles originated from leukocytes, of which 29 +/- 5% were macrophages, 15 +/- 3% lymphocytes, and 8 +/- 1% granulocytes. Plaques microparticles also derived from erythrocytes (27 +/- 4%), smooth muscle (13 +/- 4%) and endothelial cells (8 +/- 2%), but not from platelets. Plaques from asymptomatic and symptomatic patients showed no differences in microparticle origins. Microparticles were at least 200-fold more concentrated in plaque than in plasma. Plasma microparticles were primarily platelet-derived in contrast with those of plaque and showed no smooth muscle cell origin. Both plaque and plasma microparticles exposed tissue factor and generated thrombin, but this activity was twice as high in microparticles isolated from plaques, reflecting the thrombogenic contribution of the individual classes of microparticles., Conclusions: These results demonstrate that microparticles are more abundant and more thrombogenic in human atherosclerotic plaques than in plasma. The different cellular origins of plaque and plasma microparticles might explain the increased thrombogenic activity of plaque microparticles.

Objective: Extracranial carotid stenosis is a complication of external head and neck irradiation. The safety and durability of carotid artery revascularization through a radiated field has been debated. We describe the immediate and long-term results in a series of 27 consecutive patients who received treatment over 12 years., Methods: From May 1990 to May 2002, 27 consecutive patients underwent 30 primary carotid artery revascularization procedures. All patients had received previous radiation therapy within a mean interval of 10 years (range, 1-26 years), with average radiation dose of 62 Gy (range, 50-70 Gy). Moderate to severe scarring of the skin or radiation fibrosis was present in three fourths of patients. Thirteen patients (48%) had undergone radical neck dissection, and 2 patients had a permanent tracheotomy. The indications for carotid surgery included high-grade (>70%) symptomatic stenosis in 18 patients (60%) and high-grade asymptomatic stenosis in 12 patients (40%). General anesthesia with systematic shunting was used in 18 patients (60%), and regional anesthesia with selective shunting was used in 12 patients (40%). Operations included standard carotid endarterectomy (n = 20), with patch angioplasty (n = 12) or direct closure (n = 8); carotid interposition bypass grafting (n = 7); and subclavian to carotid bypass grafting (n = 3). Primary closure of the surgical wound was performed in all procedures without any special muscular or skin flaps. All patients were followed up for a mean of 40 months (range, 3-99 months)., Results: There was one (3.3%) perioperative death, from massive intracerebral hemorrhage; and 1 patient had a transient ischemic attack. In-hospital complications included neck hematoma in 2 patients, which required surgical drainage in 1 patient. There was neither delayed wound healing nor infection. Twelve patients died during follow-up, of causes not related to treatment. None of the surviving patients had further stroke, and all remained asymptomatic. Follow-up duplex scans showed asymptomatic recurrent stenosis greater than 60% in 3 patients, 2 of whom with stenosis greater than 80% underwent repeat operation. Risk for recurrent stenosis greater than 60% at 18 months was 16.6%. Recurrent stenosis occurred in 2 of these patients after saphenous vein bypass, and in 1 patient after endarterectomy with vein patch angioplasty., Conclusion: The clinical results and sustained freedom from symptoms and stroke over 40-month follow-up suggests that carotid revascularization through a radiated field is a safe and durable procedure in patients at high surgical risk, despite a marked incidence of recurrent stenosis.

Background: Interleukin (IL)-18 is a potent proinflammatory cytokine with potential atherogenic properties. Its expression and role in atherosclerosis, however, are unknown., Methods and Results: In the present study, we examined stable and unstable human carotid atherosclerotic plaques retrieved by endarterectomy for the presence of IL-18 using reverse transcription-polymerase chain reaction (PCR), Western blot, and immunohistochemical techniques. IL-18 was highly expressed in the atherosclerotic plaques compared with control normal arteries and was localized mainly in plaque macrophages. IL-18 receptor was also upregulated in plaque macrophages and endothelial cells, suggesting potential biological effects. To examine the role of IL-18 in atherosclerosis, we determined the relation between IL-18 mRNA expression and signs of plaque instability using real-time quantitative PCR. Interestingly, significantly higher levels of IL-18 mRNA were found in symptomatic (unstable) plaques than asymptomatic (stable) plaques (P<0.01)., Conclusions: These results suggest, for the first time, a major role for IL-18 in atherosclerotic plaque destabilization leading to acute ischemic syndromes.