Atheroma and the inflammasome

Atherosclerosis is a ubiquitous disorder that begins in childhood. An autopsy study of 2,876 adolescents and young adults (ages 15-34) who died of external causes found fatty streaks in the aorta of 100% of subjects, and in the right coronary artery in half the subjects. The number and extent of lesions increased with age. The incidence of fibrous plaque, a marker of a healed lesion in males was *3% in subjects 15-19, increasing to *20% in the 30–34-year-old group, suggesting that the lesions evolve over time. Macroscopic calcium in the lesion, however, was rare in these young subjects,\1% in subjects ranging from 15 to 29 years of age, increasing slightly to *1% in the 30–34-year-old age group. The pervasive presence of atheroma suggests that some of these lesions will progress to cause clinical disease. Cerebral transient ischemic attacks and stroke are major clinical manifestations of atherosclerosis in the carotid artery.Anestimated6.6millionmenandwomen[20 years of age in the US have a history of stroke. Approximately, 795,000 people experience a new or recurrent (ischemic or hemorrhagic) stroke each year. Approximately, 610,000 of these are first events and 185,000 are recurrent stroke events. In 2011, stroke caused 140,000 deaths in the US. The most common therapy for patients with severe carotid stenosis, stroke, or recurrent transient ischemic attacks is carotid endarterectomy. Approximately, 100,000 endarterectomy procedures were performed in the US in 2010. Although carotid stenting has gained popularity (accounting for *13% of carotid artery revascularization in 2008), a randomized trial of outcomes in 2,502 patients after carotid stenting or endarterectomy suggested that in patients over the age of 70, there was a lower rate of recurrent stroke in endarterectomy patients. Characteristics of carotid plaques at risk of causing a clinical event include: Thin fibrous cap (\65 lm), large lipid core, evidence of intraplaque hemorrhage, and active plaque inflammation. Additional characteristics of unstable plaque are eccentric distribution of the lesion (due to arterial remodeling) and an irregular surface. An intact thick fibrous cap (seen on CT, MR or US) has a low risk of rupture, a thin cap is associated with a mild risk of rupture and a fissured fibrous cap is associated with a high risk of rupture (often due to shear stress). Another common cause of plaque rupture is a sudden increase in plaque volume and pressure due to intraplaque hemorrhage, as is commonly seen in coronary lesions. A large number of macrophages and a necrotic core increase the likelihood of intraplaque hemorrhage due to the release of enzymes within the atheroma (e.g., matrix metalloproteinases) that weaken the fragile vasavasorum. At the time a fatty streak develops, injured endothelium and lipid laden macrophages produce chemoattractant molecules. The quantity of integrin produced increases as inflammation and lesion size progress. Progression of inflammation in atheroma causes participation of the immune system, attracting cytolytic T cells into the lesion. These T cells promote cytolysis and apoptosis of smooth muscle cells, endothelial cells, and macrophages. Plaque mineralization, once considered a ‘tombstone’ of atheroma, is now appreciated as a marker with a bimodal distribution. Initial calcium deposition is scattered in necrotic areas and in the cap. This microcalcification (calcium aggregates \60 lm) occurs in response to proinflammatory stimuli. This type of calcification, often visible on fluorine18 (F-fluoride) imaging and high resolution micro CT in laboratory studies, can increase shear stress on the cap, increasing the likelihood of rupture of a thin fibrous cap plaque. If inflammation abates, vascular smooth muscle cells may undergo osteogenic See related article, pp. 1179–1186