Inflammation, metalloproteinases, and increased proteolysis: an emerging pathophysiological paradigm in aortic aneurysm

PK Shah - Circulation, 1997 - Am Heart Assoc
PK Shah
Circulation, 1997Am Heart Assoc
Abdominal aortic aneurysm is a common and potentially lethal disease with an estimated
incidence of 20 to 40 cases per 100 000 persons per year. 1 In the United States, nearly 45
000 operations are performed annually for AAA. 2 Most aneurysms are clinically silent until
the time of rupture. Elective surgical mortality for unruptured aneurysms varies from 2% to
7%, but mortality jumps to 50% to 70% when rupture occurs before surgery. 2 Risk factors for
the development of AAA include advancing age, male sex, chronic obstructive lung disease …
Abdominal aortic aneurysm is a common and potentially lethal disease with an estimated incidence of 20 to 40 cases per 100 000 persons per year. 1 In the United States, nearly 45 000 operations are performed annually for AAA. 2 Most aneurysms are clinically silent until the time of rupture. Elective surgical mortality for unruptured aneurysms varies from 2% to 7%, but mortality jumps to 50% to 70% when rupture occurs before surgery. 2 Risk factors for the development of AAA include advancing age, male sex, chronic obstructive lung disease, cigarette smoking, hypertension, and genetic factors. 2 One of the most important determinants of risk for rupture is the size of the aneurysm. 2 The overall risk of rupture is 3% to 8% for aneurysms< 4 cm in diameter, whereas rupture occurs in 20% to 40% of patients with an aneurysm diameter> 5 cm. 2 Aneurysms between 4 and 4.5 cm in diameter carry a 10% to 12% risk of rupture. 2 Although there is a considerable variability in the rate of expansion, on average, expansion occurs in an exponential fashion with an≈ 10% diameter increase per year (0.3 to 0.6 cm/y for aneurysms 3 to 6 cm in size). 2 Expansion rate is reduced by β-blockers and enhanced in patients with uncontrolled diastolic hypertension, smoking, and chronic obstructive lung disease. 3
Recent clinical and experimental studies have challenged the long-held notion that AAA results primarily from a complication of atherosclerosis. 4 Although intimal pathological lesions characterize occlusive atherosclerotic aortic disease, one of the striking hallmarks of AAA is the extensive degeneration of the media, with evidence for extensive loss of elastin in the media and adventitia, apoptosis and decrease in the number of matrix-synthesizing medial smooth muscle cells, and an adventitial and transmural inflammatory infiltrate consisting of macrophages, lymphocytes, dendritic cells, and plasma cells. 2 5 6 7 8 9 In recent years, inflammation and excessive extracellular matrix breakdown have been identified as the putative processes that result in aortic expansion and aneurysm formation. 2 5 6 7 8 9 10 11 12 13 14 Initiation and expansion of AAA is attributed to loss of elastin, normally responsible for the resilience of the aorta, whereas loss of fibrillar collagens (types I and III), the major source of tensile strength, is believed to ultimately result in rupture. 2 11 Several studies have shown evidence for increased collagen breakdown as well as increased collagen synthesis in AAA, consistent with increased collagen turnover. 10 11 12 Because of the extremely long half-life of elastin (40 to 70 years), loss of elastin in adults is almost certainly a manifestation of excessive elastolysis rather than insufficient synthesis. The important role of elastolysis in aneurysm formation is further supported by experimental models in which aneurysms can be induced with infusion of elastase, which in turn results in recruitment of inflammatory cells, with consequent overproduction of cellular proteases. 15 The frequent coexistence of chronic obstructive lung disease, in which there is evidence of excessive elastolysis in lungs, and AAA as well as reduced elastin content in nonaneurysmal regions of the aorta in patients with AAA provides indirect evidence in favor of a pathophysiological role for excessive elastolysis in AAA. 2 Several recent studies have shown that AAA tissue, compared with normal aortic tissue, contains an excess of an arsenal of proteases, particularly members of the zinc-and calcium-requiring matrix-degrading neutral MMP family that have the capacity to degrade virtually all components of the extracellular matrix in the arterial wall. 7 13 14 MMP-1 (interstitial …
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