Abdominal Aortic Aneurysm

Abstract

Abdominal aortic aneurysm (AAA) is an increasingly common and life-threatening disease. The natural history of large and untreated AAAs is progressive expansion leading to rupture with a high mortality. Epidemiological studies point out risk factors including older age, male gender, positive family history, smoking, and associated atherosclerotic diseases. AAAs affect the population older than 50 years, with prevalence of 3–10 % for patients older than 50 years of age. Male gender is more frequently affected with a male to female ratio of 6. Positive family history of AAA is associated with doubled risk of AAA. Smoking is a major risk for aneurysm formation, expansion, and rupture. Nicotine increases AAA formation by stimulating adenosine monophosphate-activated protein kinase alpha2 (AMPKα-2) in vascular smooth muscle cells. Initial aortic diameter is the strongest predictor of AAA expansion and rupture. Pathological features of AAA are degradation of extracellular matrix proteins, elastin and collagen, apoptosis of smooth muscle cells, and infiltration of inflammatory cells including macrophages, neutrophils, lymphocytes, and mast cells. Various extracellular proteinases including matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9; cysteine proteases; and serine proteases which are secreted by macrophages, neutrophils, lymphocytes, and mast cells participate in the degradation of the extracellular matrix. The balance between proteases and antiprotease seems to be in favor of proteolysis in AAAs. Pathological processes include degradation of the extracellular matrix and impairment of biosynthesis of the extracellular matrix proteins. Although the specific etiology is unknown, aneurysms are probably initiated by aortic wall injury coupled with a series of epidemiological risk factors. Recruitment of leukocytes into the aortic media appears to be an early and pivotal event. The influx, migration, and effects of the inflammatory cells are controlled by an array of proinflammatory cytokines, chemokines, and growth factors, some of which may have dual and opposing functions depending on the specific context. AAA pathogenesis is the result of a complex interplay among distinct pathological processes, and each pathological process involves a network of signaling molecules and effector molecules of which levels of expression are differentially regulated. Various environmental and genetic stimuli may activate a final common pathway. c-Jun N-terminal kinase (JNK), one of the subfamilies of mitogen-activated protein kinases, is found to be a prime candidate for AAA. JNK inhibitor and inhibition of nuclear factor kappa B (NFκB), a critical transcription factor in cytokine signal transduction, not only prevent the development of experimental AAA but also regress the established AAA, indicating recovery of extracellular matrix synthesis. Recently, it is reported that inhibition of microRNA-29b abrogates aortic dilation in mice, suggesting that microRNA-29 may represent a novel molecular target to augment matrix synthesis and maintain vascular wall structural integrity. It is suggested that upregulation of microRNA-21 seems to be protective, as inhibiting its expression accelerates aneurysm expansion. There may be a common abnormality of cellular signaling that regulates the destructive processes. There are amount of processes that remain to be clarified in the pathophysiology of AAA.