**2. Pathogenesis**

The pathogenesis of aortic aneurismal disease is multifactorial. There is no consensus as to the cause of aortic aneurysms. Hypertension exists in about half of patients and is obviously an aggravating condition. Tertiary syphilis was once an important cause of aneurysms, particularly of the ascending thoracic aorta, but is a less common cause now.

Genetic components have been identified in Marfan's syndrome and Ehlers Danlos disease. Even in the most common, degenerative, form of aortic aneurysms there is a genetic component. Familial clustering of aortic aneurysms is evident as up to 20% of patients have one or more first-degree relatives who have also suffered from the disease.[6] More studies are clearly needed to establish details of the genetic interplay in aortic aneurysms.

At times, an aneurysm may be caused by an extrinsic factor, such as an infection (micotic aneurysm) or trauma (pseudoaneurysm).

Traditional views states that most aneurysms were caused by degenerative atherosclerotic disease but it affects different layers of the aortic wall. Atherosclerosis mainly affects the

intima, causing occlusive disease, while aortic aneurysm is a disease of the media and adventitia. They are distinct conditions that nonetheless often occur together.

Histologically, AAAs are characterized by chronic inflammation with destruction of the extracellular matrix, remodelling of the wall layers, and reduction in number of smooth muscle cells. The effectors of destruction are a group of enzymes capable of degrading the major connective tissue components: collagen, elastin, fibronectin, laminin and the proteoglycans.[7] The inflammatory infiltrate consists of macrophages as well as T and B lymphocytes, which excrete proteases and elastases causing wall degradation.[8] The reason for this migration is unclear.

Degradation of elastin has been associated with dilatation while rupture of the wall is related to collagen degradation. Experimental studies of elastase induced aneurysms indicate that an inflammatory reaction within the aortic media is crucial for aortic dilatation.

In both clinical and experimental studies, metalloproteinases (MMP), one of the most prominent group of elastases, have emerged as playing a role in the development of aortic aneurysms. [9,10] The MMPs are inhibited by the family of tissue inhibitors of metalloproteinases (TIMPs), including TIMP-1 and TIMP-2. An imbalance between the activated MMPs and their natural inhibitors may be responsible for the destruction of the aortic wall. Therapeutic trials with doxycycline, a MMP inhibitor, are ongoing and preliminary results are encouraging with less progression of aneurysmal size in treated patients.[11]

Commonly assessed in AAA are also proteins involved in, stimulated by or associated with thrombosis, for example, fibrinogen and D-dimer.[12]

A human biopsy study has confirmed the association between the extent of inflammation of the aortic wall and aortic diameter.[13] Interleukin-6 (IL-6), metalloproteinase-9 (MMP-9 gelatinase B) and C-reactive protein (CRP) are markers of inflammatory processes and have all been associated with AAA pathogenesis [13,14,15] as well as collagen type IV, fibronectin and other matrix proteins. High levels of MMP-9 and MMP-3 have been found in abdominal aortic aneurysmal tissue. Levels of MMP-9 are associated with aneurysmal size. [14,16,17] Hovsepian et al. Reported that MMP-9 plasma levels appeared to directly reflect the amount of MMP-9 produced within aneurysm tissue. MMP-9 plasma levels also decreased substantially after surgical AAA repair.[18]

Circulating concentrations of many kinds of biomarkers have been measured and compared in patients with abdominal aortic aneurysm (AAA) and subjects without AAA to assess their possible role in the pathogenesis or progression of AAA (Table 1). Circulating biomarkers could play a role in the diagnosis of AAA reflecting also the AAA activity in asymptomatic phases and may have a role in predicting subsequent progression and thus the prognosis of AAA.

Most investigated potential biomarkers show either no correlation or a weak correlation with the clinical course of AAA. Few have any potential for clinical use. Another limitation is related to the fact that many biomarkers for AAA are not disease specific; most of them also are markers for atherosclerosis.


for this migration is unclear.

intima, causing occlusive disease, while aortic aneurysm is a disease of the media and

Histologically, AAAs are characterized by chronic inflammation with destruction of the extracellular matrix, remodelling of the wall layers, and reduction in number of smooth muscle cells. The effectors of destruction are a group of enzymes capable of degrading the major connective tissue components: collagen, elastin, fibronectin, laminin and the proteoglycans.[7] The inflammatory infiltrate consists of macrophages as well as T and B lymphocytes, which excrete proteases and elastases causing wall degradation.[8] The reason

Degradation of elastin has been associated with dilatation while rupture of the wall is related to collagen degradation. Experimental studies of elastase induced aneurysms indicate that an inflammatory reaction within the aortic media is crucial for aortic dilatation. In both clinical and experimental studies, metalloproteinases (MMP), one of the most prominent group of elastases, have emerged as playing a role in the development of aortic aneurysms. [9,10] The MMPs are inhibited by the family of tissue inhibitors of metalloproteinases (TIMPs), including TIMP-1 and TIMP-2. An imbalance between the activated MMPs and their natural inhibitors may be responsible for the destruction of the aortic wall. Therapeutic trials with doxycycline, a MMP inhibitor, are ongoing and preliminary

results are encouraging with less progression of aneurysmal size in treated patients.[11]

thrombosis, for example, fibrinogen and D-dimer.[12]

substantially after surgical AAA repair.[18]

the prognosis of AAA.

also are markers for atherosclerosis.

Commonly assessed in AAA are also proteins involved in, stimulated by or associated with

A human biopsy study has confirmed the association between the extent of inflammation of the aortic wall and aortic diameter.[13] Interleukin-6 (IL-6), metalloproteinase-9 (MMP-9 gelatinase B) and C-reactive protein (CRP) are markers of inflammatory processes and have all been associated with AAA pathogenesis [13,14,15] as well as collagen type IV, fibronectin and other matrix proteins. High levels of MMP-9 and MMP-3 have been found in abdominal aortic aneurysmal tissue. Levels of MMP-9 are associated with aneurysmal size. [14,16,17] Hovsepian et al. Reported that MMP-9 plasma levels appeared to directly reflect the amount of MMP-9 produced within aneurysm tissue. MMP-9 plasma levels also decreased

Circulating concentrations of many kinds of biomarkers have been measured and compared in patients with abdominal aortic aneurysm (AAA) and subjects without AAA to assess their possible role in the pathogenesis or progression of AAA (Table 1). Circulating biomarkers could play a role in the diagnosis of AAA reflecting also the AAA activity in asymptomatic phases and may have a role in predicting subsequent progression and thus

Most investigated potential biomarkers show either no correlation or a weak correlation with the clinical course of AAA. Few have any potential for clinical use. Another limitation is related to the fact that many biomarkers for AAA are not disease specific; most of them

adventitia. They are distinct conditions that nonetheless often occur together.



**Table 1.** Summary of published studies reporting the role of circulating biomarkers in the growth and rupture of AAA

Active investigations continue to identify markers other than size that would predict a risk of rupture. Circulating biomarkers could also indicate optimal intervals between the surveillance intervals. Finally, the identification of biomarkers also may identify potential pathogenic pathways, and thus may open possibilities for pharmacological inhibition of growth, and provide a tool for monitoring this inhibition.[26]

In the future, extended longitudinal studies will be necessary to assess the true potential of matrix-turnover and other biomarkers. New methods, including proteomics and genome wide association studies, may identify new pathways and new potential biomarkers.
