Acknowledgments

It is important to acknowledge the support of the S.D. Ireland family. They have faced the threat of cancer and fought back by supporting research in a concrete and meaningful manner.

Pathogenesis of Aortic Aneurysmal Disease

Aortic aneurysm is the most prominent pathologic manifestation of the human aorta and often leads to fatal rupture of the arterial wall. The prevalence of aortic aneurysmal disease is increasing and it is the 13th most common cause of death in the United States. Pathogenesis is complex and not well defined. A number of theories have been proposed, but no single theory of pathogenesis has been universally accepted. Aortic wall degeneration induced by atherosclerosis, proteolytic enzyme activation, and inflammation is the current leading hypothesis; other theories include infectious processes, genetic predisposition and hemodynamic influences. However, it is likely that aneurysm formation is a consequence of an interaction of multiple factors rather than a single process. An increased understanding of the mechanism of aortic aneurysm formation will facilitate improvements in treatment and, most importantly, may lead to strategies that prevent aortic aneurysm formation, enlargement and rupture.

Atherosclerosis and Aortic Aneurysms

The association of aortic aneurysm with aortic atherosclerosis has long been recognized. Most patients with an abdominal aortic aneurysm have evidence of atherosclerosis in the coronary, carotid, and/or peripheral arteries. This has led to the theory that aortic aneurysmal disease is a variant of atherosclerosis that occurs at weakened sites in the aortic wall. Aortic aneurysms, therefore, are commonly referred to as atherosclerotic aortic aneurysms. Although it has been suggested that there is no etiologic relationship between atherosclerosis and aneurysm formation, evidence has accumulated that the atherosclerotic process has effects on the artery wall that can result in aneurysm formation (Fig 1.1).

Property of Adaptive Enlargement of Arteries

A characteristic feature of atherosclerosis is plaque deposition in the intima of the arterial wall. The pathogenesis of atherosclerosis is a complex and dynamic process involving cellular proliferation and migration, intimal lipid deposition, inflammation, fibrosis and necrosis with dystrophic calcification. These processes constantly induce artery wall remodeling, which act to counter the deleterious effects of intimal plaque deposition. The most prominent response of the artery to atherosclerotic plaque deposition is arterial enlargement, and this response appears to be a general characteristic of atherosclerotic arteries. This enlargement has been demonstrated in the carotid, coronary and superficial femoral arteries, as well as in the human abdominal aorta. Arterial enlargement can prevent or postpone the development of lumen

Fig. 1.1. Panel A, a gross specimen of an abdominal aortic aneurysm. The aneurysm is located in the infrarenal segment of the aorta. The longitudinal opening view shows a large atherosclerotic plaque (P) and mural thrombi (*). There are also numerous atherosclerotic lesions spreading over the aorta. Panel B, a cross section of an abdominal aortic aneurysm showing large atherosclerotic plaque (P), the reduced media thickness (arrows) beneath the plaque, and large amount of mural thrombi (*).

Fig. 1.1. Panel A, a gross specimen of an abdominal aortic aneurysm. The aneurysm is located in the infrarenal segment of the aorta. The longitudinal opening view shows a large atherosclerotic plaque (P) and mural thrombi (*). There are also numerous atherosclerotic lesions spreading over the aorta. Panel B, a cross section of an abdominal aortic aneurysm showing large atherosclerotic plaque (P), the reduced media thickness (arrows) beneath the plaque, and large amount of mural thrombi (*).

stenosis. For example, in the human coronary arteries, enlargement can maintain a normal or near-normal luminal caliber when the cross-sectional area of intimal plaque does not exceed approximately 40% of the area encompassed by the internal elastic lamina (Fig 1.2).

The human aorta enlarges with increasing age and also with increasing atherosclerotic plaque. While both the thoracic and abdominal aortas enlarge with age, abdominal aortic enlargement is more prominently influenced by the amount of atherosclerotic plaque. Since the abdominal aorta is much more prone to atherosclerosis than the thoracic aorta, this may explain the particular propensity for aneurysms to develop in the infrarenal aorta. The human superficial femoral artery also enlarges with increasing atherosclerotic plaque. However, the enlargement response may be restricted and aneurysm formation is much less common than in the abdominal aorta. It is not uncommon to have a twofold enlargement of atherosclerotic arteries as a result of large intimal plaques, with little or no alteration in lumen cross-sectional area. Failure of adequate arterial dilatation, of course, will lead to lumen stenosis. Thus, atherosclerosis characteristically causes enlargement of

Fig. 1.2. Enlargement of arteries with increasing atherosclerotic plaque. Enlargement can maintain normal or near-normal luminal caliber; when plaque does not exceed 40% of the area encompassed by the internal elastic lamina. Reprinted with permission from Glagov et al. N Engl Med 1987; 316:137.

Fig. 1.2. Enlargement of arteries with increasing atherosclerotic plaque. Enlargement can maintain normal or near-normal luminal caliber; when plaque does not exceed 40% of the area encompassed by the internal elastic lamina. Reprinted with permission from Glagov et al. N Engl Med 1987; 316:137.

arteries even though a common end result is constriction of the lumen. The time-dependent enlargement of the human aorta both in response to age and to atherosclerotic influences is an important consideration in therapies such as endovascular stent grafting, which depend on long term radial tension and friction for fixation of stent graft devices. Enlargement of the aorta over time may result in migration of the stent graft or refill of the aneurysm.

Aortic Wall Weakening

Atherosclerotic intimal plaques cause thinning of the adjacent media to it. This may eventually lead to weakening of the arterial wall. The media is the major structural unit of the aorta and is composed of layers of musculoelastic fascicles, or lamellar units. Each group of smooth muscle cells of the media is surrounded by a common collagenous basal lamina interlaced by a basketwork of type III collagen fibrils surrounded by layers of elastic fibers. Thick bundles of type I collagen fibers weave between adjacent fibromuscular layers and provide much of the tensile strength of the media. The elastic fibers distribute mural tensile stresses and provide recoil during the cardiac cycle, while the collagen network prevents over-distention, disruption and enlargement.

During atherosclerotic plaque development the media frequently becomes thin or disappears when the plaques are very large. This can greatly reduce the strength of the arterial wall. It is unclear whether this thinning is the result of atherosclerotic arterial enlargement or is caused by erosive effects of the plaque components on the artery wall. Cavitary excavations of the media are often seen in lipid-rich areas of the plaque and may be associated with regions of macrophage invasion and inflammation. Collagen and fibrous tissue in the adventitia and calcification within the plaque and media may compensate for loss of the media and provide structural support to the aortic wall.

For aortic enlargement to occur in atherosclerosis, the aortic wall matrix fibers of collagen and elastin must be degraded and/or resynthesized in new proportions. Mechanical distention of the aorta by pressure or stretch alone will not result in enlargement in excess of diastolic dimensions without rupture. Thus, during the process of atherosclerotic artery adaptive enlargement, proteolytic enzymes must be activated for this enlargement to take place. During active and rapid enlargement, which may occur during the development of aneurysms, much larger and perhaps less controlled proteolytic activities are likely to take place. Indeed, increased amounts of collagenase, elastase and metalloproteinases have been demonstrated in aortic aneurysms, with maximal concentrations occurring in rapidly enlarging and ruptured aneurysms. Experimental enzymatic destruction of the medial matrix architecture results in dilatation and rupture of the aorta, and experimental mechanical injury, which destroys the medial lamellar architecture, can result in aneurysm formation. These observations support the importance of the media in maintenance of aortic wall integrity.

Human atherosclerotic aneurysms, particularly those of the abdominal aorta, are characterized by extensive atrophy of the media. The normal lamellar architecture is almost totally effaced, and the aortic wall is replaced by a narrow fibrous band. Atrophic changes are also evident in the overlying atherosclerotic lesion to such an extent that plaques may be relatively thinned and contain little residual lipid. Fibrosis and calcification may predominate, depending on the region that is available for histologic study. It is rare to find human abdominal aortic aneurysms without evidence of atherosclerosis. Atherosclerotic plaques remain prominent in the neck of the aneurysm and in the iliac arteries. These are frequently seen posteriorly along the lumbar ostia.

The Process of Aneurysmal Dilation

Atherosclerotic degeneration may result in aneurysmal dilation of the diseased artery. With intimal plaque deposition the structural and functional lamella units of the media are gradually degraded, resulting in thinning of the media and compensatory arterial enlargement. The enlarged atherosclerotic aorta may still receive structural support from the stable, fibrotic, or calcified atherosclerotic plaque, particularly in association with adventitial fibrogenesis, which is characteristic of atherosclerosis.

In advanced atherosclerosis when the aorta is dilated, plaque senescence may occur. This results in reduction in plaque volume and alteration in composition, ulceration or regression, leading to lumen enlargement. There will be reduced tensile support with an atrophic, degenerated media, and progressive aneurysmal enlargement will follow. In addition, metabolic alteration in plaque lipid composition may induce inflammatory cell infiltration with macrophages and lymphocytes. It has been suggested that destruction and weakening of the aortic media may occur as a result of release of inflammatory mediators in response to the atherosclerotic process. The balance between plaque formation, artery wall adaptation and matrix protein synthesis and degradation likely plays a major role in aneurysm pathogenesis. Aneurysms appear to be a relatively late phase of plaque evolution when plaque and media atrophy predominate. This is in contrast to an earlier phase of atherosclerosis when cell proliferation, fibrogenesis and sequestered lipid accumulation are predominant. The observation that patients undergoing surgery for an abdominal aortic aneurysm are generally 10 or more years older than patients undergoing surgery for occlusive disease is explained by this plaque evolution.

Proteolytic Enzymes and Their Inhibitors

Destruction of the structural components of the aortic wall is necessary for aneurysmal enlargement to occur. Both collagenase and elastase activity have been shown to be elevated in aortic aneurysms, with the greatest increase occurring in rapidly enlarging or ruptured aneurysms. While significant destruction of collagen and elastin occurs, there is also synthesis and accumulation of new collagen and elastin in the expanding aorta. This accounts for the thickening of the aortic wall observed clinically in aortic aneurysms and the maintenance of normal collagen content levels. However, the newly synthesized collagen may lack the functional configuration necessary to maintain normal tensile strength. The architecture of the aortic wall is altered by alternation of the media and by accumulation of collagen in the adventitia and neointima. The elastin network is lost from the media, but unstructured elastin accumulates in the adventitia.

Both collagenolytic and elastolytic enzymes have been found in aneurysms and macrophages and inflammatory cells have been implicated as major sources of these proteolytic enzymes. Macrophages are consistently found in the adventitial layer of aneurysms as well as in association with atherosclerotic plaques. Many proteinases are released by macrophages, including a number of important matrix metalloproteinases (MMPs). These include the interstitial collagenase (MMP-1), stromelysin (MMP-3), a 72 kDa gelatinase/type IV collagenase (MMP-2), and a 92 kDa gelatinase/type IV collagenase (MMP-9). All these MMPs have the capacity to degrade all the major connective tissue components of the aortic wall, including collagen, elastin, proteoglycans, fibronectin and laminin. These proteinases are inhibited by tissue inhibitor of metalloproteinase (TIMP), which is also produced by macrophages. In addition, aortic smooth muscle cells, mesenchymal cells, mono-cytes and capillary endothelial cells are sources of MMPs and/or cytokine mediators. It is likely that all these cells interact during the process of aneurysm formation. However, it is not known which cells have primary roles.

Ongoing investigations will lead to a better understanding of the biochemical balance and control mechanisms regulating aortic matrix synthesis and degradation. This may lead to therapeutic interventions to modulate the excessive proteolytic activity associated with aneurysmal disease. Experimental trial has shown that flow-mediated arterial enlargement is limited by competitive MMP inhibition in a dose-dependent fashion. However, the definitive proof-of-principle for the therapeutic efficacy of anti-MMP or other antiproteinase strategies to prevent the growth of small aortic aneurysms awaits the results of human clinical trials.

Inflammatory Aneurysms

Inflammatory aneurysms account for approximately 5% of abdominal aortic aneurysms. Their characteristic feature is chronic inflammatory infiltrate of varying degree in the outer layers of the media and adventitia. This is not present in the normal aorta, although similar inflammatory cells are seen in association with atherosclerotic plaques. Inflammatory cells are also seen in nonatherosclerotic aortic aneurysms such as those caused by various types of aortitis, including giant cell arteritis, rheumatoid arthritis, systemic lupus erythematosus, polyarteritis nodosa, syphilis, and Takayasu's, Behcet's and Kawasaki's diseases. This suggests the possibility that inflammatory cells, through the release of proteolytic enzymes, may play a primary role in either the causation or exacerbation of aneurysmal dilation.

Macrophages, along with T and B lymphocytes, are the major cellular components of chronic inflammation. Close interdependence exists among these cells during both the initial recognition of antigen and the subsequent perpetuation of inflammation. The cytokine network may play a prominent role in the bidirectional communication among inflammatory cells. Although the exact nature of the relationship between these potent polypeptides and aneurysmal disease is unclear, higher interleukin-1 release has been noted in aortic aneurysms compared to normal aorta. It is clear that inflammatory cells play an important role in aneurysmal enlargement. Whether this role is primary or secondary remains to be determined.

In association with inflammation, infection has been also reported to be related to aneurysmal formation. For example, syphilitic aneurysms and mycotic aneurysms have been reported. In Europe, a series of investigations have demonstrated a close correlation of chlamydia pneumoniae and aneurysmal formation. Whether these specific infections are the direct cause of aortic aneurysmal formation or a coincidence remains to be investigated.

Genetic Predisposition

It is well recognized that a positive family history in a first degree relative is a risk factor for aortic aneurysm. A number of investigators have reported familial clustering of aneurysms and have suggested a genetic basis for the pathogenesis of aneurysms. Several specific genetic abnormalities have been identified in "nonatherosclerotic" aneurysm groups, such as fibrillin gene abnormalities in patients with Marfan's syndrome and procollagen type III defects in patients with vascular type Ehlers-Danlos syndrome.

The search for a genetic defect in abdominal aortic aneurysm formation has centered on abnormalities of matrix proteins, particularly collagenases, elastases, metalloproteinases and their inhibitors. Patients with familial aneurysms have been reported to have less type III collagen in the aortic media, with polymorphisms on the gene for the pro-al(III) chain of type III collagen. A genetically determined risk has been suggested by the finding of high levels of Lp(a) in the serum of aneurysm patients with a deficiency of a-l-lantitrypsin.

The study of genetic abnormalities in aneurysms is complicated by the fact that aneurysms occur only late in life. Most tests of statistical association using pedigree analysis are based on analysis of first-degree relatives and sibling pairs. Solid information in parents is scarce, and many years will pass before substantial data on the children of probands will be available.

Because 85% of patients with aortic aneurysms have no known family history of aneurysmal disease, a single primary genetic etiology is unlikely to be identified for most patients with arterial aortic atherosclerosis. Although most patients with atherosclerosis do not develop aneurysms, patients with aneurysms invariably have atherosclerotic involvement. The late onset of aneurysmal disease in affected individuals makes it highly probable that genetic factors create, at best, a predisposition and that the subsequent development of aneurysmal disease depends on environmental factors such as smoking and atherosclerotic plaque formation. Genetic factors play an important role in the development of atherosclerosis, and certain genetic predispositions may determine whether some individuals respond to atherogenic stimuli with proliferation and stenosis, while others respond primarily with dilation and aneurysmal enlargement

Hemodynamics and Aneurysm Formation

Hemodynamic and wall mechanical alterations can induce arterial dilation and aneurysm formation. For example, poststenotic aneurysms begin as poststenotic dilations. These become true aneurysms when diameter criterion is met and when ectasia becomes permanent and fixed. Coarctation of the aorta is a classic example. The hemodynamic changes in the poststenotic site are complex, including elevated lateral wall pressure, flow turbulence, abnormal shear stress and vibratory forces. Flow induced arterial enlargement can be observed in patients with arteriovenous fistulas. Long standing fistulas lead to aneurysmal degeneration of the vessels exposed to this high flow state. An experimental abdominal aortic aneurysm model induced by an arteriovenous fistula has been successfully created in rats.

Experimental Observations

Experimental observations support all of these proposed theories of aneurysm pathogenesis. Genetic animal models of aneurysm formation exist, and aneurysms can be induced by exogenous cholesterol feeding in nongenetically susceptible primates. Aneurysm formation in diet-induced atherosclerosis is enhanced by regression of the atherosclerotic plaque, supporting the concept that the interaction between the plaque and the artery wall in atherosclerosis is an important pathogenic mechanism. Hemodynamic models of arteriovenous fistula formation have documented enlargement in response to increased blood flow and wall shear stress, and animal models utilizing proteolytic enzymes in the aorta result in focal aneurysmal dilation.

Enlargement of atherosclerotic arteries can be induced in hypercholesterolemic experimental animals, and such enlargement is associated with destruction of the architecture of the media. This pathologic feature is particularly prominent in those primate species that are susceptible to aneurysm formation. Experimental destruction of aortic medial architecture by mechanical methods alone, or by mechanical injury along with hyperlipidemia, has also been shown to produce aneurysms. Thus, experimental models have supported all of the hypotheses proposed in the patho-genesis of aneurysms.

Conclusion

Pathogenesis of aortic aneurysmal disease is a multifactorial process involving genetic predisposition and atherosclerotic artery wall degeneration. Atherosclerotic plaque deposition, along with artery enlargement and thinning of the media, are important pathogenic processes. Inflammatory cellular and connective tissue responses and proteolytic enzyme activation are important components of the processes leading to weakening of the aortic wall and aneurysmal enlargement. Further understanding of the cellular control mechanisms and biochemical and mechanical responses of the aortic wall are needed to fully comprehend the pathogenesis of aortic aneurysms.

Selected Readings

1. Zarins CK, Glagov S. Artery wall pathology in atherosclerosis. In: Rutherford RB ed. Vascular Surgery. 5th edition, Vol. 1. Philadelphia: WB Saunders 2000:313-333. This chapter discusses the problem of atherosclerosis as it relates to functional biome-chanical properties of the artery wall. Both normal and pathologic responses of the artery wall are considered as well as differences in the evolution of atherosclerotic lesions. Local differences that may account for the propensity of certain areas to form extensive and complex plaques or aneurysms are discussed in detail.

2. Beckman JA, O'Gara PT. Diseases of the aorta. Adv Intern Med 1999; 44:267-91. This article supplies the reader with up-to-date knowledge of diseases of the aorta with an emphasis on aortic aneurysms. Etiology, pathogenesis and diagnosis are thoroughly reviewed.

3. Rehm JP, Grange JJ, Baxter BT. The formation of aneurysms. Semin Vasc Surg 1998; 3:193-202.

These authors summarize advanced understanding of the dynamic interactions within a diseased vessel in the fields of immunology, biochemistry, cell biology and genetics. The role of the local inflammatory infiltrates and destructive proteolytic enzymes they produce and regulate is explored. New therapeutic measures are expected to be directed at controlling critical matrix changes, and thus the formation of aortic aneurysms.

4. Vorp DA, Trachtenberg JD, Webster MW. Arterial hemodynamics and wall mechanics. Semin Vasc Surg 1998; 3:169-80.

In this article, the authors summarize basic concepts of arterial hemodynamics and wall mechanics as they relate to the development of arterial pathology. The use ofcom-puter models for the estimation of wall stresses in individual abdominal aortic aneu-rysms is also reviewed.

5. Thompson RW, Parks WC. Role of matrix metalloproteinases in abdominal aortic aneurysms. Ann N Y Acad Sci. 1996; 800:157-74.

The role of matrix metalloproteinases (MMPs) in aneurysm disease is reviewed. The possibility that these enzymes might serve as rational targets for pharmacotherapy is suggested.

6. Juvonen J, Juvonen T, Laurila A et al. Demonstration of chlamydia pneumoniae in the walls of abdominal aortic aneurysms. J Vasc Surg 1997; 3:499-505.

This study and related reports demonstrate that chlamydia pneumoniae is frequently found in the vessel wall ofabdominal aortic aneurysms. The potential etiopathogenetic role of chlamydia pneumoniae in the development of these aneurysms is discussed.

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