Pathophysiology, Epidemiology, and Prognosis of Aortic Aneurysms

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Chapter 37 Pathophysiology, Epidemiology, and Prognosis of Aortic Aneurysms

Aortic aneurysms result in significant morbidity and mortality, accounting for nearly 13,000 deaths and 55,000 hospital discharges per year in the United States.¹ Although aneurysms may affect any part of the aorta from the aortic root down to the abdominal aorta, the prognosis and outcome in patients with aortic aneurysms vary based on location and underlying etiology. Timely and appropriate intervention may improve the natural history of the disease process. This chapter reviews the pathophysiology, epidemiology, and prognosis of aortic aneurysms.

The Normal Aorta

The aorta is the large conduit vessel through which the heart delivers blood to the entire body. It courses from the heart through the thorax and abdomen, and ultimately bifurcates into the common iliac arteries (CIAs) in the abdomen. In the thorax, the aorta can be subdivided into three segments: ascending aorta (from the base of the heart to the innominate artery), transverse aorta or aortic arch (including the great vessels and extending to the left subclavian artery), and descending aorta (from the distal edge of the subclavian artery to the level of the diaphragm) (Fig. 37-1).

Figure 37-1 Magnetic resonance angiography (MRA) of the thoracic aorta.

Note the different aortic segments: ascending aorta, aortic arch, and descending aorta. Left subclavian artery separates the aortic arch from the descending aorta.

Like other arterial structures, the aorta is composed of three layers: tunica intima, tunica media, and adventitia. The innermost surface of the tunica intima is lined by a single-cell-thick layer of endothelial cells (ECs). The intima is bound by the internal elastic lamina. The tunica media is composed of smooth muscle cells (SMCs), collagen, fibroblasts, elastin fibers, and ground substance, which together control the degree of vessel constriction and vasodilation. The presence of elastin fibers in the media defines the aorta as an elastic artery and provides the tensile strength that permits the aorta to withstand pulsatile delivery of blood from the heart. Elastin content gradually decreases with distance from the heart.² The outermost layer, the adventitia, is a thin layer that contains connective tissue, fibroblasts, and the nutritive vasa vasorum.

Definition of Aortic Aneurysm

In adults, the normal diameter of the aorta is approximately 3 cm at the origin, 2.5 cm in the descending thoracic aorta, and 1.8 to 2 cm in the abdominal aorta. Aortic aneurysm is defined as a maximal aortic dimension greater than 3.0 cm, or a 50% increase in size compared with the normal segment proximal to the aneurysm. Mild expansion that does not meet these criteria may be referred to as aortic ectasia. True aneurysms are classified into two major groups on the basis of morphology: (1) fusiform (Figs. 37-2 and 37-3), defined as a circumferential expansion of the aorta, and (2) saccular, representing a focal outpouching of a segment of the aorta (Fig. 37-4). Fusiform aneurysms are the most common manifestation. In contrast to true aneurysms, which involve expansion of all three layers of the aortic wall, a pseudoaneurysm, also known as a false aneurysm, results from a disruption of the aortic wall and essentially represents a contained rupture of the aorta.

Figure 37-2 Three pathophysiological mechanisms that best characterize the process of aneurysm formation.

Aortic aneurysm specimens reveal increases in leukocyte infiltration, cytokine concentration, and leukocyte adhesion molecules. Both elastin-related and collagen-related autoantigens have been identified and may participate in initiation of process. Once process has begun, proteolytic enzymes, particularly matrix metalloproteinase (MMP)-2 and -9, increase in concentration and break down elastin and collagen. Increases in enzyme coactivators (e.g., urokinase plasminogen activator [uPA], tissue plasminogen activator [tPA]) further augment matrix breakdown. Increase in proteolysis is not accompanied by change in inhibitors of process, yielding a degenerative environment. Abdominal aorta is predisposed to aneurysm formation because of adverse blood flow patterns and its relative lack of elastin and vascular smooth muscle compared with thoracic aorta.

(Volume-rendered computed tomography image of abdominal aortic aneurysm used with permission of Joseph Schoepf, MD.)

Figure 37-3 Computed tomographic angiogram (CTA) of ascending aortic aneurysm.

Notice that proximal descending portion of aorta is ectatic as well. Aneurysm involves entire circumference of aorta and is thus fusiform. Normal ascending aorta size is less than 3 cm.

Figure 37-4 Maximal intensity projection (MIP) of magnetic resonance (MR)image of saccular aneurysm.

Note outpouching of an otherwise normal descending aorta (arrow). This pattern of aneurysm is more common in infectious aneurysms.

Pathophysiology of Aortic Aneurysms

A wide variety of pathological states are associated with aortic aneurysms (Box 37-1). These include degenerative diseases, inherited disorders, infections, inflammatory conditions (i.e., vasculitis), and trauma. Specific disorders associated with aortic aneurysms are discussed later in this chapter. Important determinants of aortic aneurysm formation include inflammation, proteolysis of the structural components of the aortic wall, and abnormal biomechanical forces³ (see Fig. 37-2). Understanding the underlying pathophysiology of aneurysm formation is critical not only for prevention of initial aneurysm formation but also for limiting aneurysm growth and expansion.

Traditionally, pathological aortic aneurysm formation was ascribed to a process akin to atherogenesis. Although advances in basic and clinical investigation in both lesion types have revealed some common themes, newer studies suggest that aneurysm formation is fundamentally different from atherosclerosis. Preferential weakening of the adventitia and media—rather than an intimal proliferative process, as in atherosclerosis—results in diminished aortic resilience and tensile strength, culminating in aortic wall thinning, dilation, and increased wall stress, all of which may result in rupture. Although atherosclerotic changes may be seen in the wall of aneurysms, these changes may be a consequence of local turbulent flow as opposed to a cause of aneurysm formation.^4,⁵ Moreover, the degree of systemic atherosclerosis does not correlate well with the degree of aneurysm formation.⁶

Development of aneurysms is associated with loss of two critical structural elements in the aortic wall: elastin and collagen. Elastin provides radial and longitudinal support, enabling the aorta to respond to pulsatile flow while maintaining normal arterial dimensions. The importance of elastin in maintaining aortic structure is highlighted by animal models where elastase infusion results in elastin breakdown and experimental aortic aneurysm formation.⁷ However, breakdown of elastin alone appears insufficient to cause aneurysmal expansion and rupture. Loss of collagen, another important structural element, is an additional contributor, and the relative balance of elastin and collagen deposition, among other factors, may be critical for determining aneurysm formation.⁸ Early in aneurysm formation, the aorta compensates for loss of elastin by increasing production of collagen,⁸ but as elastin content decreases, collagen (as the major source of tensile strength) is overwhelmed, and aortic expansion occurs. This is exacerbated by up-regulation of collagenases, resulting in further collagen degradation as described later.⁹ Structural changes in each layer of the aortic wall develop that together promote aortic stiffness. As a consequence, decrease in the vessel’s ability to distend normally with left ventricular (LV) contraction, weakening of the vessel wall, and increase in the tendency for dilation and ectasia follow.¹⁰ Some of the changes in aortic structure that promote aneurysm formation may arise as a result of the normal aging process. With normal aging, aortic stiffness due to fragmentation of elastin fibers, deposition of glycosaminoglycans, fibronectin (FN), and collagen, and reduced bioavailability of endothelium-derived nitric oxide (NO) occurs.¹¹^–¹⁴

Pathophysiologically, the major determinants of aortic aneurysm formation include proteolysis of the structural components of the aortic wall, inflammation, and abnormal biomechanical forces ³ (see Fig. 37-2). Pathology of aortic aneurysms varies in different segments of the aorta and in different predisposing diseases. Frequently observed histological features include cystic medial necrosis, mucoid infiltration, and cyst formation in the setting of elastin necrosis and vascular smooth muscle apoptosis. In patients with Marfan’s syndrome (MFS), bicuspid aortic valve (BAV), or Turner’s syndrome, cystic medial necrosis is a common feature, but in contrast, inflammation is less prominent than in abdominal aortic aneurysms (AAAs).^15,¹⁶ On the other hand, cystic medial necrosis is less likely to be observed in AAAs. Instead, AAAs typically have disrupted elastin fibers, inflammation, greater vascular smooth muscle cell (VSMC) apoptosis, and deficient glycosaminoglycan production.¹⁷ Elastin fragmentation occurs adjacent to the inflammatory cells. Despite differences in pathophysiology due to location and underlying etiology, formation of all aortic aneurysms involves to some degree the processes described in the following discussions (i.e., proteolytic degradation, inflammation, changes in biomechanical forces) that together facilitate aneurysm formation.

Proteolytic Degradation

Several proteolytic enzymes contribute to degradation of structural components of the arterial wall, ultimately increasing risk of aneurysm formation. Matrix metalloproteinases (MMPs) are endopeptidases that degrade one or more components of the extracellular matrix (ECM). Thus far, several classes of MMPs, comprising nearly 30 individual proteinases, have been characterized. They include collagenases, gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs, and other MMPs.¹⁸ Typically produced as proenzymes, MMPs may be activated both intracellularly and extracellularly, and may be secreted by endothelial cells, vascular smooth muscle cells, or adventitial fibroblasts. Extracellular regulation of activation may occur as a result of an MMP–MT-MMP interaction or via interaction with plasmin or reactive oxygen species (ROS).¹⁹^–²¹ The inhibitors of MMPs are the tissue inhibitors of matrix metalloproteinases (TIMPs) and plasminogen activator inhibitors (PAI) 1 and 2.¹⁸

Increased local production of MMPs in aortic aneurysms was first reported nearly 20 years ago.²²^–²⁴ Although elevations of several MMPs have been noted, MMP-1 (collagenase) and MMP-3 (stromelysin), MMP-2 (gelatinase A), and MMP-9 (gelatinase B) represent the principal proteinases in aortic aneurysms that result in elastin and collagen degradation.^25,²⁶ MMP-2 and MMP-9 gelatinases specifically break down collagen. They are synthesized by local cells in the aortic wall, including infiltrating macrophages and resident aortic VSMCs.^27,²⁸ MMP-9 is typically found in the adventitia near the vasa vasorum, localizing to infiltrating macrophages.²⁹ MMP-2 is synthesized constitutively by VSMCs³⁰ but can also be synthesized by infiltrating leukocytes.³¹ Interestingly, MMP-2 production is increased in the vasculature remote from the aorta, suggesting a systemic underlying disease process that manifests with aortic aneurysmal disease.³²

The centrality of these enzymes in aneurysm formation is supported by several lines of evidence. Studies have demonstrated that MMP-2 and MMP-9 levels are higher in tissue obtained from aortic aneurysms than in atherosclerotic plaque or normal arterial tissue.^30,³¹ Furthermore, MMP-9 and MMP-2 knockout mice do not form aortic aneurysms in experimental models.³³ Reinfusion of competent macrophages from wild-type mice into MMP-9 knockout mice enables aneurysm formation.³³ In addition, elevated levels of MMP-1, MMP-8 (a neutrophil collagenase), and MMP-9 have been associated with aneurysm rupture, and levels of these MMPs may vary with aneurysm size.³⁴^–³⁶ Relationship to aneurysm size is less clear for MMP-2.³⁷^–⁴⁰

Elevated levels of other proteolytic enzymes such as human macrophage metalloelastase (MMP-12) and membrane type-1 metalloproteinase (MT1-MMP) have also been demonstrated in aortic aneurysms.⁴¹ Expression of MMP-12 is increased in aortic aneurysms as a result of macrophage infiltration. However, the relevance of MMP-12 to aneurysm formation is less clear, based on the finding that MMP-12 knockout mice are not completely protected from aneurysm formation.⁴² MT1-MMP, a collagenase produced by macrophages and increased in aortic aneurysms, likely has its greatest effect as an activator of the proenzyme form of MMP-2.^43,⁴⁴

In addition to increased expression of MMPs, aneurysm formation is associated with abnormal regulation of MMP levels in tissues. Matrix metalloproteinase levels are increased in states of inflammation and oxidant stress, both known to play a role in aneurysm formation. Compared with nonaneurysmal sections of aorta, superoxide anion and markers of oxidative stress are increased in aneurysmal segments, and ROS can convert proenzymes of MMPs to their active form.⁴⁵^–⁴⁷ In addition, MMP levels can be augmented by plasminogen activators, such as urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), which are specific physiological regulators of MMP-2 and MMP-9 activation and overexpressed in aortic aneurysms but not in healthy aortic specimens.⁴⁸

Matrix metalloproteinase levels are also normally regulated by TIMPs. Although early work reported decreased concentrations of TIMPs in aneurysmal tissue,⁴⁹ more recent data have been less clear, showing no difference in certain TIMP levels between aneurysmal and healthy aortic tissue.^36,^43,^50,⁵¹ However, the relative imbalance in MMPs to TIMPs may be the more relevant factor.⁴¹ Nonetheless, experimental data have clearly demonstrated the significance of TIMPs to aneurysm formation. Local overexpression of TIMP-1 prevented aneurysm formation in a rat model of aortic aneurysm,⁵² but TIMP knockout mice have increased MMP activity and greater aneurysm formation.⁵³ Similarly, lower expression of PAI-1, a regulator of plasminogen activator activity, has been reported in aneurysmal disease.^49,⁵⁴ Increased expression of plasminogen activators without reciprocal changes in their inhibitors alters the balance toward fibrinolysis, MMP activation, and tissue degradation. Experimental overexpression of PAI-1 prevents aneurysm formation in a rat model of aortic aneurysm,⁵⁵ confirming the importance of relative rather than absolute concentrations.

The contribution of MMPs to the pathophysiology of aortic aneurysms is highlighted by the beneficial effect of medications known to reduce MMP levels on aneurysm expansion. For example, tetracyclines (e.g., doxycycline) have long been recognized as generalized inhibitors of metalloproteinases.⁵⁶ Their potential value in aortic aneurysmal disease has been demonstrated in both organ culture and rodent models of aneurysm formation.^36,⁵⁷^–⁵⁹ In humans, doxycycline limits the activity of both MMP-2 and MMP-9 in aortic wall specimens, both by reducing macrophage MMP-9 messenger ribonucleic acid (mRNA) expression and diminishing activation of the proenzyme form of MMP-2.⁶⁰^–⁶² In a few small randomized phase 2 trials, doxycycline has been shown to decrease aneurysm expansion rate.^63,⁶⁴ Although these data await confirmation in larger trials, they do support the conceptual framework of the importance of proteolytic enzymes in aortic aneurysm formation and expansion.

By reducing levels of proteolytic enzymes, several other therapies may potentially be of therapeutic benefit in aneurysmal disease. HMG-CoA reductase inhibitors, or statins, have antianeurysm properties in experimental models by virtue of reducing oxidant stress and macrophage production of MMPs.⁶⁵^–⁶⁷ However, data in humans have been inconsistent. A meta-analysis of five studies including 697 patients with small aortic aneurysms (<55 mm) treated with or without statins suggested that statin therapy was associated with lower rates of expansion.⁶⁸ On the other hand, other human studies have not shown a benefit of preoperative statin treatment on MMP or TIMP levels in aneurysm specimens, and no difference in aneurysm expansion rate.⁶⁹^–⁷¹ Indomethacin also appears to prevent aortic aneurysm formation in a rat model,⁷² and the mechanism may be related to inhibition of cyclooxygenase (COX) 2, prostaglandin E₂ (PGE2), and reductions in MMP-9.⁷³^–⁷⁵ Indeed, PGE2 expression is up-regulated more than 30-fold in aortic aneurysms.⁷⁶ Prostaglandin E₂ localizes to infiltrating macrophages, and its expression is dependent on COX activity.⁷⁷ Prostaglandin E₂, through activation of interleukin (IL)-6, may increase VSMC apoptosis, further weakening the structural elements of the aorta.^75,^76,⁷⁸

Inflammation

The contribution of inflammation to many pathological arterial processes has been well established.⁷⁹ In 1981, Rose and Dent⁸⁰ reported mild chronic inflammation in 72.5% and moderate inflammation in 15.7% in 51 consecutively resected AAAs. Subsequently it was discovered that lymphocytes and macrophages are found in greater quantity in the adventitia and media of AAAs than of atherosclerotic or normal aortas.⁸¹ In addition, surgical explant specimens from patients with aortic aneurysms demonstrated higher levels of adhesion molecules, including intracellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1, than seen in atherosclerotic and normal aortas. Similarly, tissue levels of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, monocyte chemoattractant protein (MCP)-1, interferon (IFN)-γ, and IL-6, have all been noted to be elevated in patients with aneurysms compared with control subjects.⁸² Some studies have even suggested cytokine levels are higher in ruptured aortic aneurysms than in asymptomatic aortic aneurysms,⁸³ although the data have been inconsistent.⁸⁴ Finally, other acute-phase proteins, including C-reactive protein (CRP), D-dimer, and ceruloplasmin, are also present at increased levels in plasma and in the vessel wall.^82,⁸⁵^–⁸⁷

These inflammatory mediators largely derive from infiltrating macrophages, but lymphocytes and aortic ECs and SMCs also contribute to the inflammatory milieu. The presence of inflammation in aortic aneurysms is supported by positron emission tomographic imaging with ¹⁸ fluorodeoxyglucose (FDG-PET) showing greater FDG uptake in aneurysmal compared to nonaneurysmal aortic segments from matched control subjects, and by advanced magnetic resonance imaging (MRI) techniques.^88,⁸⁹ Thus, immune cells invade the aortic wall, become activated, and create an inflammatory environment that engages the activity of local stabilizing cells, initiating the process of elastin and collagen breakdown and aneurysm formation. However, the initial signals that drive inflammatory cell recruitment remain unclear. Animal studies with experimental aneurysm models have confirmed the human studies and demonstrated that increased inflammation promotes aneurysm formation.⁹⁰

Given the contribution of inflammation to aortic aneurysms, it follows that strategies to reduce inflammation might reduce aneurysm formation or limit aneurysm growth. Indeed, as mentioned previously, some data suggest that statins, known to have beneficial antiinflammatory properties beyond their effect on cholesterol lowering, may limit aneurysm growth and expansion.^67,^91,⁹² Recent studies have also shown that limiting inflammation can reduce aneurysm formation in animal models.⁹³^–⁹⁷ Future studies will be required to clarify whether strategies to target inflammation can prevent formation of aortic aneurysms or limit expansion in humans.

Increases in Biomechanical Wall Stress

The frequency of aneurysm formation in the abdominal aorta compared to other vascular locations suggests a predisposition in this area. Variations in biomechanical factors have been noted in the differing regions of the aorta. Relative deficiencies in structural elements combined with adverse blood flow patterns predispose the abdominal aorta to aneurysm formation. Compensatory mechanisms occur after aneurysm formation have developed, but they do not stop the process. Thus, aneurysm expansion is promoted by an imbalance of biomechanical forces and compensatory mechanisms.

Several specific structural changes may predispose the abdominal aorta to aneurysm formation. For example, elastin within the aortic wall is organized into circumferential plates, or lamellae, that respond to the pulsatile load created by the heart. Each lamellar unit consists predominantly of two elastin bundles and vascular smooth muscle. However, deposition of elastin is not uniform along the aorta, with the thoracic aorta incorporating 35 to 56 lamellar units compared to only 28 in the abdominal aorta.⁹⁸ The abdominal aorta may therefore be more susceptible to elastin breakdown due to a relative increase in pressure withstood per lamellar unit, compared with the rest of the vessel. In addition, the abdominal aorta has a decreased concentration of nutritive vasa vasorum compared to more proximal aortic segments.⁹⁹ Reductions in aortic tissue perfusion stiffen the vessel, reducing compliance and ability to withstand pulsatile stress.¹⁰⁰

Vascular cells in the aorta attempt to restore elastin content in the setting of elastin degradation to compensate for reductions in tensile and radial strength. Human AAA samples show a four- to sixfold increase in tropoelastin protein compared with control arteries.^101,¹²⁶ Elastin is produced by SMCs and macrophages. In areas of macrophage infiltration, elastin deposition is not organized into mature effective bundles. Indeed, compared with normal specimens, aneurysm specimens have a ninefold reduction in desmosine, a marker for mature elastin cross-linking.¹⁰¹ Thus, compensatory elastin replacement is disordered and does not improve aortic compliance.

Another factor that may make the abdominal segment of the aorta more prone to aneurysm formation is blood flow patterns specific to that segment. In experimental models, the infrarenal segment of the aorta is subject to much higher levels of oscillating flow and reflected pressure waves compared with the suprarenal segment,¹⁰² resulting in higher levels of aortic wall tension. Turbulence and pressure are exacerbated by the aneurysm’s morphology, which promotes development of local vortices and turbulent flow patterns.¹⁰³ Excluding these flow patterns from the aneurysm by placing an aortic endograft rapidly reduces plasma MMP-9 levels in patients.^104,¹⁰⁵ In a rodent elastase infusion model of aortic aneurysm, flow conditions were examined by creating a left femoral arteriovenous fistula (AVF) or left iliac artery ligation. Increases in shear stress due to fistula formation resulted in a more stable aortic phenotype with decreased oxidative stress, decreased macrophage density in the media, increased aortic ECs and vascular smooth muscle cells, and reduced apoptosis compared to the lower shear stress introduced by femoral artery ligation.^4,^106,¹⁰⁷ Improved flow decreased aortic expansion by 26%.¹⁰⁶

In addition to adverse biomechanical forces creating an environment permissive for aneurysm formation, the role of intraluminal thrombus on wall stress and aneurysm expansion has recently been a focus of much study. Using finite element analysis in a three-dimensional (3D) model of the aorta derived from computed tomography (CT) scans, intraluminal thrombus was found to lower peak wall stress by up to 38%¹⁰⁸ relatively independent of thrombus constituents.¹⁰⁹ Thrombus decreases transmission of luminal pressure to the aneurysm wall and may prevent aneurysm rupture by reducing wall strain.¹¹⁰^–¹¹⁵ On the other hand, intraluminal thrombus may also contribute to further aneurysm formation,¹¹¹ given that thrombus has been demonstrated to have higher levels of proteolytic enzymes and enzyme activators than the aneurysm itself.¹¹⁶ Intraluminal thrombus may act as a proteolytic enzyme reservoir through polymorphonuclear leukocytes, and enzyme accumulation provides a ready source of destructive elements for the adjacent aneurysm.¹¹⁶

Understanding biomechanical factors may help improve assessment of risk of aneurysm growth and rupture above and beyond the predictive value of lumen diameter alone.¹¹⁷ Several studies have used novel computational models to incorporate biomechanical factors such as wall stress, wall strength, and extent of intraluminal thrombus for assessment of abdominal aneurysms.^112,¹¹⁸^–¹²³ Some studies have suggested that assessment of wall stress, wall strength, and the ratio of wall stress to wall strength may be better predictors of rupture risk than diameter.^124,¹²⁵

Epidemiology and Prognosis of Aortic Aneurysms

Abdominal Aortic Aneurysms

Aortic aneurysms are typically defined as an increase in diameter of 50% compared to the adjacent normal segment of the aorta; the upper limit of normal for the abdominal aorta is 3 cm. The absolute size definition for AAA is preferable, given that body size and baseline diameter may vary on the basis of height, sex, weight, and presence of a thoracoabdominal aortic aneurysm (TAAA). However, all these factors should be taken into consideration when considering risk in any given individual.

Prevalence

The prevalence of aneurysms of the abdominal aorta has been determined on the basis of several large screening studies and autopsy series (Table 37-1). In an early series of 24,000 consecutive autopsies performed over 23 years, 1.97% of the subjects were found to have an AAA.¹²⁶ Of the 473 aneurysms found, 58% were larger than 4 cm in diameter, nearly three quarters of the patients were men, and one fourth of the aneurysms had ruptured. More recent large screening programs in targeted populations have further evaluated the prevalence of AAA. The largest screening program performed was the Aneurysm Detection and Management (ADAM) Study Screening Program, which studied 126,196 veterans 50 to 79 years of age.¹²⁷ In this cohort of predominantly male American veterans, 3.6% of subjects had an infrarenal aortic diameter greater than 3 cm, and an AAA 4 cm or larger was found in 1.2%. The Multicentre Aneurysm Screening Study (MASS) also screened 27,147 of 33,830 invited men aged 65 to 74 and reported a 4.9% prevalence of AAA 3 cm or larger.¹²⁸

Table 37-1 Prevalence of Aortic Aneurysm in Large Epidemiological Studies

Several studies have demonstrated lower prevalence of AAA in women. The largest and most recent of these studies screened nearly 10,012 women (mean age, 69.6 years) and found an AAA prevalence rate of 0.7%, with only 4 of 74 detected aneurysms measuring larger than 5 cm.¹²⁹ These low prevalence rates were consistent with findings from earlier studies. Among 4237 subjects aged 65 to 80 who participated in a screening study among general practitioners in West Sussex, United Kingdom, 2290 women agreed to undergo abdominal ultrasonography.¹³⁰ Only 1.4% of the women had an AAA 3 cm or larger, and only 0.3% had an AAA 4 cm or larger. This dramatically lower prevalence in women has been confirmed in subsequent studies. In the Norwegian Tromso study, 2% of 2943 women aged 55 to 84 had an AAA 3 cm or larger, and 0.5% had an abdominal aneurysm 4 cm or larger.¹³¹ Finally, among female American veterans, the prevalence of an AAA 3 cm or larger was just 1%.¹³² However, an increasing number of cardiovascular risk factors does increase the risk of AAA in women, with a prevalence rate as high as 6.4% in this higher-risk group.¹²⁹

Risk factors

Three risk factors predict the vast majority of AAAs: age, gender, and cigarette smoking. Aneurysms usually affect the elderly, seldom occurring in those younger than 60 years of age, and there is a clear increase in incidence with increasing age, even when limiting the studies to older individuals.¹³³^–¹³⁵ In a Norwegian population-based study of 6386 men and women aged 25 to 84, the incidence of AAA in men increased from 0% in those aged 25 to 44, to 6% in those aged 55 to 64, and to 18.5% in those aged 75 to 84.¹³¹ Large North American epidemiological studies have demonstrated an increase in AAA risk ranging from 58% to 300% with each additional decade of life.¹³⁶ Gender is also an important predictor of AAA formation; in all age groups, risk of AAA is two- to sixfold higher in men than women.^131,^132,¹³⁷^–¹⁴⁰ Cigarette smoking is the most potent modifiable risk factor and increases the risk of AAA by 60% to 850%.¹⁴¹^–¹⁴⁷ In the ADAM study and the Edinburgh Artery Study, risk of an aneurysm increased threefold with any smoking history.^127,¹⁴⁸ Risk of AAA development further increases with number of cigarettes smoked, duration of smoking, and lack of filtration, indicating a dose-response relationship.¹⁴⁹ In the Whitehall study of 18,403 male civil servants examined at age 40 to 64 years, aneurysm frequency increased from sixfold with manufactured cigarettes with filters to 25-fold with hand-rolled cigarettes.¹⁵⁰ Smoking cessation can reduce the risk of aneurysm formation, with former smokers having a lower AAA risk than current smokers.^136,^149,¹⁵¹

Risk factors for cardiovascular disease in general (e.g., hypertension, hyperlipidemia) also increase the risk of AAA formation but are less potent risk factors than age, gender, and smoking.^127,^136,¹⁵²^–¹⁵⁴ In the REACH registry, there was a clear modest association of both hypertension and hyperlipidemia with AAA.¹⁵⁵ Earlier studies had suggested a less consistent relationship with hypertension,^138,¹⁵⁶ but aneurysm formation seems to correlate best with diastolic blood pressure¹⁵⁷ or use of an antihypertensive medication.¹⁴⁰ Some data suggest that hypertension may be a greater risk factor for aneurysm rupture than for initial aneurysm formation.¹⁵⁸ The association between cholesterol and AAA is clear, although hyperlipidemia is a less potent risk factor than those mentioned previously.^135,^137,¹⁵⁹ Risk of AAA formation increased 30% per 40 mg/dL total cholesterol in the Chicago Heart Association Detection Project in Industry cohort.¹³⁸ For specific components of the lipid profile, higher levels of low-density lipoprotein (LDL) and lower levels of high-density lipoprotein (HDL) cholesterol are both associated with aneurysm formation.^133,¹⁵⁹ Similarly, the presence of atherosclerosis increases risk of aneurysm formation,^133,^134,¹³⁷ although as mentioned previously, aneurysm formation is likely a process distinct from atherosclerosis. In the ADAM study of more than 100,000 subjects, hypertension, elevated cholesterol, and presence of other vascular disease increased risk of aneurysm formation by 15%, 44%, and 66%, respectively.¹²⁷ In contrast, diabetes and black race appear protective against formation of an aneurysm.^127,^132,^136,¹⁶⁰ Diabetes decreases risk of aneurysm formation by 30% to 50%.^136,¹⁵⁷

A dramatic increase in frequency of AAA formation in relatives of patients with aortic aneurysm suggests a genetic component to the disease. Although cigarette smoking numerically accounts for the vast majority of AAAs in the population,¹³⁶ the most potent risk factor for aneurysm formation is a history of aneurysm in a first-degree relative. Norgaard et al.¹⁶¹ identified an 18% incidence of aneurysms in first-degree relatives of patients with AAA. In the ADAM study, a family history doubled the risk of AAA, but was reported in only 5.1% of more than 100,000 participants.¹⁶² Investigations specific to the impact of family history demonstrate a larger risk. Several studies have demonstrated that a family history of AAA increases the risk of AAA four- to fivefold.^157,¹⁶³ Family history of AAA was also related to earlier AAA formation and rupture by nearly a decade.¹⁶⁴ Rate of rupture was nearly fourfold higher in patients with a family history than in sporadic AAA patients. Frydman et al.¹⁶⁵ screened the siblings of 400 AAA patients and found an AAA in 43% of male siblings and 16% of female siblings. More specifically, the risk of AAA formation consistently rises above 20% for men older than 50 who have a first-degree relative with AAA.^161,¹⁶⁶^–¹⁶⁹ Using segregation analysis, Majumder et al.¹⁷⁰ reported that the relative risk of developing an AAA is 3.97 and 4.03 with paternal and maternal history, respectively. Risk increases to nearly 10-fold with an affected male sibling and 23-fold when a female sibling is affected.¹⁷⁰ Twin studies further support a genetic component to AAA formation, with one study reporting an odds ratio (OR) of 71 (95% confidence interval [CI], 27-183) for monozygotic twins and 7.6 (95% CI, 3.0-19) for dizygotic twins.¹⁷¹

Despite the wealth of data supporting a genetic component to AAA formation, no clear mode of inheritance and no single candidate gene has been identified. Early studies suggested evidence of both sex-linked and autosomal dominant patterns of inheritance. Associations have been made with blood types, haptoglobin variations, α₁-antitrypsin, and human leukocyte antigen class II (HLA-II) immune response genes.¹⁷²^–¹⁷⁴ More than 100 reports on genetic associations with AAA have appeared in the literature,¹⁷⁵ including genes related to cardiovascular disease, inflammation, and related signaling pathways. One study suggested an association between reduced AAA growth and five single-nucleotide polymorphisms (SNPs) in latent TGF-β binding protein (LTBP4), as well as an allelic variant of TGFB3.¹⁷⁶ However, another study showed no association between genetic polymorphisms in the main receptors for TGF-β and AAA formation.¹⁷⁷ Two genome-wide association studies (GWAS) have suggested an association between AAA and a SNP located on chromosome 3p12.3 in a region near the gene CNTN3 for contactin-3, a lipid-anchored cell adhesion molecule.¹⁷⁸ Another GWAS in a population from Iceland and the Netherlands found a SNP on 9q33 associated with AAA with an OR of 1.21. The same SNP has been associated with coronary artery disease (CAD), peripheral artery disease (PAD), and pulmonary embolism (PE).¹⁷⁹ The SNP resides in the gene coding for DAB2IP, a gene encoding a cell growth and survival inhibitor. In addition, the same gene variant associated with myocardial infarction (MI) at locus 9p21 has been associated with AAA.^180,¹⁸¹ Finally, of interest but of unclear significance is the association between telomere length and AAA in a small cohort in the United Kingdom.¹⁸² This may represent the association of aging, telomere length, and aneurysm formation, but the direct pathophysiological link remains unclear.

Prognosis

The natural history of AAA is one of silent coexistence and sudden lethal rupture. In a large autopsy study performed over a quarter of a century, one fourth of abdominal aneurysms were ruptured on postmortem examination.¹²⁶ The frequency of rupture was dependent largely on size in this study population, ranging from 9.5% in aneurysms smaller than 4 cm to 45.6% in aneurysms 7.1 to 10 cm in diameter. In a comparison of patients with aortic aneurysms divided into two groups at a cutoff point of 6 cm, survival was markedly decreased in the patients with larger aneurysms.¹⁸³ In a single-center study that included 60 AAA ruptures over a 30-year period, only 2 occurred in patients with an aneurysm diameter smaller than 5 cm.¹⁸⁴ Similarly, in a study in Rochester, Minnesota, no ruptures occurred in aneurysms smaller than 5 cm, whereas rupture occurred in 25% of AAAs larger than 5 cm.¹⁸⁵ In 198 patients with aneurysms 5.5 cm in diameter or larger, but who were deemed too risky for surgery, 23% had presumed rupture over a mean follow-up of 1.6 years.¹⁸⁶ Mortality rates as high as 64% are observed in patients who present with a ruptured aortic aneurysm.¹⁸⁷

On the basis of these data, two large trials have been conducted to determine whether early recognition and treatment can alter the natural history of AAA. The U.K. Small Aneurysm Trial randomized 1090 patients aged 60 to 76 years with asymptomatic AAAs 4 to 5.5 cm in diameter to undergo early elective open surgery or ultrasonographic surveillance.¹⁸⁸ In the surveillance group, surgery was performed when the aneurysm reached 5.5 cm. Early surgery did not affect overall mortality. At 3 years, nearly 20% of both groups had died, although abdominal aneurysms accounted for only a quarter of the deaths in both groups. Cardiovascular mortality unrelated to the aneurysm accounted for 40% of total mortality, and cancer caused slightly more than 20% of the deaths. In a similar study performed by the U.S. Veterans Administration, 1136 subjects aged 50 to 79 years with asymptomatic AAA 4 to 5.5 cm in diameter were randomized to undergo either early elective open surgery or ultrasonographic surveillance¹⁵³ (Fig. 37-5). After 5 years, there was no significant difference in survival between the groups, each with a near 25% mortality rate. In this study, aneurysm-related deaths accounted for only 3% of total mortality. More recently, the PIVOTAL study demonstrated no difference between surveillance and early endovascular repair in patients with small aneurysms (measuring 4-5 cm), and no difference in aneurysm-related death in the two groups after 3 years of follow-up.¹⁸⁹ Together, these data suggest that early repair of small aneurysms does not alter outcomes.

Figure 37-5 Survival curves in early surgery group compared with ultrasound surveillance group in Aneurysm Detection and Management (ADAM) Veterans Affairs Cooperative Study.

No significant difference in mortality was found between the two groups.

(From Lederle FA, Wilson SE, Johnson GR, et al: Immediate repair compared with surveillance of small abdominal aortic aneurysms. N Engl J Med 346:1437, 2002.)¹⁵³

Several factors can predict the likelihood of expansion and rupture of AAAs and can help identify which patients require intervention. The factor most predictive of rupture is initial size of the aneurysm. In one study of patients too ill for surgery, aneurysm rupture rates ranged from 9.4% for AAA of 5.5 to 5.9 cm to 32.5% for AAA of 7 cm or more.¹⁸⁶ In the U. K. Small Aneurysm Study, rate of rupture was 0.9% in aneurysms 3 to 3.9 cm, 2.7% in aneurysms 4 to 5.5 cm, and 27.8% in aneurysms 5.6 cm and larger.¹⁵⁸ Larger aneurysm size also predicted a more rapid increase in diameter.¹⁹⁰ Similar to factors that predispose to initial development of AAA, cigarette smoking and higher blood pressure increase the risks of rapid expansion and rupture. In contrast to the decreased risk of AAA development in women, being female actually increases risk of rupture and death after rupture in those with established AAA.^158,^191,¹⁹² In the U.K. Small Aneurysm Study, women had a threefold higher risk of AAA rupture than men.¹⁵⁸ As mentioned previously, some have advocated use of biomechanical factors (wall stress, wall strength) to help with risk prediction. Prospective studies will be required to determine whether these factors can improve assessment of patients at high risk for aneurysm rupture and can improve selection of patients for aneurysm repair.

Thoracic and Thoracoabdominal Aortic Aneurysms

Prevalence

The most common location of involvement of thoracic aortic aneurysms (TAAs) is the ascending aorta and/or aortic root (noted in 60%), with the descending aorta affected in approximately 40% of cases and the aortic arch in 10%.¹⁹³ Thoracoabdominal aortic aneurysms are defined by contiguous involvement of the descending thoracic aorta and abdominal aorta and account for 5% to 10% of all aortic aneurysms.^193,¹⁹⁴ The prevalence of isolated TAA is poorly defined but estimated at 6 persons per 100,000 per year.¹⁹⁵ In autopsy records reported from 63% of 70,368 deaths between 1958 and 1985 in the city of Malmo, Sweden, TAAs were diagnosed in 205 of the deceased, 53% of whom were men.¹⁹⁶ Of the 44,332 autopsies performed, 63 individuals (0.14%) had died of a ruptured TAA. The relative infrequency of TAA is confirmed by a retrospective analysis in Rochester, Minnesota.¹⁹⁷ Over 30 years, of approximately 45,000 residents, 72 (0.16%) were diagnosed with a TAA; 61% were women, and 67 patients had thoracic aortic involvement only. Most studies, however, suggest that men are twice as likely to develop a TAA as women.^197,¹⁹⁸ Thoracoabdominal aortic aneurysms occur even more infrequently. Of the 44,332 people to undergo necropsy in Malmo, Sweden, a mere 10 had TAAA.¹⁹⁶ In the Rochester, Minnesota, experience the incidence was 0.37 per 100,000 person-years of follow-up.¹⁹⁷ Because of the relatively small sample sizes reported in the literature, risk factors for TAAA development are less well defined. Risk factors currently associated with development of TAAA include smoking, hypertension, and atherosclerotic vascular disease.¹⁹³

Etiology and pathophysiology

Aneurysms involving the thoracic aorta commonly develop as a result of cystic medial necrosis, a degenerative process that histologically involves degeneration of elastic fibers and SMCs. Cystic medial degeneration can arise as an isolated abnormality or as a result of an underlying connective tissue disease, such as MFS or Ehlers-Danlos’ syndrome (EDS). Degeneration of the media within the arterial wall results in impaired structural integrity of the aorta, leading to eventual aortic dilation, aneurysm formation, and risk of rupture.

As with AAA, age is a significant risk factor for development of TAA; median age for presentation varies from 64 to 69 years.¹⁹³ Cystic medial necrosis develops to some degree as a natural consequence of aging and may be accelerated by comorbid conditions such as hypertension.¹⁹⁹ Although a degenerative aneurysmal process is found in the majority of patients with TAAA, several other etiologies should be considered, including inherited collagen vascular disorders (e.g., MFS), BAV disease, aortic dissection, infection, and vasculitis (e.g., giant cell or Takayasu’s arteritis). Rarer causes of TAA include coarctation of the aorta and trauma. Finally, some aneurysms develop because of a familial predisposition termed familial thoracic aortic syndrome.

Natural history and prognosis

The natural history and prognosis for TAAs and TAAAs remain poor but not completely defined, in part because modern imaging techniques now allow for early detection and intervention of aneurysm before rupture, and because the natural history is dependent in large part on underlying etiology. However, in a study accumulated over 25 years that followed 94 patients with TAAAs who did not undergo operative repair, 76% died within 2 years of follow-up, with half of the deaths resulting from aneurysm rupture.²⁰⁰ A more recent experience with 57 TAAA patients managed without operation revealed a 69% 2-year survival, with aneurysm rupture as the cause of death in 19%.²⁰¹ Features associated with aneurysm expansion and rupture include smoking, chronic obstructive pulmonary disease (COPD), and renal insufficiency.²⁰² Dissection as an underlying cause of aneurysm formation is also associated with a greater risk of rupture compared with degenerative causes.²⁰³ Extension of a TAA into the abdomen is associated with a 50% relative increase in risk of rupture, compared with those limited to the thoracic aorta alone.²⁰⁴

The natural history of TAA depends in large part on rate of expansion. Initial aneurysm size at the time of diagnosis is the most important predictor of thoracic aneurysm growth.¹⁹³ Longitudinal data have suggested that the mean rate of growth of thoracic aneurysms averages 0.1 cm/yr.²⁰⁵ Several factors also contribute to the rate of growth. Growth rate is increased in the setting of an aortic dissection. In one study, presence of a chronic aortic dissection was associated with a 0.37 cm/yr rate of growth.²⁰⁵ Descending TAAs tend to increase in size more rapidly than ascending TAAs.^205,²⁰⁶ Those who smoke have a twofold increased rate of growth over nonsmokers.²⁰⁷

Survival rates for TAA range from 39% to 87% at 1 year and from 13% to 46% at 5 years.^201,^207,²⁰⁸ In a study of 67 patients with TAA (mean age, 65 years), those with an aortic diameter less than 5 cm had a 90% 3-year survival rate, compared to 60% for patients with a TAA larger than 5 cm.²⁰⁷ Similarly, in two other studies, patients with TAAs 6 cm or larger had a higher mortality rate than those with smaller aneurysms.²⁰⁶ Based on these data, referral for surgery is recommended when the aneurysm reaches 5.5 cm or greater in the ascending aorta.²⁰⁹

However, several factors increase risk of aneurysm rupture and may prompt earlier referral for intervention. Guidelines recommend that patients with MFS or other genetic disorders (e.g., vascular Ehlers-Danlos’, Loeys-Dietz’s, and Turner’s syndromes, BAV disease, or familial aortic aneurysm) may require intervention at smaller diameters, such as 4.0 cm to 5.0 cm, depending on clinical circumstances.^206,²⁰⁹^–²¹⁴ In addition, those with a more rapid rate of growth than expected (i.e., ≥0.5 cm/yr) may be at increased risk of rupture and require repair at diameters less than 5.5 cm.²⁰⁹ Finally, repair should be considered in patients with ascending aortic diameter greater than 4.5 cm if undergoing aortic valve surgery.²⁰⁹

For aneurysms involving the aortic arch, surgery should be considered when the diameter reaches 5.5 cm or greater.²⁰⁹ For degenerative descending TAAs, repair is recommended when the diameter exceeds 5.5 cm, although in individuals with TAAAs or those with high surgical risk, elective surgery is recommended when the diameter exceeds 6.0 cm.²⁰⁹ Other factors reported to significantly increase rate of rupture or need for surgery include older age, history of COPD, pain possibly related to the aneurysm, higher blood pressure, and extension of the aneurysm into the abdomen.^202,²⁰⁴

Inherited and Developmental Disorders

Marfan’s Syndrome

Marfan’s syndrome is an autosomal dominant inherited disorder of connective tissue arising from mutations in FBN1, a gene on chromosome 15 encoding the ECM protein fibrillin-1 (FBN1). Abnormalities in fibrillin synthesis may affect multiple tissues in patients with Marfan syndrome, including the cardiovascular, skeletal, and ocular systems. Excessive signaling through the TGF-β cascade has been suggested as a contributing factor. This is supported by experiments showing that TGF-β-neutralizing antibodies reverse aortic disease in a mouse model of Marfan syndrome, and by the demonstration that losartan, an angiotensin receptor blocker (ARB) with anti-TGF-β properties, can partially reverse aortic wall defects in these mice.²¹⁵ Clinical manifestations of MFS include ectopia lentis, hyperelasticity and ligamentous redundancy, valvular heart disease, and abnormalities in skin, fascia, skeletal muscle, and adipose tissue.

However, potentially the most lethal complication in MFS is disease of the ascending aorta resulting in aneurysm, dissection, and rupture. Dilation of the aortic root has been demonstrated early in childhood in patients with Marfan syndrome. Histologically, changes in the media seen in patients with MFS include cystic medial necrosis with fragmentation and disarray of elastic fibers, a paucity of smooth muscle cells, and separation of muscle fibers by collagen and glycosaminoglycans.²¹⁶

Ehlers-Danlos’ Syndrome

Ehlers-Danlos’ syndrome type 4 (vascular type) is a rare congenital defect in the synthesis of type 3 collagen resulting from a mutation in the COL3A1 gene.²¹⁷ Patients with EDS typically present with acrogeria (distinctive facial appearance), bruising, thin skin, and vascular or visceral rupture. Histological examination reveals a thinned, fragmented internal elastic lamina.²¹⁸ Moreover, deposition of glycosaminoglycans in the media of major arteries and intima of smaller arteries, with intimal thickening, has been noted.²¹⁹ Abnormalities in type 3 collagen fiber formation reduce stability or prevent formation of collagen, decreasing vascular wall stability.²¹⁸ In a study of 199 patients with confirmed Ehlers-Danlos syndrome, 25% of patients suffered a ruptured vessel or viscus by age 20 and 80% by age 40.²²⁰ Mean survival was 48 years. There were 131 deaths, 103 of which were due to vascular rupture. Complications of pregnancy caused the death of 15% of the women who became pregnant.

Loeys-Dietz’s Syndrome

Loeys-Dietz’s syndrome is an autosomal dominant condition arising from mutations in either the type I or type II receptor for TGF-β (TGFBR1 or TGFBR2). Individuals with Loeys-Dietz’s syndrome have several characteristic features, including abnormal uvula, hypertelorism (increased space between the eyes), and arterial aneurysms, among other abnormalities, some of which are similar to Marfan syndrome.²¹⁴ The syndrome is characterized by particularly aggressive arterial disease manifested as aortic aneurysm with high risk of aortic dissection and rupture. As such, the average age of death of 26 years. Because of the high morbidity and mortality and the high rate of aortic dissection, even with aneurysms of less than 5.0 cm in size, early repair at smaller diameters is recommended.^209,²¹⁴

Bicuspid Aortic Valve

Presence of a BAV increases the risk of ascending aortic aneurysm formation.¹⁹³ Although it was once thought that the aneurysmal dilation was a “post-stenotic” phenomenon arising secondary to abnormal flow through a diseased aortic valve, more recent data support the notion that aortic expansion occurs independently of valvular dysfunction, severity, age, and body size.²²¹ Further evidence that aortic dilation is not dependent on valve dysfunction is found in a study of 118 consecutive patients with BAV in whom the diameter of the ascending aorta was not correlated with severity of aortic stenosis.²²² Moreover, abnormalities in the aortic wall can arise even when there is no hemodynamically significant aortic valve disease, and replacement of a diseased valve does not change the rate of aortic expansion.²²³

In one study comparing aorta and pulmonary artery specimens in patients with BAV and tricuspid aortic valve disease, those with BAV had decreased FBN1 concentrations in both the aortic and pulmonary specimens, suggesting a systemic disorder.²²⁴ Vascular smooth muscle cells from patients with BAV show intracellular accumulation and reduction of extracellular distribution of several structural elements including fibrillin, fibronectin, and tenascin.¹⁶ Surgical specimens demonstrate greater amounts of inflammation and increased expression of MMP-2 and MMP-9 in patients with BAV compared to those with tricuspid aortic valve disease.^225,²²⁶ Patients with Turner’s syndrome, who are at increased risk of developing BAV, also exhibit an increased rate of aneurysm formation.²²⁷

Aortic Coarctation

Coarctation of the aorta represents 5% of congenital heart disease. The clinical consequences of aortic coarctation are varied, ranging from being life-threatening in infancy to remaining unappreciated until adulthood.²²⁸ Coarctation has long been recognized as associated with de novo aortic aneurysm development, and aneurysms can also develop at the site of coarctation repair—specifically patch angioplasty repair—in up to 20% of patients.^229,²³⁰ Some reports indicate aneurysm formation can even occur several decades after initial repair. Intermediate follow-up studies suggest that percutaneous balloon angioplasty repair results in a 2% to 5% rate of repair-site aortic aneurysm formation.^231,²³² A potential explanation for the relationship between coarctation and aortic aneurysm is the common link with the presence of BAV in approximately 15% of patients with aortic coarctation.²¹²

Other Conditions Associated with Aortic Aneurysm

Although most aortic aneurysms occur as a result of degenerative processes in the aortic wall as described earlier, certain disease states including vasculitis, infection, and inherited abnormalities of structural proteins predispose patients to aortic aneurysm formation (see Box 37-1).

Vasculitides

Giant cell arteritis

Giant cell (temporal) arteritis (GCA; see Chapter 43) is a medium-vessel chronic inflammatory vasculitis that affects the aorta and its branch vessels. It most commonly occurs in patients older than 55 years of age and is twice as common in women as men.²³³ Between 1% and 20% of GCA patients develop aneurysms, most commonly in the thoracic aorta.²³⁴ In a series of 41 patients with GCA-related TAAs, 16 developed aortic dissection, 15 had valvular annular expansion causing symptomatic aortic valve insufficiency, and 18 required surgery.²³⁵ In a series of 168 patients with GCA, 18% developed aortic aneurysm or dissection, and these occurrences were inversely associated with development of intracranial disease manifestations.²³⁴ Presence of an aortic aneurysm itself was not associated with increased mortality; however, the nine individuals who developed aortic dissection had significantly increased mortality.²³⁶ The mechanism of aneurysm formation seems to be similar to patients without GCA, with increases in MMP-2- and MMP-9-associated destruction of the vessel wall.^237,²³⁸

Takayasu’s arteritis

Named for a Japanese professor of ophthalmology, Takayasu’s arteritis (TA; see Chapter 42) is a large-vessel vasculitis that typically has its onset between the age of 10 and 30 years. The most common vascular presentation is occlusive disease, found in 80% to 94% of patients; however, aortic aneurysms may be found in up to one fourth of patients with TA.^239,²⁴⁰ Development of aneurysmal disease has been associated with worse outcome in a series of 120 Japanese patients followed for 13 years.²⁴¹ Blood levels of MMP-2 and MMP-9 are elevated in TA, but the mechanism of aneurysm formation remains unknown.²⁴²

Behçet’s disease

Behçet’s disease (see Chapter 41) is a small-vessel vasculitis originally characterized by a set of three symptoms: aphthous stomatitis, genital ulcers, and uveitis.²⁴³ Involvement of medium-sized and large arteries, as well as veins, arises not from direct vascular inflammation but rather due to vasculitis of the small arteries of the vasa vasorum that supply the vessel wall.²⁴⁴ Vascular involvement, including aneurysms, can be found in 7% to 38% of patients.^243,²⁴⁵ Management of aneurysmal disease in Behçet’s disease depends in large part on the location of the abnormality and clinical circumstances. First-line therapy includes an antiinflammatory regimen with corticosteroids. As with other vasculitides, risk of intervention is greatest during the state of active inflammation, and there is an increased risk of rupture, dissection, and/or future aneurysmal dilation at the site of revascularization.

Seronegative spondyloarthropathies

The spondyloarthropathies (see Chapter 41) are characterized by inflammation of the spine and sacroiliac joints, association with HLA-B27, and absence of rheumatoid factor (RF). These disorders are known to be associated with an increased risk of aortic aneurysm formation. Specific spondyloarthropathies include ankylosing spondylitis, Reiter’s syndrome, and relapsing polychondritis.

Ankylosing spondylitis is an HLA-B27 disease that requires the presence of four of the five following features: onset younger than 40 years of age, back pain for more than 3 months, insidious onset of symptoms, morning stiffness, and improvement with exercise. Aortic root and valve disease is present in up to 80% of patients.²⁴² In a series of 44 outpatients, aortic root disease and valve disease were found in 82%; thickening of the aortic valve was noted in 41% of patients, and aortic dilation in 25%.²⁴⁶ Aortic valve thickening manifested as nodularities of the aortic cusps, forming a characteristic subaortic bump.²⁴² Valve regurgitation was seen in almost half of patients, and 40% had moderate lesions.

Reiter’s syndrome is a reactive arthritis that affects the lower limbs, causing an asymmetrical oligoarthritis. To make the diagnosis, patients must have evidence of a preceding infection, diarrhea, or urethritis 4 weeks preceding the syndrome.²⁴⁷ Less than 1% of Reiter’s syndrome patients develop cardiovascular complications. Among this group, aortic insufficiency is a late finding.

Relapsing polychondritis is a paroxysmal and progressive inflammatory disease of the cartilaginous structures, affecting the ear, nose, and hyaline cartilage of the tracheobronchial tree. Cardiovascular disease, including aortic aneurysms, is found in 25% to 50% of patients.²⁴⁸

Infectious Aortic Aneurysms

Mycotic aneurysms

Also known as infective endarteritis (see Chapter 59), mycotic aneurysms are rare phenomena. Two large necropsy studies including 22,000 and 20,000 patients, respectively, revealed a combined incidence of 0.03% in the United States.^249,²⁵⁰ The average age of patients with mycotic aneurysms is 65, and men are threefold more likely to develop mycotic aneurysms than women.^251,²⁵² Hematogenous seeding, such as occurs in patients with endocarditis, affects a vessel that may be “at risk” because of preexisting atherosclerosis or previous damage and represents the most common cause of mycotic aneurysms.²⁵³ Indeed, as many as 15% of patients with endocarditis developed mycotic aneurysm before the antibiotic era.²⁵⁴ Other etiologies include septic microemboli, contiguous extension, and trauma with direct contamination. In contrast to the typical degenerative or vasculitic fusiform expansion, mycotic aneurysms are more likely to be saccular (see Fig. 37-4). The outpouching may range in size from 1 mm to 10 cm and include components of acute and chronic inflammation, hemorrhage, abscess formation, and necrosis.

Clinical manifestations of mycotic aneurysm most commonly include pain and fever and, if related to a new aneurysm, should prompt directed investigation. The organisms that most commonly cause mycotic aneurysms include Staphylococcus and Salmonella species, which cause 40% and 20% of mycotic aneurysms, respectively.^255,²⁵⁶ Surgery should be prompt, since rupture occurs in up to 80%.^257,²⁵⁸ Prognosis for cerebral vascular infection is dire, with 1-year mortality for patients who have cerebrovascular mycotic aneurysms reaching as high as 90%.²⁵⁸

Tuberculous aneurysms

Aortic aneurysm due to tuberculosis is quite rare. In a series of more than 22,000 autopsies performed at one urban medical center in the first half of the 20th century, only 1 of 308 aortic aneurysms had tuberculous aneurysms,²⁴⁹ whereas there were no tuberculous aneurysms among 20,000 autopsies performed in a rural setting.²⁵⁰ Three mechanisms have been postulated to facilitate tuberculous adhesion and endarteritis. It is thought that direct extension from a contiguous source, such as the spine or lung, may cause 75% of tuberculous aneurysms.²⁵⁹ Other possibilities include adhesion to a vessel damaged by atherosclerosis or infiltration of the inner layers of the aorta via the vasa vasorum.²⁵⁹ The abdominal and thoracic portions of the aorta are affected similarly. The presentation of the patient with a tuberculous aneurysm varies significantly. The patient may be asymptomatic, have a palpable or radiologically visible paraaortic mass, complain of chest or abdominal pain, or present with aortic rupture and hypovolemic shock. Tuberculous aneurysms that are symptomatic or rapidly expanding and pseudoaneurysms typically require surgical repair.

Syphilitic aneurysms

Although syphilis may once have been a common cause of aortic disease, antibiotics have greatly diminished the incidence of syphilitic aortic aneurysm (luetic aneurysm), such that fewer than 50 cases have been reported in the antibiotic era.²⁶⁰ Central nervous system (CNS) and cardiovascular complications denote the tertiary stage of syphilis. Classically, this arises after a latent phase of roughly 10 to 30 years from initial spirochete infection. Syphilitic aortitis may occur in up to 10% of patients with tertiary syphilis (Fig. 37-6). Destruction of the elastic lamina occurs as a consequence of lymphoplasmacytic infiltrate around the vasa vasorum, owing to direct spirochete infection of the aortic media. This ultimately leads to expansion but also fibrosis and calcification, producing the classic “tree bark” radiographic pattern. Luetic aortic aneurysms commonly involve the ascending aorta and are saccular. Involvement of the coronary ostia may result in coronary stenosis and resultant anginal symptoms. Survival with syphilitic aortic aneurysm is worse than the general population.