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Asian Cardiovasc Thorac Ann 2006;14:254-260
© 2006 Asia Publishing EXchange Ltd

REVIEW PAPER

Pathobiology of Idiopathic Ascending Aortic Aneurysms

EW Matthias Kirsch, MD, N Costin Radu, MD, Eric Allaire, MD, Daniel Y Loisance, MD

Department of Cardiothoracic Surgery, Hospital Henri Mondor, Créteil Cedex, France

For reprint information contact: EW Matthias Kirsch, MD Tel: 33 1 4981 2172 Fax: 33 1 4981 2152 email: matthias.kirsch{at}hmn.aphp.fr, Department of Cardiothoracic Surgery, Hospital Henri Mondor, 51 Avenue Mal de Lattre de Tassigny, Créteil Cedex 94 000, France.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 DESTRUCTIVE REMODELING OF THE...
 INFLAMMATION AND ANGIOGENESIS
 CONCLUSION
 REFERENCES
 
The majority of ascending aortic aneurysms cannot be related to any specific etiology and should be qualified as idiopathic. The pathobiology of ascending aortic aneurysms remains incompletely understood. Data from direct study are still scarce and often limited because of patient heterogenicity. Currently available information suggests that destructive remodeling of the aortic wall, inflammation and angiogenesis, biomechanical wall stress, and molecular genetics are relevant mechanisms of idiopathic ascending aortic aneurysm formation and progression. Further understanding of these mechanisms will likely provide novel diagnostic, prognostic, and therapeutical tools for the clinician.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
DESTRUCTIVE REMODELING OF THE...
 INFLAMMATION AND ANGIOGENESIS
 CONCLUSION
 REFERENCES
 
Thoracic aortic aneurysms may involve one or more aortic segments. They expose patients to life-threatening complications and represent a significant clinical challenge to the cardiothoracic surgeon. Sixty percent of thoracic aortic aneurysms involve the ascending aorta.1 In this location, they present unique physiopathological features related to the anatomical and functional complexity of the ascending aorta. The proximal portion of the ascending aorta is known as the aortic root, and can be defined as the portion of the left ventricular outflow tract which supports the aortic valve leaflets and is delineated by the bases of the valve leaflets inferiorly and the sinotubular ridge superiorly.2,3 It comprises the aortic valve leaflets and their commissures, the sinuses of Valsalva with the origin of the coronary arteries, and the interleaflet triangles. The distal part of the ascending aorta, or tubular portion, extends from the sinotubular ridge to the origin of the innominate artery.

The ascending aorta has several critically important functions.4 The aortic root complex ensures unidirectional transmission of variable volumes of blood pumped intermittently by the left ventricle, and allows adequate coronary perfusion during the cardiac cycle.4,5 Furthermore, the ascending aorta acts as an elastic buffering chamber behind the heart (Windkessel function).6 The aorta expands during left ventricular systole, storing approximately 50% of the left ventricular stroke volume. During diastole, the aorta recoils and forwards the stored blood volume into the peripheral circulation. Thus, blood flow and systemic pressure are maintained throughout the cardiac cycle. The achievement of these functions and their maintenance during a lifetime relies on the structural integrity of the highly specialized structures of the ascending aorta. The development of aneurysm will obviously interfere with these functions.

Many disorders and syndromes have been associated with ascending aortic aneurysm. The primary causes have been classified as hereditary, congenital, degenerative, mechanical, inflammatory, and infectious.7 Although precise epidemiological data is lacking, it appears that in the majority of patients, the aneurysm cannot be related to any specific etiology and should thus be referred to as idiopathic ascending aortic aneurysm. However, this frustrating situation has led to the flourishing of various denominations (sometimes based on morphological or histological characteristics) and their misuse as nosological entities. Most of our knowledge of the pathobiology of aortic aneurysms is derived from studies on abdominal aortic aneurysms.8–10 However, extrapolation of these findings to the thoracic aorta, and more particularly to the ascending aorta, is incorrect because of significant anatomical, histological, and functional differences. The normal aortic wall is composed of three concentric layers: the intima, media, and adventitia. The media of the ascending aorta has the typical lamellar structure common to elastic arteries. During development, the increase in medial thickness is mainly related to an increase in the number of lamellar units (from 35 to 56), whereas there is only a minor increase in their thickness (from 12 to 17 µm). In contrast, medial growth in the abdominal aorta is associated with an increase in thickness of the lamellar units (from 12 to 26 µm) secondary to smooth muscle cell proliferation, while there is only a minimal increase in their number (from 25 to 28). Consequently, the tension exerted on individual lamellar units in adults is greater in the abdominal than in the thoracic aorta.11 Furthermore, the relative amount of elastic tissue decreases from the thoracic to the abdominal aorta.10 These differences are believed to make the thoracic aorta less prone to aneurysm formation than the abdominal aorta. Most of the research on ascending aortic aneurysms has focused on those caused by hereditary connective tissue disorders, and more recently, on those associated with bicuspid aortic valve (BAV).12,13 However, the cellular and molecular mechanisms involved in the formation and progression of idiopathic ascending aortic aneurysms remain unclear. A recent National Heart, Lung, and Blood Institute request for applications entitled "Pathogenesis of Abdominal Aortic Aneurysm" identified four mechanisms relevant to abdominal aortic aneurysm formation: proteolytic degradation of aortic wall connective tissue, inflammation and immune responses, biomechanical wall stress, and molecular genetics.14 We will adopt a similar approach to present the current knowledge of the pathogenesis and pathobiology of idiopathic ascending aortic aneurysms.


   DESTRUCTIVE REMODELING OF THE AORTIC WALL
TOP
 ABSTRACT
 INTRODUCTION
 DESTRUCTIVE REMODELING OF THE...
INFLAMMATION AND ANGIOGENESIS
 CONCLUSION
 REFERENCES
 
HISTOLOGY
Histologically, idiopathic ascending aortic aneurysms are characterized by fragmentation of the elastic fibers, an increase of collagen fibers, loss of smooth muscle cells, and replacement of degenerated tissue with interstitial pools of basophilic mucopolysaccharide material inadequately termed "cysts".15,16 However, similar observations have been made in the aging but non-dilated thoracic aorta.11 Therefore, none of these histological changes can be regarded as a specific structural alteration responsible for aneurysm formation. Nevertheless, semiquantitative histological analysis has shown that these medial alterations are significantly more pronounced in aneurysmal than in non-dilated aortic wall specimens.16 On the other hand, no significant differences were observed between specimens taken from patients with idiopathic ascending aortic aneurysm and those with Marfan syndrome.15,16 Comparison of idiopathic with BAV-associated ascending aortic aneurysms has yielded conflicting results: investigators have reported more severe or less severe degenerative changes upon semiquantitative analysis.17–19 Others have observed thinner elastic lamellae with greater distances between them in patients with BAV-related ascending aortic aneurysm.20

EXTRACELLULAR MATRIX DEGRADATION
Numerous experimental data and studies of human abdominal aortic aneurysms have provided evidence that the alterations observed in the aortic media can be related, at least in part, to connective tissue destruction by proteolytic digestion.21,22 The best studied group of such enzymes are the matrix metalloproteinases (MMPs). Under physiological conditions, the activities of MMPs are precisely regulated at the level of gene expression, activation of pro-enzyme forms of MMPs, and inhibition by specific endogenous inhibitors (TIMPs). An imbalance between MMP activation and inhibition has been suggested as a potential mechanism for abdominal aortic aneurysms formation.21 In contrast, only a few studies have evaluated the presence of MMPs and their TIMPs in idiopathic ascending aortic aneurysm. Lesauskaite and colleagues23 reported significantly increased levels of MMP-1, MMP-2, MMP-9, and of TIMP-1 and TIMP-2 in fragments of ascending aorta taken from patients with idiopathic ascending aortic aneurysm, aortic dissection, or aortic valve disease, compared to controls. No significant differences in expression among the different pathologic groups were observed, except for MMP-2 which was more abundant in specimens from the aortic dissection and valvular groups. However, this study was limited by heterogenicity within the patient groups and a semiquantitative scaling of MMP expression. Using a tissue microarray technique, Koullias and colleagues24 recently reported significantly higher levels of MMP-1 and MMP-9 in non-dissecting thoracic aortic aneurysm in a series of 30 patients. In contrast, MMP-2 levels were not significantly different from those observed in control specimens. Similarly, tissue levels of TIMP-1 and TIMP-2 were not significantly different from those in control specimens. However, the ratio of MMP-9 to TIMP-1 was significantly increased, suggesting a shift towards a proteolytic state in idiopathic ascending aortic aneurysm. Similar results have been provided by LeMaire and colleagues25 who observed significantly increased levels of MMP-9 but no differences in MMP-2, TIMP-1, TIMP-2 in 15 patients with non-bicuspid ascending aortic aneurysms compared to control specimens. These findings suggest a similarity with abdominal aortic aneurysms in which MMP-9 also appears to be a major player among MMPs.26 Several groups have compared MMP expression in BAV-associated and idiopathic ascending aortic aneurysms. MMP-9 expression in BAV-associated ascending aortic aneurysm was lower, similar, or greater than in idiopathic ascending aortic aneurysm, whereas MMP-2 expression appeared to be higher in BAV-associated ascending aortic aneurysms.25,27,28

SMOOTH MUSCLE CELL LOSS
Aortic wall thinning and medial smooth muscle cell (SMC) loss is a common finding in aortic wall specimens taken from patients with idiopathic ascending aortic aneurysm.15,16,18,29,30 Schmid and colleagues18 observed a 25% decrease in nuclei per unit area in idiopathic ascending aortic aneurysm compared to normal aorta. In comparison, the same authors noted a 32% decrease in tissue taken from BAV-associated ascending aortic aneurysm.18 One hypothesis is that such a decrease in the number of SMCs is the consequence of programmed cell death or apoptosis. Using different techniques such as in situ end-labeling of DNA fragments, DNA fragmentation analysis, and electron microscopy, several groups have confirmed that a significantly higher number of medial SMCs express markers of apoptosis in aortic specimens taken from idiopathic ascending aortic aneurysm compared to normal aorta.18,30,31 Ihling and colleagues31 reported significantly higher numbers of medial SMCs with nuclear p53 accumulation (a potential mediator of cell cycle arrest), increased cytoplasmic Bcl2 associated protein X (Bax) expression (which counteracts the anti-apoptotic effects of several members of the Bcl2 protein family), and increased signs of apoptosis in a group of patients with aortic dissection compared to those with a normal aorta. Apoptosis can be initiated by activation of death receptors such as Fas (CD95).32 Increased expression of Fas has been evidenced in SMCs and leukocytes in aortic specimens taken from patients with idiopathic ascending aortic aneurysm, while there was no Fas antigen expression in normal aortic tissue.18 Similarly, increased perforin expression was noted in specimens of idiopathic or BAV-associated ascending aortic aneurysms, whereas none was expressed in normal aorta.18 Tissular colocalization of apoptotic SMCs, death-promoting mediators, and inflammatory infiltrates suggests that inflammatory cells might trigger apoptosis through Fas ligand production.18 As SMCs are the principal elastin- and collagen-producing cells within the aortic wall, their depletion would impair local connective tissue repair potential.


   INFLAMMATION AND ANGIOGENESIS
TOP
 ABSTRACT
 INTRODUCTION
 DESTRUCTIVE REMODELING OF THE...
 INFLAMMATION AND ANGIOGENESIS
CONCLUSION
 REFERENCES
 
INFLAMMATION
A striking feature of abdominal aortic aneurysms is extensive transmural infiltration by macrophages and lymphocytes. This cellular infiltrate is thought to initiate aortic wall destruction through the release of several cytokines and proteinases. In contrast, inflammatory cell infiltration appears to be an inconstant feature of idiopathic ascending aortic aneurysm. Thus, Schmid and colleagues18,30 reported clear evidence of macrophage, T lymphocyte, and to a minor extent, B lymphocyte and natural killer cell infiltration. Similarly, Ejiri and colleagues29 observed extensive infiltration of mononuclear cells in the adventitia and external layer of the media in some cases of thoracic aortic aneurysm. On the other hand, Lesauskaite and colleagues23 found no signs of inflammation in the media of idiopathic ascending aortic aneurysms. They specify that sparse inflammatory cells were detected in the adventitia in some cases.23 Similarly, Ihling and colleagues31 noted the absence of signs of inflammation in all 20 aortic specimens harvested from patients with aortic dissection. The discrepancy between these studies might be related to heterogenicity of the patient groups. Indeed, LeMaire and colleagues25 documented no significant inflammatory infiltrate in aortic wall specimens taken from patients with BAV-associated ascending aortic aneurysm, whereas they observed extensive macrophage and lymphocyte infiltration in the aortas of patients with idiopathic ascending aortic aneurysm. Furthermore, the harvesting site of the aortic specimen might be of importance. Most studies were performed on specimens taken at the site of maximal dilatation of the aneurysm. We observed increased macrophage infiltration in specimens taken from the distal leading edge of idiopathic ascending aortic aneurysms compared with those taken at the site of maximal dilatation. Thus, at least in some cases, the presence of inflammatory cells and their potential for extracellular matrix destruction and smooth muscle cell apoptosis contributes to the formation and progression of idiopathic ascending aortic aneurysm. However, the initial trigger for inflammatory cell recruitment remains elusive.

ANGIOGENESIS
Chronic inflammation is frequently accompanied by an angiogenic response.33 Several groups have observed that abdominal aortic aneurysms are associated with increased neovessel formation compared with normal aorta.34–36 Interestingly, the degree of neovascularization correlated with the extent of the inflammatory infiltrate and vascular endothelial growth factor expression.34,36 We recently observed the existence of neovessels in the media and adventitia of aortic specimens harvested during elective surgery in patients with idiopathic ascending aortic aneurysm. As in abdominal aortic aneurysms, neovessels were associated with inflammatory cells (Figure 1Go). More specifically, the density of CD68-positive macrophages was significantly higher in the immediate vicinity of neovessels than at a greater distance. This close colocalization strongly suggests that macrophages are involved in angiogenesis in the setting of idiopathic ascending aortic aneurysm (Figure 2Go). Indeed, activated macrophages are known to produce several growth factors that induce endothelial cell migration and/or proliferation (basic fibroblast growth factor, transforming growth factor-{alpha}, vascular endothelial growth factor).33 Furthermore, as stated previously, macrophages also release and activate MMPs and serine proteases, both of which are implicated in endothelial cell migration during angiogenesis. We also found that the density of neovessels and macrophages was significantly higher at the distal leading edge of the aneurysm than at the level of its maximal dilatation. This finding suggests that angiogenesis may be an important event in the early stages of aneurysm formation, and that its inhibition might be of therapeutic interest.


Figure 1
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  		Figure 1. Light micrographs showing the media of an idiopathic ascending aortic aneurysm (56 mm in diameter) with immunohistochemical detection of macrophages using antibody to CD68 membrane receptor. Note several small thin-walled vessels within the vascular media surrounded by inflammatory infiltrate and containing CD68-positive cells. (A) Original magnification x 20. (B) original magnification x 40.

 

Figure 2
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  		Figure 2. Light micrographs showing the media of an idiopathic ascending aortic aneurysm (57 mm in diameter) with immunohistochemical detection of endothelial cells using antibody to CD31 membrane receptor and orcein staining to demonstrate elastic fibers. Note the close colocalization of medial neovessels, inflammatory cell infiltrate, and elastic fiber destruction. (A) Original magnification x 10. (B) original magnification x 20.

 
BIOMECHANICAL FACTORS
Chronically altered mechanical forces usually instigate important adaptive alterations of vessel wall shape and composition.37 Considering the functional complexity of the ascending aorta, several hemodynamic factors might contribute to the development of idiopathic ascending aortic aneurysm.

AORTIC ROOT ASYMMTERY
The longitudinal axis of the left ventricle and the aortic root form an angle of 140° to 150°, responsible for a deviation of the blood stream of 30° to 40° toward the convexity of the ascending aorta.38 Thus, blood flow at the level of the aortic root is asymmetric, showing highest flow velocities along the noncoronary leaflet with a counter-clockwise rotation of 90° between commissures during systole.38 These asymmetric flow characteristics result in different regional aortic wall stresses, as shown by Grande and colleagues39 in a finite-element model of the aortic root. These investigators have shown that right and noncoronary sinus stresses were respectively 21% and 10% greater than in the left sinus.39 These findings might explain the consistent geometric pattern observed in human aortic roots: the noncoronary sinus is the largest, followed by the right, and then the left.40 Similarly, aortic root aneurysms have a well-known tendency to develop towards the convexity.41 Finally, studies from Naples have shown that medial degeneration in idiopathic ascending aortic aneurysm is more severe in the right posterolateral wall area, very likely in response to the hemodynamic stress asymmetry.42,43

AORTIC ROOT DILATATION
According to Laplace’s law, wall stress is directly related to the radius and intravascular pressure, and inversely to wall thickness. Thus, once an aneurysm has developed, it is likely that increased wall stress is an important contributor to accelerating dilation and increasing the risk of rupture. Recently, using patient-specific data in a cylindrical model of the aorta, Okamoto and colleagues44 confirmed that mean circumferential wall stress increases linearly with aortic diameter. Furthermore, the initial size of aortic aneurysms has been shown to influence expansion rates of thoracic aneurysms.45,46 Finally, a direct correlation between the severity of medial degeneration (quantified according to the Schlatmann and Becker classification into 3 degrees) and the aortic diameter at the site of dilatation has been reported.47

AORTIC VALVE-AORTIC ROOT INTERACTION: THE VICIOUS CYCLE
The aortic root has to be considered as one functional unit. Alteration of one of its components will have important consequences on the function of the aortic root as a whole.

Thus, optimal aortic valve function (opening and closing) closely relies on aortic root morphology (sinuses of Valsalva and sinotubular junction) and the elastic properties of its components.48,49 Modification of the elastic properties of the sinuses of Valsalva results in increased stress on the aortic valve leaflets with accelerated fibrosis.48,50 Alternatively, aortic root dilatation will result in an outward deviation of the aortic valve commissures with resultant regurgitation.51 Conversely, primary or secondary aortic valve dysfunction resulting in significant stenosis or regurgitation will obviously lead to disturbed aortic blood flow patterns, eventually contributing to the development or enhancement of aortic wall disease.52

Aortic valve stenosis results in reduced left ventricular stroke volume and turbulent post-stenotic flow. Irace and colleagues53 have shown that patients with aortic valve stenosis have lower wall shear stress at the level of the common carotid artery compared to age-matched controls. The difference was accounted for by lower blood viscosity and lower blood flow velocity. Conversely, a significant reduction of the intima-media thickness of the common carotid artery was observed after prosthetic aortic valve replacement in patients with aortic valve stenosis. This reverse remodeling process has been related to the increased wall shear stress observed after correction of the left ventricular outflow obstruction.53 In patients with aortic stenosis (aortic valve area < 2.0 cm2), the aortic root has been noted to be significantly larger at the level of the sinotubular junction than that measured in normal subjects or patients with aortic sclerosis but without stenosis.54 However, the aortic root diameters did not differ among patients with different severity of aortic stenosis (mild, moderate, or severe).54 Thus, aortic root dilatation might be an early adaptive response to decreased proximal aortic stroke volume, which does not progress subsequently. In contrast to stenosis, aortic valve regurgitation is associated with increased left ventricular stroke volume. The latter has been shown to result in increased longitudinal displacement of the aortic root during the cardiac cycle.55 Finite element modelling has provided evidence that patients with aortic valve regurgitation are likely to have enhanced longitudinal stress in the ascending aorta due to increased aortic root motion.56 The area where the most significant increased longitudinal stress was noted was approximately 2 cm above the sinotubular junction.56

MOLECULAR GENETICS
Studies are just beginning to elucidate the genes that predispose to aortic diseases.57 Familial aggregation studies have been performed to determine whether undisclosed genetic factors may contribute to the development of thoracic aortic aneurysms in patients without any of the known genetic syndromes.58,59 Coady and colleagues59 reported that at least 19% of patients undergoing surgery for thoracic aortic aneurysms with or without concomitant dissection had a family history of thoracic aortic aneurysm. Patients with familial non-syndromic thoracic aortic aneurysm were significantly younger and experienced significantly faster growth rates than patients with sporadic aneurysms. Most pedigrees suggest an autosomal-dominant mode of inheritance with marked variability in the expression and penetrance of the disorder.1 Mutations of the fibrillin-1 gene have been identified in two patients without Marfan syndrome.60 Several other mutations have been identified (including mutations on 3p24–25, 5q13–14, and 11q23.2–24).61–63 However, the defective genes have not yet been identified.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 DESTRUCTIVE REMODELING OF THE...
 INFLAMMATION AND ANGIOGENESIS
 CONCLUSION
REFERENCES
 
Thus, several mechanisms including destructive remodeling of the aortic wall, inflammation and angiogenesis, biomechanical wall stress and molecular genetics appear to be implicated in the pathobiology of IAAAs. However, the initial triggering event that leads to subsequent IAAA formation remains to be determined. Further understanding of these mechanisms and their interrelationship is warranted in order to develop therapeutic tools for the clinician.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 DESTRUCTIVE REMODELING OF THE...
 INFLAMMATION AND ANGIOGENESIS
 CONCLUSION
 REFERENCES
 

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