Regional Heterogeneity within the Aorta: Relevance to Aneurysm Disease

Abstract

Vascular remodeling within the aorta results in a loss of structural integrity with consequent aneurysm formation. This degradation is more common in the abdominal aorta, but also occurs above the diaphragm in the thoracic aorta. Conventionally, the aorta has been considered a large vascular conduit with uniform cellular and extracellular structure and function. Evidence is accumulating, however, to suggest that variations exist between the thoracic and abdominal aorta, thereby demonstrating regional heterogeneity. Further pathophysiologic studies of aortic dilation in each of these regions have identified disparities in atherosclerotic plaque deposition, vessel mechanics, protease profiles, and cell signaling pathways. Improved understanding of this spatial heterogeneity may promote evolution in the management of aneurysm disease through computational models of aortic wall stress, imaging of proteolytic activity, targeted pharmacologic treatment, and the application of region-specific gene therapy.

Introduction

Vascular remodeling within the aorta results in a loss of structural integrity with consequent aneurysm formation. This degradation is more common in the abdominal aorta, but also occurs above the diaphragm in the thoracic aorta. Conservative management of small aneurysms has included serial imaging and pharmacologic treatment of associated risk factors while surgical intervention has been withheld until the risk of rupture exceeded that of repair.¹ Despite these efforts, patients continue to suffer significant morbidity and mortality from ruptured aneurysms, therefore a great need exists for improved methods of risk stratification, prognosis prediction, and surgical decision-making.² Achieving this goal will require a fundamental understanding of aneurysm disease integrating vascular physiology, cell biology, and vessel mechanics as an adjunct to the concept of aortic regional heterogeneity. The pathophysiology of the aorta above and below the diaphragm has demonstrated disparities in atherosclerotic susceptibility, vessel mechanics, proteolytic profiles, and cell signaling pathways that have implications in the development of an aortic aneurysm. The objective of this review is to present literature describing the physical and molecular characteristics of the thoracic versus the abdominal aorta and provide evidence supporting the hypothesis that aortic regional heterogeneity exists. Additionally, we plan to delineate not only how these details influence aneurysm development, but their potential application in diverse, site-specific therapeutic strategies.

Epidemiologic Heterogeneity

Aortic aneurysms remain the 13^th most common cause of death in the United States despite advances in screening programs, imaging, and endovascular interventions.¹ Demographic studies have indicated that approximately 9% of the population greater than 65 years of age have an abdominal aortic aneurysm (AAA), but thoracic aortic aneurysms (TAAs) are far less common with a rate of 5.9 per 100,000 person-years.^{3, 4} Five-year survival for TAAs has been approximated at only 64%,¹ while a randomized prospective trial of immediate repair versus watchful waiting of AAAs has reported a survival rate of 75–80% over the 8 year study period.⁵ Men are more often effected than women in both aortic regions and shared associated risk factors also include advanced age, cigarette smoking, hypertension, chronic obstructive pulmonary disease, and coronary artery disease.^{4, 6} Aortic atherosclerotic plaque deposition, on the other hand, has been well documented in association with AAA growth without a clear cause and effect mechanism identified at this time.⁷ Although some TAAs are associated with atherosclerotic disease, many occur in the complete absence of plaque deposition.⁷ Continued investigation into disparities among patient populations may help define TAA and AAA as unique disease entities.

The genetic contribution to aneurysm disease in the thoracic and abdominal aorta has been a prominent and well-studied variation. Approximately 20% of TAAs are attributed to some form of genetic syndrome.¹ Connective tissue disorders such as Marfan Syndrome and Ehler-Danlos Syndrome type IV may effect any portion of the aorta, but preferentially cause dilation of the thoracic aorta.¹ Mutations of growth factor receptors have also been shown to predispose to TAA formation in both Loeys-Dietz Syndrome and Familial Thoracic Aortic Aneurysm and Dissection Syndrome.^{8, 9} Additionally, the common congenital anomaly of bicuspid aortic valve has been associated with TAA growth.¹⁰ In AAA, on the other hand, the genetic predisposition reported in 12–19% of AAA patients has not yet been traced to particular mutations, but coincides with a family history of a first-degree relative with aneurysm disease.¹¹ The varying contributions of genetic and environmental influences on TAA versus AAA development support the premise that the two are unique pathophysiologic entities.

Embryologic Heterogeneity

Heterogeneity between the thoracic and abdominal aortic regions begins during embryogenesis.¹² Neural crest cell precursors to the thoracic aorta and mesodermal ancestors of the abdominal aorta have demonstrated unique responses to various cytokines and growth factors. For instance, homocysteine, a nonprotein amino acid that in elevated levels conveys a predisposition for cardiovascular disease, has been shown to stimulate proliferation of neural crest derived vascular smooth muscle cells (SMCs) with no effect on mesodermal SMCs.¹³ Also, collagen precursor production is increased in neural crest, but not mesodermal, SMCs following exposure to transforming growth factor – beta (TGF-β).¹² In addition, altered DNA synthesis¹² and contractile response have been reported.¹⁴ These distinct and diverse reactions to individual stimuli, based solely upon embryologic origin, have highlighted the potential disparities in aortic wall behavior observed above and below the diaphragm, the end result of which may manifest as aneurysm disease.

Structural Heterogeneity

The aorta is a large elastic artery composed of three layers, the intima, media, and adventitia. A single layer of endothelial cells sitting upon loose connective tissue comprise the intima, while the media consists of smooth muscle cells embedded in a dense matrix of fibrillar structural proteins, and the adventitia contains fibroblasts and collagen fibers. In the thoracic as well as abdominal segments of the aorta, aneurysm formation is attributed to degradative remodeling of the medial extracellular matrix (ECM) and SMC loss,² therefore this layer of the aortic wall will be discussed in greater detail.

The aortic media provides viscoelasticity via concentric bands of elastin filaments with associated collagen fibers and SMCs, termed lamellar units.¹⁵ In the mammalian aortic media, the first 28–30 lamellar units from the luminal surface do not contain a blood supply, thereby forming an avascular zone which receives oxygen and nutrients by trans-intimal diffusion from the plasma.¹⁵ When additional units are present, vasa vasorum from the adventitia penetrate the outer media, creating a vascular zone.¹⁵ This principle remains true in humans and provides a clear distinction between the thoracic and abdominal aorta. The thoracic aorta contains 55–60 lamellar units divided into vascular and avascular zones, while the entirely avascular abdominal aortic media typically contains 28–32 units.¹⁵ Differences in oxygen, nutrient, and growth factor delivery to the cells of the thoracic and abdominal aortic media likely contribute to variations identified in vascular remodeling.

Interestingly, the media has also been shown to grow differently above and below the diaphragm. Medial thickness increases from birth to adulthood and in the thoracic aorta additional lamellar units are synthesized, whereas this expansion occurs by widening each unit of the abdominal aorta.¹⁶ The assembly of additional lamellar units may explain the increased elastin content of the thoracic aorta.¹⁷ Both of these growth mechanisms, however, maintain a constant ratio of aortic diameter to medial thickness, influencing both wall stress and tension per lamellar unit as discussed in the subsequent section.¹⁶ Aneurysm disease involves elastin fragmentation and SMC death, therefore an aortic region with fewer lamellar units, decreased elastin content, and poorer nutrient delivery to the SMCs, such as the abdominal aorta, may be at considerably increased risk of medial degeneration and aneurysm formation.

Mechanical Heterogeneity

The ultimate goal in the care of a patient with an aortic aneurysm is to prevent rupture, a material failure that occurs when the aortic wall stress exceeds the tensile strength.¹⁸ The material properties of the normal and aneurysmal aorta with regard to breaking stress and distensibility or stiffness have been an area of intense study. According to the Law of LaPlace, wall tension is influenced by intraluminal pressure, vessel diameter, and wall thickness, and the application of this tension to a defined area indicates wall stress.¹⁹ A consistent ratio of aortic diameter to medial thickness is maintained throughout all mammalian species, including the human thoracic and abdominal aorta.¹⁶ The proportional change in both aortic diameter and wall thickness observed above versus below the diaphragm, therefore, leads to uniform wall stress in the thoracic and abdominal aorta under physiologic conditions.¹⁶ As the phrase implies, the wall stress at which rupture occurs may be called the breaking stress,²⁰ and similar values for breaking stress ranging from 172 +/− 90 N/cm² to 270 +/− 150 N/cm² have been recorded in healthy thoracic and abdominal aortic regions.^{20, 21} All tissue specimens harvested from aneurysms have had reduced breaking stress, but the strength of TAA samples was roughly twice that of AAA samples (121 +/− 33 N/cm² versus 65 +/− 9 N/cm², respectively),^{18, 22} underscoring the mechanical heterogeneity of these two regions.

Additionally, the abdominal aorta has fewer lamellar units, therefore the same wall stress absorbed by the thoracic aorta is dispersed across fewer units, leading to increased wall tension per lamellar unit¹⁶ and subsequently increased tension per SMC. Many studies have demonstrated that mechanical forces can alter SMC transcriptional activity to influence matrix structure as well as cell survival.²³ This link between mechanical force and SMC synthetic activity has a potential role not only in defining the apparent increased susceptibility of the abdominal aorta, but in aneurysm initiation in general.

A change in aortic radius caused by an incremental change in pressure describes vessel distensibility, and a lack of distensibility or resistance to deformation is referred to as stiffness.^{20, 22} The reduced elastin content quantified in the abdominal aorta¹⁷ may explain the increased stiffness documented in this region at 569 +/− 138 N/cm² as opposed to 261 +/− 26 N/cm² in the thoracic aorta.^{22, 24} Additionally, studies comparing normal and aneurysmal aortic tissues have consistently demonstrated increased stiffness in both TAA and AAA specimens, potentially due to further loss of elastin fibers and accumulation of disorganized collagen.^{18, 22, 24} Continued investigation to identify heterogeneity in the material and mechanical properties of the walls of TAA versus AAA may lead to differential prognostic profiles for these disease processes.

The stiffness of the abdominal aorta and reduced breaking stress of the AAA wall has proven useful in aneurysm monitoring. The unique material characteristics of the abdominal aorta have been utilized along with patient parameters and three-dimensional imaging to formulate mathematical models of wall stress and tensile strength. Current work in AAAs has demonstrated improved ability to predict rupture as compared to the simplified Law of LaPlace and the maximal size criterion, and further application to TAAs is warranted.¹⁹ As these mathematical approximations of aortic wall stress continue to become more precise and the software progressively evolves into a marketable format, surgical intervention will rely upon serial wall stress measurements until a known high-risk tension threshold is approached. This value would likely vary by age, sex, and race in addition to aneurysm location. Further coupling of imaging techniques to quantify proteolytic activity in conjunction with wall stress could provide the surgeon with a comprehensive profile of each individual aneurysm and allow for truly patient-specific surgical decision-making.

Heterogeneity of Atherosclerotic Plaque Deposition

Atherosclerosis is a chronic, progressive disease of large elastic and muscular arteries involving lipid deposition, collagen production, and inflammatory cell infiltration,²⁵ the biochemical and molecular scope of which exceeds the focus of this review. The disease, however, effects the aorta differently above and below the diaphragm and has been closely associated with aneurysm formation, therefore the anatomic and histologic features of aortic atherosclerotic disease will be outlined to support the principle of regional heterogeneity within this vessel. The Pathological Determinants of Atherosclerosis in Youth study reported an increased incidence of atherosclerotic lesions in the abdominal aorta.²⁵ The thoracic aorta appears more resistant to plaque formation, and has demonstrated a low likelihood of fatty streak progression.²⁶ The fatty streaks identified in the abdominal aorta, on the other hand, represent early atherosclerotic lesions and have shown consistent progression to high-grade lesions over the ensuing ten years, presumably due to intimal thickening and elevated collagen production.²⁶ The preferential growth of atherosclerotic plaque in the abdominal aorta has been attributed to variations in flow and shear stress in that region.²⁵ Differing susceptibility to lipid deposition and subsequent plaque evolution also suggests disparate cellular and extracellular composition between the thoracic and abdominal aorta. Consequently, the influence of atherosclerotic plaque on aneurysmal dilation of the abdominal aorta would not be present in the thoracic aorta, supporting a separate pathophysiologic mechanism for TAA development. Further investigation into the link between atherosclerosis and aneurysm disease may concomitantly provide evidence corroborating aortic regional heterogeneity.

Heterogeneity within Proteinase Systems

The role of proteolysis in cardiovascular disease, including atherosclerosis, restenosis, thrombosis, and aneurysm formation, has been well-documented.²⁷ In particular, aneurysm formation has been attributed to lysis of elastin and collagen in the aortic media, thereby weakening the vessel wall.² The matrix metalloproteinases (MMPs), a family of major ECM remodeling enzymes, are responsible for angiogenesis, wound healing, and cardiomyopathy.²⁷ MMPs and their antagonists the tissue inhibitors of metalloproteinases (TIMPs) are instrumental in aneurysm disease.²⁷ A comprehensive understanding of the activity of these enzymes in thoracic versus abdominal aneurysm disease may define molecular diversity within the aortic wall and identify divergent pathways for novel, site-specific therapeutic interventions.

Matrix Metalloproteinases

MMPs are divided into subclasses based upon substrate specificity, such as gelatinases, elastases, and collagenases.²⁷ Members of the gelatinase subclass, MMP-2 and MMP-9, have demonstrated an ability to degrade denatured fibrillar collagen (gelatin), elastin, and native Types IV, V, and VII collagen along with other ECM components.²⁸ MMP-2, or gelatinase A, is constitutively expressed by SMCs of the aortic media and also displays interstitial collagenase capabilities, cleaving Type I collagen which comprises approximately 60% of the collagen content of the aorta.²⁸ MMP-9 is also referred to as gelatinase B and may be produced by macrophages, fibroblasts, or SMCs that have been stimulated to undergo a phenotypic switch favoring synthetic activity.²⁹ The gelatinases have been heavily studied with regard to aneurysm formation in both the thoracic and abdominal aorta.

The contribution of MMP-2 to TAAs has been difficult to define. Studies focusing upon idiopathic TAAs have failed to show an increase in MMP-2 compared to normal aorta.³⁰ TAAs associated with atherosclerosis, on the other hand, have demonstrated increased MMP-2 activity.³¹ Different biochemical tests were used to quantify MMP-2 mRNA versus active protease levels versus latent protease levels, making comparisons between studies difficult. Also, increasing age alone has been associated with elevated MMP-2 levels in the thoracic aorta, therefore the use of age-matched controls may have obscured the impact of MMP-2 on TAAs.³² A murine model of TAA development has reported elevations in MMP-2 as early as 72 hours after aneurysm induction with return to baseline by 2 weeks,³³ suggesting a role for MMP-2 in early TAA growth that perhaps has not been captured in human tissue samples harvested at the time of aneurysm repair.

In AAAs the data is more definitive that MMP-2 is instrumental to aneurysm development. Tissue samples harvested at the time of aneurysm repair have consistently shown increased MMP-2 expression and activity due to amplified production by native SMCs.^{34, 35} More interestingly, Freestone et al., demonstrated that aneurysms less than 5.5 cm had greater MMP-2 activity than larger aneurysms and proposed that early AAA growth is directed by MMP-2.³⁵ The vital role of MMP-2 in AAA formation has been corroborated in a murine model of AAA where aneurysms could not be induced in MMP-2 knock-out mice.³⁶

The observation that elevated MMP-2 activity is required for AAA growth, but may or may not influence TAA development represents an emerging concept in aortic heterogeneity. The differential contribution of this proteinase to aneurysm disease appears to vary above and below the diaphragm as well as within the thoracic aorta. Differences in MMP-2 levels have been reported in ascending versus descending TAAs, a finding which strengthens the argument for regional heterogeneity in aortic MMP production, but has not been sufficiently explored to draw any firm conclusions. Additionally, variations in TAA MMP-2 levels have been related to sample location since most specimens are harvested from the anterior wall, but evidence has suggested that greater MMP-2 levels can be measured in the posterior wall of the TAA.³⁰ The inflammatory infiltrate accompanying atherosclerotic plaque deposition may increase MMP-2 transcriptional activity in AAAs and atherosclerotic TAAs.³¹ Non-atherosclerotic TAAs, on the other hand, seem to be driven by different forces and their effect on thoracic aorta SMC gene expression does not include upregulation of MMP-2 production, supporting the premise that multiple pathophysiologic pathways can lead to aneurysm formation.

In contrast to MMP-2, MMP-9 has demonstrated a key role in TAA disease. Elevated MMP-9 levels have been reported in TAAs both with and without associated atherosclerosis.³¹ Murine TAA models have demonstrated attenuated aneurysm growth in MMP-9 knock-out mice at four weeks post-induction, and MMP-9 abundance in wild-type mice beginning 2 weeks post-induction.^{33, 37} MMP-9 levels remained elevated throughout aneurysm growth.^{33, 37} Interestingly, immunohistochemical staining has localized MMP-9 to mesenchymal cells of the aortic media and adventitia, specifically fibroblasts, myofibroblasts, and SMCs that have undergone a phenotypic switch from purely contractile to synthetically active.³⁷ In the healthy aorta these cells do not produce MMP-9, and such a shift in transcriptional activity has previously been attributed to alterations in cell-cell and cell-matrix interactions,²⁹ suggesting that ECM remodeling may precede and actually help initiate MMP-9 production in the TAA.

MMP-9 is considered the primary elastolytic enzyme within the AAA wall and is credited with accelerated aneurysm progression. Markedly elevated levels of MMP-9 have been consistently documented in AAA tissue and attributed to macrophages infiltrating the aortic media and adventitia.^{36, 38} Trends in MMP-9 expression have also been identified with regard to aneurysm size such that aneurysms between 5 and 7 cm in diameter have more MMP-9 than those either larger or smaller.³⁹ This evidence suggests a role for MMP-9 in aneurysm progression, perhaps to a point where additional proteases or hemodynamic factors become the driving force in AAA growth and rupture.³⁹ The importance of MMP-9 in AAA development has been further supported in a murine model where aneurysm induction was inhibited in MMP-9 knock-out mice.³⁶ Confirmation of the macrophage as the primary source of MMP-9 in AAA was achieved when MMP-9 knock-out mice were infused with wild-type macrophages and subsequent restoration of AAA growth was documented.³⁶

The different cellular sources of MMP-9 in TAA versus AAA have substantiated a major point in the argument favoring aortic regional heterogeneity with regard to aneurysm disease. A hypothesis of AAA formation can be constructed from the prevalence of atherosclerotic plaque leading to macrophage infiltration with consequent MMP-9 production and surrounding matrix degradation. In contrast, MMP-9 expression by native mesenchymal cells of the TAA and the low incidence of inflammatory infiltrate suggests that additional forces are acting in the thoracic aorta.

Tissue Inhibitors of Metalloproteinases

In addition to regulating MMP production and activity, factors stimulating aortic medial degeneration also effect the expression of TIMPs, the primary endogenous antagonists of MMPs. Aortic SMCs constitutively express TIMP-1 and TIMP-2, and TIMP-1 has been demonstrated to inhibit most MMPs, especially MMP-9,²⁷ but the function of TIMP-2 is more complex. Although it can inhibit MMP-2 and MMP-9, TIMP-2 is also a component of the MMP-2 activation complex.⁴⁰ The specific relationship between TIMPs and aneurysm disease has not yet been defined, but variability between TAA and AAA has become apparent.

The interplay of MMPs and TIMPs directs ECM turnover in normal, healthy tissues and the degradation associated with aneurysm growth in any location can be expected to stem from an alteration favoring proteolysis. More specifically, the ratio of MMP-9 to TIMP-1 has been used to estimate the proteolytic index of the ECM.³⁸ In TAAs, TIMP-1 levels have been decreased or unchanged from healthy aortic tissue, therefore, coupled with the elevated MMP-9 levels, a large shift in the proteolytic state favoring ECM degeneration has been noted.^{31, 41} AAA tissue samples, on the other hand, have demonstrated elevated levels of TIMP-1 compared to control aortic specimens.³⁸ Despite this amplified TIMP-1 production, the MMP-9/TIMP-1 ratio has favored proteolysis in AAAs because MMP-9 levels have been elevated to a much greater extent.³⁸ The differential role of TIMP-1 in this proteolytic shift supports the concept of disparate stimuli and mechanisms for aortic dilation in the thoracic and abdominal aorta.

The contribution of TIMP-2 to aneurysm development has been obscured by its dual role in activating as well as inhibiting MMP-2.⁴⁰ Additionally, no consistent trend in TIMP-2 expression has been identified in either TAA or AAA samples, further complicating the issue.^{31, 38, 41} This variability may be largely attributed to the assorted biochemical techniques utilized to quantify TIMP-2 expression, abundance, or activity in each report. A few studies have evaluated a second proteolytic index defined as the ratio of MMP-2 to TIMP-2.^{31, 34, 38} In TAA specimens, an increase in the MMP-2/TIMP-2 ratio has been observed,³¹ while that of AAA samples has remained unchanged from control aortic tissue.³⁸ Pertaining to TIMP-2, therefore, the SMC transcriptional response to aneurysm initiating stimuli has appeared to differ in the thoracic and abdominal aorta, potentially due to alternate etiologic factors, cell signaling, or proteolytic substrates.

Ideally, the identification and definition of proteolytic variations between the TAA and AAA will allow site-specific, minimally invasive interventions directed at slowing or halting aneurysm growth. General MMP inhibition is currently being explored,²⁷ but the utilization of gene therapy via systemic introduction or regional placement with endostents to preferentially effect particular MMPs may narrow the potential side effect profile. For instance, targeting MMP-2 activity in small AAAs versus MMP-9 in advanced disease may be a useful stratification. In TAAs, on the other hand, MMP-9 inhibition could be beneficial despite the degree of aortic dilation. More importantly, methods of quantifying MMP or TIMP activity may prove useful in surgical planning. Technitium-tagged small molecules that preferentially enter the vascular media and bind MMPs may be coupled with nuclear imaging to identify patients with elevated proteolytic activity, signifying a propensity for rapid expansion and rupture. These patients may warrant urgent repair despite their current aneurysm diameter. As mentioned earlier, the combination of computational stress analysis and proteolytic imaging may revolutionize aneurysm management.

Heterogeneity in Intercellular Signaling Pathways

Many investigators have focused upon characterizing the protease systems responsible for aortic medial degeneration, while the signaling pathways initiating protease production remain poorly understood. The regulation of aortic SMC gene expression through cytokines and growth factors has been suspected to be a major contributor to aneurysm growth.² Cytokines are intercellular mediators which direct the immune response to various stimuli, and a subfamily of cytokines, the chemokines, specifically act as potent chemoattractants and activators of leukocytes. The peptide growth factor TGF-β encompasses a large family of messengers implicated in numerous cellular pathways including angiogenesis, apoptosis, and tissue fibrosis.⁴² This growth factor can also maintain normal blood vessel morphology through stimulation of ECM production and inhibition of inflammatory mediators.⁴² Although not fully explored, current evidence suggests that the signaling pathways driven by cytokines and TGF-β differentially impact aneurysm growth in the thoracic and abdominal aorta.

Immune Mediators

The presence and nature of the aneurysm wall inflammatory infiltrate may be considered a major defining factor in the argument favoring regional aortic heterogeneity. Certain cytokines, such as tumor necrosis factor- alpha, interleukin-1 beta, and interleukin-6, have been universally elevated in both TAA and AAA tissue samples,^{43, 44} presumably related to previous evidence that these cytokines augment MMP expression.⁴⁵ The inflammatory infiltrate described in the media and adventitia of aneurysm walls has been dominated by CD4+ T-helper lymphocytes and macrophages.⁴⁴ These lymphocytes may produce a pro-inflammatory or anti-inflammatory cytokine profile, classifying themselves as Th1 or Th2 cells, respectively, and whether one subgroup preferentially drives medial degeneration has important implications. In a TAA, the presence of an inflammatory infiltrate has been a controversial issue. One particularly influential study examining TAA tissue described categories of infiltrated versus non-infiltrated aneurysms, and further reported a Th1 driven immune response.⁴⁶ The elevated levels of interferon-gamma correlated with aneurysm diameter, intimal thickness, and elastin fragmentation.⁴⁶ AAA specimens have demonstrated increased expression of many pro- and anti-inflammatory cytokines and studies aimed at defining the lymphocytic infiltrate as predominantly Th1 or Th2 have found evidence of both.^{47, 48} Collectively, the data on immunologic mediators has suggested that the initiation and growth of an infiltrated TAA is driven by pro-inflammatory cytokines, while AAA development involves a complex interaction between opposing immunologic pathways, ultimately supporting heterogeneity in the pathophysiology of aortic aneurysm formation.

TGF-β

Alterations in TGF-β expression, activation, or receptor activity may provide pathways toward aortic wall degeneration. TGF-β is associated with the ECM microfibrils in the thoracic as well as abdominal aorta and the concentration of this ligand has demonstrated tight regulation.⁴⁹ A murine model of Marfan Syndrome has described increased biologically active TGF-β in these animals and a correlation to TAA growth.⁴⁹ Additionally, TGF-β receptor mutations have been identified as the cause of the Familial Thoracic Aortic Aneurysm and Dissection and Loeys-Dietz Syndromes where currently unidentified mechanisms have allowed enhanced TGF-β signaling and TAA formation.^{8, 9} In the abdominal aorta, the opposite may be true. Evidence has suggested that enzymatic activity of MMP-2 and MMP-9 release TGF-β,⁴⁹ whose overexpression can then decrease gelatinase and increase TIMP production, potentially attenuating aneurysm development.⁵⁰ Though not fully characterized, the role of TGF-β in TAA versus AAA has demonstrated divergence, likely due to the disparate embryologic origins of the thoracic and abdominal aorta discussed earlier, and represent yet another example of heterogeneity in aneurysm disease.

Modification of upstream signaling pathways may represent a viable approach to disrupting aneurysm growth. AAAs appear to be influenced by both pro- and anti-inflammatory mediators, while a subset of TAAs are driven solely by cytokines released from Th1 type lymphocytes. Additionally, TGF-β over-expression in AAAs and inhibition in TAAs may halt aneurysm progression. Systemic upregulation or blockade of these messengers would likely be detrimental to a patient’s overall health, therefore the utilization of directed gene therapy or regional application would be required. A rodent AAA model underwent endostent-delivered gene therapy with TGF-β and demonstrated a halt in aneurysm growth.⁵⁰ Similarly delivered blockade of interferon-gamma in infiltrated TAAs may also have the potential to alter the extracellular milieu and stabilize the aortic wall. Further defining the molecular variances among TAA and AAA could aide the development of target-specific and region-specific minimally invasive aneurysm therapy.

Conclusions

An array of genetic, anatomic, biochemical, and mechanical factors have been recognized as contributors to aortic aneurysm disease, and a comprehensive model incorporating all these forces has yet to emerge. The hypothesis that heterogeneity exists within the aorta further complicates the study of this disease process. Variations among vessel mechanics, atherosclerotic plaque deposition, protease profiles, and cell signaling pathways have been identified (Table 1). This review has sought to define and explore disparate properties in the thoracic and abdominal aortic segments as they pertain to aneurysm development (Figure 1) and furthermore to suggest how these variations may be exploited to advance current management of aortic aneurysm disease. Additional research into these regional distinctions is expected to uncover novel dynamic imaging and therapeutic options.

Table 1.

Summary of heterogeneity between thoracic and abdominal aorta.

Variable	Thoracic Aorta	Abdominal Aorta	References
Epidemiology	Rare aneurysm site 20% caused by genetic syndromes	Most common aneurysm site 20% have familial predisposition	1–11
Embryology	Derived from neural crest	Derived from mesoderm	12–14
Structure	Vascular outer media More numerous lamellar units Grows by synthesizing additional lamellar units Greater elastin & collagen content	Avascular medial layer Fewer lamellar units Grows by increasing lamellar unit thickness Lower elastin & collagen content	15–17
Mechanics	Greater distensibility TAA breaking stress greater than AAA	Increased stiffness AAA breaking stress lower than TAA Increased tension per lamellar unit	18–24
Atherosclerosis	Low likelihood of lesion progression from fatty streak to atheroma	Site of most severe atherosclerosis High likelihood of lesion progression from fatty streak to atheroma	25–26
Matrix Metalloproteinases (MMPs)	Inconsistent role for MMP-2 MMP-9 produced by synthetically active SMCs and fibroblasts Lack of MMP-9 attenuated aneurysm development	Early aneurysm growth driven by MMP-2 MMP-9 produced by macrophages MMP-9 proportional to aneurysm diameter Lack of MMP-9 prevented aneurysm development	27–39
Tissue Inhibitors of Metalloproteinases (TIMPs)	No change or decreased TIMP-1 MMP-2/TIMP-2 ratio elevated	Elevated TIMP-1 MMP-2/TIMP-2 ratio unchanged	27–41
Immune Mediators	Th1 type immune response in infiltrated aneurysms	Evidence of both pro- and anti-inflammatory cytokines	43–48
TGF-β Response	Increased signaling contributes to aneurysm disease	Overexpression attenuated proteolytic state	49–50

Figure 1.

Pertinent disparities between the thoracic and abdominal aorta.

Abbreviations

AAA

abdominal aortic aneurysm

TAA

thoracic aortic aneurysm

SMC

smooth muscle cells

TGF-β

transforming growth factor – beta

ECM

extracellular matrix

MMP

matrix metalloproteinase

TIMP

tissue inhibitor of metalloproteinase

Th1 lymphocyte

T-helper lymphocyte type-1

Th2 lymphocyte

T-helper lymphocyte type-2