Reflections on the pathogenesis of abdominal aortic aneurysms

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Cardiovascular Surgery, Vol. 10, No. 4, pp. 389–394, 2002  2002 The International Society for Cardiovascular Surgery Published by Elsevier Science Ltd. All rights reserved 0967-2109/02 $22.00

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Reflections on the pathogenesis of abdominal aortic aneurysms Robert W. Thompson Departments of Surgery (Section of Vascular Surgery), Radiology, and Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, Missouri, MO 63110, USA

Introduction The care of patients with abdominal aortic aneurysms (AAAs) has served as a benchmark of progress in vascular surgery for more than 50 years. Beginning with the introduction of definitive surgical repair by Dubost et al. [1], the last half of the 20th century was marked by steady improvements in operative technique and perioperative patient care. By the early 1990s, elective aneurysm repair was regularly carried out with mortality rates less than 5% [2]. The pace of progress accelerated even further with the advent of endoluminal approaches to aneurysm repair, beginning in 1991 [3]. The minimal morbidity associated with these techniques has dramatically changed our management approach to aortic aneurysm disease, and endoluminal repair of AAAs may already be considered commonplace [4–9]. It is therefore timely to consider how our approach to AAAs is likely to change even further in the near future. Over the past two decades, a collective investment in basic research has led to greater appreciation of aneurysm disease as a unique pathobiological process. This new knowledge can be expected to lead to the development of even more novel treatment strategies for AAAs; however, in contrast to improvements in perioperative care and surgical technique, these new advances will be based on cellular and molecular biology, molecular genetics, advanced biomechanical models, and a more profound understanding of disease mechanisms. Additional influences on our approach will include the results of studies using novel animal models and pharmacological agents, application of knowledge arising from the human genome sequence, and rapid advances in Tel.: +1 314 362 7410; fax: +1 314 747 3548; e-mail: thompsonr @msnotes.wustl.edu

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computerized information technology. To illustrate some of the principles that guide our understanding of aortic aneurysms, it is useful to consider several common misconceptions that have emerged with regard to basic research on this problem. As outlined in the sections that follow, these new research concepts have already led to novel pathophysiological insights and therapeutic strategies.

Misconception #1: aneurysms happen The way that AAAs commonly come to clinical attention has often led to the perception that aneurysms arise in a sudden and spontaneous fashion. For example, ruptured aortic aneurysms present as a surgical emergency, resulting in either sudden death or the need for immediate operation, and asymptomatic nonruptured AAAs are usually found incidentally during imaging studies ordered for an unrelated reason. In each case, the presence of an aortic aneurysm is usually unknown to the patient, the family, or the primary care physician, leading to a view that aneurysm disease arises as an unexpected but unavoidable misfortune. In the parlance of bumper-sticker philosophy, “Aneurysms Happen”. Contrary to the implications of this view, we all know that aneurysms don’t just “happen”: they are the result of a chronic degenerative process that evolves over a period of many years (Fig. 1). Screening studies also reveal that AAAs are quite common: as defined by an aortic diameter greater than 3.0 cm, AAAs occur in up to 10% of the population over 65 years of age [10]. While the majority of these aneurysms are small, asymptomatic and at low risk for rupture, their natural history is characterized by gradual expansion. Thus, aortic aneurysms do not appear suddenly, but may be recognized at any point in time during their evolution. In addition to an obvious association with aging, aneurysm development is linked to atherosclerosis, 389

Reflections on the pathogenesis of abdominal aortic aneurysms: R. W. Thompson

Figure 1 Schematic diagram depicting the natural history of abdominal aortic aneurysm.

hypertension, cigarette smoking and an undefined genetic predisposition [11]. The potential role of these risk factors has led to a great deal of debate over the actual cause of AAAs, which is essentially still undefined. Clinical and basic research studies have demonstrated that aortic aneurysms arise through a complex pathophysiologic process that involves chronic inflammation within all layers of the aortic wall, as well as a gradual imbalance between the synthesis and degradation of structural connective tissue proteins, particularly elastin and collagen [12]. Recognizing that aneurysm disease evolves through a dynamic biological process has been one of the important insights of the past two decades.

Misconception #2: the legacy of Laplace The clinical behavior of aortic aneurysms is characterized by a progressive tendency to rupture with an increase in aneurysm size. In explaining this phenomenon we refer to the biophysical principle articulated in the “law of Laplace”, where tensile wall stress is directly proportional to aortic diameter and arterial blood pressure [13]. This relationship has led many to consider AAAs as a simple biomechanical problem, resulting from irreversible structural damage to the aortic wall that results in weakening, dilatation and rupture. Focusing on aortic wall tension as the cause of ruptured aneurysms has often led to a simplistic view that the behavior of AAAs is governed solely by biomechanical factors, and consistent with this “mechanical” view of disease, all of our previous approaches to treatment have centered upon “mechanical” solutions. As we are all aware, however, this view is complicated by the fact that aneurysms can rupture at virtually any size [14,15]. Our traditional notions of aneurysm disease therefore appear insufficient to explain the clinical behavior of AAAs. Current concepts indicate that aneurysm development represents a unique form of pathological arterial wall remodeling, with dilatation occuring as a result of a progressive imbalance between biome390

chanical and biological factors. Destruction of the elastic media appears to be a central event in this process, in that elastin degradation is a consistent feature of both human and experimental AAAs [16– 21]. This process appears to depend on elastolytic proteinases produced by chronic inflammatory cells, particularly tissue macrophages located at the site of tissue damage [22,23]. Recent studies demonstrate that the most prominent elastases produced in aneurysm tissue are members of the matrix metalloproteinase (MMP) family, including 72-kDa gelatinase (MMP-2), 92-kDa gelatinase (MMP-9), and macrophage elastase (MMP-12) [24–34]. MMP-9 has attracted the most interest because its expression in aneurysm tissues correlates with increasing size [35] and because it is elevated in the plasma of patients with AAAs [36,37]. In attempting to define the role of individual MMPs in experimental animal models of AAAs, studies using genetically-altered mice have demonstrated that MMP-9 is critical in this process [38]. The identification of MMPs as enzymatic mediators of aneurysmal degeneration has led to the notion that pharmacologic inhibition of MMPs might provide a useful new therapeutic strategy to suppress aneurysm growth. It is of great interest that in experimental models, treatment with antiinflammatory agents or MMP inhibitors can effectively suppress aneurysmal degeneration [39–46]. These studies have provided the first indication that the progression of aneurysms can actually be modulated in vivo by interference with biological factors alone, even within the stressful biomechanical environment of an established aneurysm. Translational clinical studies have now also shown that treatment with MMP-inhibiting tetracycline derivatives can suppress aortic wall expression of certain MMPs in patients with AAA, indicating that this may be a feasible approach for further investigation in clinical trials [47–49].

Misconception #3: Aneurysms are dominated by connective tissue destruction Basic research on AAA has focused primarily on the role of chronic inflammation and specific proteinases in the destruction of medial elastin and adventitial collagen. The degradation of medial elastin transfers virtually all of the tensile stress in the aortic wall to adventitial collagen fibers [50]. Given the elevated tensile stress that occurs with aneurysmal dilatation, it is not surprising that there is evidence for increased collagen synthesis in tissues from nonruptured AAAs [51,52]. Further studies indicate that connective tissue repair is necessary for stabilization of the enlarging aneurysm wall [53]. Biological factors influencing collagen synthesis and degradation may therefore have a dramatic influence on the biophysCARDIOVASCULAR SURGERY

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Reflections on the pathogenesis of abdominal aortic aneurysms: R. W. Thompson

ical properties of the aneurysm wall, and it is clear that accelerated collagen degradation may be a critical factor precipitating aneurysm rupture [54–56]. Recent studies indicate that several different collagenases can be produced in AAA tissue, and that their cellular sources may include both infiltrating inflammatory cells (macrophages and neutrophils) and resident vascular wall cell types (medial smooth muscle cells and adventitial fibroblasts) [57,58]. It is of interest that vascular SMC represent the dominant cell population of the normal aortic wall, but that aneurysms are characterized by pronounced SMC depletion [59]. Recent investigations indicate that one of the factors leading to medial SMC depletion is a process of programmed cell death, or apoptosis, and that this may also be linked to chronic inflammation within the aneurysm wall [59–62]. Because medial SMC likely contribute to the increased collagen production required to stabilize the expanding aneurysm wall, the onset of SMC depletion may represent a crucial stage in aneurysm disease. Recent studies also indicate that SMC derived from AAA tissues exhibit a pattern of accelerated replicative senescence in culture, but that this pattern is not observed in SMC derived from arteries adjacent to the aneurysm, even in the same patient [63]. This suggests that aneurysms may involve a localized process of cellular aging, perhaps reflecting an exhaustion of the replicative potential of SMC during earlier phases of the disease. Discovering the cellular mechanisms underlying these processes will therefore continue to be important in understanding the dynamic stages of aneurysm disease. One notion that warrants further attention is the well-established relationship between AAA size and risk of rupture. While there is clearly a biophysical basis for this relationship based on the law of Laplace, it must be borne in mind that small AAAs are also those in the earliest stages of evolution, when the capacity for connective tissue repair is high. In contrast, large AAAs are also the most longstanding AAAs, those in which there is a decreased capacity for connective tissue repair. This biological feature of large AAAs may therefore have a great deal to do with the increased risk of larger aneurysms to rupture.

Misconception #4: There is a pressing need for a more accurate screening test Despite our awareness that aortic aneurysms occur with a relatively high frequency and that elective aneurysm repair can be achieved with low operative morbidity and mortality, enthusiasm for populationbased screening programs has been limited [64,65]. This is of particular interest in that virtually all AAAs can be detected by abdominal ultrasound, a noninvasive and inexpensive test, and that ultrasound CARDIOVASCULAR SURGERY

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screening for AAAs has a higher degree of accuracy that other screening tests we routinely employ in clinical practice (e.g., prostate-specific antigen, mammography, and colonoscopy). The factors limiting the widespread use of ultrasound screening for AAAs are not the accuracy or invasiveness of the test; rather, population-based screening for AAA is not currently recommended because most AAA detected are smaller than 4.5 cm diameter [66]. Small asymptomatic AAAs are at low risk for rupture and there are currently no welldefined treatment strategies for such patients [64,66]. Thus, patients with small AAA are presently managed by “watchful waiting”, an approach that consists of clinical observation with interval measurements of aneurysm size until surgical repair is indicated [67]. With an average rate of expansion of about 0.5 cm per year [68,69], it can be expected that a substantial number of patients with small AAA will eventually require repair, or succumb to aneurysm rupture, during their remaining lifetimes [70]. Therapeutic strategies to reduce the rate of aneurysm expansion would obviously be a significant advance, potentially leading to alternate forms of treatment for patients with small AAA and justifying the broader application of ultrasound screening.

Misconception #5: Identifying the “aneurysm gene” is critical toward control of the disease Previous investigations have focused on the fact that 15% to 20% of patients with AAAs exhibit a familial pattern, suggesting an underlying genetic component that dictates individual susceptibility to develop the disease [71,72]. Efforts to identify one or more “aneurysm genes” have been further stimulated by the identification of genetic mutations responsible for some disorders associated with aortic aneurysms, particularly the Marfan syndrome and type IV Ehlers-Danlos syndrome. Unfortunately, neither genetic linkage studies or candidate gene approaches have yet been fruitful for AAAs [73,74]. With decoding of the human genome sequence and the application of high-throughput techniques for the analysis of gene expression, we may soon have new information on this problem. Despite the importance of these studies, it is necessary to emphasize that most patients with AAAs do not exhibit a recognized familial pattern and that knowledge of a specific genetic mutation linked to AAAs may not well have little impact on our clinical approach to AAAs as they occur in the general population. An example of this concern is provided by Marfan syndrome, an inherited aneurysm disease known to be caused by mutations in the gene for fibrillin-1 [75]. Fibrillin-1 is a major component of 391

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elastin-associated microfibrils, and it is clear that microfibrillar alterations have an important influence on elastic tissues, including the aorta. Nonetheless, knowledge of the genetic deficiency responsible for Marfan syndrome has not yet improved the clinical management of these patients, most of whom die from aortic dissection or aneurysm rupture. Indeed, identification of the genetic mutation causing Marfan syndrome has not influenced clinical practice as much as use of beta adrenergic blockade and improvements in aortic surgery [76–79], and studies on genetically-altered mice with fibrillin-1 deficiency reveal that the development of aortic disease involves a more complex pathophysiologic process than previously recognized [80[80],81]. More recent research studies have focused on the notion that, regardless of its actual cause, aneurysm disease is a dynamic process of chronic inflammation and connective tissue remodeling that may be amenable to biological modification [12]. These studies have emphasized the role of specific connective tissue proteinases in aortic aneurysms, and have led to the notion that pharmacotherapy targeting these enzymes might be a feasible method of treatment [47]. Developing new methods to alter the behavior of small AAAs will therefore be of potentially greater significance in controlling aneurysm disease, than identifying one or more genes that might predispose to aneurysm development.

Standing on the shoulders of giants Recognizing that the aneurysm wall represents a biologically complex tissue is one of the important insights into aneurysm disease over the past two decades, and greater understanding of the cellular and molecular events underlying aneurysmal degeneration has already begun to stimulate the development of novel treatment strategies. Reflecting on the fact that simple clinical observations are often the catalyst for dramatic shifts in our understanding of disease processes, it is interesting to consider that one such observation regarding AAAs was made in the early part of the 1980s at the University of California in San Francisco, where Dr. Stoney and his colleagues noted that patients with previously stable AAAs had a seemingly high rate of early aneurysm rupture after undergoing an unrelated operation. The seeds of conceptual change can be found in the thoughtful approach to this observation, in which it was suggested that systemic biological factors might have a great deal to do with modulating the behavior of AAAs [54]: The scar-like collagen fibers of an aneurysm wall provide the strength that permits the wall to resist rupture. There is a dynamic equilibrium between 392

synthesis and lysis of this collagen. Lysis of collagen is enhanced by injury, such as laparotomy, and by nutritional depletion and local inflammation. Collagen lysis is greatest in the area adjacent to the injury, but also occurs at remote sites as well. Lysis is greatest during the first postoperative week, after which, in the absence of sepsis or starvation, synthesis exceeds lysis and the equilibrium is restored. A thin aneurysm wall may be weakened enough during this period of negative collagen balance to allow rupture.

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