How Does the Multilayer Flow Modulator Work? The Science Behind the Technical Innovation

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1 814 J ENDOVASC THER 2014;21: ^EDITORIAL ^ How Does the Multilayer Flow Modulator Work? The Science Behind the Technical Innovation Sherif Sultan, MD, FRCS, EBQS-Vasc, PhD 1,2 ; Niamh Hynes, MB BCh, MMSc, MD, MRCS 2 ; Edel P. Kavanagh, PhD 2 ; and Edward B. Diethrich, MD 3 1 Western Vascular Institute and the Department of Vascular and Endovascular Surgery, University College Hospital Galway, Ireland. 2 Department of Vascular and Endovascular Surgery, Galway Clinic, Galway, Ireland. 3 Arizona Heart Foundation, Phoenix, Arizona, USA. The intuitive mind is a sacred gift and the rational mind is a faithful servant. We have created a society that honors the servant and has forgotten the gift. Albert Einstein, a casualty of aneurysm rupture The mechanism of action of the Multilayer Flow Modulator (MFM; Cardiatis, Isnes, Belgium) in the treatment of abdominal aortic aneurysm (AAA) still remains elusive to most endovascular specialists. The crosslinks between pressure, wall stress, shear stress, wall displacement, blood flow vortex development, and aneurysm wall dysplasia are concepts that are not commonplace in the clinical vernacular. In the absence of a keen understanding of biomechanics, common practice dictates that one should adhere to a more simplified measure of rupture risk and so maximum aortic diameter remains the parameter most commonly used to determine rupture risk. An arbitrary line of 5.5 cm has been drawn for aortic diameter, beyond which the risk of rupture is such that intervention is required to prevent death. However, experienced clinicians can attest to the fact that the majority of elective aneurysm repairs are in patients whose aortic diameters far exceed the 5.5- cm threshold. In fact, aneurysms with diameters more than double the cutoff value remain intact prior to elective repair, while on the other hand, up to 23% of aortic aneurysms have been reported to rupture at diameters below 5 cm. 1 6 These inconsistencies lead one to believe that a 2-dimensional (2D) marker such as diameter may be too basic a measure and really only of historic relevance. Mounting evidence suggests that an aneurysm growth rate based on 3-dimensional (3D) volume measurements of the AAA and intraluminal thrombus (ILT) is significantly associated with the need for aortic repair, while the same does not hold for growth rates determined by 2D indices of maximum diameter and ILT thickness. 7 Further still, more sophisticated tools, such as finite element (FE) modeling, computational fluid dynamics (CFD), and individualized fluid suture interaction models using 4-dimensional measurements allow for more patient-specific rupture risk analysis. Although these are not common in clinical practice, these biomechanical tools have confirmed the inaccuracy of aneurysm diameter as a predictor of rupture risk For example, Fillinger et al. 11,12 demonstrated that peak wall stress is superior to diameter in assessing rupture risk of patient-specific AAAs. These studies used large cohorts to determine statistical significance of their results and concluded that not only is peak wall stress significantly higher in those cases that The authors declare no association with any individual, company, or organization having a vested interest in the subject matter/products mentioned in this article. Corresponding author: Prof. Sherif Sultan, Consultant Vascular & Endovascular Surgeon, Western Vascular Institute, Department of Vascular & Endovascular Surgery, Galway University Hospital, Ireland. sherif.sultan@hse.ie Q 2014 INTERNATIONAL SOCIETY OF ENDOVASCULAR SPECIALISTS doi: / Available at

2 J ENDOVASC THER MULTILAYER FLOW MODULATOR ;21: Sultan et al. ruptured, 11 but it is also superior to diameter in differentiating patients under observation who will succumb to aortic rupture. Several other authors have confirmed these findings EINSTEIN LEGACY When one of the most influential minds of the 20th century, Albert Einstein, had his AAA wrapped in cellophane by Dr. Rudolph Nissen in December 1948, the repair ultimately failed and he died from rupture in April The fundamental error in this treatment modality was the presumption that the biomechanical properties of the abdominal aorta would conform to the law of Laplace, which states that the larger the vessel radius, the larger the wall tension required to withstand a given internal fluid pressure. However, the application of the law of Laplace to an aortic aneurysm has two major flaws; first, the aorta is not a homogenous, spherical, uniform shape of a constant radius of curvature for which the law of Laplace is valid. Rather, the geometry of the aneurysm wall is complex and varies spatially. 16,17 AAA wall tissue is characterized by hyperelastic/ viscoelastic material properties and significant anisotropy. Secondly, the rupture potential is highest where the ratio of peak wall stress to peak wall strength is higher. Therefore, the maximum diameter criterion to predict rupture risk ignores the important roles of vessel wall topography, geometry, wall stiffness, intraluminal thrombus thickness, calcification, iliac bifurcation angle, rate of aneurysm growth, and peak wall stress. 11,12,15,16,18 26 WHY ANEURYSMS EXPAND AND RUPTURE The pathophysiology of aneurysmal disease is characterized by thinning of the aortic media resulting from proteolytic injury to the extracellular matrix and to smooth muscle cell senescence and apoptosis, allowing further proteolytic injury leading to dilation and rupture Aneurysms of the aortic root and ascending aorta are most commonly related to cystic medial degeneration. On the other hand, inflammation and oxidative stress appear to play more of a key role in the development and progression of aneurysms of the descending thoracic and abdominal aorta. 34 However, in addition to atherosclerotic factors, certain hemodynamic factors must be considered as acting in a synergistic fashion with atherosclerotic degeneration in the development of aortic disease and rupture risk. 35 The development of aortic aneurysm results in elevated wall stresses and disturbed hemodynamics. 36 The geometry of the normal healthy aorta does not vary greatly from patient to patient and as a result wall stresses would not be expected to vary. On the other hand, it has been shown that large variations exist in aneurysm geometries and thus there are large differences in wall stress, 36,37 with some studies demonstrating aneurysms with 3 times greater wall stress than the normal aorta. This increase can be attributed to the larger size, larger curvature, and stiffer wall of the aneurysm compared to normal aorta. The mechanical forces that contribute to aortic remodeling are 3 distinct fluid-induced forces: (1) pressure created by hydrostatic forces, (2) circumferential stretch exerting longitudinal forces, and (3) shear stress created by the movement of blood. The net force includes a component perpendicular to the wall, the pressure, and a component along the wall, the shear stress. Disturbed flow conditions, such as turbulence, contribute to aneurysm growth by causing injury to the endothelium and accelerating degeneration of the arterial wall. Areas of flow oscillation and extremes in shear stress (high or low) correlate with development of atherosclerosis and ultimately aneurysm formation or dissection in the aorta. 38,39 The balance between positive and negative stresses determines aortic disease progression. For example, laminar shear stress increases expression of superoxide dismutase and endothelial nitric oxide synthase in cultured human endothelial cells, whereas turbulent shear stress does not induce these protective genes. Aortic aneurysms do not rupture because of tension, pressure, or dispensability, i.e., increase in sac diameter. Rather, it is when the stress on the aortic wall at a vulnerable point

3 816 MULTILAYER FLOW MODULATOR J ENDOVASC THER Sultan et al. 2014;21: Figure 1 ^ Histological appearance of (A) normal aortic elastin and (B) aortic elastin damaged by vortex turbulence. 40 exceeds the wall s strength, i.e., the ability of the wall to withstand that stress. The development of flow vortices increases peak wall stresses and alters viscoelasticity, plasticity, and cellular wall activity; this in turn leads to damage at a particular point on the aneurysm wall. Studies done by White et al. 40 on the pathogenesis of adventitial elastolysis as the primary event in aneurysm formation demonstrated elastin damage by the turbulence of flow vortices acting on the aortic wall (Fig. 1). The continuous local vortex produces wall damage through a very low but persistent shear stress of ~0.4 mmhg or 50 Pascal. Rupture Potential Index Vorp et al. 41 calculated the rupture potential index (RPI) for aortic aneurysms, which is the ratio of acting wall stress to the wall strength at a particular point on the aneurysm wall. They and others found that the RPI is elevated in ruptured aortic aneurysm. 41,42 A significant differentiation of rupture risk by RPI was found for aneurysm diameters ranging between 55 and 75 mm in both asymptomatic and ruptured aortic aneurysm, whereby the maximum diameter criterion failed to adequately predict risk. 42 MFM BIOMECHANICS The MFM is a 3D device of interconnected wires that forms a mesh with a specific porosity and permeability (Fig. 2). The MFM modulation porosity is 60% to 70%, depending on its application for aneurysm or dissection repair or in patients with high thrombus burden. Figure 2 ^ The Multilayer Flow Modulator is a mesh of interconnected wires of a specific porosity and permeability. Differences Between a Stent-Graft and the MFM The implantation of a stent-graft is theoretically thought to reduce stresses and improve hemodynamics to levels similar to that experienced within a normal nonaneurysmal aorta. However, endovascular aortic repair with stiff, noncompliant stent-grafts creates complications due to drag forces acting on the graft and high aortic neck stresses, with the consequences of stent-graft migration and aortic neck dilatation. 43,44 Conversely, the MFM avoids such drawbacks, firstly, because its compliance is similar to that of the native aorta and, secondly, because its propensity for rapid endothelialization means that it quickly becomes embedded within the aortic wall. Therefore, the effect of peak wall stress is grossly diminished. 45 Peak Wall Stress The Multilayer Flow Modulator directs blood flow along the wall in the same direction as the systemic pressure flow, so the MFM eliminates the damaging flow vortex pressure. Figure 3A depicts the flow in the central lumen of the aneurysm with maximum intra-arterial pressure. At 0.4 mmhg, this pressure is minimal on the wall; however, the turbulence creates a vortex that is transmitted as stress on the AAA wall. Figure 3B demonstrates how the MFM laminates the flow outside the device and along the aneurysm wall in the same direction of the flow, thus eliminating the turbulence and its vortex.

4 J ENDOVASC THER MULTILAYER FLOW MODULATOR ;21: Sultan et al. Figure 3 ^ (A) Computational flow analysis of an aortic arch aneurysm (A) preoperatively and (B) after MFM stent deployment shows alignment of flow through the stent. Peak wall stress (C) before and (D) after MFM deployment. Wall displacement (E) before MFM (0.05 lm) and (F) after MFM (0.01 lm). A study conducted by the National French Institute of Agronomy involved surgical placement of a biosensor on the aneurysm wall in 3 porcine models. They found a 60% reduction in wall stress (Fig. 3C,D) from 120 N/m 2 or 0.9 mmhg to 55 N/m 2 or 0.4 mmhg (unpublished data). An unpublished CFD study of the MFM shows that local turbulent flow vortices are laminated by the MFM, with an 80% reduction in wall displacement from 0.05 lm to 0.01 lm after MFM implantation (Fig. 4). This results in an immediate 55% reduction in wall stress, which is transferred from the mid-distal aortic wall to the MFM mesh wall (Fig. 3E,F). Other studies have also shown that a reduction in peak wall stress occurs when deranged flow vortices are abolished and the flow is laminated to unidirectional vectors (Fig. 4A,B). 47 These modifications in flow patterns reduce the peak wall stresses, which have been demonstrated to independently predict rupture risk Wall Strength As demonstrated by Vorp et al., 47 the potential of an aneurysm to rupture depends not only on reducing peak wall stresses but also on increasing wall strength. The factors that have been shown to reduce the integrity of the aortic wall and increase rupture risk include asymmetry, 47 heterogeneity, 48 and reduced compliance or stiffness. 41 The MFM addresses the issues by providing a uniform interface between the aortic wall and the blood flow. However, its favorable compliance means that the MFM is not subjected to the same drag forces 43 or increased pulse wave pressures 49 that conventional endografts undergo. The MFM protects the aortic wall from malignant stresses by the induction of shear forces, which leads to a reduction in laminar flow and subsequent formation of ILT. This redirection of flow toward the lumen and away from the dilated aortic wall promotes healing and modulation of the dilated aorta.

5 818 MULTILAYER FLOW MODULATOR J ENDOVASC THER Sultan et al. 2014;21: Figure 4 ^ (A) Before MFM, turbulence shears the wall of the aneurysm and (B) after MFM deployment, the speed of the shearing vortex is reduced. MFM and side branches: (C) turbulent flow into the aneurysm and (D) the MFM laminates the flow into the aneurysm. Intraluminal Thrombus The MFM promotes thrombus formation, which causes an initial increase in aortic aneurysm volume post implantation. 45,46 However, the volume increase does not pertain to rupture; rather, it is an active mechanism by which the body self-modulates healing. Some investigators have postulated that thrombus may affect aneurysm expansion, with diameter having been reported to correlate with the plasma concentrations of fibrin formation and degradation products, 50,51 as well as with the concentration of the circulating complex plasmin-a2-antiplasmin, 51 which is potentially related to thrombus turnover. Others have suggested that thrombus may be a source of proteases contributing to aneurysm evolution following the initial report of high matrix metallopeptidase 9 activity in thrombus. 33 Some investigators have hypothesized that increasing thrombus thickness leads to local hypoxia at the inner layer of the media, which may induce increased medial neovascularization and inflammation. 21 However, more clinical-based studies have demonstrated a less innocuous 52 or even a positive effect of ILT. 53 Inzoli et al. 54 were the

6 J ENDOVASC THER MULTILAYER FLOW MODULATOR ;21: Sultan et al. first group to introduce an important concept: that ILT acts to reduce aortic aneurysm wall stress and provides a shielding or buffering effect. Therefore, the effect of the MFM on thrombus formation synergizes its effect on reduction of peak wall stresses. Endothelialization One of the most promising effects of the MFM is rapid promotion of endothelialization. The endothelium is the most important cell in the vasculature because of its role in vascular hemostasis, cell-signaling, smooth muscle cell function, and ultimately in arterial healing. 55 The bare metal structure of the MFM provides a framework for neointimal growth without occluding side branches. Endothelialization of bare metal stents occurs via three mechanisms: migration of endothelial cells through the stent struts, migration of endothelial and fibroblastic cells from the adjacent aorta at the margins of the stent, and circulating myofibroblasts. The continued laminar flow into major side branches inhibits this process across the branch ostia and maintains patency of the side branches. Preclinical animal studies report that the MFM promotes rapid re-endothelialization compared with other commercially available, single-layered, self-expanding and balloonexpandable stents. 56 Clinical studies of an MFM explanted from an aortic specimen demonstrate that the MFM is fully integrated and endothelialized, with patent side branch and no intimal hyperplasia. 57 Aortic Branches The versatility of the MFM is its ability to preserve and enhance flow patterns in arterial side branches. The side branches act as a vacuum, augmenting the lamination and abolishing the vortices, which results in rapid shrinkage of the aneurysm and increased side branch flow. FE analysis (unpublished data) of aneurysms with side branches shows that the MFM eliminates damaging erratic flow vortices by redirecting the flow into laminar flow patterns, thereby reducing peak wall stresses on the aneurysm wall, while simultaneously increasing flow into the aneurysm side branches (Fig. 4C,D). CONCLUSION The addition of the MFM to mainstream vascular practice has introduced us to the discipline of bioengineering and compelled us to re-evaluate our core concepts of aneurysm treatment and shift our focus from anatomical to physiological therapies. A lack of understanding of the mechanics of the MFM has produced skepticism and trepidation on the one hand, while on the other hand, it has contributed to the misuse of the device. Human nature dictates that it is these errors that are more widely publicized, rather than the positive outcomes. In order to advance, we need to be open to new concepts. The key components of MFM function are its manipulation of blood flow, preservation and enhancement of flow into arterial side branches, compliance, encouragement of endothelialization, and influence on thrombus formation, all of which reduce peak wall stresses while simultaneously enhancing wall strength and promoting healing. REFERENCES 1. Powell JT, Gotensparre SM, Sweeting MJ, et al. Rupture rates of small abdominal aortic aneurysms: a systematic review of the literature. Eur J Vasc Endovasc Surg. 2011;41: Pape LA, Tsai TT, Isselbacher EM, et al. Aortic diameter 5.5 cm is not a good predictor of type A aortic dissection: observations from the International Registry of Acute Aortic Dissection (IRAD). Circulation. 2007;116: Darling RC, Messina CR, Brewster DC, et al. Autopsy study of unoperated abdominal aortic aneurysms. The case for early resection. Circulation. 1977;56:II161 II Hall AJ, Busse EF, McCarville DJ, et al. Aortic wall tension as a predictive factor for abdominal aortic aneurysm rupture: improving the selection of patients for abdominal aortic aneurysm repair. Ann Vasc Surg. 2000;14: Knipp BS, Deeb GM, Prager RL, et al. A contemporary analysis of outcomes for operative repair of type A aortic dissection in the United States. Surgery. 2007;142: Simao da Silva E, Rodrigues AJ, Magalhaes Castro de Tolosa E, et al. Morphology and diameter of infrarenal aortic aneurysms: a

7 820 MULTILAYER FLOW MODULATOR J ENDOVASC THER Sultan et al. 2014;21: prospective autopsy study. Cardiovasc Surg. 2000;8: Kontopodis N, Metaxa E, Papaharilaou Y, et al. Value of volume measurements in evaluating abdominal aortic aneurysms growth rate and need for surgical treatment. Eur J Radiol. 2014; 83: Chandra S, Raut SS, Jana A, et al. Fluidstructure interaction modeling of abdominal aortic aneurysms: the impact of patient-specific inflow conditions and fluid/solid coupling. J Biomech Eng. 2013;135: Gasser TC, Nchimi A, Swedenborg J, et al. A novel strategy to translate the biomechanical rupture risk of abdominal aortic aneurysms to their equivalent diameter risk: method and retrospective validation. Eur J Vasc Endovasc Surg. 2014;47: Doyle BJ, Hoskins PR, McGloughlin TM. Computational rupture prediction of AAAs: what needs to be done next? J Endovasc Ther. 2011; 18: Fillinger MF, Raghavan ML, Marra SP, et al. In vivo analysis of mechanical wall stress and abdominal aortic aneurysm rupture risk. J Vasc Surg. 2002;36: Fillinger MF, Marra SP, Raghavan ML, et al. Prediction of rupture risk in abdominal aortic aneurysm during observation: wall stress versus diameter. J Vasc Surg. 2003;37: Raghavan ML, Vorp DA, Federle MP, et al. Wall stress distribution on three-dimensionally reconstructed models of human abdominal aortic aneurysm. J Vasc Surg. 2000;31: Truijers M, Pol JA, SchultzeKool LJ, et al. Wall stress analysis in small asymptomatic, symptomatic and ruptured abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2007;33: Venkatasubramaniam AK, Fagan MJ, Mehta T, et al. A comparative study of aortic wall stress using finite element analysis for ruptured and non-ruptured abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2004;28: Elger DF, Blackketter DM, Budwig RS, et al. The influence of shape on the stresses in model abdominal aortic aneurysms. J Biomech Eng. 1996;118: Sacks MS, Vorp DA, Raghavan ML, et al. In vivo three dimensional surface geometry of abdominal aortic aneurysms. Ann Biomed Eng. 1999; 27: Doyle BJ, Callanan A, Burke PE, et al. Vessel asymmetry as an additional diagnostic tool in the assessment of abdominal aortic aneurysms. J Vasc Surg. 2009;49: Wang DH, Makaroun MS, Webster MW, et al. Effect of intraluminal thrombus on wall stress in patient-specific models of abdominal aortic aneurysm. J Vasc Surg. 2002;36: Vande Geest JP, Wang DH, Wisniewski SR, et al. Towards a noninvasive method for determination of patient-specific wall strength distribution in abdominal aortic aneurysms. Ann Biomed Eng. 2006;34: Vorp DA, Lee PC, Wang DH, et al. Association of intraluminal thrombus in abdominal aortic aneurysm with local hypoxia and wall weakening. J Vasc Surg. 2001;34: Duprey A, Khanafer K, Schlicht M, et al. In vitro characterisation of physiological and maximum elastic modulus of ascending thoracic aortic aneurysms using uniaxial tensile testing. Eur J Vasc Endovasc Surg. 2010;39: Brown PM, Zelt DT, Sobolev B. The risk of rupture in untreated aneurysms: the impact of size, gender, and expansion rate. J Vasc Surg.2003;37: Hatakeyama T, Shigematsu H, Muto T. Risk factors for rupture of abdominal aortic aneurysm based on three-dimensional study. J Vasc Surg. 2001;33: Sonesson B, Sandgren T, Lanne T. Abdominal aortic aneurysm wall mechanics and their relation to risk of rupture. Eur J Vasc Endovasc Surg. 1999;18: Stenbaek J, Kalin B, Swedenborg J. Growth of thrombus may be a better predictor of rupture than diameter in patients with abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2000; 20: Campa JS, Greenhalgh RM, Powel JT. Elastin degradation in abdominal aortic aneurysms. Atherosclerosis. 1987;65: Menashi S, Campa JS, Greenhalgh RM, et al. Collagen in abdominal aortic aneurysm: typing, content and degradation. J Vasc Surg. 1987;6: Reilly JM. Plasminogen activors in abdominal aortic aneurysmal disease. Ann N Y Acad Sci. 1996;800: Rizzo RJ, McCarthy WJ, Dixit SN, et al. Collagen types and matrix protein content in human abdominal aortic aneurysms. J Vasc Surg. 1989;10: Ruddy JM, Jones JA, Spinale FG, et al. Regional heterogeneity within the aorta: relevance to aneurysm disease. J Thorac Cardiovasc Surg. 2008;136: Sakalihasan N, Heyeres A, Nusgens BV, et al Modifications of the extracellular matrix of aneurysmal abdominal aortas as a function of their size. Eur J Vasc Surg. 1993;7: Sakalihasan N, Delvenne P, Nusgens BV, et al. Activated forms of MMP2 and MMP9 in

8 J ENDOVASC THER MULTILAYER FLOW MODULATOR ;21: Sultan et al. abdominal aortic aneurysms. J Vasc Surg. 1996;24: Reeps C, Essler M, Pelisek J, et al. Increased 18F-fluorodeoxyglucose uptake in abdominal aortic aneurysms in positron emission/computed tomography is associated with inflammation, aortic wall instability, and acute symptoms. J Vasc Surg. 2008;48: Vollmar JF, Pauschinger P, Paes E, et al. Aortic aneurysms as a late sequelae of above-knee amputation. Lancet. 1989;2: Xenos M, Rambhia SH, Alemu Y, et al. Patientbased abdominal aortic aneurysm risk prediction with fluid structure interaction modeling. Ann Biomed Eng. 2010;38: Gasser TC, Auer M, Labruto F, et al. Biomechanical rupture risk assessment of abdominal aortic aneurysms: model complexity versus predictability of finite element simulations. Eur J Vasc Endovasc Surg. 2010;40: Ku DN, Giddens DP, Zarins CK, et al. Pulsatile flow and atherosclerosis in the human carotid bifurcation: positive correlation between plaque location and low oscillating shear stress. Arteriosclerosis. 1985;5: Chen XL, Varner SE, Rao AS, et al. Laminar shear stress induction of antioxidant response element-mediated genes in endothelial cells: a novel anti-inflammatory mechanism. J Biol Chem. 2003;278: White JV, Haas K, Phillips S, et al. Adventitial elastolysis is a primary event in aneurysm formation. J Vasc Surg. 1993;17: Vorp DA, Raghavan ML, Muluk SC, et al. Wall strength and stiffness of aneurysmal and nonaneurysmal abdominal aorta. Ann N Y Acad Sci. 1996;800: Maier A, Gee MW, Reeps C, et al. A comparison of diameter, wall stress, and rupture potential index for abdominal aortic aneurysm rupture risk prediction. Ann Biomed Eng. 2010;38: Molony DS, Kavanagh EG, Walsh MT, et al. A computational study of the magnitude and direction of migration forces in patient-specific abdominal aortic aneurysm stent-grafts. Eur J Vasc Endovasc Surg. 2010;40: Sampaio SM, Panneton JM, Mozes G, et al. Aortic neck dilation after endovascular abdominal aortic aneurysm repair: Should oversizing be blamed? Ann Vasc Surg. 2006;20: Sultan S, Sultan M, Hynes N. Early mid-term results of the first 103 cases of multilayer flow modulator stent done under indication for use in the management of thoracoabdominal aortic pathology from the independent global MFM registry. J Cardiovasc Surg (Torino). 2014;55: Sultan S, Hynes N, Tawfick W. Disruptive endovascular technology with multilayer flow modulator stents (MFM) as a therapeutic option in the management of thoracoabdominal aortic aneurysms: early results from the global independent MFM registry. Ital J Vasc Endovasc Surg. 2012;19: Vorp DA, Raghavan ML, Webster MW. Mechanical wall stress in abdominal aortic aneurysm: influence of diameter and asymmetry. J Vasc Surg. 1998;27: Vallabhaneni SR, Gilling-Smith GL, How TV, et al. Heterogeneity of tensile strength and matrix metalloproteinase activity in the wall of abdominal aortic aneurysms. J Endovasc Ther. 2004;11: Kadoglou NP, Moulakakis KG, Papadakis I, et al. Changes in aortic pulse wave velocity of patients undergoing endovascular repair of abdominal aortic aneurysms. J Endovasc Ther. 2012;19: Yamazumi K, Ojiro M, Okumura H, et al. An activated state of blood coagulation and fibrinolysis in patients with abdominal aortic aneurysm. Am J Surg. 1998;175: Lindholt JS, Heegaard NH, Vammen S, et al. Smoking, but not lipids, lipoprotein(a) and antibodies against oxidised LDL, is correlated to the expansion of abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2001;21: Golledge J, Iyer V, Jenkins J, et al. Thrombus volume is similar in patients with ruptured and intact abdominal aortic aneurysms. J Vasc Surg. 2014;59: Li ZY, U-King-Im J, Tang TY, et al. Impact of calcification and intraluminal thrombus on the computed wall stresses of abdominal aortic aneurysm. J Vasc Surg. 2008;47: Inzoli F, Boschetti F, Zappa M, et al. Biomechanical factors in abdominal aortic aneurysm rupture. Eur J Vasc Surg. 1993;7: Coen M, Gabbiani G, Bochaton-Piallat ML. Myofibroblast-mediated adventitial remodeling: an underestimated player in arterial pathology. Arterioscler Thromb Vasc Biol. 2011; 31: Sultan S, Kavanagh E, Hynes N. Endothelialization processes and kinetics of stents. Presented at the International Society for Vascular Surgery Annual Meeting held in Guangzhou, China, on July 10 12, Lazaris AM, Maheras AN, Vasdekis SN. A multilayer stent in the aorta may not seal the aneurysm, thereby leading to rupture. J Vasc Surg. 2012;56: