The flow in the bypass connection with the IA, LCCA and LSA are shown in **Figure 12**. Vortices are found at the exit point from the SG to the IA, at the anastomosis to the LCCA and at the connection point of the bypass with the IA and LSA.

In the hybrid graft case (**Figure 13**), a vortex is seen at the branching point of the graft with the aorta. Smooth flow is seen in the graft and bifurcation. Vortices also appear at the stumps of the IA, LCCA and LSA. Vortices are also found at the bypass connection to the LCCA and LSA (**Figure 14**) and at the LSA stump.

**Figure 14.** Hybrid bypass (a) CFD particle trace (b) visualization.

#### **4. Discussion**

In this study, four numerical models were built and verified using an in vitro experimental method. The models represent aortic arch aneurysm and three different treatment approaches. Comparison of flow patterns between the numerical and experimental results exhibits similar flow regimes in all four models, indicating the validity of the numerical model.

In the aneurysm case, poor hemodynamics is well demonstrated. A large vortex occupies the entire aneurysm sac, and in its center, a single significant stagnation point is observed, espe‐ cially during diastole as seen in **Figure 9**. This induces poor particle washout and has a high risk of thrombus formation, as shown in previous studies as well [25, 26].

The surgery graft case demonstrated the best hemodynamics performance of all cases. The flow patterns deduced from the numerical analysis are clearly seen in the visualization (**Figures 9**–**14**). The helical flow that is generated at the aortic arch as seen in the numerical solution is noticed in vitro as well. This type of flow is consistent with findings from literature [27–29].

The chimney case (**Figures 11** and **12**) presented the most disturbed flow of all the three approaches. The large vortex at the insertion point of the stent‐graft provokes a strong shear layer and vortical area downstream. A second large vortex at the bend toward the IA is well shown in the numerical model, but was not visually confirmed by the experiments due to local reflections and light scattering from the model. In addition, a series of vortices forming in the stubs of the arteries where they connect to the bypass are clearly seen numerically and experimentally (**Figure 12**).

In the hybrid graft case, a single vortex is noticed at the connection with the aortic arch (seen in **Figure 13**), followed by clean flow in the hybrid grafts branching point. Visualization con‐ firms these findings. The bypass connection between the LSA and LCCA shows a vortex in the stub and is confirmed visually (**Figure 14**). Light did not reach the LCCA, and thus, visional confirmation was not possible.

This study is aimed at validating the numerical models using methods of visualization. The two methods were compared qualitatively by means of flow patterns analysis.

The resulted time‐dependent flow presented similar flow regimes and vortex configurations.

The analysis did not take into consideration the motion of the aortic wall [30], and we did not use patient‐specific geometries or boundary conditions. Nor turbulence or non‐Newtonian effects were considered. Yet, we believe that our models represent the dominant factors influ‐ encing the hemodynamics in the different cases.

The reason for model simplifications is that patients' anatomy and physiology come in large variations, and whatever models used will lead to inaccuracy for the global analysis. Therefore, the models are based on representative prototype anatomical geometries, the boundary conditions are based on typical time functions from literature and the flow models were simplified. These assumptions might lead to some inaccuracies in the calculated values for specific patients, especially in WSS and pressure; however, it should not change the over‐ all conclusions of the study.

In conclusion, this study was aimed at introducing a valid numerical model for the differ‐ ent cases. Future research will use more accurate experimental analysis and will examine flow parameters in the different numerical models, including specific regions (like gutter and stumps), wall shear stress, pressure drops and perfusion.

#### **Author details**

**4. Discussion**

50 Aortic Aneurysm

**Figure 14.** Hybrid bypass (a) CFD particle trace (b) visualization.

experimentally (**Figure 12**).

confirmation was not possible.

In this study, four numerical models were built and verified using an in vitro experimental method. The models represent aortic arch aneurysm and three different treatment approaches. Comparison of flow patterns between the numerical and experimental results exhibits similar

In the aneurysm case, poor hemodynamics is well demonstrated. A large vortex occupies the entire aneurysm sac, and in its center, a single significant stagnation point is observed, espe‐ cially during diastole as seen in **Figure 9**. This induces poor particle washout and has a high

The surgery graft case demonstrated the best hemodynamics performance of all cases. The flow patterns deduced from the numerical analysis are clearly seen in the visualization (**Figures 9**–**14**). The helical flow that is generated at the aortic arch as seen in the numerical solution is noticed in

The chimney case (**Figures 11** and **12**) presented the most disturbed flow of all the three approaches. The large vortex at the insertion point of the stent‐graft provokes a strong shear layer and vortical area downstream. A second large vortex at the bend toward the IA is well shown in the numerical model, but was not visually confirmed by the experiments due to local reflections and light scattering from the model. In addition, a series of vortices forming in the stubs of the arteries where they connect to the bypass are clearly seen numerically and

In the hybrid graft case, a single vortex is noticed at the connection with the aortic arch (seen in **Figure 13**), followed by clean flow in the hybrid grafts branching point. Visualization con‐ firms these findings. The bypass connection between the LSA and LCCA shows a vortex in the stub and is confirmed visually (**Figure 14**). Light did not reach the LCCA, and thus, visional

flow regimes in all four models, indicating the validity of the numerical model.

risk of thrombus formation, as shown in previous studies as well [25, 26].

vitro as well. This type of flow is consistent with findings from literature [27–29].

Asaph Nardi, Barak Even‐Chen and Idit Avrahami\*

\*Address all correspondence to<EMAIL_ADDRESS>
Ariel Biomechanics Center, Ariel University, Ariel, Israel

#### **References**

[21] Buth, J., et al., Combined approach to stent‐graft treatment of an aortic arch aneurysm. *Journal of Endovascular Therapy* 5.4 (1998): 329–332.

[6] Makaroun, M.S., et al., *Five‐year results of endovascular treatment with the Gore TAG device compared with open repair of thoracic aortic aneurysms.* Journal of vascular surgery, 2008.

[7] Moulakakis, K.G., et al., *The chimney‐graft technique for preserving supra‐aortic branches: a*

[8] Naughton, P.A., et al., *Emergent repair of acute thoracic aortic catastrophes: a comparative*

[9] Avrahami, I., et al., *Hemodynamic and mechanical aspects of fenestrated endografts for treatment of Abdominal Aortic Aneurysm.* European Journal of Mechanics‐B/Fluids, 2012. 35: pp. 85–91.

[10] Nardi, A., et al. Hemodynamical Aspects of Endovascular Repair for Aortic Arch Aneurisms. *ASME 2014 12th Biennial Conference on Engineering Systems Design and*

[11] Ohrlander, T., et al., The chimney graft: a technique for preserving or rescuing aortic branch vessels in stent‐graft sealing zones. *Journal of Endovascular Therapy* 15.4 (2008):

[12] Cires, G., et al., *Endovascular debranching of the aortic arch during thoracic endograft repair.*

[13] Chuter, T.A.M., et al., *Modular branched stent graft for endovascular repair of aortic arch aneu‐*

[14] Brinkman, W.T., W.Y. Szeto, and J.E. Bavaria, *Stent graft treatment for transverse arch and descending thoracic aorta aneurysms.* Current Opinion in Cardiology, 2007. 22(6): p. 510.

[15] Gottardi, R., et al., *An alternative approach in treating an aortic arch aneurysm with an ana‐ tomic variant by supraaortic reconstruction and stent‐graft placement.* Journal of Vascular

[16] Ishimaru, S., *Endografting of the aortic arch.* Journal of Endovascular Therapy, 2004.

[17] Saleh, H.M. and L. Inglese, *Combined surgical and endovascular treatment of aortic arch aneu‐*

[18] Yang, J., et al., *Endovascular chimney technique of aortic arch pathologies: a systematic review.*

[19] Nardi, A. and I. Avrahami, *Approaches for treatment of aortic arch aneurysm, A numerical*

[20] Brand, M., et al., Clinical, Hemodynamical and Mechanical Aspects of Aortic Aneurisms and Endovascular Repair in Cardiology Research and Clinical Developments. 2013: Nova

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*study.* Journal of Biomechanics, 2016. BM‐D‐16‐01127.

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*review.* Annals of Cardiothoracic Surgery, 2013. 2(3): pp. 339–346.

*analysis.* Archives of Surgery, 2012. 147(3): pp. 243–249.

*Analysis*. American Society of Mechanical Engineers, 2014.

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52 Aortic Aneurysm

427–432.

## **Thoracic Aortic Aneurysm**

**Provisional chapter**

### **Role of Interventional Treatment of Thoracic Aorta Role of Interventional Treatment of Thoracic Aorta**

Ibrahim Akin, Uzair Ansari and Christoph A. Nienaber Nienaber Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Ibrahim Akin, Uzair Ansari and Christoph A.

http://dx.doi.org/10.5772/66520

#### **Abstract**

An aging western and oriental population coupled with breakthrough advances in modern diagnostic imaging modalities has evoked renewed interest in the hitherto underdiagnosed acute and chronic diseases of the aorta, which also include aortic aneurysm and aortic dissection. Although classical surgical strategies still dominate the clinical management of acute and chronic pathologies of the ascending aorta and the proximal arch region, the emergence of novel endovascular concepts has offered an interesting therapy alternative for the treatment of descending aortic pathology in suitable patients and is highly likely to evolve as the primary treatment strategy in majority of the cases. Moreover, the use of hybrid approaches combining surgical head-vessel debranching and interventional stent-graft implantation in an attempt to improve clinical outcome in aortic arch pathologies has helped avoid the high risk of open arch repair or complete replacement. Notwithstanding these recent advancements, the complex nature of the underlying vascular disease still dictates that the proposed management of every diagnosed patient is discussed in a team constituting cardiologists, cardiac surgeons, anesthesiologists, and radiologists, with the conceptualization of individualized therapeutic strategies and conducted in a center with significant surgical and endovascular experience.

**Keywords:** aortic dissection, aortic aneurysm, stent graft, endoleak, malperfusion

#### **1. Introduction**

The pathophysiological underpinnings initiating the development of thoracic aortic disease are complex and not fully understood. Standard treatment options in most instances have included surgical resection and interposition of vascular prostheses despite the risk of severe complications arising from surgical trauma [1–3]. Although significant advancements in surgical procedures and intraoperative management have mitigated the risk of some of these adverse events, the perioperative mortality and morbidity remains high. Additionally, the

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

changing dynamics of demographic distribution in the western and oriental world have skewed the incidence of disease to an increasingly aging population, a patient group inherently afflicted with a variety of comorbidities, thus foretelling the compounded risk of a sobering surgical outcome.

The use of an endoluminal stent-graft prosthesis initiated as a revolutionary treatment concept more than two decades ago for patients with thoracic aortic disease offered an interesting alternative to open surgery by circumventing certain obvious risks. The induction of reconstructive remodeling of the diseased aorta by triggering a natural healing process through exclusion and depressurization of the aneurysmal process was an innovative interventional approach [4–6], with initial reports suggesting encouraging results for the treatment of various aortic pathologies (e.g., degenerative aneurysm, mycotoxins aneurysm, traumatic injuries, aortic dissections, and penetrating aortic ulcers (PAU)). Scarce randomized data as well as the absence of long-term surveillance of treated patients has strengthened critique against this approach, and with the lack of a satisfying rebuttal, its universal adoption has consequently been hindered [7–10]. This comprehensive chapter describes current indications, techniques, and advancements in endovascular strategies in the treatment of thoracic aortic disease.

#### **2. Classification**

Aortic dissection and aortic aneurysm have been listed as the most commonly encountered pathologies of the thoracic aorta. The incidence of aortic dissection in the clinical arena is still relatively rare, with an estimated 2.6–4 cases per 100,000 in the general population reported in a year [11–13]. Statistics reveal that only around 0.5% of the patients presenting with chest or back pain in the emergency room (ER) suffer from aortic dissection [14]. The early phase of this disease, associated with significantly high mortality, is labeled an acute aortic dissection as documented symptom-onset is less than 2 weeks on presentation. Patients surviving the initial 2 weeks without any intervention are classified as suffering from a subacute form, while the chronic patients, who constitute about one-third of all patients with aortic dissection, survive longer than 90 days. The Stanford and DeBakey classifications of aortic dissection are further attempts to group different presentations according to the anatomical location of disease (**Figure 1**). The fundamental distinction lies in the presentation of either a proximal (involving the aortic root or ascending aorta) or distal (beyond the subclavian artery) loci. An untreated proximal aortic dissection is characterized by an initial mortality rate of more than 1% per hour, which if left untreated results in death due to cardiac rupture, tamponade, heart failure from acute aortic regurgitation, or from major coronary closure [11–13]. The prognosis of a distal aortic dissection, popularly known as a Type B aortic dissection, is comparatively better clocking a 30-day mortality rate of about 10% [11–13].

In retrospect, little has been elucidated about the true prevalence and mortality rates of thoracic aortic aneurysms (TAA). An older population-based study reported an age- and genderadjusted incidence of 5.9 new aneurysms per 100,000 people-year in a Midwestern community over a 30-year period. The median ages for men and women were 65 years and 77 years, respectively, with the primary distribution of cases reflecting an affliction of the ascending aorta in 51% of the patients, of the arch in 11% and of the descending thoracic aorta in 38% [15]. The Crawford classification that attempted to classify these aneurysms based on the origin of distal to the subclavian artery (Types I–IV) has recently been adapted and tweaked by Safi (Type V) [16] (**Figure 2**).

**Figure 1.** Classification of thoracic aortic dissection.

changing dynamics of demographic distribution in the western and oriental world have skewed the incidence of disease to an increasingly aging population, a patient group inherently afflicted with a variety of comorbidities, thus foretelling the compounded risk of a sober-

The use of an endoluminal stent-graft prosthesis initiated as a revolutionary treatment concept more than two decades ago for patients with thoracic aortic disease offered an interesting alternative to open surgery by circumventing certain obvious risks. The induction of reconstructive remodeling of the diseased aorta by triggering a natural healing process through exclusion and depressurization of the aneurysmal process was an innovative interventional approach [4–6], with initial reports suggesting encouraging results for the treatment of various aortic pathologies (e.g., degenerative aneurysm, mycotoxins aneurysm, traumatic injuries, aortic dissections, and penetrating aortic ulcers (PAU)). Scarce randomized data as well as the absence of long-term surveillance of treated patients has strengthened critique against this approach, and with the lack of a satisfying rebuttal, its universal adoption has consequently been hindered [7–10]. This comprehensive chapter describes current indications, techniques, and advancements in endovascular strategies in the treatment of thoracic aortic disease.

Aortic dissection and aortic aneurysm have been listed as the most commonly encountered pathologies of the thoracic aorta. The incidence of aortic dissection in the clinical arena is still relatively rare, with an estimated 2.6–4 cases per 100,000 in the general population reported in a year [11–13]. Statistics reveal that only around 0.5% of the patients presenting with chest or back pain in the emergency room (ER) suffer from aortic dissection [14]. The early phase of this disease, associated with significantly high mortality, is labeled an acute aortic dissection as documented symptom-onset is less than 2 weeks on presentation. Patients surviving the initial 2 weeks without any intervention are classified as suffering from a subacute form, while the chronic patients, who constitute about one-third of all patients with aortic dissection, survive longer than 90 days. The Stanford and DeBakey classifications of aortic dissection are further attempts to group different presentations according to the anatomical location of disease (**Figure 1**). The fundamental distinction lies in the presentation of either a proximal (involving the aortic root or ascending aorta) or distal (beyond the subclavian artery) loci. An untreated proximal aortic dissection is characterized by an initial mortality rate of more than 1% per hour, which if left untreated results in death due to cardiac rupture, tamponade, heart failure from acute aortic regurgitation, or from major coronary closure [11–13]. The prognosis of a distal aortic dissection, popularly known as a Type B aortic dissection, is comparatively

In retrospect, little has been elucidated about the true prevalence and mortality rates of thoracic aortic aneurysms (TAA). An older population-based study reported an age- and genderadjusted incidence of 5.9 new aneurysms per 100,000 people-year in a Midwestern community over a 30-year period. The median ages for men and women were 65 years and 77 years, respectively, with the primary distribution of cases reflecting an affliction of the ascending

better clocking a 30-day mortality rate of about 10% [11–13].

ing surgical outcome.

58 Aortic Aneurysm

**2. Classification**

**Figure 2.** Classification of thoracic aortic aneurysms.

#### **3. Indications for endovascular stent-graft therapy**

In the event of an aortic dissection, the sealing of proximal entry tears with a customized stent graft has proven to be the most effective method for excluding a growing aneurysmal false lumen. Although the closure of a distal reentry tear is also desirable, this is not particularly necessary to achieve optimal results [12, 13, 17]. A favorable postinterventional outcome would constitute adequate depressurization and shrinkage of the false lumen, supplemented in an ideal scenario by a complete thrombosis of this lumen with consequent remodeling of the entire dissected aorta [18] (**Figure 3**).

**Figure 3.** Concept of interventional reconstruction of the dissected aorta with sealing of the proximal entries, depressurization of the false lumen, and initiation of false lumen thrombosis.

Life expectancy of more than 6 month

**3. Indications for endovascular stent-graft therapy**

the entire dissected aorta [18] (**Figure 3**).

**Figure 2.** Classification of thoracic aortic aneurysms.

60 Aortic Aneurysm

In the event of an aortic dissection, the sealing of proximal entry tears with a customized stent graft has proven to be the most effective method for excluding a growing aneurysmal false lumen. Although the closure of a distal reentry tear is also desirable, this is not particularly necessary to achieve optimal results [12, 13, 17]. A favorable postinterventional outcome would constitute adequate depressurization and shrinkage of the false lumen, supplemented in an ideal scenario by a complete thrombosis of this lumen with consequent remodeling of

**Figure 3.** Concept of interventional reconstruction of the dissected aorta with sealing of the proximal entries,

depressurization of the false lumen, and initiation of false lumen thrombosis.

**Table 1.** Current indication for stent-graft implantation.

The role of percutaneous fenestration in the management of aortic dissection is debatable and should be in all likelihood avoided considering its profile of unproven benefits and interventional risk. The relevance of a team of professionals experienced in treating aortic disease is absolute considering the necessity for a thorough evaluation of the clinical, technical, and anatomical criteria before a treatment strategy has been defined. The general indication for emergency placement of stent grafts has been extended to scenarios where patients have intractable pain associated with a descending dissection, develop a rapidly expanding false lumen diameter, percolate extra-aortic blood (as a sign of imminent rupture), or show signs of a distal malperfusion syndrome [11–13] (**Table 1**). The use of endovascular stent grafting as the primary strategy may be justified in the event of late-onset complications like malperfusion of vital peripheral aortic branches.

#### **4. Anatomical measurements for thoracic aortic pathology**

Multi-slice computed tomography (CT) has special relevance in the diagnosis of aortic disease. In addition to the reconstruction of a three-dimensional perspective, certain descriptive features of the thoracic aorta outlining the condition of the aortic wall (atheroma, calcification, and thrombus) as well as shape and size of the aortic pathology (diameter, length, and shape) need to be elucidated before the formulation of treatment strategies [19].

Although an initial CT angiography/magnetic resonance (MR) angiography is considered as the primary diagnostic tool for aortic pathologies, the use of transesophageal echocardiography and intravascular ultrasound to ascertain additional valuable information has also been advised. For instance, flow-sensitive MR sequences or contrast-enhanced TEE not only shows the communication sites between true and false lumen, but it also highlights the dynamic flow pattern in the false lumen prior to stent-graft placement. The use of contrast angiography has limited potential in this scenario as measured values are generally unreliable.

The measurement of vessel diameters is generally not defined by any set of conventional practice and operators usually refer to calculations derived from the inner vessel wall (endothelial trailing edge) hinging their assumption on the basis that this will guarantee some degree of oversizing, a potentially desirable outcome for endograft placement. Our in-house protocol delineates the diameter of the normal appearing proximal aorta (inner edge to edge) measured from a transverse plane perpendicular to the long axis of the aorta (preferentially from contrast-enhanced multi-slice CT images) (**Figure 4**).

The evaluation of access vessels for size and tortuosity is also pertinent because stent-graft delivery systems are quite large (up to 24F), and there is an associated risk of significant trauma to the femoral access site and iliac arteries. Severe aortic angulation or tortuosity, friable atheroma or thrombus lining the aortic wall, and aortic pathology involving the ascending aorta are some features that preclude the use of thoracic stent grafts. Additionally, the role of appropriate peri-interventional image reconstruction in aortic arch pathology is further cemented when considering the placement of a stent graft for a Type B dissection, where the demarcation of nearby aortic branches (including the left subclavian or left common carotid artery) is vital.

**Figure 4.** CT scan of a patient with dilated thoracic aorta. Due to the fact that the aorta follows a curved and threedimensionally tortuous path, the axial scans are inadequate for measuring aortic diameters, as are sagittal and coronal planes for measuring aortic lengths.

#### **5. Initial treatment**

and anatomical criteria before a treatment strategy has been defined. The general indication for emergency placement of stent grafts has been extended to scenarios where patients have intractable pain associated with a descending dissection, develop a rapidly expanding false lumen diameter, percolate extra-aortic blood (as a sign of imminent rupture), or show signs of a distal malperfusion syndrome [11–13] (**Table 1**). The use of endovascular stent grafting as the primary strategy may be justified in the event of late-onset complications like malperfu-

Multi-slice computed tomography (CT) has special relevance in the diagnosis of aortic disease. In addition to the reconstruction of a three-dimensional perspective, certain descriptive features of the thoracic aorta outlining the condition of the aortic wall (atheroma, calcification, and thrombus) as well as shape and size of the aortic pathology (diameter, length, and shape)

Although an initial CT angiography/magnetic resonance (MR) angiography is considered as the primary diagnostic tool for aortic pathologies, the use of transesophageal echocardiography and intravascular ultrasound to ascertain additional valuable information has also been advised. For instance, flow-sensitive MR sequences or contrast-enhanced TEE not only shows the communication sites between true and false lumen, but it also highlights the dynamic flow pattern in the false lumen prior to stent-graft placement. The use of contrast angiography has limited potential in this scenario as measured values are gen-

The measurement of vessel diameters is generally not defined by any set of conventional practice and operators usually refer to calculations derived from the inner vessel wall (endothelial trailing edge) hinging their assumption on the basis that this will guarantee some degree of oversizing, a potentially desirable outcome for endograft placement. Our in-house protocol delineates the diameter of the normal appearing proximal aorta (inner edge to edge) measured from a transverse plane perpendicular to the long axis of the aorta (preferentially from

The evaluation of access vessels for size and tortuosity is also pertinent because stent-graft delivery systems are quite large (up to 24F), and there is an associated risk of significant trauma to the femoral access site and iliac arteries. Severe aortic angulation or tortuosity, friable atheroma or thrombus lining the aortic wall, and aortic pathology involving the ascending aorta are some features that preclude the use of thoracic stent grafts. Additionally, the role of appropriate peri-interventional image reconstruction in aortic arch pathology is further cemented when considering the placement of a stent graft for a Type B dissection, where the demarcation of nearby aortic branches (including the left subclavian or left common carotid

**4. Anatomical measurements for thoracic aortic pathology**

need to be elucidated before the formulation of treatment strategies [19].

contrast-enhanced multi-slice CT images) (**Figure 4**).

sion of vital peripheral aortic branches.

62 Aortic Aneurysm

erally unreliable.

artery) is vital.

An acute aortic disease is a medical emergency and suspected patients require urgent admission to an intensive care or monitoring unit with an emphasis on immediate diagnostic evaluation [20]. Initial management strategies include the treatment of pain and maintenance of a systolic blood pressure of 110 mmHg with the use of morphine sulphate and intravenous beta-blockers (metoprolol, esmolol, or labetolol), respectively. The use of additional anti-hypertensives like angiotensin-converting enzyme inhibitors or vasodilators like sodium nitroprusside has been prescribed in refractory cases, while the intravenous use of verapamil or diltiazem is recommended for patients in whom betablockers are contraindicated. Although monotherapy with beta-blockers sufficiently controls cases of mild hypertension, the addition of sodium nitroprusside at an initial dose of 0.3 μg/kg/min proves to be an effective combination in a severe hypertensive state. A careful evaluation for blood loss, pericardial effusion, or heart failure (by echocardiography) is a prerequisite before administering volume in normotensive or hypotensive patients. Additionally, the control of heart rate is of utmost importance in this scenario [21]. Hemodynamic instability compounds to the gravity of the clinical situation, with patients often requiring endotracheal intubation, mechanical ventilation, and urgent bedside transesophageal echocardiography or rapid CT for confirmation of the provisional diagnosis. In rare instances, the diagnosis of cardiac tamponade as quantified by transthoracic echocardiography may justify an immediate sternotomy in order to obtain surgical access to the ascending aorta, thus reducing the risk of shock, ischemic brain damage, and circulatory arrest.

#### **6. Technique of endovascular stent-graft placement**

The use of individually selected stent grafts to cover up to 20 cm (and sometimes even more) of the diseased aorta relies on measurements derived from different diagnostic modalities. These tests also have certain additional benefits. The transesophageal echocardiography is mandatory for detection of small entries, while contrast-enhanced CT (Computed tomography) angiograms have proven to be the preferred tool for diagnosis of unstable patients in an emergency situation. The use of intravascular ultrasound (IVUS), using a 10 MHz ultrasound catheter-mounted transducer with the potential of manual maneuverability through the diseased aorta, can be used to better identify communications, partial thrombosis, or other anomalies.

The operative placement of an endovascular stent graft is usually performed in a Cathlab or a hybrid operating room equipped with digital angiography and necessary support for general anesthesia (a compulsory prerequisite for all patients). The femoral artery generally serves as the access-site as it could typically accommodate a 20–24 stent-graft system. After the employment of the Seldinger technique to position the initial sheath, a 260 cm stiff wire (e.g., Amplatzer) is placed over a pigtail catheter and navigated along with a soft wire in the true lumen under both fluoroscopic and transesophageal ultrasound guidance. The "embracement technique" augmented by the use of two pigtail catheters could prove useful in maintaining the true lumen during complex cases when multiple reentries into the abdominal aorta are required. Essentially, a catheter inserted via the left brachial artery navigates through the true aortic lumen and meets the femoral pigtail catheter in the true lumen of the abdominal aorta, thence pulling it up into the aortic arch. This technique ensures the definitive positioning of the stiff guide wire within the true lumen necessary for the ensuing endovascular intervention. The subsequent launch of the stent graft is performed by carefully advancing the graft over the stiff wire in the true lumen while briefly maintaining a low blood pressure through rapid right ventricular pacing [22]. To improve apposition of the stent struts to the aortic wall in the event of incomplete sealing of the proximal thoracic communications, a latex balloon may be shortly inflated at the target site postdeployment of graft and sealing of entry flap. Doppler-ultrasound and contrast fluoroscopy are useful techniques instrumental in confirming the immediate result and play a vital role when initiating adjunctive maneuvers. The navigation of wires and instruments is less cumbersome in the setting of a thoracic aortic aneurysm (TAA) or aortic ulcer; however, meticulous intraprocedural ultrasound imaging and fluoroscopy are essential to monitor the interventional progress. The close vicinity of the left subclavian artery origin to the primary tear in Type B dissections presents a unique anatomical problem, often requiring a radical solution. A complete closure of the left subclavian artery (LSA) ostium may be necessary at times to ensure the proper placement and debranching of the stent graft, else use of extra-anatomical bypasses would have to be considered [23]. Observational evidence dictates that prophylactic surgical maneuvers are not always required but could be performed electively after the endovascular intervention in the event of developing ischemia. Additionally, the existence of potential supra-aortic variants (e.g., presence of a lusorian artery, an incomplete vertebra-basilar system, or vertebral arteries directly originating from the arch) must be considered before the intentional occlusion of LSA [24].

#### **7. Device sizing and length**

**6. Technique of endovascular stent-graft placement**

64 Aortic Aneurysm

the arch) must be considered before the intentional occlusion of LSA [24].

The use of individually selected stent grafts to cover up to 20 cm (and sometimes even more) of the diseased aorta relies on measurements derived from different diagnostic modalities. These tests also have certain additional benefits. The transesophageal echocardiography is mandatory for detection of small entries, while contrast-enhanced CT (Computed tomography) angiograms have proven to be the preferred tool for diagnosis of unstable patients in an emergency situation. The use of intravascular ultrasound (IVUS), using a 10 MHz ultrasound catheter-mounted transducer with the potential of manual maneuverability through the diseased aorta, can be used to better identify communications, partial thrombosis, or other anomalies. The operative placement of an endovascular stent graft is usually performed in a Cathlab or a hybrid operating room equipped with digital angiography and necessary support for general anesthesia (a compulsory prerequisite for all patients). The femoral artery generally serves as the access-site as it could typically accommodate a 20–24 stent-graft system. After the employment of the Seldinger technique to position the initial sheath, a 260 cm stiff wire (e.g., Amplatzer) is placed over a pigtail catheter and navigated along with a soft wire in the true lumen under both fluoroscopic and transesophageal ultrasound guidance. The "embracement technique" augmented by the use of two pigtail catheters could prove useful in maintaining the true lumen during complex cases when multiple reentries into the abdominal aorta are required. Essentially, a catheter inserted via the left brachial artery navigates through the true aortic lumen and meets the femoral pigtail catheter in the true lumen of the abdominal aorta, thence pulling it up into the aortic arch. This technique ensures the definitive positioning of the stiff guide wire within the true lumen necessary for the ensuing endovascular intervention. The subsequent launch of the stent graft is performed by carefully advancing the graft over the stiff wire in the true lumen while briefly maintaining a low blood pressure through rapid right ventricular pacing [22]. To improve apposition of the stent struts to the aortic wall in the event of incomplete sealing of the proximal thoracic communications, a latex balloon may be shortly inflated at the target site postdeployment of graft and sealing of entry flap. Doppler-ultrasound and contrast fluoroscopy are useful techniques instrumental in confirming the immediate result and play a vital role when initiating adjunctive maneuvers. The navigation of wires and instruments is less cumbersome in the setting of a thoracic aortic aneurysm (TAA) or aortic ulcer; however, meticulous intraprocedural ultrasound imaging and fluoroscopy are essential to monitor the interventional progress. The close vicinity of the left subclavian artery origin to the primary tear in Type B dissections presents a unique anatomical problem, often requiring a radical solution. A complete closure of the left subclavian artery (LSA) ostium may be necessary at times to ensure the proper placement and debranching of the stent graft, else use of extra-anatomical bypasses would have to be considered [23]. Observational evidence dictates that prophylactic surgical maneuvers are not always required but could be performed electively after the endovascular intervention in the event of developing ischemia. Additionally, the existence of potential supra-aortic variants (e.g., presence of a lusorian artery, an incomplete vertebra-basilar system, or vertebral arteries directly originating from A key factor influencing strategies in aortic dissection and TAA interventions is the length of the true lumen that needs scaffolding with an endoprosthesis. The instinctual choice between covering primarily the proximal entry point and alternatively lining a longer length of the true lumen (where the descending thoracic aorta down to the level of the diaphragm is also treated) can significantly alter the course and prognosis of the intervention. Although a longer scaffold provides potentially greater stability and is associated with lower recurrence, the grave risk of potential paraplegia resulting from compromise in spinal arterial supply serves as the single biggest reason to avoid extensive coverage. Observational evidence indicates that stent-graft coverage exceeding 20 cm, previous abdominal aortic surgery, overstenting of the LSA, or use of the left mammary artery for coronary bypass is associated with an increased risk of spinal ischemia. Essentially, all scenarios leading to compromised collateral flow in the spinal cord arterial network are associated with an increased risk for neurological complications, thus underlining the need to avoid overstenting the LSA or use long stent grafts. The angiographic identification of the anterior spinal artery in this scenario has recently shown prognostic relevance.

The disadvantage of shorter coverage lengths is primarily associated with potential multiple reentries presenting themselves in the distal portions of the descending aorta and maintaining perfusion of the false lumen despite proximal entry-site closure. This deviant presentation can be managed by the use of uncovered bare metal stents ensuring distal reapposition of the dissecting lamella without any compromise to abdominal side branches or spinal arteries, in effect sustaining the distal extension of the scaffolding concept of endoluminal repair.

The proximal aspect of the device should be sized to the internal luminal diameter of the aorta, close to the left subclavian origin in order to achieve attachment and fixation at the proximal "neck." TAA interventions may require a degree of device oversizing by about 10–15%, while the endoprosthesis used in aortic dissection should never be oversized. Fatal complications are associated with excessive device oversizing, typically as a result of ensuing trauma to the aortic wall, thus resulting in either a retrograde dissection into the arch or conversion of a Type B dissection into a Type A dissection. Cases of aortic perforation and formation of pseudoaneurysms have also been reported in literature. The countereffects of oversizing further distally into the descending thoracic aorta include the risk of tears in the membrane between the two channels, thus forming a new reentry point, and consequently sustaining the ongoing pressurized perfusion of the false lumen. However, if absolute measures do dictate the extensive scaffolding of the aortic lumen, the operator could choose to use two different shorter grafts instead of a single long graft. The final decision represents a compromise between the reduced number of modular junctions and additional frictional forces associated with the deployment of a long stent graft. The concurrent employment of two stent grafts, when deemed necessary, requires them being fashioned in a "telescopic" manner, with the amount of overlap exceeding 30 mm in straight anatomic segments and measuring up to 50 mm or more in the angulated or curved segments of the aorta. The geometry of the presumed junction between the grafts provides some assistance in estimating the length of overlap required at the connecting zones. A key deciding factor in this situation is the length of the radius of the curve, with shorter radii requiring a longer stent overlap on the lesser curve. Another prominent factor influencing the decision regarding overlap is the degree of support provided by the native aorta at the modular junction. If the junction occurs in the sac of a large fusiforme aneurysm rather than in a segment of aorta with a normal diameter, the required overlap should be longer. The reason for this approach is a tendency for the graft to move out toward the greater curve of the aneurysmatic aortic segment due to mechanical forces associated with the pulsatile motion of the aorta, potentially causing a migration or a disconnection of the modular components.

#### **8. Extended scaffolding with bare stents**

The general consensus on management of entry tears dictates treatment with a covered stent graft, while the remaining distal thoracic or even abdominal aorta may be additionally supported by uncovered stents [25]. In selecting the suitable stent graft, the following principles should be followed:

#### **9. Landing zone**

The three-dimensional mechanical forces associated with the pulsatile flow that "play" on an endoprosthesis in the thoracic aorta are far greater and more complex than those in the abdominal aorta. It is for this reason that an extremely stable graft-anchorage and optimal graft-apposition are prerequisites for a satisfying result. The proximal and distal landing zones should ideally be free of aortic wall atheroma or thrombi and circumscribe 15 mm in length. The contemporary hypothesis suggesting that the left subclavian artery is a natural barrier beyond which it is impossible to deploy stent grafts has been now rendered redundant.

The suitable presentation of the aortic arch between the left subclavian artery and the origin of the left common carotid artery, coupled with its relatively horizontal orientation in comparison to the aorta distal to the LSA, has encouraged interventionists to use this segment of the aorta as a preferred anchor zone (with or without bypassing the LSA). To ascertain optimal cerebral circulation, it is considered prudent to perform a preinterventional digital subtraction angiography (DSA), CT, or magnetic resonance angiography. This could help identify patients with an incomplete circle of Willis or other limitations or abnormalities of cerebral vascular supply. In patients affected with a cerebrovascular pathology, prophylactic measures such as carotid-subclavian bypass might be considered prior to the stent-associated covering of the LSA. An obvious alternative is the use of bare stents proximally for better alignment while foregoing the risk of occluding a vital branch.

#### **10. Hybrid arch procedures**

presumed junction between the grafts provides some assistance in estimating the length of overlap required at the connecting zones. A key deciding factor in this situation is the length of the radius of the curve, with shorter radii requiring a longer stent overlap on the lesser curve. Another prominent factor influencing the decision regarding overlap is the degree of support provided by the native aorta at the modular junction. If the junction occurs in the sac of a large fusiforme aneurysm rather than in a segment of aorta with a normal diameter, the required overlap should be longer. The reason for this approach is a tendency for the graft to move out toward the greater curve of the aneurysmatic aortic segment due to mechanical forces associated with the pulsatile motion of the aorta, potentially causing a migration or a

The general consensus on management of entry tears dictates treatment with a covered stent graft, while the remaining distal thoracic or even abdominal aorta may be additionally supported by uncovered stents [25]. In selecting the suitable stent graft, the following principles

The three-dimensional mechanical forces associated with the pulsatile flow that "play" on an endoprosthesis in the thoracic aorta are far greater and more complex than those in the abdominal aorta. It is for this reason that an extremely stable graft-anchorage and optimal graft-apposition are prerequisites for a satisfying result. The proximal and distal landing zones should ideally be free of aortic wall atheroma or thrombi and circumscribe 15 mm in length. The contemporary hypothesis suggesting that the left subclavian artery is a natural barrier beyond which it is impossible to deploy stent grafts has been now rendered

The suitable presentation of the aortic arch between the left subclavian artery and the origin of the left common carotid artery, coupled with its relatively horizontal orientation in comparison to the aorta distal to the LSA, has encouraged interventionists to use this segment

permit ease of use and provide accurate placement at the desired zone.

disconnection of the modular components.

to assure optimal conformability.

should be followed:

66 Aortic Aneurysm

**9. Landing zone**

redundant.

**8. Extended scaffolding with bare stents**

The relative proximity of supra-aortic branches needing preservation poses a strict interventional challenge, considering that the aortic arch anatomy and pathology is complicated by varying degrees of length and angulation [26–28]. The traditional open arch surgical reconstruction techniques requiring perioperative hypothermic cardiac arrest, extracorporeal circulation, and selective cerebral perfusion have been shown to manage aortic arch pathologies effectively. However, these major surgical procedures carry the risk of significant mortality, paraplegia, and cerebral stroke. Younger patients with a smaller risk-profile qualify for such an open repair, while highrisk patients constitute the group of candidates ill-suited for this surgical approach. Hybrid arch procedures are a combination of methods preserving cerebral perfusion (like the debranching bypass with supra-aortic vessel transposition) on the one hand, while objectively providing patient-centric solutions for complex aortic arch lesions through thoracic endografting on the other (**Figure 5**). Hybrid arch procedures are performed without hypothermic circulatory arrest or extracorporeal circulation, thus expanding the treatable population demographic to older and high-risk patients with severe comorbidities currently not eligible for open surgical repair.

**Figure 5.** Contrast-medium enhanced MR-angiography of the aorta in a case of an arch aneurysm. (a) Aneurysm of the aortic arch involving the supra-aortic branches. (b) Result after hybrid procedure with debranching of the supraaortic vessels and stent-graft placement in the aortic arch.

#### **11. Aftercare and long-term follow-up**

The long-term care of patients successfully treated for an acute aortic dissection is pivoted on the appreciation of this disease as a systemic illness. Estimates suggest that nearly one-third of patients surviving an acute dissection of the thoracic aorta will either experience complications like extension of the dissection and late aortic rupture or require surgical correction of a newly formed aortic aneurysm, within 5 years of initial presentation [29]. All patients merit aggressive medical therapy, follow-up visits, and serial CT-imaging. The medical management of these patients is primarily centered on therapy with beta-blockers, in essence serving as the cornerstone of successful aftercare. High blood pressure values and steeper curves representing changes in the blood volume and pressure (dp/dt) have been shown to accelerate aortic expansion in Marfan's syndrome and also in patients with chronic abdominal aortic aneurysms (AAA). The aim in patients with thoracic aortic disease is to balance blood pressure values to less than 135/80 mmHg, while patients diagnosed with Marfan's syndrome are advised to maintain blood pressure levels below 130/80 mmHg [11–13]. Additionally, an adequate control of heart rate under 60 beats per minute has been associated with significantly fewer secondary adverse events (aortic expansion, recurrent aortic dissection, aortic rupture, and/or need for aortic surgery) in Type B aortic dissection patients [21].

Serial CT imaging of the aorta is an essential component of long-term management (before and after surgery or stent-graft placement). The choice of imaging modality, CT or magnetic resonance, is dependent on institutional availability and expertise. Past recommendations have suggested follow-up imaging at 1-, 3-, 6-, 9-, and 12-month intervals following discharge, and annually thereafter [11–13]. This aggressive strategy, in effect, underlines the observation that both hypertension and aortic expansion/dissection are common and not easily predicted in the first months following hospital discharge. The risk of dissection progression and aneurysm formation anywhere along the entire length of the aorta cements the need for consistent follow-up imaging of the complete thoracic aorta and in exceptional cases, imaging of the thoracoabdominal as well as abdominal aorta.

#### **12. Management of complications**

#### **12.1. Endoleaks**

An endoleak is a condition defined by the persistence of blood flow outside the endovascular stent-graft lumen, contained within the aneurysm sac, or in certain cases adjacent to the vascular segment treated by the stent graft. Endoleaks generally persist for a long duration, with a few eventually developing a late aneurysmal rupture, while some may also resolve and close spontaneously.

The classification of endoleaks according to time of onset permits their grouping into "primary endoleaks," when it occurs during the perioperative period (lesser than 30 days) or secondary leak when it is detected later. Further subcategorization requires precise information on periprosthetic blood flow. A Type I endoleak is an indicator of a persistent perigraft channel of blood flow caused by an inadequate seal at either the proximal (I-a) or distal (I-b) stent-graft end or attachment zones. A Type II endoleak is attributed to retrograde flow into the aneurysmal sac via aortic side branches, while a Type III endoleak is caused by component disconnection (III-a) or fabric tear, fabric disruption, or graft disintegration (III-b). Type III-b can be further stratified as minor (<2 mm), or major (>2 mm). The Type IV endoleak is caused by blood flow through an intact but otherwise porous fabric, observed during the first 30 days after stent-graft implantation. If an endoleak is detected on imaging studies but the precise source cannot be determined, the endoleak is categorized as an endoleak of undefined origin.

Various strategies have been outlined for the treatment of endoleaks. The conservative line of management, essentially constituting strict observation and follow-up is especially suggested for Type II and Type IV endoleaks. An endovascular reintervention (e.g., balloon-inflation and/or implantation of an additional stent graft) is suggested for the management of Type I and Type III endoleaks. If these endovascular maneuvers fail in their attempt to exclude the aneurysm from circulation, the resulting increase in TAA-diameters could be corrected by open surgery.

#### **13. Aneurysm evolution after stent-graft treatment**

**11. Aftercare and long-term follow-up**

68 Aortic Aneurysm

thoracoabdominal as well as abdominal aorta.

**12. Management of complications**

**12.1. Endoleaks**

close spontaneously.

The long-term care of patients successfully treated for an acute aortic dissection is pivoted on the appreciation of this disease as a systemic illness. Estimates suggest that nearly one-third of patients surviving an acute dissection of the thoracic aorta will either experience complications like extension of the dissection and late aortic rupture or require surgical correction of a newly formed aortic aneurysm, within 5 years of initial presentation [29]. All patients merit aggressive medical therapy, follow-up visits, and serial CT-imaging. The medical management of these patients is primarily centered on therapy with beta-blockers, in essence serving as the cornerstone of successful aftercare. High blood pressure values and steeper curves representing changes in the blood volume and pressure (dp/dt) have been shown to accelerate aortic expansion in Marfan's syndrome and also in patients with chronic abdominal aortic aneurysms (AAA). The aim in patients with thoracic aortic disease is to balance blood pressure values to less than 135/80 mmHg, while patients diagnosed with Marfan's syndrome are advised to maintain blood pressure levels below 130/80 mmHg [11–13]. Additionally, an adequate control of heart rate under 60 beats per minute has been associated with significantly fewer secondary adverse events (aortic expansion, recurrent aortic dissection, aortic rupture,

Serial CT imaging of the aorta is an essential component of long-term management (before and after surgery or stent-graft placement). The choice of imaging modality, CT or magnetic resonance, is dependent on institutional availability and expertise. Past recommendations have suggested follow-up imaging at 1-, 3-, 6-, 9-, and 12-month intervals following discharge, and annually thereafter [11–13]. This aggressive strategy, in effect, underlines the observation that both hypertension and aortic expansion/dissection are common and not easily predicted in the first months following hospital discharge. The risk of dissection progression and aneurysm formation anywhere along the entire length of the aorta cements the need for consistent follow-up imaging of the complete thoracic aorta and in exceptional cases, imaging of the

An endoleak is a condition defined by the persistence of blood flow outside the endovascular stent-graft lumen, contained within the aneurysm sac, or in certain cases adjacent to the vascular segment treated by the stent graft. Endoleaks generally persist for a long duration, with a few eventually developing a late aneurysmal rupture, while some may also resolve and

The classification of endoleaks according to time of onset permits their grouping into "primary endoleaks," when it occurs during the perioperative period (lesser than 30 days) or secondary leak when it is detected later. Further subcategorization requires precise information on periprosthetic blood flow. A Type I endoleak is an indicator of a persistent perigraft

and/or need for aortic surgery) in Type B aortic dissection patients [21].

The thoracic aorta is defined by a set of unique anatomical features and habits a distinctive biomechanical and hemodynamic environment, which explains some of the rare late complications specific to device use seen in this region. The descending thoracic aorta, unlike the abdominal aorta, is relatively mobile in the thorax and is subject to complex and vigorous threedimensional motion. The only points of fixation are the aortic root and sites of origin of major branches, thereby permitting the mobility of a long aortic segment extending from the LSA to the celiac artery. This contributes to the elongation, angulation, and eventual enlargement of the thoracic aorta between these points, thus promoting the development of an aneurysm. The mechanical forces exert a complex pattern of dynamic circumferential, radial, and axial forces on thoracic stent grafts, resulting in a stress field significantly different than that exerted on abdominal stent grafts. It is, however, still relatively rare to see aneurysms develop in the dissected aorta post stent-graft treatment. The relevance of strict clinical and imaging follow-up to monitor anatomical changes in the thoracic aorta is highlighted by the fact that the development of a false lumen thrombosis secondary to thoracic endografting is essential to the prevention of late aortic expansion.

A pertinent issue of concern is the fate of the distal aortic segment despite successful thoracic stent-graft placement. In the presence of large reentry points, the thoracoabdominal segment of the false lumen has a tendency to remain patent and remodel completely, setting the stage for late complications such as aneurysmal enlargement at the proximal or distal end of the stent graft. Some other complications include perforations of the fragile aortic intima by the ends of the metallic stent (especially in the early phase of acute aortic dissection), and injuries caused by stiff guide-wires and device manipulation potentially setting the stage for an evolving aneurysm. The risk of these complications is noticeably diminished by the introduction of a more flexible and soft tip delivery system aided by minimally traumatic thoracic guide-wires specifically designed for these interventions. Additionally, the time required to perform an endovascular intervention could provide insight to complications such as stroke or bleeding; both of which could be significantly reduced by experienced interventionists requiring less than 30 min to complete a case. It has been also suggested that the patency of the abdominal aortic false lumen may be related to persisting communications between the true and false lumen. Treatment of these communications at the level of distal thoracic and abdominal aorta could potentially obliterate the false lumen and reduce the aortic diameter. In clinical practice, however, the closure is difficult to achieve because of the proximity or involvement of the visceral branches. Another late complication of graft treatment is related to the mechanical weakness of dissected aortic walls causing distention of the aorta beyond the portion covered by the stent graft. Prevention of these complications can be partially achieved during the primary procedure by ensuring adequate landing zones proximal and distal to the stent graft, and closure of large fenestrations along the length of the false lumen. The use of a provisional bare metal stent as a distal extension to the stent graft has been reported to facilitate aortic remodeling and help completely repair the distal dissected segments without compromising important side-branches (Provisional Extension To Induce Complete Attachement after stent-graft implantation (PETTICOAT) technique) [25]. This would address the problem of persistent perfusion within the false lumen as well as any increase in aneurysmal size.

#### **14. Stent-graft infection**

The infected prosthetic graft represents a rare complication that could be difficult to diagnose despite extensive work up, with consensus reached only after thorough analysis of imaging, hematological, and clinical parameters. The presence of air, soft tissue accumulation, and progressive enlargement of the aneurysm sac is usually pathognomonic, and suspicious changes spotted in imaging coupled with raised markers of systemic inflammation and clinical symptoms are generally suggestive of an infective process. The diagnostic use of positron emission tomography (PET) radionuclide studies is a helpful tool in most cases. Prior to initiation of treatment against thoracic endograft infections, data concerning diagnostic certainty, pathogenesis of the infecting microbe, the extent of infection, the presenting features, and the medical co-morbidities of a given patient need to be evaluated.

As with the treatment of all prosthetic graft infections, multiple management strategies have been proposed in this scenario. These include a conservative line of treatment with targeted intravenous antibiotics or also alternatively by direct puncture and application into the perigraft space; insertion of another stent graft into the potentially infected graft or excision of the infected stent graft with debridement of the surrounding tissue; and in-situ/extra-anatomic vascular reconstruction. Irrespective of the applied strategy, the treatment of aortic graft infection remains difficult and problematic. In the absence of management algorithms defining treatment strategies in the varying forms of presentation and degrees of infection, individualized therapies need to be devised while weighing the risks in each scenario. In general, a decision must be made as to whether treatment is to be potentially curative or palliative. The curative treatment approach encompasses an aggressive open surgery, justified only in certain cases in lieu of the relatively high mortality associated with the procedure.

The palliative approach suggests placement of an endovascular graft (graft-in-graft approach) thereby preventing the risk of life-threatening bleeding or fistulation. Patients with complex graft disease should always be treated in experienced centers equipped to conduct all treatment variations.

#### **15. Retrograde Type A dissection following stent-graft placement**

There have been cases reporting a proximal aortic dissection after placement of an endograft; the incidence of this complication, according to existing data, ranges presumably between 1 and 2% and generally occurs shortly after the intervention [30, 31]. Chest pain or symptoms of an ischemic heart or brain should immediately alert the suspicion that a Type B dissection has modified itself to a Type A dissection, with a higher morbidity and mortality risk. An emergency Computed tomography angiography (CTA) and subsequent surgery are the only lifesaving options for the patient. There are several reasons why Type A dissections may occur after stent-graft placement in the descending thoracic aorta (**Table 2**).

The initial misinterpretation of a Type A dissection as a Type B dissection

evolving aneurysm. The risk of these complications is noticeably diminished by the introduction of a more flexible and soft tip delivery system aided by minimally traumatic thoracic guide-wires specifically designed for these interventions. Additionally, the time required to perform an endovascular intervention could provide insight to complications such as stroke or bleeding; both of which could be significantly reduced by experienced interventionists requiring less than 30 min to complete a case. It has been also suggested that the patency of the abdominal aortic false lumen may be related to persisting communications between the true and false lumen. Treatment of these communications at the level of distal thoracic and abdominal aorta could potentially obliterate the false lumen and reduce the aortic diameter. In clinical practice, however, the closure is difficult to achieve because of the proximity or involvement of the visceral branches. Another late complication of graft treatment is related to the mechanical weakness of dissected aortic walls causing distention of the aorta beyond the portion covered by the stent graft. Prevention of these complications can be partially achieved during the primary procedure by ensuring adequate landing zones proximal and distal to the stent graft, and closure of large fenestrations along the length of the false lumen. The use of a provisional bare metal stent as a distal extension to the stent graft has been reported to facilitate aortic remodeling and help completely repair the distal dissected segments without compromising important side-branches (Provisional Extension To Induce Complete Attachement after stent-graft implantation (PETTICOAT) technique) [25]. This would address the problem of persistent perfusion within the false lumen as well as any increase in aneurysmal size.

The infected prosthetic graft represents a rare complication that could be difficult to diagnose despite extensive work up, with consensus reached only after thorough analysis of imaging, hematological, and clinical parameters. The presence of air, soft tissue accumulation, and progressive enlargement of the aneurysm sac is usually pathognomonic, and suspicious changes spotted in imaging coupled with raised markers of systemic inflammation and clinical symptoms are generally suggestive of an infective process. The diagnostic use of positron emission tomography (PET) radionuclide studies is a helpful tool in most cases. Prior to initiation of treatment against thoracic endograft infections, data concerning diagnostic certainty, pathogenesis of the infecting microbe, the extent of infection, the presenting features, and the

As with the treatment of all prosthetic graft infections, multiple management strategies have been proposed in this scenario. These include a conservative line of treatment with targeted intravenous antibiotics or also alternatively by direct puncture and application into the perigraft space; insertion of another stent graft into the potentially infected graft or excision of the infected stent graft with debridement of the surrounding tissue; and in-situ/extra-anatomic vascular reconstruction. Irrespective of the applied strategy, the treatment of aortic graft infection remains difficult and problematic. In the absence of management algorithms defining treatment strategies in the varying forms of presentation and degrees of infection, individualized therapies need to be devised while weighing the risks in each scenario. In

medical co-morbidities of a given patient need to be evaluated.

**14. Stent-graft infection**

70 Aortic Aneurysm

Spread of the dissection into the ascending aorta or aortic arch due improper placement of the stent graft relatively distant to the LSA, or the possible maneuvering into the false lumen

Under- or oversizing of the stent graft, with consequent leaks or additional injuries to the aortic wall

Malapposition of the stent graft to the aortic wall at the proximal landing zone resulting in subsequent collapse of the proximal stent graft

Ballooning of the proximal end of the stent graft resulting in injury of the diseased aortic wall, thus causing the extension of the dissection in the aortic arch and ascending aorta

Development of a Type A dissection independent of the existing Type B dissection

**Table 2.** Cause of Type A aortic dissection after stent-graft implantation.

In these cases, it is of absolute importance to advance the guide-wire, catheter, and endograft in the true lumen only. If doubts persist concerning the correct positioning of the guide wire (in the true or false lumen), the use of angiography and transoesophageal echocardiography is instrumental before initiation of the next step. Signs differentiating the true from the false lumen include luminal size, where the false aortic lumen is usually larger than the true lumen, as well as flow at entry, which is generally directed into the false lumen. This explains the damping of the pulse amplitude and a poorly palpable pulse in many of these patients.

Precise measurement of the proximal aortic dimensions is essential for the selection of the size of stent graft and successful sealing of aortic tears. In Type B dissection, the stent graft is normally placed with its proximal end directly at the origin of the LSA. The proximal landing of a stent graft is usually close to the LSA, even though the tear could be in the middle portion; so performed, when considering the possibility of a dissection membrane developing a new tear between LSA and proximal end of the stent graft. In successful cases, angiography demonstrates a good result with complete sealing of the leak and absence of signs showing renewed opacification of the false lumen. Occasionally, a stiff endograft chafes on the fragile dissection membrane and a new endoleak may develop. This could possibly require additional stent grafting or eventually lead to open surgery.

#### **16. Paraplegia after stent-graft placement**

The risk of spinal cord ischemia is of significant concern post stent-graft placement as there is a frequent need to cover multiple intercostal arteries as also the artery of Adamkiewitz (the single prominent intersegmental branch from the aorta at the lower thoracic or upper lumbar level). Interestingly, around 3–12% of the stent-graft patients treated for aneurysms, dissections, ulcers, intramural hematoma, or aortic traumatic transsection are at risk to develop spinal cord ischemia. Although occlusion of important radicular arteries that originate from vertebral, intercostal, and lumbar arteries is primarily responsible for ischemia of the spinal cord, associated factors such as ischemia-reperfusion and hypotension may also play a causal role in the development of paraplegia. This is a telling contradiction to the widely held impression that the coverage of the segmental artery or the orifices of the intercostal/ interlumbar arteries by the stent graft represents the single possible and most critical cause of spinal ischemia. Measures to prevent occurrence of paraplegia in stent-graft patients should include several aspects (**Table 3**).

o Coverage of long segment (>20 cm)

H2 O to generate space for collateral arteries to fill and perfuse better)

**Table 3.** Factors influencing the rate of paraplegia.

Symptoms of paraplegia or paraparesis could be possibly reversed if a spinal tap is introduced without any delay and arterial perfusion pressure is maintained at a systolic pressure of 140 mmHg by pharmacological means or volume replenishment.

Screening for high-risk patients

o Age > 75

o Anticipated endograft coverage between T9 and T12 (location of anterior spinal artery)

o Compromised collateral pathways (e.g., LIMA as coronary artery bypass, infrarenal surgical aortic repair)

o Long extent of atherosclerotic lesions

<sup>-</sup>Early detection of spinal cord ischemia

o Somatosensory-evoked potentials

o Motor-evoked potentials

#### **17. Stroke after stent-graft placement**

normally placed with its proximal end directly at the origin of the LSA. The proximal landing of a stent graft is usually close to the LSA, even though the tear could be in the middle portion; so performed, when considering the possibility of a dissection membrane developing a new tear between LSA and proximal end of the stent graft. In successful cases, angiography demonstrates a good result with complete sealing of the leak and absence of signs showing renewed opacification of the false lumen. Occasionally, a stiff endograft chafes on the fragile dissection membrane and a new endoleak may develop. This could possibly require addi-

The risk of spinal cord ischemia is of significant concern post stent-graft placement as there is a frequent need to cover multiple intercostal arteries as also the artery of Adamkiewitz (the single prominent intersegmental branch from the aorta at the lower thoracic or upper lumbar level). Interestingly, around 3–12% of the stent-graft patients treated for aneurysms, dissections, ulcers, intramural hematoma, or aortic traumatic transsection are at risk to develop spinal cord ischemia. Although occlusion of important radicular arteries that originate from vertebral, intercostal, and lumbar arteries is primarily responsible for ischemia of the spinal cord, associated factors such as ischemia-reperfusion and hypotension may also play a causal role in the development of paraplegia. This is a telling contradiction to the widely held impression that the coverage of the segmental artery or the orifices of the intercostal/ interlumbar arteries by the stent graft represents the single possible and most critical cause of spinal ischemia. Measures to prevent occurrence of paraplegia in stent-graft patients should

Symptoms of paraplegia or paraparesis could be possibly reversed if a spinal tap is introduced without any delay and arterial perfusion pressure is maintained at a systolic pressure

of 140 mmHg by pharmacological means or volume replenishment.

O to generate space for collateral arteries to fill and perfuse better)

o Anticipated endograft coverage between T9 and T12 (location of anterior spinal artery)

o Compromised collateral pathways (e.g., LIMA as coronary artery bypass, infrarenal surgical aortic repair)

tional stent grafting or eventually lead to open surgery.

**16. Paraplegia after stent-graft placement**

include several aspects (**Table 3**).

Screening for high-risk patients

o Coverage of long segment (>20 cm)

o Long extent of atherosclerotic lesions -Early detection of spinal cord ischemia o Somatosensory-evoked potentials o Motor-evoked potentials

**Table 3.** Factors influencing the rate of paraplegia.

o Age > 75

72 Aortic Aneurysm

H2

Stroke is a grave complication occurring post stent-graft replacement and reports of incidence vary between 0 and 18%. The instrumentation in the aortic arch has been known to produce an embolic shower in the brain, and the use of guidewires and catheters as well as bulky delivery systems carrying the stent grafts in endovascular interventions in this region supplements to the risk. The need for balloon dilatation of stent grafts adds to the possibility of dislodgement of particles from the aortic arch. It is also well known that proper flushing of the stent-graft delivery system does not guarantee the elimination of air contained in the crimped stent graft. Moreover, bubbles are also released with the deployment of the stent graft. The confirmation of an open contralateral vertebral artery with correct formation of the basilar trunk and absence of intracranial branch anomalies is a basic prerequisite in patients in whom subclavian artery closure is considered.

In summary, there is an absolute need to completely define the left vertebral artery with depiction of its origin, patency, and size, as well as the size and condition of the right vertebral artery including the constitution of the basilar artery and its branches before conducting a procedure involving the closure of the LSA. In patients with compromised cerebral circulation, prior diagnosis of the four vessels with cerebral angiography is the recommended standard. When the left vertebral artery takes off from the aortic arch, occlusion of the LSA can result in severe ischemia of the left arm. If the left vertebral artery takes off from an aneurysm that is being excluded, it could result in a Type II endoleak, a severe steal phenomenon or even present as an ipsilateral posterior stroke. In such cases, a transposition of the LSA prior to the intervention is required.

#### **18. Conclusions**

Endovascular stent grafting represents an exciting therapeutic advancement and has emerged as an alternative therapy to open surgical repair in thoracic aortic pathologies. Although it is apparent that high-risk patients will benefit from this technology, the exact role of stent grafting needs to be defined as long-term data is constantly accumulated and analyzed, and further influenced by evolving devices and technology. Rather than replacing conventional surgical treatment, endovascular repair will likely play a complementary role and offer a less invasive option in the treatment armamentarium. Clearly, there are limitations to both approaches; however, while high-risk surgery is defined by clinical parameters, comorbidities and physiological reserve, contraindications for endovascular stent-graft treatment are defined mostly by anatomical criteria such as a too wide aorta to provide landing zones for an endoprosthesis or already irreversible paraplegia. Nevertheless, treatment should be carried out only in a center with experience in both endovascular and surgical procedures, and with adequate technical facilities. Treatment of thoracic aortic pathologies should be subject to prior multidisciplinary discussion, particularly with regard to risks of conversion and need for cardiopulmonary bypass. All patients should have access to a structural follow-up plan offering both regular clinical assessment and professional imaging follow-up by CT or MR angiography.

#### **Conflict of interest**

No conflict of interest for authors.

#### **Author details**

Ibrahim Akin1 \*, Uzair Ansari1 and Christoph A. Nienaber2

\*Address all correspondence to<EMAIL_ADDRESS>

#### **References**

[8] Evangelista A, Mukherjee D, Mehta RH, O'Gara PT, Fattori R, Cooper JV, Smith DE, Oh JK, Hutchison S, Sechtem U, Isselbacher EM, Nienaber CA, Pape LA, Eagle KA; International Registry of Aortic Dissection (IRAD) Investigators. Acute intramural hematoma of the aorta: a mystery in evolution. Circulation 2006; 111: 1063–1070.

discussion, particularly with regard to risks of conversion and need for cardiopulmonary bypass. All patients should have access to a structural follow-up plan offering both regular

clinical assessment and professional imaging follow-up by CT or MR angiography.

and Christoph A. Nienaber2

[1] Cooley DA, DeBakey ME. Resection of the thoracic aorta with replacement by homo-

[2] Svensson LG, Crawford ES, Hess KR, Coselli JS, Safi HJ. Experience with 1,509 patients undergoing thoracoabdominal aortic operations. J Vasc Surg 1993; 17: 357–368.

[3] Trimarchi S, Nienaber CA, Rampoldi V, Myrmel T, Suzuki T, Bossone E, Tolva V, Deeb MG, Upchurch GR Jr, Cooper JV, Fang J, Isselbacher EM, Sundt TM 3rd, Eagle KA; IRAD Investigators. Role and results of surgery in acute type B aortic dissection: insight from the International Registry of Aortic Dissection (IRAD). Circulation 2006; 114(1 Suppl):

[4] Volodos NL, Shekhanin VE, Karpovich IP, Troian VI, Gur'ev IuA. A self-fixing synthetic

[5] Dake MD, Miller DC, Semba CP, Mitchell RS, Walker PJ, Liddell RP. Transluminal placement of endovascular stent-grafts for the treatment of descending thoracic aortic aneu-

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[7] Coady MA, Rizzo JA, Hammond GL, Pierce JG, Kopf GS, Elefteriades JA. Penetrating ulcer of the thoracic aorta: what is it? How do we recognize it? How do we manage it?.

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**Conflict of interest**

**Author details**

Ibrahim Akin1

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**References**

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No conflict of interest for authors.

\*, Uzair Ansari1

\*Address all correspondence to<EMAIL_ADDRESS>1 Universitätsmedizin Mannheim, Mannheim, Germany

rysms. N Engl J Med 1994; 331: 1729–1734.

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2 Royal Brompton Hospital and Harefield Trust, London, UK

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[19] Salvolini L, Renda P, Fiore D, Scaglione M, Piccoli G, Giovagnoni A. Acute aortic syn-

[20] Estrera AL, Miller CC 3rd, Safi HJ, Goodrick JS, Keyhani A, Porat EE, Achouh PE, Meada R, Azizzadeh A, Dhareshwar J, Allaham A. Outcomes of medical management of acute

[21] Kodama K, Nishigami K, Sakamoto T, Sawamura T, Hirayama T, Misumi H, Nakao K. Tight heart rate control reduces secondary adverse events in patients with type B acute

[22] Nienaber CA, Kische S, Rehders TC, Schneider H, Chatterjee T, Bünger CM, Höppner R, Ince H. Rapid pacing for better placing: comparison of techniques for precise deploy-

[23] Rehders TC, Petzsch M, Ince H, Kische S, Korber T, Koschyk DH, Chatterjee T, Weber F, Nienaber CA. Intentional occlusion of the left subclavian artery during stent-graft implantation in the thoracic aorta: risks and relevance. J Endovasc Ther 2004; 22: 659–666.

[24] Peterson BG, Eskandari MK, Gleason TG, Morasch MD. Utility of left subclavian artery revascularization in association with endoluminal repair of acute and chronic thoracic

[25] Nienaber CA, Kische S, Zeller T, Rehders TC, Schneider H, Lorenzen B, Bünger C, Ince H. Provisional extension to induce complete attachment after stent-graft placement in type B aortic dissection: the PETTICOAT concept. J Endovasc Ther 2006; 13: 738–746. [26] Schumacher H, von Tengg-Kobligk H, Ostovic M, Henninger V, Ockert S, Böckler D, Allenberg JR. Hybrid arch procedures for endoluminal arch replacement in thoracic

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76 Aortic Aneurysm

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**Provisional chapter**

#### **Inflammatory Mediators in Abdominal Aortic Aneurysms Inflammatory Mediators in Abdominal Aortic Aneurysms**

Ismail Cassimjee, Regent Lee and Jyoti Patel Ismail Cassimjee, Regent Lee and Jyoti Patel Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/65961

#### **Abstract**

Aortic wall dilatation in abdominal aortic aneurysms is characterized by extracellular matrix degradation together with a loss of smooth muscle cells from the aortic media. This occurs in conjunction with a marked inflammatory cell infiltration. The inflammatory cell is characteristic of the second phase of aneurysmal development–progression. It is widely accepted that usually there are three phases involved in the development of abdominal aortic aneurysms: initiation, progression and rupture. In this chapter, we present an overview of the inflammatory mediators in abdominal aortic aneurysms and intraluminal thrombus, highlighting evidence from experimental models and human disease.

**Keywords:** inflammation, vascular, thrombus, macrophage, T cell

#### **1. Introduction**

An abdominal aortic aneurysm (AAA) is an abnormal dilatation of the infrarenal aorta to more than 1.5 times its normal diameter. It poses a risk of rupture which is associated with a significant mortality, and a prophylactic repair is recommended at 5.5 cm in diameter [1–3]. The diameter of an aneurysm is used as a surrogate predictor of rupture risk, and it is at this size that the procedure-related mortality approximates the rupture risk for an overall net benefit in patient survival. There has been much progress in treating aneurysms over the past two decades. The ability to treat aneurysms as minimally invasively, alongside improved perioperative care, has decreased the mortality from elective repair [2—4].

Evidence indicates AAAs as being a disease characterized by an underlying inflammatory cell infiltrate. The inflammatory cell infiltrate consists of differing cell types [macrophages, CD4/CD8 T cells, B cells, natural killer (NK) cells], which interact with each other creating a

microenvironment that produces factors, which result in wall degradation as well as further recruitment of other inflammatory cells.

An imbalance in collagen formation and degradation is thought to be responsible for aortic wall rupture [5]. It is a degenerative disease that shares many of the risk factors that predispose a person to atherosclerosis, but it is thought to be a separate pathological process from atherosclerosis (**Table 1**). Atherosclerosis presents typically as an occlusive disease; however, aneurysmal disease is characterized by elastin degeneration and smooth muscle cell apoptosis together with compensatory collagen deposition in the wall of the aneurysm. This may be a result of differing cytokine responses to the underlying inflammatory cell infiltrate [6].

The process of aneurysm formation is complex, and the progression is typically slow. It is multifactorial and requires a combination of anatomical predisposition and common risk factors to trigger its development. The natural history encompasses stages: initiation, formation, growth and rupture [7].

**Table 1.** Key differences between atherosclerosis and abdominal aortic aneurysm pathology.

#### **2. Risk factors for AAA development**

The development of degenerative AAAs is significantly related to major risk factors such as smoking, advanced age, hypertension and male gender. Having a first-degree relative with an AAA significantly increases the risk of developing an aneurysm. More especially in young patients, there may be an underlying connective tissue disease, like Ehlers-Danlos (Type IV) or Marfan's syndrome. Rarely, inflammatory conditions such as Takayasu's arteritis and Bechet's disease or infective conditions like HIV may present with an aneurysm [4].

#### **3. The aneurysm prone infrarenal aorta**

The combination of altered haemodynamics, a different smooth muscle cell derivation and a decrease in the elastic lamella of the infrarenal aorta predisposes it to aneurysm development. The embryological origin of the smooth muscle cells in the aorta of the infrarenal aorta may contribute to aneurysm propensity as they are derived from the splanchnic mesoderm, whereas the arch and thoracic aorta are derived from the neural crest and somite-derived cells, respectively [8]. There is a decrease in the elastin fibre and a decrease in the thickness of the wall of the aorta as it descends from the thorax into the abdominal aorta [9, 10]. In addition, the infrarenal aorta has its maximum number of elastin cells (which produce elastic fibres) at birth [11]. Also, the infrarenal aorta has an increased susceptibility due to reflected pressure waves from the iliac bifurcation leading to a disturbance of the laminar flow and an alteration in the wall shear stress. When compared to the supracoeliac aorta, the infrarenal aorta has, at times, a reversal of flow during diastole, and this can lead to an upregulation of factors that increase the inflammatory infiltrate and proteolytic pathways [12].

#### **4. Mouse models of AAAs**

microenvironment that produces factors, which result in wall degradation as well as further

An imbalance in collagen formation and degradation is thought to be responsible for aortic wall rupture [5]. It is a degenerative disease that shares many of the risk factors that predispose a person to atherosclerosis, but it is thought to be a separate pathological process from atherosclerosis (**Table 1**). Atherosclerosis presents typically as an occlusive disease; however, aneurysmal disease is characterized by elastin degeneration and smooth muscle cell apoptosis together with compensatory collagen deposition in the wall of the aneurysm. This may be a result of differing cytokine responses to the underlying inflammatory cell infiltrate [6].

The process of aneurysm formation is complex, and the progression is typically slow. It is multifactorial and requires a combination of anatomical predisposition and common risk factors to trigger its development. The natural history encompasses stages: initiation, formation,

Atherosclerosis Abdominal aortic aneurysm Infiltrate through intima Adventitial inflammation TH1 predominately early on TH2 response in the late stages Diabetes is a significant risk factor Diabetes may be protective Stenosing with plaque burden Dilating with wall rupture

Affects both genders equally Predominantly affects males

**Table 1.** Key differences between atherosclerosis and abdominal aortic aneurysm pathology.

The development of degenerative AAAs is significantly related to major risk factors such as smoking, advanced age, hypertension and male gender. Having a first-degree relative with an AAA significantly increases the risk of developing an aneurysm. More especially in young patients, there may be an underlying connective tissue disease, like Ehlers-Danlos (Type IV) or Marfan's syndrome. Rarely, inflammatory conditions such as Takayasu's arteritis and

Genetic associations with familial hypercholesterolaemia Genetic associations with soft tissue degeneration (Col3A1, FBN-1)

The combination of altered haemodynamics, a different smooth muscle cell derivation and a decrease in the elastic lamella of the infrarenal aorta predisposes it to aneurysm development. The embryological origin of the smooth muscle cells in the aorta of the infrarenal aorta may

Bechet's disease or infective conditions like HIV may present with an aneurysm [4].

recruitment of other inflammatory cells.

**2. Risk factors for AAA development**

TH1: T-helper cell type 1, TH2: T-helper cell type 2.

**3. The aneurysm prone infrarenal aorta**

growth and rupture [7].

80 Aortic Aneurysm

The pathogenesis of AAAs is multifactorial with contributions from a few key risk factors. Aortic tissues received from human subjects reflect a late stage of the disease and may not reflect the early factors involved in initiation. Thus, animal models may provide a better insight into the mechanisms behind aneurysmal degeneration. One of the major advantages of using experimental models of AAA is the ability to knock out or replace endogenous genes, enabling the assessment of the influence of protein expression on the development of disease.

There are several mouse models of chemical-induced AAAs such as elastase infusion into the infrarenal segments of mouse aortas and periaortic administration of calcium chloride between the renal branches and the iliac bifurcation. A more widely used model administers Angiotensin II to induce reproducible AAA. The Angiotensin II-infused mouse model mimics several features of AAAs in humans such as a male gender bias, dilatation of the lumen, degeneration of elastin fibres, inflammatory cell recruitment and thrombus formation [13].

Angiotensin II, a hormone of the renin-angiotensin system, is produced both systemically and locally in the vessel wall [14]. It has diverse actions on signalling pathways that ultimately promote cell growth, proliferation and vascular inflammation [14]. Accordingly, Angiotensin II-induced vascular inflammation can be studied by treating hyperlipidaemic mice with Angiotensin II to investigate long-term chronic inflammatory responses such as plaque formation or short-term acute inflammatory processes such as cellular infiltration. This is thought to occur via activation of the NF-ĸB cascade, resulting in elevation of cytokines. Furthermore, there is a growing body of evidence that suggests chemokines are involved in the modulation of Angiotensin II-accelerated leucocyte recruitment to the vessel wall [15].

#### **5. Inflammatory cells in AAA**

The inflammatory milieu consists of macrophages, monocytes, T cells, NK cells, B cells and other polymorphonuclear cells. They produce various inflammatory factors and mediators, which add to the degradation of collagen, elastin and smooth muscle cells in the aortic wall. The striking histological feature of AAAs is the adventitial and medial inflammatory infiltrate together with medial elastin destruction and fragmentation, and destruction of structural collagens (type 1 and 3) [16, 17]. This excessive elastolysis and collagen destruction are mediated by proteases, most notably the matrix metalloproteases (MMP) family [18]. Several MMPs have been implicated in aneurysm development (MMP-2, 8, 9, 12), with the most evidence for MMP-9 [19]. The other proteases involved are serine proteases (tpa, U-pa, plasmin, neutrophil elastase) and cysteine proteases (Cathepsin D, K, L and S) [16]. The MMPs and the other proteases can be secreted by most of the cells in the aorta (endothelial cells, vascular smooth muscle cells, fibroblasts and macrophages) [16, 20]. MMPs interact closely with tissue inhibitors of MMPs (TIMPS) and these are largely secreted by macrophages, and the process is regulated by cytokines through a feedback loop.

Inflammatory cells occur with a greater frequency in the aneurysmal aorta when compared to the atherosclerotic or non-diseased aorta. The T-cell pattern is different when compared to that of atherosclerotic tissue [21]. The predominant cell types are CD4 T cells, macrophages and B cells [22], and this has led to the assertion that an aortic aneurysm is an inflammatorymediated condition. It is still not definitively known if the inflammatory cell infiltrate is a cause of, or a reaction to AAAs. It is the microenvironment created by the cellular infiltrate that mediates the production of the proteases that underlie aneurysm progression and probably rupture. One theory suggests that aortic atherosclerosis diverges into aneurysmal formation through a Th2 cytokine response under environmental or genetic stimulation [23].

It has been proposed that an AAA is a specific antigen-driven T-cell disease, where the antigenic specificity remained to be determined [24]. AAA may be an autoimmune disease, and this theory is supported by the following [25]:

The pattern of cytokine production by the inflammatory cells influences matrix degradation by regulating their MMP, serine protease and cathepsin production. In murine models of AAA, an IL-4 upregulation and interferon-γ (IFN- γ) blockade together with a predominance of macrophages are the features of early aneurysm formation [23]. The macrophages produce MMP-12, which are stimulated by IL-4 production from T cells, reinforcing the role of IL-4 in early atherosclerosis development [23]. The downstream effects of murine cytokine expression are not always applicable to humans; thus, mechanistic animal studies are difficult to interpret. Also, studies are carried out on tissues *in vitro*, and the complex interaction of the various cytokines is not entirely reproducible [6].

#### **5.1. Macrophages**

together with medial elastin destruction and fragmentation, and destruction of structural collagens (type 1 and 3) [16, 17]. This excessive elastolysis and collagen destruction are mediated by proteases, most notably the matrix metalloproteases (MMP) family [18]. Several MMPs have been implicated in aneurysm development (MMP-2, 8, 9, 12), with the most evidence for MMP-9 [19]. The other proteases involved are serine proteases (tpa, U-pa, plasmin, neutrophil elastase) and cysteine proteases (Cathepsin D, K, L and S) [16]. The MMPs and the other proteases can be secreted by most of the cells in the aorta (endothelial cells, vascular smooth muscle cells, fibroblasts and macrophages) [16, 20]. MMPs interact closely with tissue inhibitors of MMPs (TIMPS) and these are largely secreted by macrophages, and the process is

Inflammatory cells occur with a greater frequency in the aneurysmal aorta when compared to the atherosclerotic or non-diseased aorta. The T-cell pattern is different when compared to that of atherosclerotic tissue [21]. The predominant cell types are CD4 T cells, macrophages and B cells [22], and this has led to the assertion that an aortic aneurysm is an inflammatorymediated condition. It is still not definitively known if the inflammatory cell infiltrate is a cause of, or a reaction to AAAs. It is the microenvironment created by the cellular infiltrate that mediates the production of the proteases that underlie aneurysm progression and probably rupture. One theory suggests that aortic atherosclerosis diverges into aneurysmal formation through a Th2 cytokine response under environmental or genetic stimulation [23].

It has been proposed that an AAA is a specific antigen-driven T-cell disease, where the antigenic specificity remained to be determined [24]. AAA may be an autoimmune disease, and

**1.** The presence of mononuclear inflammatory cell infiltrates consisting mainly of T and B

**2.** Mononuclear cells infiltrating the aneurysm wall show early (CD69), intermediate (CD25, CD38) and late (CD45RO, HLA Class II) activation antigens, suggesting an ongo-

**3.** IgG antibody purified from the wall of AAA is immunoreactive with protein derived

The pattern of cytokine production by the inflammatory cells influences matrix degradation by regulating their MMP, serine protease and cathepsin production. In murine models of AAA, an IL-4 upregulation and interferon-γ (IFN- γ) blockade together with a predominance of macrophages are the features of early aneurysm formation [23]. The macrophages produce MMP-12, which are stimulated by IL-4 production from T cells, reinforcing the role of IL-4 in early atherosclerosis development [23]. The downstream effects of murine cytokine expression are not always applicable to humans; thus, mechanistic animal studies are difficult to interpret. Also, studies are carried out on tissues *in vitro*, and the complex interaction of the

**4.** AAA is associated with particular alleles such as the HLA DRB1 [27].

**5.** Molecular mimicry may be responsible for T-cell responses in AAA [25].

regulated by cytokines through a feedback loop.

82 Aortic Aneurysm

this theory is supported by the following [25]:

cells, macrophages and NK cells [22].

ing inflammation [24].

from normal aortic tissue [26].

various cytokines is not entirely reproducible [6].

Macrophages are recruited early into the aneurysmal wall, and macrophage cytokines play an important role in AAA progression. This response is associated with innate immunity as opposed to adaptive immunity. Macrophages exhibit plasticity with regard to their phenotypic cytokine output. They can either be M1 or M2 and can change between the two depending on the prevailing conditions. Typically, M1 macrophages are pro-inflammatory, whereas M2 macrophages are involved in repairing tissue. A balance between M1 and M2 is thus vital in preventing a chronic inflammatory cell infiltrate, which leads to persistent inflammation and aneurysm progression. IL-6, tumour necrosis factor (TNF)-α, IL-1β and interferon (IFN)-γ have been detected peripherally and are associated with aneurysm formation [28].

In murine models of AAA, M1 macrophages are strongly associated with aneurysm formation and elastin degradation; conversely, an M2 phenotype is protective for AAA development [29]. Investigation of human aneurysm tissue has revealed an M1 phenotype, though this tissue represents an end stage of the disease. Most human studies have focused on circulating monocytes and their link to increased elastases and ECM breakdown [30]. ECM breakdown is a recruiter of monocytes, and the use of a monoclonal antibody has been shown to decrease this infiltration and prevent further ECM degradation [31]. Furthermore, the monocytes have demonstrated CD14 and CD16 cell surface marker positivity, and this pattern is associated with M1 macrophage activation [32].

#### **5.2. T cells**

As a broad categorization, T cells can be divided up into CD4+ and CD8+ cells. CD4 cells can be further categorized into Th1, Th2, Th17 or regulatory (Treg) cells. This is dependent on drivers of cellular output as well as their cytokine expression. Similar to M1 and M2 macrophages, it would appear that the balance in the different subsets is important for regulation.

Th1 cells are activated by IL-12 and output INF-γ. Aneurysmal tissue displays features of Th1 upregulation with increased INF-γ in the aneurysm tissue and in the circulating blood [28, 33, 34]. Although Th2 cells are found in some specific inflammatory diseases, they are considered to be anti-inflammatory. IL-4 activity is responsible for Th2 differentiation of CD4 T cells, and results are conflicting in murine and human models as to the role of Th2 cells. This discrepancy may be a result of a similar cytokine profile to NK cells (Th0) [35] or from differences in the measurement of the cytokines. Th17 cells produce IL-17, are related to several inflammatory diseases and play a key role in vascular superoxide production [36]. Their role in AAA has not been fully clarified, but they appear to be related to aneurysmal progression.

The frequency of CD4+CD25+FOXP3+ T cells (Treg) is decreased in the peripheral blood of patients with AAA when compared to occlusive atherosclerotic disease or healthy donors [37]. Treg cells are a unique class of T cells that serve as a counter-inflammatory mechanism. In the normal autoregulation of bodily function, there is a balance between T effector cells, which promote inflammation, and Treg cells which counteract this [38]. In inflammatory conditions such as rheumatoid arthritis [39], scleroderma [40], inflammatory bowel disease [41] and transplant organ rejection [42], a dysfunction of Treg cells has been implicated. Treg cells express forkhead box P3 (Foxp3) and are also known as Foxp3+CD4 T cells. They make up approximately 5% of the total CD4+ T cells [43]. The majority of Treg cells express CD25. In the human, Treg cells can be identified by a high expression of CD25 and an absence of IL-7Rα [44].

#### **5.3. Other cell types**

Mast cells have been found in the adventitia and media of AAAs and are implicated in AAA formation [45]. They have been found in areas of neovascularization and are able to secrete various cytokines and chemokines. Inhibition of mast cells in experimental mouse models decreases the incidence of aneurysmal formation, furthermore implicating mast cells in the pathogenesis of aneurysms [46]. Neutrophils are early responders to injury and are found in the aneurysm wall as well as the intraluminal thrombus [47]. They interact with many cells including platelets resulting in further inflammatory cell recruitment [48]. In human studies, they have been associated with larger aneurysms, and in animals that are neutrophil deficient, there is a decrease in aneurysm formation [49, 50].

#### **6. Micro-RNAs**

Micro-RNAs (miRNA) are a class of non-coding RNA, which are regulators of posttranslational gene expression [51]. They have emerged as potential therapeutic targets due to their ability to control multiple downstream processes. Mir-21 is a regulator of smooth muscle homoeostasis and is upregulated in human as well as animal models of AAA [52]. The mir-29 family encodes multiple ECM targets including elastin and collagen isoforms (type 1 and 3) and fibrillin-1 [53]. Thus, it is important in aneurysm formation. Mir-29b has been found to be downregulated in humans and animal models of AAA as well as in animal models of ageing [54].

#### **7. Intraluminal thrombus (ILT)**

The majority of AAAs requiring surgery contain ILT. They are thought to develop secondary to an activated endothelium in combination with disturbances of flow within the aneurysm sac. The volume of ILT is related to growth of the aneurysm, and the thrombus-lined segment of the aorta is structurally different to the non-thrombus-lined area of the aneurysm [55, 56].

There are two major theories on the effect of aneurysmal growth on aortic aneurysm formation. The first relates it to hypoxia of the wall due to the layered thrombus, and the second ascribes it to the inflammatory cell constituents of the thrombus acting in a paracrine manner [57]. The inflammatory cell infiltrate contains macrophages, T cells, granulocytes and NK cells as well as activated platelets [58, 59]. These cells are phenotypically different to the cells found in the wall and the peripheral blood [60]. The exact pathway of interaction between the wall and the ILT has not been fully elucidated, but one theory suggests that microvesicles (ADAM10/ADAM17) shed from the luminal to the abluminal area result in wall breakdown through the formation of elastases in the wall [61].

#### **8. Conclusion**

conditions such as rheumatoid arthritis [39], scleroderma [40], inflammatory bowel disease [41] and transplant organ rejection [42], a dysfunction of Treg cells has been implicated. Treg cells express forkhead box P3 (Foxp3) and are also known as Foxp3+CD4 T cells. They make up approximately 5% of the total CD4+ T cells [43]. The majority of Treg cells express CD25. In the human, Treg cells can be identified by a high expression of CD25 and an absence of

Mast cells have been found in the adventitia and media of AAAs and are implicated in AAA formation [45]. They have been found in areas of neovascularization and are able to secrete various cytokines and chemokines. Inhibition of mast cells in experimental mouse models decreases the incidence of aneurysmal formation, furthermore implicating mast cells in the pathogenesis of aneurysms [46]. Neutrophils are early responders to injury and are found in the aneurysm wall as well as the intraluminal thrombus [47]. They interact with many cells including platelets resulting in further inflammatory cell recruitment [48]. In human studies, they have been associated with larger aneurysms, and in animals that are neutrophil deficient,

Micro-RNAs (miRNA) are a class of non-coding RNA, which are regulators of posttranslational gene expression [51]. They have emerged as potential therapeutic targets due to their ability to control multiple downstream processes. Mir-21 is a regulator of smooth muscle homoeostasis and is upregulated in human as well as animal models of AAA [52]. The mir-29 family encodes multiple ECM targets including elastin and collagen isoforms (type 1 and 3) and fibrillin-1 [53]. Thus, it is important in aneurysm formation. Mir-29b has been found to be downregulated in

The majority of AAAs requiring surgery contain ILT. They are thought to develop secondary to an activated endothelium in combination with disturbances of flow within the aneurysm sac. The volume of ILT is related to growth of the aneurysm, and the thrombus-lined segment of the aorta is structurally different to the non-thrombus-lined area of the aneu-

There are two major theories on the effect of aneurysmal growth on aortic aneurysm formation. The first relates it to hypoxia of the wall due to the layered thrombus, and the second ascribes it to the inflammatory cell constituents of the thrombus acting in a paracrine manner [57]. The inflammatory cell infiltrate contains macrophages, T cells, granulocytes and NK cells as well as activated platelets [58, 59]. These cells are phenotypically different to the cells found in the wall and the peripheral blood [60]. The exact pathway of interaction between

humans and animal models of AAA as well as in animal models of ageing [54].

IL-7Rα [44].

84 Aortic Aneurysm

**5.3. Other cell types**

**6. Micro-RNAs**

rysm [55, 56].

there is a decrease in aneurysm formation [49, 50].

**7. Intraluminal thrombus (ILT)**

Abdominal aortic aneurysms are regulated by complex and multifactorial processes. At a cellular level, there is a chronic inflammatory cell infiltrate that controls these processes, which lead to growth and rupture. The role of these inflammatory cells has been elegantly demonstrated in experimental models of AAA, and genetic interventions targeting their recruitment and signalling have been known to prevent the development of disease. However, the lack of experimental tools to test the efficacy in human AAA in the preclinical phase and the composition of the thrombus in experimental models has yet to be explored. There has been much work done to understand the inflammatory process, and the hope is that this will lead us to new biomarker discovery and potential therapeutic targets in treating this disease.

#### **Acknowledgements**

We would like to acknowledge support from the BHF Centre of Research Excellence, Oxford (RE/13/1/30181).

#### **Author details**

Ismail Cassimjee1 , Regent Lee<sup>1</sup> and Jyoti Patel2, 3\*

\*Address all correspondence to<EMAIL_ADDRESS>
1 Nuffield Department of Surgery, University of Oxford, UK

2 Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, John Radcliffe Hospital, Oxford, UK

3 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

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88 Aortic Aneurysm

**Provisional chapter**

## **Sexual Dimorphism of Abdominal Aortic Aneurysms**

**Sexual Dimorphism of Abdominal Aortic Aneurysms**

Yasir Alsiraj, Sean E. Thatcher and Lisa A. Cassis Cassis

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

Yasir Alsiraj, Sean E. Thatcher and Lisa A.

http://dx.doi.org/10.5772/64611

#### **Abstract**

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Sex is the largest nonmodifiable risk factor for the development of abdominal aortic aneurysms (AAAs) in humans and experimental models. Data from several studies con‐ sistently demonstrate a higher AAA prevalence in males than in females, contributing to divergent recommendations for AAA screening in men and women. Despite a higher AAA prevalence in males, females have more rapid rates of aneurysm dilation, and aneurysms rupture at smaller sizes. Unfortunately, no therapies have been effective to retard aneurysm dilation in either sex. Results from experimental AAA models indicate a protective role for estrogen in AAA development and progression, while male tes‐ tosterone has been demonstrated to markedly promote angiotensin II (AngII)‐induced AAAs. Potential mechanisms implicated in sex hormone regulation of AAAs include regulation of inflammation, matrix metalloproteinases, aromatase activity, oxidative stress, stem cells, and transforming growth factor‐beta. In addition to sex hormones, sex chromosomes have been implicated in diseases of the aorta. Turner's syndrome (mono‐ somy X) patients have a high incidence of thoracic aortic rupture. Recent studies indicate a novel approach to define the relative role of sex hormones versus sex chromosomes in experimental AAAs.

 Introduction**

As defined by the Society of Vascular Surgery, abdominal aortic aneurysms (AAAs) are a per‐ manent dilation of the infrarenal aorta (ratio of ≥1.5‐fold increase in normal abdominal aortic diameter) [1], leading to infrarenal aortic diameters >3 cm that can expand to more than 5.5 cm [2]. AAAs are typically asymptomatic, which is of concern due to the high mortality rate from aneurysm rupture. The prevalence of asymptomatic AAAs in geriatric men and women

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ranged from 4 to 14.2% and from 0.35 to 6.2%, respectively [3–5]. Between the ages of 50 and 84 years, it has been estimated that AAA prevalence could be as high as 1.1 million people in the United States [6]. AAAs are responsible for 1.3% of all deaths in men between the ages of 65 and 85 years [7]. According to the Society of Vascular Surgery, in the United States, there are 200,000 people diagnosed with an AAA each year, and it is the 10th leading cause of mortality in men more than 55 years of age [8]. Impending rupture of AAAs is associated with sudden, severe, and constant groin, abdominal, and lower back pain. Because the aorta is the main sup‐ plier of blood throughout the body, AAA rupture can result in fatal bleeding with 85% chance of death. Depending on AAA expansion rate and size, treatment might vary from frequent monitoring (typically by ultrasound) to open or endovascular aneurysm repair. As AAA size increases (diameter > 5.5 cm), the probability of rupture also increases. While age, smoking, male sex, and family history are positively associated with AAA development, female sex, smoking cessation, and a healthy diet are negatively associated with AAA formation [6].

#### **2. Sex differences in AAA prevalence in human and experimental models**

Sex is considered a strong nonmodifiable risk factor for AAA formation. The incidence of AAAs has been reported to range from 4‐ to 5‐fold higher in men compared to women [9, 10], with studies indicating that men are at a 10‐fold higher risk to develop AAA compared to age‐matched women [10]. Results from the Tromsø Study demonstrate that male sex con‐ tributes a 2.66 relative risk for AAA formation [11]. Epidemiological studies have shown an increased AAA incidence and rupture in men originating from western countries [12, 13]. In a community‐based older population screening study, it was found that the AAA prevalence was 1.3% in women in comparison to 7.6% in men [14]. Correspondingly, the male:female ratio in a surgical series was ≈5:1. Hospitalization for ruptured or intact AAA was 5 times more prevalent among men than women [9]. After controlling for time of surgery and age, men were around 1.8 times as likely to have an intact AAA treated surgically and 1.4 times to have a ruptured AAA in comparison to women. Current screening recommendations are to screen annually by ultrasound for men between the ages of 65 and 75 years with either a family history of AAA or who smoke. Conversely, studies have also shown that female sex decreases the AAA risk [10]. These results indicate that across a broad range of large‐scale clinical trials, AAAs are much more prevalent in men as compared to women. In addition to male sex, the most predominant risk factors for AAAs are age, smoking, and family history.

Even though women have far lower AAA prevalence compared to men, women have worse prognosis than men, as AAAs in women progress faster and rupture at smaller sizes [15, 16]. Using the Vascular Study Group of New England database, Lo et al. have shown that women are older when diagnosed with an AAA, have smaller aortic diameters, and stay in the hospital longer than men diagnosed with an intact AAA [17]. Furthermore, women more frequently experience complications (e.g., leg and bowel ischemia) and have a higher mortality after 30 days than men after open AAA repair [17]. Also, according to the National Service hospitals in England, all cause and aortic‐related mortalities were higher in women at all‐time points (30 days, 1 year, and 5 years) in both open and EVAR surgeries [18]. Additional studies have shown that the survival rate in women after surgical repair is lower than that of men; however, mechanisms for these effects are largely undefined [19, 20]. Differences in AAA rupture and progression between men and women could relate to vascular anatomy. For example, Lo and Schermerhorn noted that if the ratio of infrarenal to suprarenal diam‐ eter is ≥1.2 or a definition of ≥1.5 times the normal aortic diameter, then AAA prevalence in women could be as high as 6.2–9.8% [21]. This would indicate that using the same vascular anatomic criteria for men and women could lead to underdiagnosis of small AAAs in women [21]. While there is general consensus that men should be screened at 65 years of age or older, only the Society for Vascular Surgery recommends screening women (65 or older) who have smoked or have a family history of AAA [21]. In fact, some studies have indicated that women who smoke are more likely than nonsmoking men to develop AAAs [22]. An additional area of concern relates to recommendations for endovascular aneurysm repair as women having this procedure with a small AAA have poor outcomes (and also for open AAA repair) [17, 18]. Another issue related to the use of endovascular aneurysm repair in women is poor access to smaller vessels. These access‐related complications lead to arterial injury of vessels which may result in additional surgeries and/or problems with stent engraftment.

ranged from 4 to 14.2% and from 0.35 to 6.2%, respectively [3–5]. Between the ages of 50 and 84 years, it has been estimated that AAA prevalence could be as high as 1.1 million people in the United States [6]. AAAs are responsible for 1.3% of all deaths in men between the ages of 65 and 85 years [7]. According to the Society of Vascular Surgery, in the United States, there are 200,000 people diagnosed with an AAA each year, and it is the 10th leading cause of mortality in men more than 55 years of age [8]. Impending rupture of AAAs is associated with sudden, severe, and constant groin, abdominal, and lower back pain. Because the aorta is the main sup‐ plier of blood throughout the body, AAA rupture can result in fatal bleeding with 85% chance of death. Depending on AAA expansion rate and size, treatment might vary from frequent monitoring (typically by ultrasound) to open or endovascular aneurysm repair. As AAA size increases (diameter > 5.5 cm), the probability of rupture also increases. While age, smoking, male sex, and family history are positively associated with AAA development, female sex, smoking cessation, and a healthy diet are negatively associated with AAA formation [6].

92 Aortic Aneurysm

**2. Sex differences in AAA prevalence in human and experimental models**