Vascular Surgery: A Clinical Guide to Decision-making

Vascular Surgery: A Clinical Guide to Decision-making is a concise but comprehensive resource for operating vascular surgeons and clinicians. It serves as an essential reference manual, particularly to young vascular surgeons, for consulting the basic scientific knowledge of pathogenesis of various illnesses, as well as how to approach them in a clinical setting. Adopting a translational approach, this book dissects the background of vascular pathology and links it to application in surgical techniques, as well as providing practical tips and tricks for surgical maneuvers.

With insights and suggestions from various experienced and skilled vascular surgeons, this book covers a range of topics including the origin of diseases, clinical presentation, and therapeutic options, from medical therapy to surgical or endovascular approach. Each chapter also reviews international cutting-edge research in the vascular field and its clinical application, illuminating future developments in the field.

With the contributions of first-class vascular surgeons, this book also covers uncommon and advanced case studies while exploring the pros and cons of each intervention option, helping practitioners make informed decisions when facing difficult cases. This unique reference also helps young surgeons to make quick decisions in challenging cases, such as how to choose between open and endo treatment.

• Presents indications, techniques and results for various vascular surgery procedures completed with an overview about pros and cons of a treatment, allowing readers to make a quick decision when facing peculiar clinical cases
• Adopts a translational approach, dissecting the background knowledge of vascular pathology and linking it to application in surgical techniques, along with a summary tips and tricks regarding surgical maneuvers
• A global involvement from experienced vascular surgeons in the field, covering surgical techniques and important research from around the world, devising the future developments of the field

• Language: English
• Publisher: Academic Press
• Release date: Oct 14, 2021
• ISBN: 9780128221518

Book preview

Preface

With the publication of any new scientific book, it is customary to ponder a few questions: Do we really need another textbook in this field? Does it offer a new perspective? Does it fill a gap in our current reference library?

In the case of Vascular Surgery edited by Prof. Settembrini, the answer is yes on all counts. This field has a massive and authoritative textbook now in its 10th edition, multiple compendia of various symposia presentations, procedural atlases, and a large number of textbooks focused on the details of a particular facet of vascular surgery such as complex aortic interventions, vascular trauma, or endovascular techniques. However, what it does not have is a concise yet comprehensive guide intended for quick consultation by our younger colleagues about a wide variety of clinical situations, and this is the exact concept of the current work.

The editors aimed to cover the spectrum of treatment options in different clinical settings, from conservative medical management to both open and endovascular interventions providing pragmatic guidance to decision-making. They arranged for a diverse and multinational list of contributors, both young and senior experts in their fields, to provide 28 compact chapters covering almost all potential clinical presentations that a vascular surgeon commonly encounters.

The organization of the book is mostly aimed at providing the reader with a quick listing of the basic factual elements that would guide evaluation and decision-making, rather than an exhaustive discussion of all facets of the disease. Common problems are mostly discussed from a treatment choice perspective. An excellent example is the chapter on the evaluation of abdominal aneurysms and the selection of open or endovascular options for both elective and ruptured aortic abdominal aneurysm.

Less common and more complex problems are treated more extensively while providing more details about the disease process, pathology, classification, workup, treatment choices and tips for safe and effective interventions. The chapters on thoracic outlet, thoracoabdominal aneurysms, and deep vein and pulmonary embolism management pack a tremendous amount of information in a succinct format and easy reading style. The salient features that would impact decision-making are listed for quick reading as a theme noted throughout the textbook.

Even rare diseases are covered with enough information and guidance to facilitate management. The chapter by the editor on carotid dissections, aneurysms, and paragangliomas is remarkably complete in a brief format that touches on all essential elements of three rare presentations. The chapter dealing with genetic disorders of the aorta is another reference chapter providing a complete description of rare problems that a treating physician may want to consult quickly, when encountering a patient with unusual presentation.

What stands out throughout the textbook is the deliberate avoidance of unbridled enthusiasm for a certain therapy at the exclusion of others. Even more so, an entire chapter is devoted to the potential drawbacks and limitations of endovascular therapy in aortic disease, bringing a measured approach to the wholistic treatment of the patient, emphasizing that all treatment options have their risks and benefits as well as limitations.

Also included in the book are general chapters about basic pathobiology, wound care, vasculitis, risk factors for vascular disease, and medical therapy. The coverage of clinical entities is extensive for a volume this size, including dialysis access, vertebral disease, and an excellent contribution on the basics and management guidelines for aortic dissection. Practical advice is provided for all phases of management, and all chapters are richly referenced and illustrated to provide additional reading for those wishing more in-depth coverage.

The editors and contributors should be congratulated for this new textbook that should find its way into the hands of almost all trainees and young vascular surgeons. It will be a worthwhile addition to the reference library of vascular surgery worldwide.

Michel Makaroun, M.D., The Marshall W. Webster M.D. Chair in Vascular Surgery, Co-Director, UPMC Heart and Vascular Institute, Professor of Surgery and Clinical Translational Science, University of Pittsburgh

Chapter 1

Is pathology useful in vascular surgery?

Fabio Bertani, Alice Fuggirai and Francesca Boccafoschi,    Department of Health Sciences, University of Piemonte Orientale, Novara, Italy

Abstract

Understanding the molecular and cellular mechanisms at the basis of every disease is fundamental in modern medicine. Each vascular condition is caused by molecular events occurring in the cellular components of the blood vessel wall.

Keywords

glycosaminoglycans; tunica adventitia; endothelial cells; aortic abdominal aneurysm; type 2 diabetes mellitus; von Willebrand factor

Introduction

Understanding the molecular and cellular mechanisms at the basis of every disease is fundamental in modern medicine. Each vascular condition is caused by molecular events occurring in the cellular components of the blood vessel wall.

Blood vessels create both macro- and microanatomical networks. Arteries and veins are macroscopic vessels carrying the blood from and to the heart, while arterioles, capillaries, and venules constitute the microanatomical compartment, responsible for tissue nutrient supplementation.

Blood vessels, with the exception of capillaries, are composed of tunica adventitia, media, and intima. Arteries and veins differ in the composition of these layers depending on their mechanical needs.

Tunica adventitia is the outermost layer, the most resistant and elastic layer that ensure veins and expecially arteries resist the blood’s pressure and facilitate blood transportation. Tunica media is characterized by muscular layers interspersed in matrix proteins such as collagen, elastin, and glycosaminoglycans (GAGs). Tunica intima is the luminal layer, the one in contact with the blood, composed of a basal membrane and a thin monolayer of endothelial cells (ECs).

Cellular pathology of abdominal aortic aneurysms

Among surgical conditions most strongly affected by molecular mechanisms, aortic abdominal aneurysm (AAA) is possibly the most represented.

AAA is a multifunctional degenerative disease characterized by complex interactions between genetic, inflammatory, and hemodynamical factors. Its development depends on the failure of the structural proteins of the aorta, leading to a progressive weakening of the aortic wall characterized by elasticity and strength deterioration [1].

Epidemiologically, AAA primarily affects male patients. Risk factors can be divided into nonmodifiable, such as gender and genetic predisposition, and modifiable, such as cigarette smoking, which, per se, has an odds ratio greater than 3.0. Intriguingly, unlike most cardiovascular diseases, type 2 diabetes mellitus (T2DM) is not a risk factor for AAA [2–4].

Hallmarks of AAA are inflammation, degradation of the extracellular matrix, and thinning of smooth muscle layers due to vascular smooth muscle cell apoptosis. The destruction of the lamellar structure of the aortic medial layer is the predominant histopathological feature related to this pathology. Indeed, abdominal aorta is structured in lamellar units with increasing wall elasticity and resistance [5], and most frequently, AAA develops in the infrarenal tract, where the number of lamellar units is decreased [6].

The most common form of AAA dilation is due to the presence of atherosclerotic plaque, inflammatory processes, traumatic events, or connective tissue defects [7]. The etiology is not well understood but a chronic inflammatory process affecting the aorta has been identified as a driving factor. Incidentally, macrophages, lymphocytes, and cellular debris are found through the wall of the aorta, compatible with a chronic inflammatory state that may possibly characterize AAA development and progression [8,9].

Vascular endothelial and smooth muscle cells play key roles in maintaining vascular functionality

The endothelium is a thin layer of ECs that constitutes the inner cellular lining of blood vessels. ECs are maintained together by their interactions with the basal lamina and tight junctions between adjacent cells [10].

Depending on the tissue function, we may observe the presence of three functionally distinguished endothelia classified as continuous, fenestrated, or discontinuous [11,12]. Continuous endothelium is found in most arteries, veins, and capillaries; it is normally associated with continuous basal lamina and characterized by the presence of tight intracellular junctions. Fenestrated endothelium is characterized by the presence of transcellular wide pores, sealed by a diaphragm. This structure is observed in tissue compartments requiring an active transcellular exchange such as glands, gastrointestinal, choroid plexus, glomerulus, and others. Finally, discontinuous endothelium is associated to a poorly structured basal lamina and loose intracellular junctions creating wide pores. It is typically present in hepatic microcirculation and in spleen and bone marrow capillaries [13].

The endothelium plays a pivotal role in several physiopathological processes, such as vasomotor tone control via nitric oxide (NO) release, barrier functions, leukocyte adhesion homeostasis, and inflammation [14].

Several autocrine and paracrine substances are released by ECs in response to various physical, chemical, and biochemical stimuli [15]. Besides representing a strong influence on vascular tone by secreting vasoactive peptides as well as vasodilator and vasoconstrictors [16], endothelium has a pivotal role in hemostasis. In fact it is the strongest anticoagulant player in our body under physiological conditions, shifting to a potent procoagulant upon inflammatory stimulation [17].

Physiologically, the endothelium exhibits an antithrombotic phenotype, allowing the blood to flow fluidly throughout the vessels. This is achieved by the secretion of soluble factors, such as prostacyclin and NO. Additionally, the luminal portion of the endothelial cell displays a highly antiinflammatory, antithrombotic, and antiaggregating phenotype that contributes to the maintenance of blood fluidity. On the other hand, proteins composing the basal lamina are highly thrombogenic; therefore any process impairing endothelial integrity is a potential stimulus for thrombus formation, leading to life threatening risks for the patient.

When this happens, platelet interaction with subendothelial components, such as, collagen fibers, fibronectin, laminin, leads to their activation and the triggering of coagulation cascades [18].

Subendothelial basal lamina proteins bind highly thrombogenic factors such as von Willebrand factor (vWF) and tissue factor (TF) and allow platelet adhesion and coagulation cascade initiation, respectively, leading to the formation of a stable hemostatic plug.

Platelet activation requires the binding of subendothelial components via integrins receptors (e.g., gpIb, gpIX, gpV), ultimately leading to degranulation of several chemical mediators that impact vascular homeostasis and coagulation [19].

Serotonin, for instance, is a strong vasoconstrictor released by activated platelets while thromboxane A2 and ADP have a double role both in vasoconstriction and platelet aggregation enhancement [20].

TF exposition is the triggering signal in extrinsic coagulation pathway initiation, that, through a series of highly regulated and concerted proteolytic cleavages, will eventually lead to a secondary, stable hemostatic plug [21].

vWF is a multimeric glycoprotein primarily synthesized by ECs and stored in Weiber-Palade bodies and α-granules. With specific stimuli, vWF can be secreted and remain attached to ECs surfaces [22,23], where it can be subsequently released into the circulatory system after proteolytic cleavage by ADAMTS13. In the circulation, vWF is able to stabilize factor VIII, prolonging its half-life.

The ability of vWF to modulate thrombosis and inflammation is related to its multimeric composition: the bigger it is, the higher is its prothrombotic effect. Hence, high proteolytic activity by ADAMTS13 is correlated with small size multimers leading to compromised hemostatic functionality.

Conversely, the inability to cleave vWF multimers by ADAMTS13 is associated with thrombotic thrombocytopenic purpura characterized by disseminated microthrombi formation due to vWF-dependent platelet activation.

ADAMTS13 is also believed to be implied in several immune phenomena because of its role in vWF cleavage, supporting the concept that immunological processes are related to vWF function [24].

vWF binds to collagen VI when it is exposed under ECs due to damage occurring to the blood vessel, contributing to plug formation at the injury site [25].

vWF multimeric structures are also conditioned by shear stress. It has been demonstrated that high shear stress magnitudes positively correlate with proteolytic cleavage resulting in the production of small size vWF multimers [26–28].

Moreover, during inflammation, the endothelium is fundamental as transport mechanism for leukocytes to access inflamed districts upon chemo attraction via chemokines. Intact and resting endothelium expresses a very low concentration of adhesion molecules, although, upon a triggering stimulus, ECs start producing large quantities of molecules required for polymorphonucleates (PBMC) adhesion and diapedesis, such as ICAM-1, VCAM-1, E-selectin, and P-selectin [29,30].

Leukocytes and ECs have a close relationship upon which several physiopathological processes are based. Immune response, wound healing, atherosclerosis, acute and chronic inflammation are just a few of the several processes regarding endothelium–leukocyte interactions.

Vascular smooth muscle cells (VSMCs) are differentiated cells represented within the tunica media layer of blood vessels and are highly specialized. The main function of this layer is to control vascular lumen diameter through contraction–relaxation processes. Depending on their functionality, we can divide VSMCs on the basis of their contractile or synthetic phenotype expressed [31]. Contractile VSMCs are placed circumferentially to the longitudinal axis of the vessel to ensure vasocontraction while secreting a small proportion of extracellular matrix proteins, contributing to arterial wall homeostasis [32,33]. Synthetic cells, instead, secrete copious amounts of extracellular matrices, including collagen I, III, IV and proteoglycans, perlican, hyaluronan, laminin, and elastin. Due to their extraordinary ability to dynamically modulate their phenotype, they also participate in physiological and pathological vascular remodeling. A synthetic phenotype is considered as a dedifferentiation process occurring at atherosclerotic regions, possibly as a mechanism to stabilize plaque and reduce the risk of rupture [34,35].

A contractile phenotype is supported by transforming growth factor (TGF) signaling, myocardin (MYOCD) family proteins, and cell–cell contacts; it is characterized by the expression of markers such as smooth muscle α-actin (SMαA), SM-22α, SM myosin heavy chains SM-1 and SM-2, calponin, and smoothelin. In vitro experiments have also underlined the pivotal role of shear stress in phenotype maintenance [36].

In a healthy setting, VSMCs are characterized by a predominant contractile phenotype displaying elevated levels of MYOCD responsible for the expression of contractile proteins. MYOCD expression decreases during the first stages of atherosclerosis determining a dedifferentiation process eventually leading to the expression of a matrix rich in proteoglycans and glycosaminglycans. These switches enhance the lipid retention potential of VSMCs, determining the production of foam cells and eventually leading to oxidized-LDL mediated apoptosis [37]. VSMCs uptake of oxidized-LDL from intimal accumulations results in foam cell formation and apoptosis, leading to the loss of contractile function and reduced strength of the arterial wall [38]. Deregulated lipids uptake by VSMC is directly responsible for the phenotypic switch by reducing the level of VSMC-tropoelastin proteins via increased degradation rate.

Medial layer calcification is one of the hallmarks of an aneurysm [39]. It is determined by osteochondrogenic transition and stimulated by local and systemic stimuli. Indeed, uremia and high serum calcium and phosphate levels are associated with increased arterial calcification [40]. High urea levels are typically present in chronic kidney disease patients and are thought to act positively on vascular calcifications through uremic toxins, determining oxidative stress state [41]. Studies have demonstrated in vitro the positive correlation between high levels of calcium or phosphate and VSMCs mineralization [42,43].

As a whole, these modifications in VSMCs biology results in increased apoptosis and loss of cellularity in the tunica media, ultimately leading to arterial wall weakening that can be expanded by mechanical and biochemical forces.

Experimental models of AAA and therapeutic targets

Basic research in this field is supported by the use of in vitro experimental approaches and, most importantly, animal models of the disease. There are different mouse and rat models for AAA, such as elastase infusion, calcium chloride sponge, and angiotensin II (Ang II) infusion. Each model can mimic only a fraction of the whole pathogenesis of AAA; therefore researchers need further approaches in order to obtain animal models which may realistic represent this vascular pathology.

Historically, aortic calcification after β-aminopropionitrile ingestion in rats was demonstrated in the 1950s and 1960s on. In the 1980s, Gertz suggested a pathogenic link between calcium deposition and aneurysm formation, producing a carotid artery aneurysm in rabbits infused with calcium chloride [44].

CaCl2-induced AAA is still one of the most common animal models widely used in research laboratories, although the current protocol is based on the use of gauze soaked in a calcium chloride solution placed over the aorta producing inflammation on the luminal and medial layers eventually increasing the vessel diameter [45].

Genetically induced AAA mouse models are characterized by gene knockout involved in arterial wall homeostasis, such as lysiloxidase (Lox), MMP-3, TIMP-1, lipids transportation, and uptake proteins. Lox-deficient mice are unable to cross-link collagen and elastin fibers resulting in reduced wall strength [46–49], while MMP-3 and TIMP-1 downregulation is associated with reduced matrix remodeling and hence, enhancing aneurysm formation.

The infusion of elastase into the infrarenal segment of rat aortas has been frequently used to chemically induced AAA. The rationale for its development is based on the disruption of elastin in the media layer [50]. Although this model lacks all the molecular events leading to AAA in normal conditions, it is only useful in drug evaluations or surgical treatments.

Recently, Lareyre and colleagues developed a novel murine AAA model. This new model combines topical application of elastase with systemic inhibition of TGF-β via intraperitoneal injection of neutralizing antibodies (anti-TGF-β) [51].

Finally, Ang II-induced mouse models are normally produced in hyperlipidemic, LDL (low-density lipoprotein) receptor−/− (LDLR−/−), and ApoE−/− (apolipoprotein E) strains [52]. AAA created using this method showed some similarities, but also important differences, when compared to the AAA characteristics in humans. Similarities include the degradation of the aortic media layer, aortic dilation, higher incidence in males, presence of atherosclerosis, and the presence of wall thrombus [53–55], and the differences are the higher dissection and rupture risk in infused mice than in humans and the anatomical location of AAA development.

Endothelial dysfunction is the impairment of these processes carried out by ECs, and it is considered the primum movens in most cardiovascular disease such as atherosclerosis and aneurysm development, considered one of the earliest events in AAA development ([20]), since ECs changes occur earlier than those of the media and adventitia. Further ECs–VSMCs interactions result in VSMCs deregulation causing the disease to progress [56].

The endothelium mainly affects AAA because of its ability to secrete proteins such as angiopoietin II, tethrahydrobiopterin (BH4) which is a cofactor for endothelial NO synthase (eNOS), the producer of the most important vasoactive molecule, NO [57,58]. BH4 levels are associated to eNOS function, and higher BH4 levels are associated with improved eNOS activity [59]. It has been demonstrated in animal models that BH4 modulates sensitivity to Ang II-induced vascular remodeling, blood pressure, and AAA [60]. eNOS impairment, as a result of endothelial dysfunction, is also characterized by oxidative stress, resulting in several systemic implications, mainly borne on the cardiovascular system itself [61,62].

Shear stress (SS) is another fundamental factor able to modulate endothelial function, indeed, subphysiological shear stress values are associated with endothelium activation and enhanced permeability to leukocytes ([45]). As for atherosclerosis, it is possible that AAA is more likely to develop in regions of oscillatory, nonuniform, or reduced wall shear stress while high values of shear are correlated to lower probabilities of disease development.

Moreover, it is now commonly accepted that AAA regions with a lower shear stress magnitude represent a higher risk of rupture [63].

During AAA pathogenesis, it is possible to observe the reduction in the number of vascular smooth cells due to increased apoptosis as a consequence of the loss of homeostasis. As the cellular component diminishes due to apoptosis, matrix component turnover is more maintained [64], paving the way for vascular role weakening and ultimately, tunica media and adventitia thinning and expansion.

As previously demonstrated, VSMCs are highly plastic cells. Unlike previous findings, demonstrating that VSMCs are driven toward a synthetic fibroblast like phenotype in atherosclerosis pathogenesis, it is now believed that they can adopt a wide range of phenotypes, resembling foam cells, macrophages, mesenchymal stem cells, and osteochondrogenic cells. Indeed, VSMCs are able to quickly shift from a specialized contractile phenotype to a less differentiated osteochondrogenic phenotype, directly promoting plaque calcification. Osteochondrogenic transition is characterized by the expression of bone-related molecules such as bone morphogenetic protein-2, homeobox protein MSX-2, and osteopontin [65,66].

VSMCs phenotype transition in AAA is accompanied by a downregulation of contractile markers followed by an upregulation of metalloproteases (MMPs) synthesis leading to enhanced proliferation and migration ability [56,67].

Several researchers have underlined the fundamental role of MMPs in vascular physiopathology [68]. Historically, MMP family members are classified into four groups depending on their substrate degradation activity: archetypal MMPs, matrilysins, gelatinases, and furin-activated MMPs. Advances in biochemical sciences have allowed a further classification based on molecular structure [69,70].

Interestingly, MMPs are differently expressed in pathological samples depending on the progression stage of the disease. This concept is more evident in the setting of AAA [71,72].

MMPs are locally secreted by VSMCs, ECs infiltrating leukocytes, and most importantly, macrophages. MMPs activity is modulated by inflammatory cells such as monocytes. Monocytes are able to produce proinflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) promoting matrix metalloproteinases (MMP) secretion, mainly via mitogen-activated protein kinase pathways (MAPK) [73].

Indeed, macrophages and T lymphocytes infiltrate AAA segments enhancing the production of chemokines, cytokines, perphorins, and proapoptotic molecules such as FasL, the natural ligand of Fas receptor (CD95) [74]. In this way, the immune system plays a pivotal role in modulating VSMCs ostochondrogenic transition. Additionally, inflammatory cells (macrophages) infiltrating AAA express MMPs, in particular MMPs 8, 9, and 12. In contrast, MMP-2 seems to be associated with the synthetic phenotype of VSMCs and might be useful as a potential marker of AAA progression [75].

Another mechanism involved in AAA development is CD40L (CD154) ([46–49]) which is the ligand for CD40 receptor expressed by activated T lymphocytes. CD40-CD40L axis is related to the TNF-α pathway, playing a pivotal role in vascular inflammation. AAA patients have increased levels of IL-1β, TNF-α, CCL2, IL-6, and IFNγ [76] which are released by T cells and macrophages. These cytokines are known to promote CD40L expression [77,78].

CD40L deficiency strongly reduces the incidence of dissecting aneurysms, limits inflammation, and degrades the extracellular matrix in the arterial wall. However, once the aneurysm has developed, the CD40L deficiency can no longer prevent its progression. Therefore the data reveal that a block of CD40L protects the arterial wall from dissecting aneurysm formation, reducing the proteolytic profile, preceded by reduced inflammation. The deleterious role of CD40-CD40L in AAA development seems to be related to its activation of MMPs, MMP-2 and MMP-9 in particular [79].

Thus, therapies that inhibit CD40L may represent an interesting option for the stabilization of AAAs.

Moreover, the ratio of expression between MMP and TIMP (endogenous tissue inhibitor) is higher in pathological samples [80], suggesting that in AAA pathogenesis, MMPs levels are no more controlled by the tissue-producing deleterious effects clinically observed.

Physiologically, MMP-mediated ECM turnover allows cell migration within healthy tissues, and this is vital in maintaining the structural integrity of the aorta. Therefore pharmaceutical approaches aiming at downregulating MMP through global interference may be somehow a problem; instead a more precise approach to tightly localize regulation of MMPs expression in a microanatomical specific fashion is more desirable [69].

JNK pathway has been proposed as a crucial step in MMPs secretion and hence, it is likely to be one of the most important deregulated pathways in AAA progression [81].

Murine models knocked out JNK pathway’s components resulted in a decrease of AAA development in genetically predisposed mice. JNK pathway is also associated with ECM biosynthesis, via its activation of biosynthetic enzymes like prolyl 4-hydroxylase subunit alpha-1 (P4ha1) responsible for the hydroxylation of proline residues in procollagen enhancing three-dimensional folding, and lysyl-oxidase (Lox) required for collagen cross-linking. JNK-targeted therapy could therefore provide nonsurgical therapeutic options for AAAs [82].

In AAA, collagen type I is typically reduced while collagen type III is overexpressed. It has been proposed that the protective role of collagen III in maintaining aortic wall integrity is a healing process mechanism within the abdominal aortic wall. This is supported by reduced AAA incidence in patients long term treated with angiotensin converting enzyme inhibitors, which have already been described to increase the synthesis of collagen III [83,84]. TGF-β is one of the main pathways involved in matrix deposition, and despite being initially considered as a valuable target for inhibition to counteract aneurysm progression, TGF-β is now considered a positive and protective pathway [85,86]. The TGF-β pathway promotes extracellular matrix synthesis, activates regulatory T cells, inhibits inflammation and matrix degradation, and protects vascular smooth muscle cell dysfunction [87].

Another crucial step in AAA pathogenesis is ADAM17 deregulation [88]. This metalloproteinase is required in epithelial growth factor receptor (EGFR) transactivation in VSMCs [89,90] and has been demonstrated to drive AAA development in murine models [91]. ADAM17-tailored approaches are complicated by its indispensable regulator of almost every cellular event from proliferation to migration [92].

EGFR itself is activated by Ang II, which is one of the hormones implied in AAA pathogenesis, which acts by stimulating the expression of ADAM17. ADAM17 silencing results in the protection from AAA development, and the molecular basis of this effect seems to be related to EGFR stimulation’s suppression.

ADAM17’s overexpression was also observed in the endothelium and adventitia of AAAs. Therefore the inhibition of ADAM17 is a possible target for the treatment of AAA, because its presence guides the development of AAA [91].

Noncoding RNAs (NcRNAs) are gaining attention from the biomedical community as a revolutionary tool to approach diseases’ treatment.

Novel advances in molecular basis of AAA pathogenesis are a useful source of inspiration for new therapeutical approaches, such as cell therapy. Both micro-RNAs and long NcRNAs [93] have been studied in recent years to better understand their role in AAA development, potentially giving novel markers and therapeutical targets via antisense oligonucleotides approaches ([94]).

Another family of noncoding RNAs, circular RNA transcripts (circRNAs) have been a recent addition to the functionally relevant noncoding RNAs in our genomic landscape [95,96]. New methods allowing a more precise detection has led to interesting insights on their role in different diseases ([97]; [98,99]). Although highly probable, until now, none of these circRNAs have been used in AAA development ([45]).

The role and therapeutic potential of several miRNAs (miR-21, 24, 29, 33, 143/145, 181b, 195, 205, and 712) have been demonstrated in AAA animal models, and some of these findings were also present in aneurysm tissue samples. Conversely, the clear association between lncRNAs and AAA has only been possible for one (H19), although several lncRNAs (SENCR, SMILR, lnc-Ang362, HOTAIR, Pi5, lnc-HLTF-5, Hif1α-AS1, AK056155, and lnc00540) are good candidates for roles in some pathophysiological processes of AAA development ([45]).

The possibility to target ncRNAs in AAA treatment is potentially a game changer in the field of vascular surgery. Still, more efficient and specific delivery systems are required for the modulation of ncRNAs in vivo to minimize off-targets and translate basic research findings into clinical practice.

If the exploitation of the therapeutic potential of miRNAs is still at an early stage, several studies have been identified and demonstrated their diagnostic potential as markers for aneurysms [100,101]. Some groups have also identified statistically different miRNAs expression levels in fast- or slow-growing AAAs, although in a limited cohort of patients [102].

Current management of aortic aneurysms relies exclusively on prophylactic operative repair of larger aneurysms. Great potential exists for successful medical therapy that halts or reduces aneurysm progression and hence, alleviates or postpones the need for surgical repair [103].

The possibility to modulate disease prone VSMCs to obtain a reparative phenotype constitutes one of the most promising cell-based approaches regarding AAA treatment (Fig. 1.1).

Figure 1.1 Summary of contents.

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Chapter 2

Risk factors and pharmacological therapy in patients with vascular