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FIGURE 5.9 Proximal aortic dissection with severe aortic regurgitation. Left: 2D five-chamber TEE view (arrow, dissection flap); right: 2D five-
chamber colored TEE view.
FIGURE 5.10 Isolated aortic root dissection. The right coronary ostium is dissected from aortic root and the right ventricle restricted the tear. RC, right
coronary ostium.
becomes chronic and is left untreated, the pathology usually terminates with aortic root dilatation with/without spreading
of dissection into the coronary ostia. Involvement of the aortic valve and aortic root can cause pathophysiologic changes
to the aortic valve apparatus and result in severe aortic regurgitation, which can confuse cardiac surgeons to prefer either
conservative or aggressive repair [45]. If the aortic root is spared, the untouched root grows slowly with lower secondary
root events, but similar excellent long-term outcomes [46,47]. If the aortic root could not be spared, aortic root replacement
is the single option to salvage the patient-live and to prevent all early and late adverse outcomes [48].
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Chapter 6
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Cellular Mechanisms of Ascending Aortic
Aneurysms
Aruna Poduri
Stanford University, Palo Alto, CA, United States
Chapter Outline
Structure, Size, and Location of Aorta 79
Diagnosis and Risk Factors of Ascending Aortic Aneurysm 79
Characterization of Ascending Aortic Aneurysms 80
Cellular Mechanisms of Ascending Aortic Aneurysm 80
Endothelial Cells 80
Smooth Muscle Cells 80
Fibroblasts 80
Immune Cells 81
Elastin 81
Collagen 81
Microfibrils and Fibrillin 81
Fibulin 81
Additional Factors Involved in Ascending Aortic Aneurysm 82
Potential Drug Treatments for Ascending Aortic Aneurysm 82
Summary 82
Acknowledgments 82
References 82
STRUCTURE, SIZE, AND LOCATION OF AORTA
Aorta is a major vessel that distributes oxygenated blood to the different tissues in the circulatory system. It is also the larg-
est known blood vessel in humans. Structurally, aorta is a big tube and its size is directly equivalent to person’s height and
weight. Aorta is broadly divided into four parts: ascending, descending, abdominal, and infrarenal [1]. In general, aorta is
largest in size at the ascending region and smallest at the infrarenal. The normal diameter range of aorta is variable with
age, gender, and lifestyle. The normal diameter of ascending aorta is <2.1 cm/m2, whereas of descending and abdominal
is <1.6 cm/m2 and 3 cm, respectively [2]. Ascending is the most anterior region of the aorta and closest to the heart, where
the coronary arteries arise to supply blood to the heart. The ascending aorta is present in the thoracic cavity; therefore,
ascending aortic aneurysm (AAA) is also referred as thoracic aortic aneurysms. The region below the left subclavian artery
is known as the descending aortic region, whereas the abdominal area begins at the level of the diaphragm and at vertebrate
level T12. The region below the kidney is defined as the infrarenal aorta. Abdominal aorta and infrarenal are also sites for
aneurysm development in humans and as well in rodents besides the ascending aortic area. This chapter focuses on studying the cellular mechanisms of AAAs.
DIAGNOSIS AND RISK FACTORS OF ASCENDING AORTIC ANEURYSM
Every year, around 50,000 deaths are reported due to aortic diseases and the rate of incidence with each decade is on a rise
[3,4]. This number may fluctuate a lot as many cases are undiagnosed or wrongly categorized as a cardiac attack. In major-
ity of the cases, AAA is asymptomatic and can occur at any age in both genders. AAA is diagnosed during general medical
check-ups, which includes X-ray or ultrasound of thoracic cavity. Further, it is validated with echocardiogram and computerized tomography or magnetic resonance angiography to determine the precise location, size, diameter, and damage in the
ascending aorta. In the case of aneurysm, the diameter of the ascending aorta expands within a range of 4–5.5 cm [5]. The
associated risk factors with AAA include age, hypertension, smoking, genes, atherosclerosis, dyslipidemia, inflammation,
angle bend of ascending aorta, and strenuous exercise [6]. Numerous diagnostic and risk elements have been associated
with the pathological changes of AAA.
New Approaches to Aortic Diseases from Valve to Abdominal Bifurcation. http://dx.doi.org/10.1016/B978-0-12-809979-7.00006-7
Copyright © 2018 Elsevier Inc. All rights reserved.
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Once being diagnosed with AAA, it makes a big impact on the lifestyle of the person. Cure for AAA is restricted mainly
to surgery [7–9]. Surgery mainly involves endovascular stent grafting or open surgical aortic repair. However, with modern
equipment and technology, less invasive medical practices are present but they are still at early stages. Alternative medicine
is necessary to identify the predisposing factors to avoid the treatment from a surgery. Therefore, the main aim of the present research is alternative interventions, which can advance the impaired ascending aorta and reestablish vascularization in
the region. To progress in this direction, a mechanistic approach is required to solve the puzzle of AAA, which will make a
new and clear picture about the etiology.
CHARACTERIZATION OF ASCENDING AORTIC ANEURYSMS
The location and heterogeneous nature of ascending aortic tissue make it unique and susceptible to many pathological
states. This site is subjected to dilation, elastin fragmentation, dissection, and rupture and thrombus formation [1,10,11].
AAA is a severe and complex disorder, which is characterized as luminal dilation of ascending aorta. It is a progressive
disease, where the intima and the media are torn and allow the blood cells to enter into the aortic layers. Further this leads
to the split of the layers that opens up into a new channel called as false lumen. At this point, several changes are occurring
in media as well such as elastin degradation, medial thickening, ultimately changing the aortic blood flow. Consequently,
this leads to a progressive expansion and weakening of the aortic wall that predisposes it to dissection and rupture.
CELLULAR MECHANISMS OF ASCENDING AORTIC ANEURYSM
The ascending aorta is comprised of three main zones: intima, media, and the adventitia. The innermost layer is the endothelium. It is a single cell lining along the length of the artery and is in direct contact with the blood. The adjacent smooth
muscle cells comprise the medial layer and are responsible for contraction. Adventitia is primarily heterogeneous in composition with a wide array of cells; fibroblasts, macrophages, nerve cells, adipose, immune cells deposited in a collagen-rich
extracellular matrix. Each level is separated by elastic fibers and laminae. The influence of every cellular element in the
AAA is discussed below.
Endothelial Cells
The cell type identifies and responds to various fluid shear stress and other environmental factors. Results have shown that
there is a cross-talk between endothelial and adjacent smooth muscle cells [12,13]. In an animal model of AAA, absence
of angiotensin II receptor in this cell type causes ascending aortic wall dilation, elastin fragmentation, and interlamellar
spaces are increased [10]. A recent report showed that the condition of intimal cells has higher susceptibility to AAAs [14].
The exact signaling mechanism that commenced in the endothelium and transmitted to smooth muscle cells is not clearly
defined.
Smooth Muscle Cells
The primary composition of the media is aortic smooth muscle cells, which are separated by elastin fibers. This cell type
is plastic in nature and switches its phenotype under different conditions [15,16]. One being the synthetic or proliferative
phase and the other is contractile, which is the differentiated form or in the form of a mature smooth muscle cell. Phenotype
switching depends on the environment as it is temporary and reversible contraction of smooth muscle cell is due to the presence of actin and myosin complexes that are linked to filamin A and cytosketelon proteins [17]. This cell type cross-talks
with extracellular matrix proteins–collagen, elastin, fibrillin, and integrins [15,18–20]. Aortic smooth muscle cells regulate
the cell shape, alignment, proliferation, and migration. These proteins are altered and disrupted in AAA, further changing
vascular smooth muscle cells function. In AAA, this cell type undergoes apoptosis and fragmentation of elastin fibers [21].
Medial thickening and medial hyperplasia are observed in AAA [22]. Single-nucleotide mutations have been reported in
actin assembly proteins, beta-myosin heavy chain, and filamin A genes, which are encoded by this cell type and are associated with AAA and other aortic diseases [23–25].
Fibroblasts
This cell type is the main element of the adventitial layer. Fibroblasts are involved in inflammation, remodeling of the
aorta, AAA, medial hyperplasia, rupture, and dissection [22,26–28]. Functional variation of fibroblasts is linked to changes
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in elastin fibers and smooth muscle cells. Any change in the environment or damage, fibroblasts change its phenotype to
myofibroblasts. Myofibroblasts are different from fibroblasts as they acquire the characteristic of smooth muscle cell such
as α-actin and myosin heavy chain. In the animal model of AAA, the presence of myofibroblasts was significantly increased
in the aortic tissue [28]. A possible mechanism can be that fibroblasts migrate into the nearby medial layer in response to a
stimuli; however, the factors that initiate this mechanism is yet to be defined [22]. Fibroblasts and fibroblasts-derived cells,
myofibroblasts, can be a likely candidate to revascularize the ascending aorta in AAA.
Immune Cells
The main role of immune cells that are involved in shielding the body against both contagious disease and foreign intruders.
T lymphocytes and macrophages cells are increased in AAA tissues [21]. Cytokines released by different immune cells play
a significant role in AAA. TGF-beta cytokine is augmented in AAA both in mouse models and in human tissue [29,30].
Monocyte chemoattractant protein-1 (MCP-1) released by immune cells is increased in AAA [31].
Elastin
One of the most critical component of the aorta is elastin that maintains the structure of the aortic wall. Elastin reacts to any
kind of external stimuli comprising mechanical or chemical and regulates signaling between different cell types. Elastin
interacts with medial aortic smooth muscle cells, extracellular matrix present in the adventitia, and endothelial cells to
maintain the structure and organization of the tissue [32]. It limits the migration and proliferation of the cells between the
aortic layers [33]. In AAA, elastin undergoes fragmentation, where elastin fibers become weak and break in arterial wall.
Deficiency of elastin is associated with deformed smooth muscle cells and results in death [34].
Collagen
The basement membrane, media, and adventitial layers are enriched in collagen to provide tensile strength and stiffness
to ascending aortic artery wall. Many types of collagen are present; Type I–IV. These different collagens are expressed in
artery wall but Type I and III are relatively more in abundance. These regulate many signaling mechanisms including adhesion and proliferation of cells [35,36]. Alternations in these genes are associated with the development of AAA. In addition,
genetic mutations in Col1A1, Col1A2 Col4A1, and Col4A5 are linked to aneurysm development [37,38]. During AAA,
collagen Type I and III are increased leading to collagen deposition, elastic fragmentation, and weakening of arterial wall.
Further it advances to vessel stiffness, enlargement of aorta causing to dissect and rupture.
Microfibrils and Fibrillin
Microfibrils are a part of elastin fibers, which provide extra strength to the vascular tissue. Elastin microfibrils interface located
(EMILIN) proteins are present in the extracellular matrix. EMILINs are further categorized into EMILIN 1–3. Absence of
EMILIN 1 decreases aortic aneurysm formation with asymmetrical composition of smooth muscle cells and elastin fibers [39].
Absence of EMILIN 2 is linked with the increased risk of heart diseases. This protein binds to fibulin and elastin [40].
Microfibrils are comprised of fibrillins. Two isotypes of fibrillins are identified; 1 and 2. Fibrillins interact with collagen
and extracellular matrix. The function of fibrillins is to provide strength to aorta. Fibrillin 1 isoform is expressed throughout
life and contribute in regulating integrin receptor signaling and proteoglycans. Absence of fibrillin 1 gene is associated with
Marfan’s syndrome, a type of AAA [29,41,42]. Fibrillin 1 genetic mutation at C1039 G predisposes the person to this disease.
With this mutation, the thickening of aortic wall, increased expressions of transforming growth factor β1, inflammation, elastin
degradation, and extracellular matrix. On the other side, fibrillin 2 is present during the embryonic stages and involves in the development of aorta [43]. Unlike the absence of fibrillin 1 gene, the fibrillin 2 gene mutation has no effect on aneurysm development.
Fibulin
Fibulin belongs to the family of extracellular matrix proteins. The purpose of this gene is to organize and maintain the structure of the aortic wall. Till date, five fibulins are identified that regulate the lamellar structure by cross-links with elastin and
smooth muscle cells [44]. Mutations in fibulin 4 and 5 are related to aortic aneurysms with ascending aortic enlargement
[45,46]. Aortic wall represents tortuosity, slack skin, and disordered elastin fibers [47,48]. The other forms of this family
are fibulin 1, 2, and 3 and have no direct effects on aortic aneurysms.
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ADDITIONAL FACTORS INVOLVED IN ASCENDING AORTIC ANEURYSM
Besides the above mentioned cellular factors associated with AAA, there are biochemical-signaling, transcription, and
microRNA-mediated mechanisms that also play a significant role in this disorder. Mechanisms through external stimuli are
also involved in the development of AAA, namely increased oxidative stress, transforming growth factor-β, and angiotensin II. Alternations in the gene expression of these pathways magnify the manifestation of the disease. Genetic mutations
are also associated with the development of AAA and other forms of the disease: Marfan’s syndrome, Loeys–Dietz syndrome, and Ehlers–Danlos syndrome [49–54]. Additionally, there are other mediators regulating the TAA formation such
as mechanical pathways that includes sheer wall stress and radial strain on the aortic wall. The activated mechanotransduction signaling pathways and the resident mechanical environment plays an important role in facilitating different cellular,
matrix responses and influences the blood flow [55,56]. Any malfunctioning of a biomechanical signal can implicate on the
structure and function of aortic resident cells.
POTENTIAL DRUG TREATMENTS FOR ASCENDING AORTIC ANEURYSM
Currently, no direct pharmacological drug is there for AAA treatment. Nevertheless, recent scientific reports have demonstrated the possible mechanistic role of few drugs for treating AAA. Losartan, an angiotensin II receptor blocker (ARB), when
administrated into fibrillin 1 −/− mice, a mice model of AAA, showed attenuation of aortic diameter and improved the aortic
structure [29]. Another drug, β-adrenoreceptor blocker, also exhibited comparable results of ARB. A matrix metalloproteinase inhibitor, doxycycline, when given to the same mice model showed the reduction of extracellular matrix proteins 2 and
9 [57,58]. A neutralizing antibody against transforming growth factor β1 induced into an AAA animal model has shown the
restoration of aortic wall structure [29]. Another study showed that TGF-beta neutralization increases the AAA formation [59].
Amlodipine, calcium channel blocker showed reduction of AAA [60]. Given these results in animal model studies, some of
these drugs have entered into clinical trials for AAA treatment [61,62].
SUMMARY
Given the heterogeneous tissue composition of AAA, it is a complex disorder. However, modern and state-of-the-art facilities have helped us to visualize the discovery of new results, which provides valuable information about the etiology of
AAA. These results have laid the groundwork in the new path to identify novel therapeutic targets for AAA therapy. A
continuous and persistent research in this direction will elucidate and complete the whole picture of AAA. This information
will move us closer to more pharmacological therapies, which can be driven by personalized medicine. Future holds more
clinical insights for better cure and management for AAA.
ACKNOWLEDGMENTS
The author would like to thank colleagues at Stanford University, California, for their valuable inputs to improve the article.
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Chapter 7
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Mathematical Modeling of Aortic
Aneurysm Progression
Piotr Formanowicz
1
Poznan University of Technology, Poznan, Poland; 2Polish Academy of Sciences, Poznan, Poland; 3Poznan University of Medical Sciences, Poznan,
Poland
Chapter Outline
Introduction 85
Mathematical Modeling and Systems Analysis of Biological
Phenomena 85
1,2
, Michał Nowicki3, Dorota Formanowicz
3
Petri Net–Based Model of Aortic Aneurysm Progression 86
Acknowledgments 89
References 89
INTRODUCTION
Numerous studies on the mechanisms initiating and stimulating progression of aortic aneurysms (AA) reveal the complexity of the studied phenomenon. This is particularly important given the fact that it seems that only taking into account this
complexity can help in predicting the dynamics of the development of aneurysms and a full risk assessment. The main
problem arises from a variety of environmental (including increased oxidative stress, inflammation, altered shear stress)
and genetic factors that are involved in the formation and progression of aneurysms [1,2]. Patients with AA frequently have
atherosclerosis and many studies show the association of coronary heart disease and peripheral atherosclerosis with AA.
However, whether the relationship between AA and atherosclerosis is causal or simply just due to the common risk factors
is not known. There are at least several alternative theories. In this study, the results of studies available in the literature and
the authors’ own experience are taken into account. Because the issue is complex, systems approach has been used to build
and analyze a model of the studied phenomenon. For this purpose, the theory of Petri nets, which gives a better insight into
this complex process, has been used.
MATHEMATICAL MODELING AND SYSTEMS ANALYSIS OF BIOLOGICAL PHENOMENA
It becomes more and more evident that living organisms as well as their functional blocks such as organs, tissues,
cells, etc., are complex systems (cf. [3]). Hence, to analyze their properties, methods suitable for an analysis of
complex systems should be used. Such methods have been developed in the area of system sciences and are used for
decades for an analysis of technical systems. At least to some extent some of them can also be used in the area of
biological sciences. Obviously, biological systems have their own specificity, hence often these methods should be
adapted to the analysis of them or even new methods should be developed. However, in any case, a basis for systems
analysis is a formal model of the analyzed phenomenon (cf. [4]). Such a model can be expressed in a language of
some mathematical theory. Usually differential equations are used (cf. [5]). They are a powerful tool; however, they
have some limitations. Among others, models expressed as such equations require precise values of some parameters,
which correspond to quantitative properties of the modeled system. In practice, determining these values in the case
of biological systems is usually very difficult or even impossible. This is one of the reasons that models of different
types are recently constructed. Among them it appears that those expressed in the language of Petri net theory are
especially promising [6].
Such nets have a structure of weighted directed bipartite graphs. It means that they are composed of nodes of two types
connected by arcs labeled with positive integer numbers. Nodes of one of the types are called places and they correspond to
New Approaches to Aortic Diseases from Valve to Abdominal Bifurcation. http://dx.doi.org/10.1016/B978-0-12-809979-7.00007-9
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