POLITECNICO DI MILANO Dipartimento di Matematica F. Brioschi Ph. D.

course in Mathematical Engineering

XXI cycle

Computational hemodynamics of the cerebral circulation: multiscale modeling from the circle of Willis to cerebral aneurysms
Ph. D. candidate: Tiziano PASSERINI
Mat. D02436 MSc Degree in Biomedical Engineering Politecnico di Milano

Supervisor: Prof. Alessandro VENEZIANI Tutor: Prof. Alessandro VENEZIANI Coordinator: Prof. Paolo BISCARI

Milano, 2009

Contents
Abstract 1 Introduction 1.1 Anatomy and physiology of the cerebral circulation . . 1.1.1 The circle of Willis . . . . . . . . . . . . . . . . . 1.2 Morphology and uid dynamics of cerebral aneurysms 1.2.1 The role of hemodynamics . . . . . . . . . . . . 1.3 Modeling the cerebral circulation . . . . . . . . . . . . . 1.3.1 The circle of Willis . . . . . . . . . . . . . . . . . 1.3.2 Cerebral aneurysms . . . . . . . . . . . . . . . . 1 3 3 4 6 10 12 13 14 15 15 16 17 19 21 27 28 29 30 30 32 34 35 39 39 40 41 41 43 44 44 48 50

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2 One-dimensional models for blood ow problems 2.1 Wave propagation phenomena in the cardiovascular system . . . . . . . 2.1.1 Modeling the vascular wall . . . . . . . . . . . . . . . . . . . . . . 2.2 Formulation of the model . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1 A viscoelastic structural model for the vessel wall . . . . . . . . . 2.2.2 The linearized model . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Networks of 1D models . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Numerical discretization . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1 Numerical solution of the viscoelastic wall model . . . . . . . . . 2.5 Results and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.1 Validation of the numerical model versus an analytical solution . 2.5.2 Wave propagation in a single 1-D vessel: a Gaussian pulse wave 2.5.3 Wave propagation in a single 1-D vessel: a sinusoidal wave . . . 2.5.4 A 1D model network: the circle of Willis . . . . . . . . . . . . . . 3 Three-dimensional models for blood ow problems 3.1 Blood ow features in arteries . . . . . . . . . . . . 3.2 Geometry and Flow . . . . . . . . . . . . . . . . . . 3.2.1 Reynolds number . . . . . . . . . . . . . . . 3.2.2 Dean number . . . . . . . . . . . . . . . . . 3.2.3 Womersley number and Reduced Velocity 3.3 The Navier-Stokes equations . . . . . . . . . . . . 3.3.1 Formulation . . . . . . . . . . . . . . . . . . 3.3.2 Numerical discretization . . . . . . . . . . . 3.4 Wall shear stress in the Navier-Stokes problem . .

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Contents 3.4.1 Approximation for the velocity gradient . 3.4.2 Oscillatory Shear Index . . . . . . . . . . Working on regions of interest . . . . . . . . . . . 3.5.1 Decomposition of bifurcation branches . 3.5.2 Relating surface points to centerlines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 52 53 53 54 59 59 60 62 71 74 77 77 78 79 80 85 86 88 89 91 93

3.5

4 An application of three-dimensional modeling 4.1 Cerebral hemodynamics . . . . . . . . . . . . . . . . . 4.2 The Aneurisk project . . . . . . . . . . . . . . . . . . . 4.3 Hemodynamic features of the Internal Carotid Artery 4.3.1 Discussion . . . . . . . . . . . . . . . . . . . . . 4.3.2 Wall shear stress as a classication parameter .

5 A geometrical multiscale model of the cerebral circulation 5.1 The compliant vessel problem . . . . . . . . . . . . . . . . 5.2 Matching conditions in 3D rigid/1D multiscale models . 5.2.1 Numerical algorithm . . . . . . . . . . . . . . . . . 5.2.2 Matching conditions including compliance . . . . 5.2.3 Parameters estimation . . . . . . . . . . . . . . . . 5.2.4 Results . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 A 1D-3D-1D coupling . . . . . . . . . . . . . . . . . . . . . 5.3.1 Results . . . . . . . . . . . . . . . . . . . . . . . . . 5.4 The 3D carotid model and the multiscale coupling . . . . 5.4.1 Remarks and perspectives . . . . . . . . . . . . . . 6 Computational tools 6.1 An introductory note on C++ . . . . . . . . 6.2 LifeV: a C++ nite element library . . . . . 6.2.1 Code features . . . . . . . . . . . . . 6.3 Implementation of networks of 1D models 6.3.1 Building the graph . . . . . . . . . . 6.3.2 Interface conditions . . . . . . . . . 6.3.3 A simple example . . . . . . . . . . . 7 Conclusions Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

94 . 94 . 95 . 96 . 97 . 100 . 102 . 106 109 111

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Abstract
In this work we address the mathematical and numerical modeling of cerebral circulation. In particular, one-dimensional (1D) models are exploited for the representation of the complex system of cerebral arteries, featuring a peculiar structure called circle of Willis. These models, based on the Euler equations, are unable to capture the local details of the blood ow but are suitable for the description of the pressure wave propagation in large vascular networks. This phenomenon is driven by the mechanical interaction of the blood and the vessel wall, and is therefore affected by the mechanical features of the wall. Chap. 2 deals with 1D models taking into account the wall viscoelasticity. In particular, the derivation of the nonlinear model is presented in Sec. 2.2, while a linearized set of equations is presented in Sec. 2.2.2. An analytical solution is found for the latter formulation and is used to validate the adopted numerical scheme (Sec. 2.4 and Sec. 2.5). Finally, the effect of wall viscoelasticity on the wave propagation phenomena is studied in some numerical experiments representative of realistic conditions in the cardiovascular and cerebral arterial systems. The details of the blood ow can be studied by means of three-dimensional (3D) models, based on the Navier-Stokes equations for incompressible Newtonian uids introduced in Sec. 3.3. These models can correctly describe blood ow patterns in medium and large arteries, and in particular allow the evaluation of the stress eld in the uid. Thus, it is possible to estimate the traction exerted by the blood ow on the vessel wall (wall shear stress, dened in Sec. 3.4). Moreover, by exploiting the representation of the vascular tree in terms of centerlines, it is possible to easily identify regions of interest in the computational domain, in which to restrict the uid dynamics analysis: this approach is presented in Sec. 3.5. Cerebral aneurysms are a disease of the vascular wall causing a local dilation, which tends to grow and can rupture, leading to severe damage to the brain. The mechanisms of initiation, growth and rupture have not been completely explained yet, but the effects of blood ow on the vascular wall are generally accepted as risk factors, as discussed in Sec. 1.2. In the context of Aneurisk project, an extensive statistical investigation has been conducted on the geometrical features of the internal carotid artery, nding that certain spatial patterns of radius and curvature are associated to the presence and to the position of an aneurysm in the cerebral vasculature (Sec. 4.2). Starting from this observation, a classication strategy for vascular geometries has been devised. In the present work, blood ow has been simulated in the patient-specic vascular geometries reconstructed in the context of the Aneurisk project, and an index of the mechanical load exerted by the blood on the vascular wall near the aneurysm has been dened. Finally, it has been shown that certain values of the mechanical load are associated to the presence and the location of an aneurysm in the cerebral circulation. Adding this

Contents hemodynamic parameter in the classication technique improves its efcacy (Sec. 4.3). The interaction between local and global phenomena is a typical feature of the circulatory system. It is believed to be crucial in the context of cerebral circulation, since defects or diseases at the level of the circle of Willis can induce local ow conditions associated to the initiation of an aneurysm. Geometrical multiscale models are a promising tool for the modeling of this interaction. They are based on the coupling of reduced models taking into account the dynamics of the vascular network and detailed models describing the local blood features. In Sec. 5.4 a geometrical multiscale model of the cerebral circulation is presented, based on the coupling of a 1D representation of the circle of Willis and the 3D representation of a carotid artery. A novel method to describe the interface between the two models is discussed in Sec. 5.2. The number of potential applications of reduced models, due to their proven effectiveness in the study of vascular networks, calls for the design of efcient and robust software tools. In Chap. 6 we address this issue, by presenting some excerpts of the software specically written in the context of this work for the simulation of the circulatory system (Sec. 6.3).

1 Introduction
In this Chapter we discuss the motivation of this work, assessing the problems of interest. A description of the cerebral circulatory system and a review on the state of the art knowledge on cerebral aneurysms are presented in Sec. 1.1 and Sec. 1.2, respectively. Most of the material here presented is taken from the work by Khurana & Spetzler [65]. More details and additional references to the medical literature for these topics can be found therein. The modeling of cerebral circulation, with specic attention to the blood ow problems related to the development of vascular diseases, can enhance the comprehension of the pathology mechanisms and therefore help in devising treatment procedures. On the other hand, the complexity of the physical systems at hand calls for the denition of effective modeling strategies, balancing the need for a detailed description of the physical phenomena and the computational cost. These issues, together with a description of the original contribution of this work in the presented framework, are discussed in Sec. 1.3.

1.1 Anatomy and physiology of the cerebral circulation

Cerebral vasculature is a complex structure, ensuring the adequate perfusion to all the brain districts [39]. Cerebral blood vessels are responsible for feeding the brain with oxygen and nutrients (brain arteries) and for the draining of metabolic waste products from the brain (brain veins). To illustrate the typical features of a cerebral artery, we refer for the sake of clarity to the schematic representation of its cross section, depicted in Fig. 1.1. The intima of brain arteries (the innermost part of the wall) is composed of a single layer of endothelial cells (represented as light blue cells in the gure), resting on a protein-rich layer called the basal lamina (inner part of the black circle). The outer part of the black circle represents the elastic lamina, whose main component is elastin protein, while smooth muscle cells (large red cells) form the media. Fibroblasts (thin green cells) and nerve bers (orange bers) are located in the adventitia (the outermost layer of the wall) and are respectively responsible for the production of collagen bers and for the innervation of smooth muscle cells. The astrocytes, one of which is shown in the gure as a dark blue cell, are present only at the level of the smallest brain vessels (the brain capillaries) and provide biochemical support to the endothelial cells [65].

1 Introduction

Figure 1.1: Cross-section of a brain artery, showing the layers and components of the wall. The innermost part is a hollow space (the lumen) containing serum and blood cells. The cells here illustrated are not to scale for the vessels in and around the circle of Willis. from http://www.brain-aneurysm.com/

1.1.1 The circle of Willis

Four main arteries enter from the neck under the surface of the brain. The two internal carotid arteries enter at the front, while the two vertebral arteries enter at the back. All the four of this trunks end in a ring of arteries known as the circle of Willis (see Fig. 1.2, left). This is the main collateral pathway of the cerebral circulation (see Fig. 1.2, right), made of the right and left posterior cerebral arteries (rPCA and lPCA), the right and left posterior communicating arteries (rPCoA and lPCoA), the right and left anterior cerebral arteries (rACA and lACA) and the anterior communicating artery (ACoA). The two internal carotid arteries (rICA and lICA) feed the anterior circulation, delivering blood in the anterior part of the brain, while the two vertebral arteries (rVA and lVA) join into the basilar artery (BA), feeding the posterior circulation which delivers blood in the posterior region of the brain. All the arteries forming the circle lie on the surface of the brain in the so-called subarachnoid space. From these vessels depart smaller arterial branches such as the perforating arteries, which supply the deep structures of the brain, and the pial arteries. The latter course over the brain surface (cortex) and into the brain valleys (sulci), originating perforating arterioles feeding the deeper cerebral tissue. The arterioles end in capillaries, which drain rst into venules and then into larger veins. A high-volume, low-pressure venous system (the dural venous sinuses) collects blood and empties into the jugular veins in the neck, eventually closing the circuit into the right atrium of the heart. The complex structure of the circle of Willis has two advantages. On the one hand it can supply blood to the brain even when one or more vessels are occluded or missing.

1 Introduction
Anterior communicating artery

Middle cerebral artery

Anterior cerebral artery Ophthalmic artery

Internal carotid artery Posterior communicating artery

Anterior choroidal artery

Posterior cerebral artery Superior cerebellar artery Basilar artery

Pontine arteries

Anterior inferior cerebellar artery

Vertebral artery

Anterior spinal artery

Posterior inferior cerebellar artery

Figure 1.2: Representation of the circle of Willis. Left: overview of the undersurface of the brain. Right: the arteries composing the ring. from http://www. wikipedia.org

It is well known in fact that in almost 50% of the population one of the branches of the circle is absent or partially developed [74], but this nding is regarded as a normal variation of brain vessels anatomy. On the other hand, the circle protects the brain from disuniform or excess supply of blood, distributing it uniformly. The study of blood ows in normal cerebral arteries and the circle of Willis is essential for better understanding the hemodynamics environment in which pathologies such as aneurysms develop, and is relevant in clinical practice for many intracranial or extracranial procedures like the endoarterectomy, the carotid stenting or the compression carotid test (see e.g. [60]).

1 Introduction

Figure 1.3: A saccular brain aneurysm (A) arising from the wall of a brain artery (ba). Black arrows indicate the aneurysm neck. from http://www. brain-aneurysm.com/

1.2 Morphology and uid dynamics of cerebral aneurysms

An aneurysm (named after the greek word anerisma, meaning widening), is a sac-like structure which forms where the blood vessel wall weakens, ballooning outwards (see Fig. 1.3). The most common type of cerebral aneurysm is the saccular or berry aneurysm, similar to a sack sticking from the side of a blood vessel wall. It is usually characterised by a neck region (indicated in Fig. 1.3 by black arrows), and tends to grow and rupture. Less frequently, fusiform cerebral aneurysms are found: they look like vessels expanded in all directions, do not feature a neck region and they seldom rupture. Furthermore, they are typically associated to fatty plaque or atherosclerosis in the artery or with an injury or break in the arterial wall. From now on, we will focus our attention on berry aneurysms, due to their greater clinical relevance. Classication Aneurysms can be classied according to their size, as shown in the following table: Diameter < 10 mm 11 - 15 mm 20 - 24 mm > 25 mm Class Small Large Near-giant Giant

1 Introduction Small and large aneurysms behave actually in similar ways in that they tend to grow and rupture, while most of the near-giant and giant aneurysm cause symptoms by compressing or irritating the surrounding brain structures. However, a threshold value for the diameter has not been precisely dened, and this explains the uncertain classication of aneurysms with diameter comprised between 16 and 19 mm. Location Most brain aneurysms form on the arteries of the circle of Willis or from their main branches. Moreover, most tend to occur in the anterior circulation, preferentially in regions where arteries branch. Indeed brain blood vessels could be naturally weaker in such locations, which are also preferential sites for fatty plaques deposition [65]. An extensive statistical investigation of the location of cerebral aneurysms has been one of the goals of the Aneurisk research project which motivated the present work. We will discuss this point more thoroughly in Chap. 4. Risk factors Aneurysms may be congenital, but most of them are nowadays thought to be acquired. The main risk factors for aneurysm formation are listed in the following table: The main risk factors for aneurysm formation Hypertension Previous aneurysm Family history of brain aneurysm Connective tissue disorder Older than 40 years Female Blood vessel injury or dissection Some inherited genetic defects may predispose to the forming of aneurysms and be compounded by added insults due for instance to smoking or hypertension. The hemodynamic factor is considered most relevant in the initiation of aneurysms. This topic will be dicussed later on in this Chapter and will be further expanded in Chap. 4. Indeed, the Aneurisk project proposed an integrated analysis of the morphological and uid dynamics features of pathologic vessels, with the aim of dening a classication of vascular geometries based on the probability of developing an aneurysm in specic locations [119]. Symptoms Most aneurysms are silent, and are discovered at the time of rupture. The typical symptom associated to this event is a sudden, extremely severe headache. In the minority of cases, the aneurysm may be found because of symptoms caused by the mass effect, in other words the compression or irritation of surrounding brain structures due to the

1 Introduction aneurysm large size. In this case, symptoms include chronic headaches, nausea, loss of functions in the nerve bundles in the brain causing disturbs such as double vision. In other cases, aneurysms may be found simply by chance. Rupture The rupture of an aneurysm is an event which can cause a stroke, the so-called brain attack, with effects comparable to those of the blockage of a blood vessel. Some aneurysms, prior to the rupture, tear a little and release a small amount of blood: this event is referred to as a warning leak. The bleed occurring after the rupture is known as subaracnoid hemorrage (SAH). In case the ow slows down in the aneurysm lumen, a thrombus may form, either before or after the rupture. Thrombosis can stop the bleeding after a rupture, but may also cause additional stresses to be exerted on the wall, by transmitting the blood pulsation through the mass of the clot. Moreover, the thrombus may host small channels of blood (recanalization), which can be associated to the growth, rupture and rerupture of the aneurysm. On the other hand, the rupture itself may cut off the supply of oxygen and other nutrients to the cells in the wall, thus further weakening it and predisposing it to a subsequent rupture. Complications Rehemorrage is one of most frequent and severe complications of cerebral aneurysms. Multiple SAHs may occur from the same aneurysm, especially in patients suffering from hypertension, since the walls are weakened after the initial rupture. Moreover, the risk of rebleeding increases with time, therefore an early treatment is mostly important for the patient outcome. Another feared complication is vasospasm, a temporary overcontraction of cerebral arteries which can result in a stroke. It may be triggered by a SAH, due to the presence of blood in the subarachnoid space, and can last few days to three weeks. Less frequent or severe complications include hydrocefalus, seizures, cardiac stunning and sodium and uid imbalance [65]. Detection Cerebral angiography is frequently used to detect brain aneurysms. One of its main disadvantages is invasivity, since it requires the femoral artery to be punctured and a catheter to be inserted and navigated through the arterial tree to inject an opaque dye near to the observed region. Radiographs are taken while the dye is advected by the blood ow. This technique can show the course of arteries, their pattern of communication, their length and diameter and the presence of abnormalities such as aneurysms. However, in presence of a clot it may not show the real extent of the aneurysm. Moreover, large areas of relative stagnation can cause the concentration of the dye in these regions to be low leading ultimately to undersegmentation.

1 Introduction Magnetic resonance techniques (MRI, MRA) are less invasive than cerebral angiography, but have a limitation in that they cannot detect the smallest aneurysms as well as cerebral angiography can. A new technique which is recently gaining popularity is CTA: it is based on a combination of computed tomography (CT) scanning and angiography. More precisely, an intravenous dye is injected into the patient during CT scanning. The resulting technique is quicker, cheaper and less invasive than the traditional cerebral angiography and able to produce high-resolution, color and 3D images. Ultrasound techniques and common radiography have no role in the detection of aneurysms [65].

Treatment If an aneurysm is detected but has not ruptured, the choice between immediate treatment or observation is controversial. The latter implies that the patients need to undergo repeated scans to determine if the aneurysm is enlarging, therefore facing the risk of excessive postponement of the treatment and, depending on the imaging technique, the exposition to multiple invasive procedures. The former exposes patients to perioperatory risks associated to the chosen procedures. The general criterium associating a risk of rupture to aneurysms based on their size is not practically accepted, since it is believed that each brain aneurysm should be evaluated on an individual basis, with consideration of patients age and medical conditions (in particular the history of previous SAHs), the aneurysm site, size and shape [146]. The rst option for the treatment is open surgery, which is usually recommended as early as possible after a rupture. Most of the different types of open surgery are based on the insertion of metallic clips across the neck of the aneurysm (direct clipping) or across the arteries feeding or draining the sac, in order to exclude it from the blood pathway or to make it clot off and eventually shrink. Another therapeutic choice, less certain than the clipping, is the surgical reconstruction of the aneurysmal part of the wall. On the other hand, endovascular intervention requires the insertion of a catheter, typically into the femoral artery, which is navigated through the aorta and up into the brain to the region of the aneurysm. Then platinum microcoils or a glue or other composite materials can be placed in the lumen of the aneurysm in order to slow the ow of blood. Alternatively, a balloon can be placed in the parent artery feeding the aneurysm, or a stent can be inserted across the aneurysmal portion of the artery to cut off its blood supply. Even combinations of the presented procedures can be performed. In all cases, open surgery is not needed, the effectiveness of the treatment can be comparable to that of surgery especially in small aneurysms and sometimes aneurysms which would be difcultly reached by open surgery can be treated endovascularly. However, aneurysms treated by coiling may persist or reoccur, thus needing to be treated again (by recoiling or open surgery) [84].

1 Introduction

1.2.1 The role of hemodynamics

It is accepted in the literature that hemodynamics plays a major role in the process of aneurysm formation, progression and rupture. This introduction briey summarizes the state of the art knowledge on the topic, following the excellent review recently proposed by Sforza et al. [124]. Arteries feature an adaptive response to blood ow and in particular to wall shear stress (WSS, see Chap. 3). A chronic increase of the WSS, due to increased blood ow, causes a reaction by endothelial cells and smooth muscle cells, which leads to vessel enlargement in order to reduce WSS to physiological values [38, 76]. However, this kind of structural remodeling can be potentially destructive, when triggered by locally increased WSS: in this situation, a damage to the arterial wall and a subsequent focal enlargement may take place [124]. On the other hand, endothelial cells can sense WSS and consequently adapt their spatial organization: uniform shear stress elds cause the cells to be stretched and aligned in the direction of the ow, while irregular shapes and orientation are assumed under the action of low and oscillatory wall shear stress. The latter situation promotes intimal wall thickening and potentially atherogenesis [31, 43, 50, 68], however in the particular case of cerebral aneurysms could be a protective factor against wall weakening and rupture [124]. Many clinical and experimental observations support the theory of a relation between cerebral aneurysm initiation and the effects of high-ow hemodynamic forces on the arterial wall. Studies pointed out the association of cerebral aneurysms with arterial anatomic variations and pathological conditions such as hypoplasia or occlusion of a segment of the circle of Willis [64, 81, 117]. High-ow arteriovenous malformations inducing a local increase of blood ow in the cerebral circulation [96] can promote the disease. Furthermore, aneurysms usually localize in sites of ow separation and elevated WSS such as bifurcations. These conditions were found to be associated in animal models to fragmentation of the internal elastic lamina of blood vessels [130], alterations in the endothelial phenotype or endothelial damage [129]. Moreover, experimental cerebral aneurysms can be created in rats and primates through systemic hypertension and increased blood ow [58, 66, 67, 90]. Aneurysm growth is nowadays understood as a passive yield to blood pressure. While the aneurysm diameter increases, the wall progressively heals and thickens. Hystological evidences and direct measurements on cadaveric and surgical specimens show that the aneurysmal wall is mostly composed by collagen and that it can tolerate stresses in the range of those imposed in vivo by the mean blood pressure. The rupture of an aneurysm is thought to be the result of a process of weakening of the wall, whose mechanisms have not been explained yet. In particular, it is not clear if either low or high shear stresses have to be considered the main responsibles. According to the high-ow theory, the process of wall remodeling and potential degeneration is induced by elevated WSS [91]. More precisely, the arterial wall can weaken under the action of abnormal shear stress elds, due to biochemical processes leading ultimately to apoptosis of the smooth muscle cells and loss of arterial tone [51]. There-

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1 Introduction fore, the prevalence of blood pressure forces over internal wall stress forces may cause a local dilation, which then grows under the action of non physiological blood shear stresses. The wall stiffens, because of stretching of elastin and collagen bers in the medial and adventitial layers. Eventually an equilibrium can be reached, in which elastin and collagen are constantly under a non physiologically large mechanical load: in this situation wall remodeling may take place. Low blood ows in the aneurysm can cause blood stagnation in the dome, and this is believed to be the major responsible for wall damage in the low-ow theory. Stagnation promotes the aggregation of red cells, the accumulation and the adhesion of platelets and leukocytes along the intimal surface [57]. This may be a cause of inammation, due to the inltration of white blood cells and brin in the intimal layer [29]. The wall tissue then degenerates and becomes unable to support blood pressure with physiological tensile forces. In this situation the aneurysmal wall progressively thins and may nally rupture. As previously discussed, a strong correlation between the size of aneurysms and their rate of rupture has been documented in literature. This led to the denition of a clinical measure termed aspect ratio (dened as the depth of the aneurysm divided by the neck width): it has been found that an aspect ratio bigger than 1.6 is correlated to a risk of rupture [139]. On the other hand, it is known that ow velocities in aneurysms depend inversely on the volume [72, 98, 131] and that shear stresses in the sac are usually signicantly lower than in the parent artery, in particular for bigger aneurysms. These evidences support the theory of a decisive role of low shear stress in the rupture mechanism. However, recent patient-specic modeling based on computational uid dynamics (CFD) showed that areas of elevated shear stress are commonly found in the body and dome of aneurysms, even if the spatial average WSS is still lower than in the parent artery. Thus, the size and position of the ow impingement region, and therefore the presence of high shear stresses on the wall may represent other risk factors for aneurysm rupture [22]. Moreover, narrow necks in large aneurysms geometrically induce concentrated inow jets and localized impact zones: the correlation between big aspect ratio and rupture rate may then be explained also by the high stress theory. During its growth, an aneurysm moves in the peri-aneurysmal environment (PAE), coming in contact with structures such as bone, brain tissues, nerves and dura mater. A clinical evidence of this phenomenon comes from symptoms related to the pressure exerted by the aneurysm on the surroundings, such as bone erosion, obstructive hydrocephalus and cranial nerve palsy [63,105]. The effect of PAE on the aneurysm evolution is not well known. The contact with external structures can be protective for the aneurysm in that it can locally decrease stresses [122]. However, complex interactions with the PAE can cause non uniformly distributed or unbalanced contact, with either protective or detrimental effect on the evolution of the aneurysm [116].

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1 Introduction

1.3 Modeling the cerebral circulation

The complexity of the vascular system demands for the set up of convenient mathematical and numerical models. Computational hemodynamics is basically based on three classes of models, featuring a different level of detail in the space dependence. Fully three-dimensional models (3D, see Chap. 3) are based on the incompressible Navier-Stokes equations possibly coupled to appropriate models that describe the blood rheology and the deformation of the vascular tissue. These models are well suited for investigating the effects of the geometry on the blood ow and the possible physiopathological impact of hemodynamics. Unfortunately, the high computational costs restrict their use to contiguous vascular districts only on a space scale of few centimeters or fractions of meter at most (see e.g. [8], [56], [107]). By exploiting the cylindrical geometry of vessels, it is possible to resort to one dimensional models (1D), reducing the space dependence to the vessel axial coordinate only (see Chap. 2). These models are basically given by the well known Euler equations and provide an optimal tool for the analysis of wave propagation phenomena in the vascular system. They are convenient when the interest is on obtaining pressure dynamics in a large part of the vascular tree with reasonably low computational costs (see [47, 89, 97]). However, the space dependence still retained in these models inhibits their use for the whole circulatory system. In fact, it would be unfeasible to follow the geometrical details of the whole network of capillaries, smaller arteries and veins. A compartmental representation of the vascular system leads to a further simplication in mathematical modeling, based on the analogy between hydraulic networks and electrical circuits. The fundamental ingredient of these lumped parameter models (0D) are the Kirchhoff laws, which lead to systems of differential-algebraic equations. These models can provide a representation of a large part or even the whole circulatory system, since they get rid of the explicit space dependence. They can include the presence of the heart, the venous system, and self-regulating and metabolic dynamics, in a simple way and with low computational costs (see e. g. [89, 97]). All these models have peculiar mathematical features. They are able to capture different aspects of the circulatory system that are however coupled together in reality. In fact, the intrinsic robustness of the vascular system, still able to provide blood to districts affected by a vascular occlusion thanks to the development of compensatory dynamics, strongly relies on this coupling of different space scales. Feedback mechanisms essential to the correct functioning of the vascular system work over the space scale of the entire network, even if they are activated by local phenomena such as an occlusion or the local demand of more oxygen by an organ. This is particularly evident in the cerebral vasculature, as mentioned earlier in this Chapter. To devise numerical models able to cope with coupled dynamics ranging on different space scales a geometrical multiscale approach has been proposed in [47]. Following this approach, the three different classes of models are mathematically coupled in a unique numerical model. Despite the intuitiveness of this approach, many difculties arise when trying to mix numerically the different features of mathematical models, which are self-consistent and however not intended to work together. Some of these

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1 Introduction difculties have been extensively discussed recently in [112].

1.3.1 The circle of Willis

Several studies have been carried out for devising a quantitative analysis of the blood ow in the circle of Willis. After the rst works based on hydraulic or electric analog models [11,26,41,88,115], most of the research has been based on modeling the circle of Willis as a set of 1D Euler problems (see Chap. 2) representing each branch of the circle, with an appropriate modeling of the bifurcations [2,32,61,62,77,78,143]. More recently, metabolic models have been added to simulate cerebral auto-regulation, which is a feedback mechanism driving an appropriate blood supply into the circle on the basis of oxygen demand by the brain [3]. Furthermore, a complete 3D image based numerical model of the circle of Willis has been presented in [20]. This model, however, requires medical data that are currently beyond the usual availability in common practice, and is computationally intensive compared with the 1D counterpart. In the present work, the modeling of the circle of Willis is addressed from several different viewpoints. The features of the arterial ring per se are discussed in Chap. 2, where a one-dimensional model (previously published by Alastruey et al. [2]) is studied with particular attention to the problem of correctly modeling the mechanical behaviour of the arterial wall. Its viscoelastic features affect indeed the time and space pattern of pressure waves propagating in the cerebral circulatory system, as can be seen by comparing the results obtained with a viscoelastic model for the wall to those obtained by using a linear elastic model (see Sec. 2.5.4). The computational study here presented is carried out with a software tool specically written and based on the C++ nite element library LifeV (see Sec. 6.2). The cerebral circulation is represented as a network of interacting vessels, each one described by a 1D model. The design of algorithms and data structures for the implementation of this approach is presented in Chap. 6. The arteries of the circle of Willis can suffer from pathologies such as cerebral aneurysms, associated to local damages of the vascular wall or induced by geometrical features of the vessels which need to be studied in detail. Reduced models (such as 1D models) are not suitable for this task: on the other hand, a full 3D modeling of a large and complex system of arteries can be unaffordable, both because of high computational costs and because of the lack of medical data to completely set up the problem. In Chap. 5 we present a geometrical multiscale model for the cerebral circulation, coupling a detailed 3D model of a carotid bifurcation together with a reduced 1D model of the circle of Willis. The different models entail different assumptions on the mechanical behaviour of the vascular wall: its compliance is the driving mechanism for the propagation of pressure and ow rate waves, and is differently modeled at different geometric scales. Proper matching conditions have been devised to retrieve the correct description of the dynamics of the coupled system (see Sec. 5.2).

http://www.lifev.org

13

1 Introduction

1.3.2 Cerebral aneurysms

In the last years, the study of the blood ow dynamics of cerebral aneurysms has been carried out with different tools. Experimental and clinical studies, focused on idealized aneurysm geometries or on surgically created aneurysms on animals, were able to show the complexity of intra-cerebral hemodynamics [121]: however, they did not explain the relation between hemodynamics and clinical events. The same limitation holds for in vitro studies, which on the other hand can give a very detailed description of the ow mechanics inside idealized geometries [73]: the main drawback for this approach is the unfeasibility of patient-specic analyses. Computational models have been extensively and successfully used due to their capabilities in circumvent some limits of the other approaches. In particular, thanks to recent advances in medical imaging tools, it is relatively easy to obtain accurate patientspecic geometrical models of cerebral circulation. The blood motion inside arteries and aneurysms can be then simulated by means of CFD techniques [21, 59, 133] or experimental studies based on realistic anatomical models reconstructed from images using rapid prototyping techniques [136]. The limitation of these approaches is mainly their validation, since the in vivo correct estimation of blood ow patterns is still an open problem within nowadays imaging technology. However, employing virtual or simulated angiography, it has been shown that CFD models are able to reproduce the ow patterns observed in vivo during angiographic examinations [23, 44]. In the context of the Aneurisk project (see Chap. 4) a study of the internal carotid artery as a preferential site for aneurysms formation has been proposed. More precisely, starting from patient-specic geometrical modeling based on medical images [103], the parent arteries have been classied on the basis of their morphological features [120]. These features have been found to be signicantly correlated to the presence and the location of aneurysms. A CFD analysis on the same dataset shows that a similar correlation holds with hemodynamics features of the parent artery (see Sec. 4.3). More than that, we show that by considering uid dynamics parameters together with geometrical parameters for the description of the considered cerebral vessels, the classication can be enhanced. It is indeed our belief that an integrated approach, starting from the medical image and systematically collecting different sources of information for the characterization of the physical system at hand, can lead to a greater insight in the understanding of the pathology development.

http://www2.mate.polimi.it:9080/aneurisk

14

2 One-dimensional models for blood ow problems

Reduced models for blood ow problems prove to be effective in capturing the main features of the wave propagation phenomena in the human cardiovascular system [19, 45, 126]. In particular, one-dimensional models based on the Euler equations offer a reliable description of the mechanics of blood-vessel interaction under the assumption of cylindrical arteries, the direction of the cylinder axis being the main direction of ow considered in the model. This approximation easily applies to large parts of the circulatory system, whenever we are not interested in the detailed description of ow features in complex vascular geometries such as bifurcations, stenoses, aneurysms [46, 125]. In this Chapter we present a quick review of 1D models for blood ow problems and their application. We start by recalling the well known Euler equations (Sec. 2.2), focusing on different models for the vessel mechanics and in particular on a simple way to take into account the viscoelastic features of the vascular wall (Sec. 2.2.1). Under proper assumptions, an analytical solution for a linearized version of the Euler equations can be obtained. Its derivation and the validation of the numerical discretization used to solve the equations are presented in Sec. 2.2.2 and Sec. 2.5.1 respectively. The fully non linear problem is solved in some test cases (Sec. 2.5), showing the ability of the model at hand to capture the main features of the studied problems. In the spirit of 1D representation, the circulatory system as a whole can be seen as a network of interconnected vessels. By this representation we build one-dimensional models of large regions of the circulatory system (Sec. 2.3), each vessel being described by Euler equations. The application of this approach to the study of cerebral circulation is discussed in Sec. 2.5.4.

2.1 Wave propagation phenomena in the cardiovascular system

The circulatory system is responsible for the distribution of blood ow through the human body. Blood is pumped by the heart into the network of arteries, reaches the capillaries where most of the biochemical phenomena associated to the tissue nutrition take place, and is nally collected by the network of veins bringing it back to the heart (see Fig. 2.1). We can divide each cardiac cycle in an early phase (systole), associated to the ejection of blood from the hearts ventricles, and a late phase (diastole), in which blood motion

15

2 One-dimensional models for blood ow problems

Figure 2.1: Schematic representation of the human cardiovascular system. In each cardiac cycle, blood ows from the heart towards the peripheral circulation (arterioles, capillaries) and is collected back to the heart from the veins. from http://www.williamsclass.com/ is driven by the compliance of the vascular wall. In systole, the contraction of the heart induces a pressure wave which travels along the arterial tree causing the dilation of the vessels. In diastole, arteries deate and push blood towards the capillaries and the venous compartment, featuring the so-called reservoir effect [1]. The study of the time and space pattern of pressure and ow rate waves propagating in the circulatory system can help in understanding the correlation between local pathologies and systemic features. An interesting case in this respect is the effect of arterial remodeling and stiffening due to aging or diseases (such as atherosclerosis); this is a documented cause of increased systolic pressure due to pressure wave reections, and it is associated to overload to the left ventricle (the so-called hemodynamic overload [75]). This condition can determine left ventricular hypertrophy and altered coronary perfusion, with consequent heart damage.

2.1.1 Modeling the vascular wall

The interaction between blood and the vascular wall plays a fundamental role in the functionality of cardiovascular system. Indeed, the mechanical properties of the wall determine the wave propagation, and this suggests that pathologies which affect the wall may be associated to non physiological pressure waveforms. Besides giving a better insight on the behaviour of the wall under the effect of stresses exerted by the

16

2 One-dimensional models for blood ow problems blood ow, an accurate mechanical modeling of the vessels could in principle allow the detection of vascular diseases from information on the pulse propagation patterns of pressure and ow rate in the circulatory system [30]. The mechanical modeling of blood vessels requires the denition of a constitutive law describing the relationship between stress and strain elds in the vessel structure. The latter being a complex layered tissue, its mechanical characterization is still an open problem. Many different constitutive models have been proposed in the literature: vessel wall can be treated either as a homogeneous material or described by a heterogenous model taking into account the micro-structure (cells, bers and their mechanical interaction) [144]. Hereafter we will focus our attention on homogeneous models, since in the spirit of 1D representation the local detail of the physical phenomena at hand can be foresaken. In the simplest approach, the wall can be treated as a linearly elastic membrane [36, 45, 125]. This leads to a reliable description of the main features of the wave propagation, both in physiological and pathological situations [3]. Still, an oversimplied linear mechanical model for the vessel wall structure is not able to reproduce its viscoelastic behaviour, which is observed in vivo. Several different approaches have been proposed to address the modeling of viscoelastic features of vessel vascular wall [144]. Armentano et al. showed that even a simple Kelvin-Voigt type model can be used to obtain a good agreement between in vivo measured data and numerical experiments [9,28]. A similar approach was followed by Canic et al. [19], who exploited a linearly viscoelastic cylindrical Koiter shell model for the arterial wall, based again on a Kelvin-Voigt type description of the structure viscoelastic features. A slightly more complex model was employed by Bessems et al. [17], who described the wall of large arteries with the standard linear solid approximation. This same approximation was employed by Olufsen et al. [36], who also noted that the strain relaxation, which is not modeled by the simpler Kelvin-Voigt model, can be relevant in the study of large arteries [140]. In the following we extend the analysis on a previously published model for blood ow in viscoelastic vessels [46], with the aim of validating the numerical scheme there proposed against an analytical solution for a linearized version of the equations. Moreover we highlight the viscoelastic features in the arterial wall dynamics, which are not captured from linearly elastic structural models, as we show in some test cases. Finally we use the presented model to devise a one-dimensional description of the cerebral circulation, based on the work by Alastruey et al. [3].

2.2 Formulation of the model

Let us consider a one-dimensional domain R representing the cylindrical vessel depicted in Fig. 2.2 and let I R be a time interval. Given S (x, t) a cross section located along the vessel at axial coordinate x, considered at time t, A(x, t) is the area of S , P (x, t) is the mean pressure on S and Q(x, t) is the uid velocity ux through S . For all x and for all t I we can express the uid mass conservation principle (2.1a) and the uid momentum conservation principle (2.1b) by means of the Euler

17

2 One-dimensional models for blood ow problems

Figure 2.2: A cylindrical compliant vessel. The shaded plane highlights a section S at axial coordinate x and at time t. equations [40]: A Q + =0 t x Q + t x Q2 A + A P Q + KR = 0 x A (2.1a) (2.1b)

In (2.1), is the so-called momentum-ux correction (or Coriolis) coefcient, is the uid mass density and KR is a strictly positive quantity which represents the viscous resistance of the ow per unit length of tube. The closure of the previous system of two equations in the three unknowns A, P and Q can be recovered by introducing a relation linking the pressure P to the area A (see [49]), thus taking into account the vessel wall mechanics. Let us denote by Pext the pressure external to the vessel: the wall mechanics can therefore be given in terms of a function establishing the dependence of the transmural pressure P (x, t) Pext on the vessel kinematics (in turn driven by the blood ow): P (x, t) Pext = (A(x, t); x, t). (2.2)

We may dene in a simple yet rather general way, as a function of A (together with its derivatives) and of a set of parameters which may depend on x, t or A. Under the hypothesis that the pressure depends on A, on the reference cross-sectional area A0 and on parameters = (0 , 1 , . . . , p ) describing the mechanical properties of the wall, a possible choice for is: (A(x, t); A0 (x), 0 (x), 1 (x)) = 0 (x) A A0 (x)
1 ( x)

1 .

(2.3)

For the ease of the notation, we will hereby refer to A0 and , noting that in general they are to be considered as functions of the axial coordinate x.

18

2 One-dimensional models for blood ow problems In the previous, 0 is an elastic coefcient, while 1 > 0 is normally obtained by 1 tting the stress-strain response curves obtained by experiments. Whenever 1 = 2 and 0 =
1 A0

h0 E 1 , A0 1 2

(2.3) is equivalent to the following relation: A A0 , (A(x, t); A0 , ) = A0

(2.4)

which is derived from the linear elastic law for the wall mechanics of a cylindrical vessel and where E (x) is the Youngs modulus, h0 the wall thickness and the Poisson ratio [49]. The adoption of a linearly elastic model for the vessel wall mechanics is convenient since it simplies the derivation of the equations, and is still able to capture the main features of the wave propagation phenomena in vascular system [16, 46, 82]. However, more accurate and complex mechanical models can be exploited, accounting for the vessel wall inelastic behaviour which is veried in vivo [144]: in the following we will discuss this aspect more thoroughly. Remark Set U = [A Q]T . We derive a conservative form of system (2.1) [45]: U F(U) + + B(U) = 0 , t x where 0 Q F(U) = , B(U) = 2 Q A C1 . Q KR + + C1 A x x A We denote by C1 the following quantity
A

(2.5)

C1 =
A0

c2 1 d ,

c1 =

A , A

where c1 is referred to as the celerity of the propagation of waves along the tube and A0 indicates a reference value for A, here taken equal to the cross-sectional area in an unloaded conguration.

2.2.1 A viscoelastic structural model for the vessel wall

As we already pointed out in Chap. 1, vascular wall is a complex biological tissue, formed by different materials organized in an anisotropic structure [53]. The interplay of the different anatomical components determines its mechanical behaviour [9,10,144]. A simple model, derived from the Navier equation for linearly elastic membranes, was proposed in [113]. It is referred to as the generalized rod model, since it takes into account inner longitudinal actions, in a way similar to what is done in the classical vibrating rod equation:
2 2 4 + g P Pext = a + b 2 +c 4 d t x x2

(2.6)

19

2 One-dimensional models for blood ow problems where = R R0 = A A0

is a generic t function of the time derivative of the displacement. According to (2.6), the transmural pressure on the vascular wall is balanced by ve terms, describing different mechanical features of the structure. The elastic response of the material is represented by the rst term a , while the inertial effects are described by the term involving the second order time derivative of the wall displacement, where b = w h is the product of the wall mass density and the wall thickness. Resistance to bendings is expressed in this model by the term involving a fourth order space derivative, while resistance to traction is taken into account by the term involving the second order space derivative. One of the most interesting mechanical features of the vascular wall is its viscoelastic nature. Arteries exhibit creep, stress relaxation and hysteresis in the stress-strain relation. Equation (2.6) accounts for viscoelastic effects, by describing them with term g . Following formal mathematical arguments, Quarteroni et al [113] proposed t the following formulation 3 = e g , t t 2 x are positive coefcients and g is the wall radial displacement, a , b, c , d involving a third order mixed derivative of , which shows good agreement with experimental results [113]. For the sake of simplicity, we will consider hereafter a simpler term, based on the Voigt viscoelastic model [52]. Moreover, we will neglect for the sake = 0. of simplicity the other non elastic effects, setting b=c = d This leads to the following differential equation linking the transmural pressure to the wall radial displacement : P Pext = a + , t (2.7)

where is the so-called modulus. viscoelastic A A0 Recalling that = , and noting that typically in hemodynamic problems the range of variation of cross-sectional area A is small, we approximate 1 A = t 2 A t 1 A . 2 A0 t

Moreover, the elastic response term can be recast in form (2.4), by setting a =

. A0 The wall mechanics model may now be rewritten in terms of A including viscoelasticity as follows: A P Pext = (A(x, t); A0 , a ) + (2.8) t

20

2 One-dimensional models for blood ow problems with =

. 2 A0

Therefore, assuming Pext independent of x, A dA0 d a 2A P = + + + , x A x A0 dx a dx xt

and we note that the second order mixed derivative of A can be recast into a second order derivative of Q by exploiting the mass conservation equation (2.1a). Substitution of the previous in (2.1b) gives: Q + t x Q2 A + A A 2Q Q A dA0 A d a 2 + KR + + =0. A x x A A0 dx a dx

With respect to the conservative form (2.5), we set F= and, analogously, B= B1 , B2 B1 = 0 , B2 = KR Q A dA0 A d a C1 + + A A0 dx a dx x F1 , F2 F1 = Q , F2 = Q2 + C1 A

so that system (2.1) can be rewritten as follows: A Q + =0 t x Q F2 A 2 Q + 2 + B2 = 0 t x x (2.9a) (2.9b)

Clearly, the introduction of the viscoelastic term makes this system of equations no longer hyperbolic. However, we may assume that the elastic response function plays a leading role in determining the wall mechanics. On the basis of this assumption, an operator splitting approach can be devised [45]. More details on this technique will be presented later on in Sec. 2.4.1.

2.2.2 The linearized model

A linearized version of equations (2.1) can be derived in the following way. First, we Q2 = 0; moreover, we linearize the coefneglect the nonlinear term, therefore x A cients with respect to A, setting A(x, t) A0 . The resulting linear system of rst order partial differential equations reads: A Q + =0 t x Q A0 P KR + + Q=0. t x A0 (2.10a) (2.10b)

21

2 One-dimensional models for blood ow problems We will consider relation (2.8) linking the pressure to the cross-sectional area, and assume for the sake of simplicity = 0, therefore A dA0 d a P = + + . x A x A0 dx a dx Now (2.10b) becomes A0 dA0 A0 d a Q A0 A KR + + Q+ + =0, t A x A0 A0 dx a dx and system (2.10) may be written in non conservative form as follows: U U + HL + SL = 0 , t x where 0 A HL = 0 A 1 0 , SL = K
R

(2.11)

A0 dA0 A0 d a . Q+ + A0 A0 dx a dx

A conservative form reads: U FL + + BL = 0 , t x where FL =

A

(2.12)

Q , CL

0 BL = SL CL x

and CL = A0 c2 L d . System (2.11) is said to be strictly hyperbolic if H is similar to a diagonal matrix and its eigenvalues are real and distinct. In particular, the eigenvalues of matrix HL A0 are 1,2 = cL , cL = being the wave celerity in the linearized problem. A A > 0, necessary and sufcient condition for the eigenvalues to be real and distinct is A which is satised being typically A > 0 in blood ow problems and a = . A 2 A Linearization of the previous relation yields A a =a. 2 A0

22

2 One-dimensional models for blood ow problems A0 a. We now denote by L, R the matrices whose rows (columns) are the left (right) eigenvectors of HL , respectively: In the following we set cL = L= lT 1 lT 2 , R = r1 r2 ,

with the additional (non restrictive) hypothesis LR = I. Then LHL R = = diag(1 , 2 ) . and the following equivalent form for system (2.11) is obtained: L U U + L + LSL = 0 . t x (2.13)

If there exist two quantities W1 , W2 such that W =L, U W = [W1 , W2 ]T ,

then we can rewrite system (2.13) in diagonal form: W W + + GL = 0 , t x where GL = LSL W dA0 W d a . A0 dx a dx (2.14)

The values W1 , W2 are the so-called Riemann invariants for the hyperbolic system at hand. Left eigenvectors l1,2 read cL l 1 ,2 = 1 where = (A, Q) is an arbitrary, positive smooth function of its arguments. Therefore W1 = cL , A W1 =, Q W2 = cL , A W2 =. Q

We now impose the integrability of the two differential forms W1 and W2 by choosing such that 2 Wi 2 Wi = , i = 1, 2 , AQ QA which yields cL = Q A

23

2 One-dimensional models for blood ow problems thus we may simply choose = 1. We now nd (see e. g. [49] for a detailed presentation of the procedure) that the linearized characteristic variables are given by integration of the resulting differential form: W1,2 = cL A + Q . We choose (A0 , 0) as the zero state in the (A, Q) plane, in which the characteristic variables are zero, and nd after integration: W1,2 = Q cL (A A0 ) . Adding viscoelasticity Lets now consider the viscoelastic term > 0 in (2.8): this yields P A 2A dA0 d a =a + + + , x x xt A0 dx a dx and with arguments similar to those leading to system (2.9) we obtain A Q + =0 t x Q FL2 A0 2 Q + + BL2 = 0 , t x x2 with FL = and BL = BL1 , BL2 BL1 = 0 , BL2 = A0 dA0 A0 d a KR CL Q+ + . A0 A0 dx a dx x FL1 , FL2 FL1 = Q , FL2 = CL (2.15a) (2.15b)

An analytical solution The linearized equations (2.15) describe the propagation of area and ow rate waves in the space-time domain. We may look for solutions in the form of harmonic waves: (k ) exp i (k )t kx A(x, t) = A (k ) exp i (k )t kx Q(x, t) = Q . (2.16a) (2.16b)

In the previous, k is the wave number, dened as the number of complete oscillations (k ), Q (k ) represent the wave in the range x [0, 2 ]; is the (angular) frequency and A (k ), Q (k ) C, however it is understood amplitudes in x = 0, t = 0. In general, , k, A that we will be interested in the real part of the solution.

24

2 One-dimensional models for blood ow problems Substituting (2.16) in the linearized Euler equations yields: ik Q exp i (k )t kx i A =0 =0. (2.17a) (2.17b)

+ i + k 2 C2 + C3 Q exp i (k )t kx iC1 k A

For the sake of simplicity, in the previous we assume that all the parameters are constant with respect to x and set C1 = A0 a , C2 = A0 , C3 = KR . A0 (2.18)

and Q on k . Moreover, we omit to indicate explicitly the dependency of A The problem of nding solutions to system (2.17) for each t and x is recast into the existence of non trivial solutions to the following linear system: ik Q =0 i A + (i + k 2 C2 + C3 )Q =0, (iC1 k )A which yields the following condition: (iC3 ) + k 2 (C1 + iC2 ) = 0 . (2.20) (2.19a) (2.19b)

We can now study the dispersion relation (k ), linking the angular frequency to the wave number: solutions to system (2.17) are travelling waves with angular frequency 1,2 (k ) = i C2 k 2 + C3 (C2 k 2 + C3 )2 + 4C1 k 2 2 .

For the problem at hand, the phase velocity cp = (k )/k depends on the wave number, so that the solution to system (2.17) will be affected by wave dispersion: in other words, this means that waves with different wave length propagate with different speed, given by . 2 We can conversely express the wave number k as a function of the frequency : k ( ) = ( iC3 ) , C1 + iC2 (2.21) cp (k ) = i (C2 k + C3 /k ) (C2 k + C3 /k )2 + 4C1

and we note that k is in general a complex number even when is real. It can be therefore written as k = (k ) + i (k ) . (2.22) We remark that, due to the rst equation of system (2.17), the solution is such that = ik Q , i (k )A

25

2 One-dimensional models for blood ow problems or Q (or both) are complex numbers. We may which implies that, if R, then A choose A R, therefore (recalling (2.22)): (k ) exp A(x, t) = A Q(x, t) = (k ) + i Q (k ) Q (k )x exp i (k )t (k )x exp (k )x exp i (k )t (k )x .

In particular, we are interested in the real part of the solution, which reads (k ) exp A(x, t) = A Q(x, t) = exp (k )x (k )x cos (k )t (k )x . (2.24a) (2.24b)

) cos t (k )x (Q ) sin t (k )x (Q

It follows from the previous that the imaginary part of the wave number is associated to an exponential factor modulating the wave amplitudes. When (k ) < 0, this is a damping factor corresponding to an exponential decay with variable x. We now consider the contribution of the three different terms C1 , C2 and C3 to the denition of k . When C1 = 0 and C2 = C3 = 0, k ( ) = 2 , C1

where we choose the positive root. To force C3 = 0 means that we are considering an inviscid uid, for which the friction term KR vanishes. On the other hand, C2 is equal to 0 when we neglect the viscoelasticity of the blood vessel wall (see (2.18) and (2.7)). In this case, k is a real number and the solutions we nd are a set of travelling waves of the form (2.16). If C1 , C3 = 0, the denition of k reads k ( ) = ( iC3 ) , C1

and k has an imaginary part. This case corresponds to the problem of a viscous uid owing inside a linearly elastic vessel. We can reformulate the previous denition as follows: C3 2 k 2 ( ) = i , C1 C1 which in polar notation reads k 2 ( ) = r exp i( + 2n ) , C3 r= + C1 C3 . = arctan 2 C1
2

nN,
2

26

2 One-dimensional models for blood ow problems Therefore k ( ) = r exp i + n 2 , nN,

and we choose one of the two roots, such that (k ) > 0. We remark that, since (k 2 ) > 0 and (k 2 ) < 0, /2 < < 0: this implies + n , n N [/4, 0] 2 or + n , n N [3/4 , ] , 2 the latter being excluded by the request (k ) > 0. This ensures that (k ) < 0 and therefore the term C3 = 0 is responsible for an exponential damping of the signal amplitude. In the general case C1 = 0, C2 = 0, C3 = 0, recalling (2.21), k 2 ( ) = 2 (C1 C2 C3 ) ( iC3 )(C1 iC2 ) (C1 C3 + C2 2 ) = i . 2 + C 22 2+C 2+C C1 C1 C1 2 2 2

With a similar procedure to that applied to the previous case it can be seen that, under the hypothesis C1 > C2 C3 , corresponding to assume A0 > KR , 2

i. e. a Young modulus large enough, both the uid viscosity (term C3 ) and the viscoelasticity of the wall (term C2 ) cause an exponential decay of the travelling waves amplitudes.

2.3 Networks of 1D models

Once having set up the model for a single tube, we can move towards the study of networks: from a mathematical point of view, this means to nd suitable interface conditions for connected tubes. Following [49], we adopt a domain decomposition approach, and request that the solutions in interfacing domains are such that the conservation of certain physical quantities is ensured at the interface. Lets consider as an example the two tubes depicted in Fig. 2.3. We take as a reference system the simmetry axis x, which is the same for both vessels, and impose that the mass ow and the total pressure are conserved across the interface: Q1 = Q2 Pt,1 = Pt,2 t > 0, at x = (2.25)

1 2 where Pt = P + 2 (Q A ) stands for the total pressure and the subscripts 1, 2 indicate that the subscripted quantity is relative to tube 1 or 2, respectively.

27

2 One-dimensional models for blood ow problems

x=0

x=

x=L

Figure 2.3: Two connected tubes 1 and 2 : the interface is located at coordinate x = .

Formaggia et al. [45] proved that this set of interface conditions guarantees an energy inequality for the coupled problem. On the other hand, they noted that typically in blood ow problems the value of the pressure P is much greater than the kinetic energy Q 2 1 2 ( A ) , therefore in practice the continuity of pressure can be prescribed at the interface without encountering stability problems. Other possible interface conditions can be designed to take explicitly into account the fact that the total pressure decreases as a function of the ow rate, along the ow direction, in correspondence with the interface . The second of (2.25) may then then be written as follows [45]: Pt,2 = Pt,1 sign(Q)f (Q) t > 0, at x =

f being a positive, monotone function satisfying f (0) = 0 and referred to as dissipation function. However, appropriate formulations for f are usually not available, therefore a typical choice is f 0 corresponding to the continuity of the total pressure.

2.4 Numerical discretization

Let us refer for the sake of simplicity to system 2.5. Following [45], we adopt a discretization based on a second order Taylor-Galerkin scheme which can be seen as a generalization of the classical Lax-Wendroff scheme for systems of conservation laws [71]. Given Un the approximation of the solution U(tn ) at time tn , Un+1 is obtained by solving the following system: t n n t2 n Fn Fn Fn H S + SU + Hn x 2 2 x x x t n n S S , n = 0, 1, . . . , (2.26) t Sn + 2 U

Un+1 = Un t

28

2 One-dimensional models for blood ow problems S (Un ) and Hn , Sn and Fn are dened in a similar way. The Galerkin U nite element method is applied to (2.26), yielding where Sn U =
+1 n n Un h , h = (Uh , h ) + t FLW (Uh ),

h x

t2 2

SU (Un h)

F(Un h) , h x
0 h Vh . (2.27)

t2 2

H(Un h)

F n h (Uh ), x x

t (SLW (Un h ), h ) ,

t In the previous equation we used the notation FLW = F(Uh ) + 2 FU (Uh )S(Uh ) and t SLW = S(Uh ) + 2 SU (Uh )S(Uh ). All the details on the derivation of the scheme can be found in [45]. In all the simulations presented in Sec. 2.5, we adopt a linear approximation of the solution, based on P1 nite elements.

2.4.1 Numerical solution of the viscoelastic wall model

The addition of a viscoelastic term to the constitutive law for the vessel wall (see (2.8)) and the adoption of the operator splitting approach previously mentioned yield the following equivalent form of system (2.9) [45]: A Q + =0 t x Qe F2 (A, Q) + = B2 (A, Q) t x Qv A 2 Q =0, t x2 where Q is decomposed into two contributions Q = Qe + Qv , due to the elastic and viscoelastic behaviour of the wall mechanics, respectively. Equations (2.28a), (2.28b) compose a hyperbolic system involving the time derivative of Qe , while (2.28c) is a parabolic equation of variable Qv . On each time interval [tn , tn+1 ], n 0, the rst two equations in (2.28) are solved by the Taylor-Galerkin scheme previously presented. The explicit time advancing scheme +1 as functions of An and Qn . The third equation is used to correct gives An+1 and Qn e the ow rate, and is solved by adopting an implicit Euler time advancing scheme and +1 +1 0 the following nite element formulation [45]: given An and (Qe )n h h , nd (Qv )h Vh such that
n+1 n+1 (Qv )h , h Ah

(2.28a) (2.28b) (2.28c)

+ t

+1 Qn h h , x x

= 0,

0 h Vh ,

where we exploit the simplifying assumption that homogeneous Dirichlet boundary conditions are imposed to the correction term Qv . This corresponds to correcting the

29

2 One-dimensional models for blood ow problems ow rate only inside the computational domain, and not on the boundary. Moreover, this allows an easy treatment of branchings or anastomoses of vessels: the correction term vanishing on the interface between different models, there is no need of decoupling the term in the different segments. +1 + Qn+1 , we can write Now, knowing that Qn+1 = Qn e v
n+1 +1 (Qv )h , h An h

+ t

+1 (Qv )n h h , x x

= ,
0 h Vh . (2.29)

+1 (Qe )n h h , x x

2.5 Results and discussion

This section presents a set of numerical experiments designed to test the reliability of the model. Particular attention is devoted to the effects of the wall viscoelasticity on the propagation of waves in blood vessels. We start by using analytical solutions (2.24) as a benchmark case, for validating the code. Then we discuss the effect of dissipative terms associated with the uid viscosity and the wall viscoelasticity. More precisely, following the arguments exploited for the linearized model, we analyse the role of viscous dissipations in the non linear model (2.1). Furthermore, a simple numerical experiment shows that the model at hand can reproduce the hysteresis in the P (A) relation, which is a typical viscoelastic feature of blood vessels in vivo. Finally, a model for the circle of Willis is presented, based on the published work by Alastruey et al. [3] and modied by including a description of the viscoelastic effects in the vessel wall mechanics. A comparison of the results obtained by the two models is drawn at a qualitative level.

2.5.1 Validation of the numerical model versus an analytical solution

We simulate the propagation of a cosinusoidal ow rate wave in a cylindrical vessel. The solution we are looking for is of the form (2.24), which is the real part of solution R. We will assume = 2 s1 , and obtain the corre(2.16), when we assume , A sponding solution exploiting the dispersion relation (2.21). The geometrical and physical features of the simulated vessel are summarized in Tab. 2.1. The tube at hand is very long, in order to clearly show the damping effect of the wall viscoelasticity and blood viscosity on the wave amplitude, discussed in Sec. 2.2.2. The wall mechanical parameters are in the range of physiological values for large arteries (see e. g. [52]). In particular, the value for the viscoelastic modulus =6 4 3 10 dyn s cm is taken from [19] and corresponds to the estimated viscous modulus of a human femoral artery.

30

2 One-dimensional models for blood ow problems Name length radius thickness mass density Poisson modulus Youngs modulus viscoelastic modulus [28] friction parameter Symbol L R0 h E KR Value 1000 1 0.15 1.05 0.5 4 106 6 104 2.633 Measurement unit cm cm cm g cm3 dyn cm2 dyn s cm3 P

Table 2.1: Geometrical and mechanical parameters for the simulated vessel. Based on these values, we nd C1 = 3.8095 105 dyn cm g1 , and k (2 ) = (k ) + i (k ) = 0.0093286 i0.0027481 . The initial conditions for the problem are A(x, 0) = A0 = Q(x, 0) = exp (k )x ) cos (k )x (Q ) sin (k )x (Q . C2 = 2.8571 104 dyn cm s g1 , C3 = 0.83811 g cm2 s1

= A(0, 0) = , we nd Recalling the rst equation in system 2.19 and knowing that A that = A = (Q ) + i (Q ) = 619.76 + i 182.58 . Q k The boundary conditions on the left and right boundaries prescribe two periodic ow rates: Q(xb , t) = exp (k )xb ) cos t (k )xb (Q ) sin t (k )xb (Q , xb = 0, 10 m .

The wave propagation is simulated on the time interval t [0, 1] seconds, with a time step of dt = 104 s. The mesh size is dx = 0.5 cm. Since we are considering a viscoelastic model for the arterial wall and blood is considered as a Newtonian uid, the wave amplitude is damped by an exponential factor (see Sec. 2.2.2). This effect is clearly visible in Fig. 2.4, where red lines represent the damped amplitude of the wave: Qdamp (x, t) = (k ) exp Q (k )x . (2.30)

We remark that the operator splitting approach presented in Sec. 2.4.1 is able to recover a good approximation of the analytical solution (see Fig. 2.5). We estimated the approximation error as follows Qdx Qexact Qexact
L2 (0,T ;L2 ())

= 1.2122 104 ,

L2 (0,T ;L2 ())

where we indicate by Qexact the analytical solution and by Qdx the numerical solution.

31

2 One-dimensional models for blood ow problems

2000 1500 1000 500 Q 0 500 1000 1500 2000 0 t=0 t = 0.4 t = 0.8

10

Figure 2.4: Solution of the linearized model with the presented numerical setup. Y-axis: ow rate (in cm3 /s); X-axis: tube axial coordinate (in m). The plot shows snapshots of the travelling wave at different time. The superimposed red lines represent the damping term (2.30) associated to blood viscosity and wall viscoelasticity.
2000 analytical solution computed solution 1500

1000

500

500

1000 0

10

Figure 2.5: Solution of the linearized model with the presented numerical setup. Y-axis: ow rate (in cm3 /s); X-axis: tube axial coordinate (in m). The plot shows the superposition of the analytical solution (blue) and the numerical solution (red) on the whole domain, at t = 0.1s.

2.5.2 Wave propagation in a single 1-D vessel: a Gaussian pulse wave

This numerical experiment describes the propagation along a vessel of a narrow, Gaussian shaped wave, a continuous approximation to a unit pulse (t) located at t = t0 (i. e. (t0 ) = 1 and (t) = 0 for t = 0). The unit pulse waveform was used in [145] to track the multiple transmissions and reections in the arterial system, while its Gaus-

32

2 One-dimensional models for blood ow problems sian approximation was used in [4] for the study of the effects of outow boundary conditions in 1D blood ow simulations. Here we aim to evaluate the dissipative effects of wall viscoelasticity and blood viscosity on the travelling wave amplitude. The simulated vessel has the same characteristics as the vessel described in the previous section (see Tab. 2.1), but is described this time by the non linear model (2.1). The boundary condition prescribed on the left boundary is a ow rate of the form: Q(xl , t) = exp t t0 ,

with = 0.01 and t0 = 0.05 s. Absorbing boundary conditions are prescribed on the right boundary [49]. The wave propagation is simulated on the time interval t [0, 1] seconds, with a time step of dt = 104 s. The mesh size is dx = 0.5 cm. The results of the numerical experiment of propagation are shown in Fig. 2.6. When considering an inviscid ow inside an elastic shell, we can see that the shape of the wave travelling along the vessel is not altered (red line). The addition of uid viscosity to the model attenuates the wave amplitude, in a similar way with respect to what can be seen in the linearized model (green line). If we model blood as a viscous uid and the wall as a series of viscoelastic rings (see eq. (2.7)), we observe that the wave amplitude is extremely reduced (blue line). Again, this is qualitatively in accordance with what has already been said about the linear problem.
1.2 1 0.8 0.6 Q 0.4 0.2 0 0.2 0

0.2

0.4

0.6

0.8

Figure 2.6: Propagation of a gaussian ow rate wave in a 10m long vessel (here only the tract x [0, 1]m is represented) . Viscoelasticity of the wall and blood viscosity attenuate the amplitude of the travelling wave. Red: elastic wall, inviscid uid; Green: elastic wall, viscous uid; Blue: viscoelastic wall, viscous uid. X-axis: position along the tube (m); Y-axis: ow rate (cm3 /s)

33

2 One-dimensional models for blood ow problems

2.5.3 Wave propagation in a single 1-D vessel: a sinusoidal wave

This numerical experiment describes the propagation of a half-sinusoidal input wave along a vessel. The inow condition mimics a realistic cardiac output, while a lumped parameter model of the peripheral circulation is coupled to the outow of the vessel. More precisely, the resistance R and the compliance C of vessels peripheral to the considered 1D domain are simulated by a three-element windkessel model, as proposed by Alastruey et al. [4]. They showed that by coupling this model to a 1D representation of the aorta, some features of in vivo aortic measurements can be reproduced, such as the pressure dicrotic notch and the exponential diastolic decay of the pressure. We reproduce here the same experiment, by considering a 40 cm long vessel, with the same other geometric and mechanical features as the vessel considered in previous sections (see Tab. 2.1), and described again by the non linear model (2.1). Moreover, R = 1.89 103 dyn s cm5 , C = 6.3 104 cm5 GPa1 . The initial conditions for the vessel are A = A0 = and Q = 0. The ow rate boundary condition prescribed on the left boundary is a periodic function of time, with period T = 1s: 310 sin( 2 T t) 0 t < s Q(t) = 0 s t < T with s = 0.3 s. The simulation was run with dx = 0.5 cm and dt = 104 s.

(a) Flow rate waveform. The thin line represents the inow waveform.

(b) Pressure waveform

Figure 2.7: Flow rate and pressure waveforms, once a quasi-steady state is reached, in the middle of a 1D vessel coupled with a 0D outow model. The wall viscoelasticity affects the wave propagation. The present model is able to capture a slightly increased wave speed associated to viscoelastic phenomena (Fig. 2.7). Moreover, Fig. 2.8 (left) shows that the contribution of the viscoelastic term to the overall pressure (see (2.8)) is not negligible.

34

2 One-dimensional models for blood ow problems

(a) Comparison between elastic and viscoelastic contribution to the overall pressure wave.

(b) A-P curve for the sin wave propagation numerical experiment.

Figure 2.8: Propagation of a half-sinusoidal ow rate wave in a 40 cm long vessel. The A-P curve (Fig. 2.8, (b)) shows hysteresis, which is a typical behaviour of a viscoelastic vascular wall. In particular, it can be seen at a qualitative level that the diastolic phase, in which P is proportional to A, is clearly distinct from the systolic phase in which pressure and area waves show a signicant phase shift. A more quantitative analysis of these results, based possibly on the comparison with clinically measured data or with other available models in the literature, is required to assess the accuracy of the model in the description of the physical phenomena at hand.

2.5.4 A 1D model network: the circle of Willis

The proposed simulation is based on the set-up presented by Alastruey et al. [3]. The circle of Willis is immersed in a larger network of 1D models describing the main arteries bringing blood to the brain (see Fig. 2.9), and the inow boundary condition for the whole network is provided by the heart. Peripheral circulation is accounted for by a three elements Windkessel model coupled to each outow of the network [2]. In our model the network is represented by an oriented graph (see Chap. 6). The edges of the graph correspond to the vessels, while the nodes are the junctions. Each edge is described by system (2.1) where appropriate initial conditions are assumed. The junctions are modelled by prescribing balance equations for the mass and the total 2 pressure Pt = P + 1/2 ( Q A ) (see [45, 82] and Sec. 2.3). The ow rate boundary condition prescribed on the left boundary of the vessel representing the aortic arch is a periodic function of time, with period T = 1s [3]: 485 sin( 2 T t) 0 t < s Q(t) = 0 s t < T with s = 0.3 s. The simulation was run with dx = 0.5 cm and dt = 104 s.

35

2 One-dimensional models for blood ow problems

Figure 2.9: 1D model of the circle of Willis: embedding into a larger arterial network (from [3], courtesy of Dr. J. Alastruey). The name and the characteristics of the numbered vessels in gure are reported in Fig. 2.10.

In Fig. 2.11 we illustrate a snapshot of the solution in the brachial artery, comparing the pressure waveforms obtained by the elastic and viscoelastic models for the vessel wall. The viscoelastic modulus = 104 dyn s cm3 is taken equal in all the vessels (it is in the range of values proposed in [19] for the femoral arteries, and is assumed here as a reference value for medium-size vessels). It can be seen that the wave propagation speed is increased in the viscoelastic wall, as we already noticed in previous experiments. Moreover, the dicrotic notch is more evident: indeed, faster dynamics of the wall, as found in systole and in particular at the very end of the systole, are associated to a more signicant contribution of the viscoelastic term to the overall pressure (see (2.8)). The amplitude of the notch can be quantied by considering pressure PA at the systolic peak tA and pressure PB at tB , as shown in Fig. 2.11. These values, in the two

36

2 One-dimensional models for blood ow problems

Figure 2.10: Physiological data used in the model shown in Fig. 2.9 (from [3]). different models, are shown in the following table: tB tA PA PB Elastic wall 0.06 s 7052 dyn cm2 Viscoelastic wall 0.078 s 8826 dyn cm2

We remark that the qualitative pressure waveform is not signicantly affected by the wall viscoelasticity, and is comparable to the results presented in [3]. Deeper and more extensive studies are needed to quantify the role of wall viscoelasticity in specic vascular districts or under particular conditions, in which the elastic approximation may not be adequate for the correct description of the wave propagation phenomena.

37

2 One-dimensional models for blood ow problems

P_A P_B 160.000 P

elastic wall viscoelastic wall

140.000

120.000

t_A t_B

0.5 t

0.75

Figure 2.11: Pressure wave (in dyn/cm2 ) in the middle of the brachial artery, after 10 cardiac cycles. In blue, the solution obtained with an elastic model for the wall mechanics; in red, the solution obtained with a viscoelastic model. X-axis: time (in s)

38

3 Three-dimensional models for blood ow problems

In this Chapter we present an overview of the methods and the models that we used for the study of blood ow in three-dimensional vascular geometries. In particular, the dynamics of the velocity and pressure elds for an incompressible Newtonian uid is described by the Navier-Stokes equations, presented in Sec. 3.3. When the velocity and pressure elds of a uid are known, derived quantities such as the stress eld can be obtained. In hemodynamic problems, the wall shear stress has particular importance: the force per unit area exerted by the uid tangentially to the wall is relevant in relation to some vascular diseases, due to the reaction it induces on endothelial cells. This specic topic is discussed more carefully in Sec. 3.4. In general, we are interested in the analysis of ow features in specic locations of the physical system at hand: in Sec. 3.5 we present a method to select regions of interest in the computational domain.

3.1 Blood ow features in arteries

One of the most evident features of blood ow in the arteries is pulsatility due to the pumping action of the heart [92]. In particular, most locations in the arterial tree experience unsteady, pulsatile ow, which can induce ow reversals and recirculation near to the wall, with potentially pathogenic effect (such as, for instance, atherogenesis). The time pattern of pulse waves in the circulatory system, however, is not perfectly periodic, because it is adjusted in order to t the body blood demand. The approximation to a periodic phenomenon therefore, usually accepted in hemodynamic computations, may hold only for short periods of time, in which the overall physical conditions are essentially not changing. The driving mechanism for the pulse wave propagation in the circulatory system is the mechanical interaction of the owing blood and the vascular structure: in this respect, the compliance of the vessel wall plays a crucial role. However, an accurate computation of the uid structure interaction problem in hemodynamics is costly, due to the strong mechanical coupling of the two systems (uid and structure). A review of the available techniques for the study of this problem is presented in [48]. It is worth observing that, in most part of the cardiovascular system, the movement of the vascular wall is relatively small compared to the vessel diameter. The radius changes may be at most of the order of 15% in larger arteries, and are smaller in the peripheral arteries. Depending on which district we are interested in, the assumption

39

3 Three-dimensional models for blood ow problems of vascular xed geometry may be reasonable, and allow to capture the main characteristics of the ow in a by far smaller amount of computational time, with respect to moving geometry models. On the other hand, compliance of the vascular wall is often neglected also due to the lack of measured data for specic subjects and the unavailability of a reliable mechanical characterization of the vessel structure. It has to be noted that rigid wall models may be less precise in specic applications with respect to compliant models [48, 100]. Recent works [35, 94] show that, in the case of the cerebral vasculature, hemodynamic computations based on rigid models reproduce the same ow patterns as compliant models, the latter giving slightly different estimates of the ow quantities. Therefore, the introduction of the vascular compliance seems not to be required in order to understand the main features of cerebral blood ow. This evidence, and the lower computational cost, motivated us to adopt rigid geometry models. Moreover, even in rigid wall simulations part of the compliance is accounted for by the shape of the pulsatile waveform, since it is the compliance of the system which leads to different pulsatile waveforms. The blood ow regime is usually laminar in most part of the cardiac cycle. In systole, however, the ow may become unstable in specic vascular districts, due to many different reasons: in the aortic arch, for instance, the systolic peak velocity can be very high even in physiological conditions. The presence of vessel stenosis or an increased blood demand from the organs due to physical exercise may promote in certain locations the transition of the ow regime towards instability. Some of the parameters used for the characterization of the ow regime and their physical signicance are discussed in the following section.

3.2 Geometry and Flow

Generally speaking, the purpose of a model is to reproduce the features of a physical system. More precisely, the model should be similar to the system from a geometrical and dynamical point of view (see [37]). Geometric similarity is provided by an accurate morphologic description of the system. In the case of vascular geometries, this depends on the quality of medical images at hand and on the effectiveness of the segmentation process and geometry reconstruction tools. Dynamic similarity is guaranteed by the identication and the control of the so-called similarity parameters, i. e. dimensionless parameters whose values in the model should match those in the real case. In the case of a uid ow in curved pipes, important parameters are the Reynolds and Dean numbers, together with the Womersley number and/or Reduced Velocity in the case of unsteady ows. We recall hereafter their denition (see e. g. [37]).

40

3 Three-dimensional models for blood ow problems

3.2.1 Reynolds number

The Reynolds number Rea in an internal ow of mean sectional velocity W within a pipe or vessel of characteristic radius a is given by Rea = aW (3.1)

where is the kinematic viscosity of the Newtonian uid, while sufx a here indicates the reference length used in the denition of the Reynolds number [114]. A different possible choice is to use the pipe diameter d = 2a, thus obtaining a Reynolds number Red = 2Rea . This parameter can be physically thought of as the ratio of inertial forces to viscous forces, as is made more evident by rearranging terms in equation (3.1): Rea =
2

W , W /a

where W = W W can be interpreted as the ux of the momentum over the pipe, while W /a is an estimate of the wall shear stress, where is the dynamic viscosity. When we have a large Reynolds number, inertial forces are dominant over viscous forces and vice versa. This makes Reynolds number the key parameter which identies the transition of the ow to turbulence and therefore helps in determining ow stability. Moreover, ows with higher Rea are characterised by a greater persistence of geometric inuences downstream of a bend or other disturbances [37]. Typical values for Re in the human cardiovascular system range from few thousands (in bigger arteries such as aorta, iliac arteries, brachial arteries and in bigger veins) to less than 1000 in medium-size vessels (such as carotid arteries, the main coronary arteries and medium-size veins) and even less than 1 (arterioles, capillaries, venules) [48].

3.2.2 Dean number

The original form of the Dean number was dened by Dean [34]: K=2 a R aW
2

(3.2)

where R is the radius of curvature (see Fig. 3.1), a is the pipe radius and W is dened as a constant having the dimensions of a velocity. According to Berger et al. [15], who proposed an extensive review of the literature about ow in curved pipes, the preferable denition for Dean number is however the following: = 2 1/2 Rea = a R
1/2

2aW

(3.3)

41

3 Three-dimensional models for blood ow problems

(a)

(b)

Figure 3.1: (a) A torus (from www.wikipedia.org). (b) Toroidal coordinate system. The pipe is a cylinder with circular cross section of radius a. Its axis is a circle of radius R, centered in O and belonging to a plane normal to z axis. A point P inside the pipe is identied by the coordinates r , , s : the rst two are polar coordinates dened on the cross section which P belongs to; s is the position of that cross section along the pipe axis, which can be recast in terms of the angle dened in the plane containing the torus axis. The uid velocity in the pipe has three components: u and v are the radial and circumferential velocity (respectively) in the cross section, while w is the axial velocity. This set up was exploited by Berger et al. in their analysis of ow in curved pipes. [15]
a where = R . This denition is in fact based on W , the mean axial velocity, which has the advantage of being readily measured in most cases. If we take W = W in (3.2), then = (2K )1/2 . Other denitions for Dean number may be based on pressure gradient [15]. More precisely, in the case of fully developed ow, the following has been widely used in literature:

D=

2a3 2R

1/2

G a2 =4

2a R

1/2

G a3 4

(3.4)

which is related to (3.2) by D = 4K 1/2 . Here G represents the (constant) axial pressure gradient. This approach however has two main disadvantages: on the one hand, it is more difcult to measure the pressure gradient than the mean axial velocity; on the other hand, when the ow is not fully developed, the pressure gradient is generally not constant (it varies with axial location and position in the cross section): this is true even in pipes of given cross section and xed ow conditions, where instead W is constant. A physical interpretation for the Dean number can be provided in terms of the bal-

42

3 Three-dimensional models for blood ow problems ance of the forces due to inertia and centripetal acceleration versus the viscous forces:
R a aW R W a 2

= 2 1/2 Rea = 2

centripetal forces inertial forces viscous forces

2

R aW In the above, we note that aW is an R is a measure of the angular velocity, thus a R approximation of the force producing the centripetal acceleration. If we consider helical pipes, having a torsion, additional similarity parameters may be introduced such as the Germano number:

Gn = (D/2) Red where is a measure of the torsion; or combinations of Gn and [37].

3.2.3 Womersley number and Reduced Velocity/Strouhal number

Figure 3.2: Representation of the laminar boundary layer (in blue) in a viscous uid motion. The boundary layer thickness grows over time due to the action of viscosity. (after [37]) The (Sexl-)Womersley number [123, 147] can be physically interpreted as the ratio of the pipe diameter to the laminar boundary layer growth over the pulse period T : Wo = a 2 d T T

where d = 2a is the pipe diameter and we exploit a dimensional argument commonly used in laminar boundary growth over at plates, namely the fact that the boundary layer growth (due to viscous forces) is proportional to T [37] (see Fig. 3.2). The Womersley number is used in the denition of an exact solution for the motion of a Newtonian uid in a straight circular pipe subject to a periodic pressure difference [147]. In fully developed ow, the solution is periodic with only the velocity axial component uz different from zero. If Wo is small (1 or less), the frequency of pulsations

43

3 Three-dimensional models for blood ow problems is sufciently low so that a parabolic velocity prole has time to develop during each cycle. Conversely, if Wo > 10 the velocity prole is relatively at. Larger arteries and, less markedly, larger veins feature high Womersley numbers (Wo = 5 10), whereas in smaller vessels Wo O(1). Indeed, in larger arteries the viscous layer has not enough time to grow to such an extent to dominate the solution (as is conversely seen in Poiseuille ow), and the velocity prole tends to be at rather than parabolic [48]. A potential limitation of Wo is that it is related to physical scales within a given cross section of the pipe: in other words, the role of the longitudinal geometry is not represented, and this may reduce the physical signicance of the parameter when the ow has signicant changes in the streamwise direction. Other non-dimensional similarity parameters may be introduced in order to take into account different length scales as well, which are relevant in specic ow problems (for instance the ow in multiple bends or through stenoses). The Reduced Velocity can be useful to describe different ow regimes, and can be seen as a non-dimensionalised pulsatile period: Ured = Distance travelled by mean ows WT D Diameter

In particular, Ured is a more appropriate parameter than Wo for unsteady ows where there are signicant streamwise ow variations, since it explicitly involves an axial length scale. Note also that Ured and Wo are related through Red : Ured = Red . 2 Wo2

3.3 The Navier-Stokes equations

In general, mainly due to the presence of red cells, blood exhibits a complex rheology. However in larger vessels it can be approximated to a homogeneous Newtonian uid [48]. In this case, the ow is governed by the classical Navier-Stokes equations.

3.3.1 Formulation
Let I R be a time interval and let B E be the spatial domain representing a blood vessel (with E a three-dimensional euclidean space) (see Fig. 3.3). A regular motion of points belonging to B is a function x : B I E such that x C2 (I ): in particular we : B I R3 may dene the material velocity of points of B as the function x (p, t) = x x(p, t) . t

Denoting Bt := x(B , t), we may now introduce the trajectory T := {(q, t) : t I, q Bt }

44

3 Three-dimensional models for blood ow problems

out,3 out,4 out,2

out,1 w

in
Figure 3.3: An example of spatial domain representing a basilar artery with a berry cerebral aneurysm (geometry from the Aneurisk project). The letters indicate the inow, outow and wall boundaries. (x1 (q, t), t). and the spatial velocity u : T R3 such that u(q, t) := x We analogously dene the uid mass density (q, t) as a function of the spatial position and the time. By exploiting the mass conservation principle we obtain the continuity equation: + (div(u)) = ,t + div( u) = 0 , (3.5) where is the material derivative of = with respect to t, dened as follows:
,t

d (q (p, t), t) = dt

+ u.

We indicate by ,t the partial derivative with respect to time of the considered variable, the spatial position being xed. We recall now that, thanks to the Cauchy theorem, the momentum balance equation reads = b + div(T) , u where b : T R3 is a eld of volume forces and T is the so-called Cauchy stress tensor: (q, t) T, T(q, t) L(R3 ), L(R3 ) being the space of linear tensors over R3 . For Newtonian uids, T is thought to depend linearly on the velocity gradient L = u (and more precisely, according to the objectivity principle, on the symmetric part

45

3 Three-dimensional models for blood ow problems D = sym(L) and its rst invariant trD = div(u)): T = P I + (div(u))I + 2D , (3.6)

where P is the uid pressure, while and are constant viscosity coefcients depending on the uid characteristics. When considering incompressible uids, for which div(u) = 0, (3.6) becomes T = P I + 2D . We remark also that, under the same assumptions and recalling equation (3.5), (x(p, t), t) =
0 (p, t),

(3.7)

p B , t I

where 0 (p, t) is the uid density in the reference conguration. Lets now focus our attention on a xed spatial domain which for all the time of interest is inside the portion of space lled by an incompressible Newtonian uid, i. e. T. By applying the momentum conservation principle we recover the well-known incompressible Navier-Stokes equation:
0 (u,t

+ (u)u) = b P + u ,

in ,

(3.8)

where we exploited the fact that 2div(D) = u + (div(u)) and the incompressibility constraint. (kinematic viscosity), P0 = P0 , b0 = b , (3.8) may be rewritten By introducing = 0 0 in the following form: u,t + (u)u = b0 P0 + u , together with the incompressibility constraint div(u) = 0 . Non-dimensional form A uid ow problem can be characterized by a typical spatial scale l and a characteristic value for the uid velocity modulus u. The choice of these values is arbitrary and in general related to the ow features. In blood ow problems l is generally taken equal to the blood vessel diameter, while u is the average uid speed. The Navier-Stokes equations are modied by introducing these non-dimensionalized quantities: u tu x u = , t = , x = , u l l the pressure being non-dimensionalised as follows:
P0 =

(3.9a)

(3.9b)

P0 . u2

46

3 Three-dimensional models for blood ow problems Moreover, the time and space derivatives are referred to the non-dimensional variables t and x : x P0 = u,t = u2 , x P0 l x u = u x u , l2

u2 u , l ,t

(x u)u =

u2 (x u )u . l

By substituting the previous denitions in (3.9a), where we set b0 = 0 for the sake of simplicity, and after some algebraic calculations, we obtain the following non-dimensional formulation: x u . u ,t + (x u )u = x P0 + ul Remembering (3.1) we can write
u ,t + (x u )u = x P0 +

1 x u , Re

(3.10)

where we identify the Reynolds number Re. Let now l1 and l2 be the characteristic spatial scale of two ows, such that l1 = l2 , R. Moreover, let Re1 and Re2 be the Reynolds numbers for the two ows, such that Re1 = that is l1 u1 l2 u2 = = Re2 1 2

u1 u2 = . Then (u 1 , P0,1 ) and (u2 , P0,2 ) satisfy the same set of differential 1 2 equations in non-dimensional form (3.10). Two such ows are termed geometrically and dynamically similar. Boundary conditions and initial condition Considering the vascular geometry depicted in Fig. 3.3, we can identify different boundary regions, corresponding to the xed vascular walls w and to the articial inlet and outlet sections for the uid. The latter do not correspond to a physical interface between the uid and the exterior, but they are introduced in order to separate the region of interest from the remaining part of the circulatory system. More precisely, we distinguish a proximal section in (that is closer to the heart with respect to the mean blood ow direction) and four distal sections out,i , i = 1, . . . , 4. They are also referred to as one inow and four outow sections, even if during the cardiac cycle the ow can be exiting the inow section and entering the outow sections, due to ow reversal which is likely to happen especially in major vessels. Typically we prescribe a velocity prole at in , able to reproduce measured data (when available). We prescribe zero velocity on w , corresponding to a no-slip condition for the uid in contact with the wall. Finally, on out,i the normal stress T n is prescribed, n being a vector eld dened on out,i and aligned to the direction normal to the section.

47

3 Three-dimensional models for blood ow problems Other possible choices for the prescription of boundary conditions can be exploited, in particular in the context of multiscale modeling [48, 141] (see Chap. 5). In that case, the Navier-Stokes equations describing specic vascular districts are coupled with reduced models taking into account the remainder of the circulatory system, so that the boundary conditions on the articial sections come from interface conditions between the different models. An example of this approach is presented in Chap. 5, where we discuss specic issues arising in the coupling of 3D models based on the incompressible Navier-Stokes equations and 1D models based on the Euler equations. The initial status of the uid velocity is prescribed through suitable initial conditions, typically in the form u(q, t0 ) = u0 (q ) , q,

with the additional incompressibility constraint div(u0 ) = 0. The choice of u0 is arbitrary (usually u0 = 0), since in general a physically relevant initial condition is not known in hemodynamic computations. This inuences the computed solution u(q, t): provided that the boundary conditions are correct, the dynamics of u(q, t) is recovered only after a transient in which the effect of the initial condition fades away. In practice, this transient is commonly assumed to last for two or three heart beats, after which the solution is dominated by the boundary conditions.

3.3.2 Numerical discretization

In order to compute a numerical solution ( , ) of system (3.9), we carry out a discretization of such equations with respect both to the space and to the time variables. For what concerns the time discretization, a typical approach is based on the nite difference approximation, that means to split the time interval of interest (0, T ] into subintervals with time step t, such that tk = k t (k N) and approximate the time derivatives with suitable incremental ratios evaluating the unknowns at the instants tk . In the sequel, we will assume to discretize the equations through a backward Euler time discretization. For what concerns the space discretization, we refer to the nite element method. The discretization of the problem according to the nite element method is based on the Galerkin approximation of (3.9), that we are going to introduce. In the sequel, we denote by L2 () the space of square integrable scalar functions in , L2 () the analogous functional space for mdimensional vector functions, H m () the functions belonging to L2 () together with their rst m spatial derivatives and Hm () the functions belonging to L2 () together with their rst m spatial derivatives. In particular, H1 0 () denotes the functions belonging to L2 () together with their rst spatial derivative and whose trace vanishes on . For the sake of simplicity, we will assume smooth enough and homogeneous Dirichlet conditions = 0 on for equations (3.9). Then, the backward Euler-Galerkin approximation of the problem (3.9) reads: for

48

3 Three-dimensional models for blood ow problems

+1 n+1 each n 0, nd n Vh and h Qh such that: h

+1 n+1 n+1 m n h , vh + a h , vh + g h , vh + n+1 +b vh , h = f n+1 vh d + m ( n h , vh ) vh Vh +1 b n qh Qh , h , qh = 0

(3.11)

where {Vh , h > 0} and {Qh , h > 0} are families of nite-dimensional subspaces of H1 0 () k denote the discrete for the velocity and of L2 \ R for the pressure, respectively, k , h h velocity and pressure computed at tk and: m (w, v) 1 t

w vd, a (w, v) =

w : vd, (3.12) (w) w vd.

b (w, q ) =

wqd,

g (w, v) =

In particular, in the nite element method, we introduce a triangulation Th of the domain , i. e. a nite decomposition of into tetrahedrons. Here h denotes the maximum of the diameters of the triangles of Th . Then, assume that Vh is the space of piecewise polynomial functions on every element of Th , continuous in and vanishing on the boundary . Similarly, Qh is the space of piecewise polynomial functions on every element of the decomposition, not necessarily continuous. Due to the presence of the nonlinear convective term in the momentum equation (3.9a), (3.11) yields the solution of a system of non linear equations when using full implicit time-stepping procedures. In this work, we follow a semi-implicit strategy, based on the approximation:
n+1 g wh , vh n+1 n (wh ) wh vd

However, different strategies can be considered as well (see e.g. [108]). We remark that the well posedness of problem (3.11) is ensured when the Ladyzhenskaja-Babuska-Brezzi (LBB) condition, which requires a compatibility between the choice of the polynomial degrees for the velocity and the one for the pressure, is satised [111]. On the basis of the presented formulation, different solution techniques can be devised to manage the resulting system of algebraic equations. We mention in particular block factorization methods, based on the splitting of the problem, for instance generating separate subproblems for the velocity and the pressure [109111]. A slightly different nite element method for the discretization of the Navier-Stokes problem has been introduced by Burman et al. [18], consisting in a stabilized Galerkin formulation using equal order interpolation for pressure and velocity and therefore reducing the dimension of the resulting algebraic problem.

49

3 Three-dimensional models for blood ow problems

(a) Domain represents an aneurysmatic Internal Carotid (b) Zoom on a part of the domain Artery. boundary : the aneurysmal bleb.

Figure 3.4: Visualization of an example of computational domain (a). Particular (b) of the domain boundary, with a graphical representation of the normal vectors to the surface.

3.4 Wall shear stress in the Navier-Stokes problem

Let u represent the uid velocity in a domain E and let n be the normal on (see Fig. 3.4): the stress exerted by the uid over the boundary of the domain reads = T n, T being the Cauchy stress tensor (see (3.6)). The tangential component of is referred to as the wall shear stress, and may be derived as follows: WSS = t = ( n) n. Note that t by denition takes only into account the viscous component of the stress, the pressure being responsible only for a normal stress.

3.4.1 Approximation for the velocity gradient

It follows from the denition of T (see (3.7)) that in order to estimate the stress eld (and in particular the wall shear stress) over the computational domain it is necessary to retrieve a suitable approximation of the velocity gradient. This issue has been extensively treated in the literature: we mention in particular several works by Zienkiewicz & Zhu [150152] proposing a cost effective procedure for the recovery of the gradient of nite element solutions at the nodes. In the following we focus on the L2 projection method [13, 153], which is proven to provide a superconvergent approximation of the gradient on linear elements.

50

3 Three-dimensional models for blood ow problems Let P be the Navier-Stokes problem dened over . Suppose that we have an approximation uh of the velocity eld solution for P , obtained with a Galerkin nite eler ]d , u () Rd , where X r is the space of r -th degree piecewise ment method: uh [Xh h h polynomial functions on a tessellation Th of . We compute an approximation G(uh ) of uh , such that (L2 projection of the gradient r ]dd ): over [Xh G(uh ) : vd =

uh : vd,

r dd v [Xh ] .

The componentwise formulation reads: Gkl (uh )vd =

(uh )k vd, xl

r v Xh .

r = span( , In standard Galerkin nite element theory Xh i = 0, . . . , N ), N being i the number of degrees of freedom of the problem and i the scalar nite element nodal function associated to the i-th degree of freedom. Each component Gkl may then be expressed as a linear combination of the nite element basis functions:

Gkl (uh )(x) =

Nj

Gkl (uh )(Nj )j (x)

where Nj is the j -th degree of freedom, x . It can be seen that the values Gkl (uh )(Nj ) are therefore solutions of the following linear system: i j d Gkl (uh )(Nj ) =
Nj

(uh )k i d, xl
Nj (Uj )k j (x),

i = 0, . . . , N we can write

On the other hand, knowing that (uh )k (x) = (uh )k i d = xl

(Uj )k
Nj

j (x) xl

The overall problem reduces therefore to the solution of d d linear systems of the form Mg = f where M(i, j ) =

i j d is a mass matrix while g = Gkl (uh )(Nj ) , f = Dl (U)k ,

with Dl (i, j ) =

j (x) d . Having at hand the approximate solution uh , which is xl a piecewise polynomial function over the tessellation Th of the computational domain, the right hand side of these systems can be computed exactly. i

51

3 Three-dimensional models for blood ow problems

3.4.2 Oscillatory Shear Index

Several studies focused on the effect of wall shear stress on the remodeling mechanism in blood vessels. Not only the mean WSS is associated to anatomic changes of vascular wall: the rate of change of wall shear is believed to play a role in the development of pathologies such as atherosclerosis [25]. In particular, it has been found that laminar shear stress is atheroprotective for endothelial cells, whereas nonlaminar, disturbed, or oscillatory shear stress correlates with development of atherosclerosis and neointimal hyperplasia [31]. In specic locations of the circulatory system, the blood ow may be reversed during part of the cardiac cycle: this causes the wall shear stress to signicantly vary its direction. Ku et al. [68] proposed an oscillatory shear index (OSI) in order to quantify this effect, and looked for a correlation between vascular wall locations featuring high OSI and the local initiation of atheroma in the human left carotid artery. The original formulation is the following:
T

|WSS |dt , |WSS|dt (3.13)

OSI =

0 T 0

where T is the duration of the cardiac cycle, WSS is the wall shear stress vector and WSS is dened as the stress component acting in the opposite direction with respect to the direction of the mean shear stress (in time). Taylor et al. [138] proposed a similar formulation, which encompasses a strategy to estimate the deviation of WSS from its temporal mean direction: OSI = 1 2 1 WSSmean WSSmag , (3.14)

where WSSmean is the mean shear stress, dened as the magnitude of the time-averaged stress vector t (see (3.6)), while WSSmag is the time-averaged magnitude of the stress vector: 1 T 1 T WSSmean = t dt , WSSmag = |t |dt T 0 T 0 According to the latter formulation, OSI is minimum (and equal to 0) if WSS is constantly directed along its average direction. OSI is maximum (and equal to 0.5) if the mean WSS over the heart beat is = 0. A different approach has been followed by Steinman et al. [85], who weighted the positive values of the scalar product of WSS and the mean shear direction n:
T

n=
0

WSS dt . |WSS|

52

3 Three-dimensional models for blood ow problems The OSI is then dened as follows:
T

|WSS n|H (WSS n)dt OSI =

0 T

, |WSS n|dt

(3.15)

H (x) being the Heaviside unit function. In this formulation, high values for OSI indicate that WSS direction is not opposite to the mean shear direction for the most part of the cardiac cycle.

3.5 Working on regions of interest

It is usually relevant to quantify the mechanical stress exerted by the blood ow on a vessel wall in locations where it may be associated to the development of vascular pathologies. This is the case of cerebral aneurysms, in which typically we want to quantify the WSS only in the neighbourhood of the aneurysmal sac.

Figure 3.5: Schematic representation of a region of interest in a vessel (in red). The vessel centerline is also represented. On the other hand, the unknowns of a uid dynamics problem are approximated on the whole computational domain . If we are interested in evaluating some quantities on specic (sub-)regions of (see Fig. 3.5), we need to dene those regions and restrict there the uid dynamics analysis. One possible approach is based on the extraction of the vessel centerline.

3.5.1 Decomposition of bifurcation branches

Blood vessels can be effectively represented by centerlines, synthetic descriptors of the geometry and the topology of vascular networks. For the purposes of this work, a centerline is dened as the weighted shortest path traced between the inlet and the

53

3 Three-dimensional models for blood ow problems outlet of a vessel, the weight being the distance from the surface [6, 7, 103]. More precisely, a centerline is traced on the medial axis of the vascular geometry, that is the locus of the centers of the maximal inscribed spheres in the shape of the vessel. Therefore, each point of the centerline is the center of such a sphere and carries the information about its radius. Moreover, a natural parametrization for the centerline is given by the associated curvilinear abscissa, which ranges over the line and relates each point to its Euclidean distance from a point chosen as the origin (see Fig. 3.8(a)). In formal terms, a centerline can then be seen as a parametric curve c(s), s [0, L] being the curvilinear abscissa and L the centerline arc length. The envelope of the maximal inscribed spheres along the centerline denes a scalar function called tube function T , which can be expressed as follows: T (x) = min
s[0,L]

|x c(s)|2 r2 (s)

where x R3 is a point in the Euclidean space and r is the radius of the maximal inscribed sphere whose center is the centerline point c(s). The zero isosurface of T is referred to as tube or canal surface, and by construction is strictly contained inside the vascular lumen. The function T is negative inside the tube. The construction of centerlines and tubes is particularly useful in the study of bifurcating vessels, since it allows the identication and characterization of the bifurcation points [7]. For the sake of clarity, we refer to the case depicted in Fig. 3.6. First of all, the centerlines for the surface at hand are computed, yielding a set of curves running from the bifurcation inlet to each outlet. Then, two reference points are dened for each centerline: the rst is the point in which one centerline crosses the tube surface generated by the other (and is labelled as point 1 in black ink, in Fig. 3.6); the second is the center of the nearest upstream sphere touching point 1 (and is labelled as point 2 in black ink in the gure). These four points and the associated spheres describe the position of the bifurcation and the size and shape of the vessel at the bifurcation point. Moreover, they split the centerlines into tracts corresponding to single bifurcation branches and to the bifurcation center, labelled respectively as tract 1, 3, 4 and 2 in red ink in Fig. 3.6. Each point of the space can then be associated to the nearest centerline tract, thus inducing a partition in regions of inuence of the different tracts. These regions of the space cross the vessel surface in the bifurcation region, decomposing it in branches. We remark that the same approach can be applied to the study of aneurysms: the aneurysmal bleb may be regarded as a branch with respect to its parent vessel, and can be therefore decomposed from the vessel surface. An example of this procedure applied to the geometrical model of a pathological Internal Carotid Artery is depicted in Fig. 3.7.

3.5.2 Relating surface points to centerlines

By splitting each bifurcation in its branches, a simplication of the topology of the vascular network is achieved. Each branch is now topologically equivalent to a cylinder,

54

3 Three-dimensional models for blood ow problems

Figure 3.6: Representation of a bifurcating vessel (from http://vmtk.org). Left: centerlines. Middle: tubes constructed as envelopes of the maximal inscribed spheres along each centerline. Right: identication of two reference points for each centerline, for the description of the position, size and shape of the bifurcation (in black); decomposition of the centerlines in distinct tracts (in red). thus its geometrical characterization is easier. For instance, it is possible to robustly generate cross-sections of the vessel along the centerline [69]. More than that, each branch can be mapped into a rectangular parametric space: this allows the comparison among geometrical models in the same parametric space, and has been recently investigated by Antiga et al. [7]. A curvilinear reference system can be dened on each centerline branch, centered in the considered bifurcation. Each surface point y can be associated to its nearest centerline point cy , by minimizing the tube function T (y). An example of this procedure is depicted in Fig. 3.8. Following the same idea, regions of interest can be identied on a computational mesh, automatically selecting the nodes in which to evaluate uid dynamic variables or derived parameters. In the context of Aneurisk project this approach was exploited for the evaluation of the spatial average wall shear stress in a specic location of the Internal Carotid Artery. In that particular case, the last tract of the ICA surface was considered, as a preferential site for aneurysm development. Having associated the centerline abscissa

55

3 Three-dimensional models for blood ow problems

(a) Surface representing an internal carotid artery with a berry aneurysm.

(b) Each point of a centerline is the center of the maximal inscribed sphere in the surface and is associated to its radius.

(c) Decomposition of the surface in bifurcation branches.

(d) Selection of a region of interest on one branch.

Figure 3.7: From the geometrical model of a blood vessel to the selection of a region of interest. The denition of the vessel centerline allows the decomposition of the surface into branches. Undesired branches are excluded from the region of interest.

to the surface points, the problem was recast into the selection of an abscissa interval on the centerlines. To this aim, two geometric landmarks were considered. The rst is the center of the main bifurcation of the ICA, the second is the point delimiting the last ICA bend prior to the bifurcation. Following [119] we dene a vascular bend or siphon as a segment included between two points of approximately zero curvature of the centerline. Therefore the selected region comprises the last ICA siphon and the last few centimeters of the vessel, prior to the bifurcation, and the average value of WSS

56

3 Three-dimensional models for blood ow problems

(a) Curvilinear reference system in a vessel bifurcation: the origin is placed in the center of the main bifurcation (where the aneurysm is located).

(b) Each point of the surface is associated to a curvilinear abscissa.

(c) A region of interest is selected (in red), by considering an interval of curvilinear abscissa and neglecting undesired branches (such as the aneurysmal bleb).

(d) Wall shear stress values in the region of interest.

Figure 3.8: Evaluation of wall shear stress on a region of interest selected on the vessel surface and corresponding to an interval of curvilinear abscissas on the centerline. Undesired branches are excluded from the analysis. over can be dened as follows: WSSd WSS =

. d

(3.16)

57

3 Three-dimensional models for blood ow problems Figure 3.8 shows the application of this technique to the study of uid dynamics inside a realistic ICA geometry. More details on the results of this analysis in the context of Aneurisk project will be presented in Chap. 4.

58

4 An application of three-dimensional modeling to the study of cerebral aneurysms

In this Chapter we focus on the study of cerebral vasculature: an introductory overview on its hemodynamic features is provided in Sec. 4.1. In particular, in the context of the Aneurisk project (presented in Sec. 4.2) we proposed WSS as a hemodynamic parameter for the classication of internal carotid artery geometries (Sec. 4.3).

4.1 Cerebral hemodynamics

A typical assumption is that blood is a continuous incompressible Newtonian uid, so that its dynamics can be described by the three-dimensional unsteady incompressible Navier-Stokes equations (see (3.8)). It has been shown [70, 98, 101] that this approach is reasonable when looking at large arteries. The same assumption may however not hold inside the aneurysmal sac, due to the presence of slow-ow regions [14]: several studies have been presented dealing with the non-Newtonian characteristics of blood ow in such conditions [22, 83]. In the following, we will not deal specically with the ow features inside the aneurysm, hence we will refer only to Newtonian models for the blood. The wall motion is usually neglected in blood ow modeling [99, 132, 137]. For the case of intra-aneurysmal ow, the effect of moving boundaries has not yet been assessed, though recently some works moved towards this direction [24,127,137,148,149]. One of the major issues when considering uid-structure interaction problems is the mechanical characterization of the wall, together with the lack of intra-arterial pressure measurements [24]: this limitation can be circumvented by using measured wall movements as boundary conditions in CFD models. Instead of solving a structural dynamics problem, driven by the stress exerted by the uid on the structure, the position in time of the interface between the blood and the wall can be recovered for instance from dynamic angiography images through nonrigid registration algorithms. The rst results obtained with this technique suggest that the main characteristics of the ow (location and size of the inow jet, complexity and stability of the patterns) are not altered by the movement of the domain, while the computed WSS and velocity magnitude can be affected [35, 93]. Intra-aneurysmal ow patterns develop in a wide variety and complexity: vortical structures may form inside the bleb and they can be stable or move during the cardiac cycle becoming unstable. Not only the size and shape of the aneurysm determine the

59

4 An application of three-dimensional modeling ow structures, but the geometry of the parent artery also inuences the way the blood enters and ows into the aneurysm. In particular, an inow jet is usually generated, which impacts the wall producing a region of locally elevated WSS. The size of the inow jet and the location of the impingement region strongly depend on the patientspecic vascular geometry [124].

4.2 The Aneurisk project

The Aneurisk research project (2005-2008) was developed by a joint venture of different subjects: academic and non academic research centers (MOX - Department of Mathematics, Politecnico di Milano; LaBS - Department of Structural Engineering, Politecnico di Milano; M. Negri Institute for Farmacological Research, Bergamo), medical centers (Dipartimento di Neurochirurgia, Universit degli Studi di Milano; Ospedale Niguarda Ca Granda di Milano; Ospedale Maggiore Policlinico di Milano), industrial partners (Siemens Medical Solutions Italy; Fondazione Politecnico di Milano). The main goal of Aneurisk project was to develop a framework for the analysis of cerebral vascular geometries. The project was based on the idea of a stream of information starting from the medical image and passing through a series of steps, each one adding a layer of knowledge to the overall process. The rst step is image segmentation, together with geometry reconstruction and morphology characterization. It is followed by a modeling step for the simulation of blood ow in realistic geometries and the characterization of the wall mechanics. Statistical analyses represent the interpretive step, for the organization and the extraction of information from the complete data set. The nal product of this process is intended to be an enhanced medical image, analysed in its more signicant features which are then synthetized in a diagnostic (and possibly prognostic) perspective. A particularly interesting case study for Aneurisk was the Internal Carotid Artery (ICA), a renowned site for cerebral aneurysm development. The data set of the project consisted in 134 three-dimensional computed rotational angiography (3D CRA) scans, obtained during clinical routine at the Neuroradiology Division of the Ospedale Niguarda Ca Granda in Milan, for assessment of cerebral aneurysms. Patient-specic models of cerebral arteries have been reconstructed from these images, after a segmentation process. Geometry characterization was performed on the models employing a set of tools part of VMTK (www.vmtk.org), an open source software project for vascular modeling [5], mainly developed at Mario Negri Institute in Bergamo. This analysis was carried out by Piccinelli et al. and showed preferential locations of the pathology in the distal upper tract of the vessel, on the outer wall of ICA bends in correspondence of local curvature maxima [102,103]. Moreover, ruptured aneurysms were found typically in more distal positions along the vessel centerline (see Fig. 4.1). A conjecture formulated by neuroradiologists at Ospedale Niguarda Ca Granda was tested, namely that some geometrical features of ICA are different according to the presence and the location of an aneurysm (see Fig. 4.2). The idea was conrmed by a classication of Aneurisk data set, proposed by Sangalli et al. [120]. They considered

60

4 An application of three-dimensional modeling

Figure 4.1: Position of the aneurysm along the centerline of pathological ICAs: in the whole population, in patients with ruptured aneurysms and in patients with unruptured aneurysms. The point of zero abscissa is set at each ICA bifurcation, so that centerline abscissas represent distance to the bifurcation. Black dots represent mean value; crosses represent standard deviation [103].

two groups of patients. The rst (blue dots in Fig. 4.3) is composed of patients with an aneurysm located at or after the terminal bifurcation of the ICA; the second group (red dots in Fig. 4.3) is composed by patients having an aneurysm before the terminal bifurcation or healthy. Radius and curvature proles were studied in the last tract of ICA prior to the bifurcation [118, 119] (see Fig. 4.2), and patients in the blue group were found to have signicantly wider, more tapered and less curved ICAs. Moreover within this group there is a lower variability of radius and curvature of the ICA. On the basis of this result, a similarity index was dened to measure how the geometrical features of each vessel compare to those of the representatives of the morphological classes (see Fig. 4.3). It is well known that blood ow features strongly depend on the vascular morphology: therefore we believe that the differences in the geometry of ICA of patients belonging to the described groups induce different hemodynamic features and that these may trigger the pathologic response of the arterial wall. We then propose a CFD analysis over the Aneurisk dataset, in order to study the blood ow features in the last tract of ICA. Moreover, we look for parameters able to synthetically describe the effects of blood ow on the vessel wall, such as the spatial average of wall shear stress. This information could be used to have a better understanding of the mechanisms of aneurysm development in the vascular district at hand; on the other hand, it could be used to enhance the classication proposed in [120] by combining the mechanical and the morphological characterization of the vessels.

61

4 An application of three-dimensional modeling

Figure 4.2: Curvature proles along the centerline in the internal carotid artery [119]. Negative values for the curvilinear abscissa identify proximal vessel locations, with respect to the origin of the reference system which is placed at the ICA bifurcation. The top of the gure shows the estimate of the probability density function of the location of aneurysms along the ICA.

0.9

Upper group membership probability

0.1

0.1

Figure 4.3: Classication of Aneurisk data set based on morphological features of the Internal Carotid Artery. Red dots represent ICAs with an aneurysm before the terminal bifurcation or healthy. Blue dots represent ICAs with an aneurysm at or after the terminal bifurcation.

4.3 Hemodynamic features of the Internal Carotid Artery

We chose 21 ICA geometry models, based on their score in the morphological classication [120] (see Fig. 4.3). Seven geometries were elicited from the group of vessels with high similarity to the representative of the red group (see Fig. 4.4), other seven from the group of vessels similar to the representative of blue group (see Fig. 4.6), the remaining were chosen among the cases whose features do not t in either class (see Fig. 4.5). We

62

0.9

Lower group membership probability

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.8

0.7

0.6

0.5

0.4

0.3

0.2

4 An application of three-dimensional modeling will refer to the latter as to the green group.

(a) 81256

(b) 93817

(c) 100170

(d) 146842

(e) 149198I

(f) 187618

(g) 218122

Figure 4.4: Data set for the numerical simulations: ICA geometries classied as belonging to the red group. All the reconstructed geometries in Aneurisk data set were available as three-dimensional surface models represented in StL format . These models represent in general a large part of the cerebral vasculature, featuring the presence of one or more aneurysms. For this particular study, we were interested specically in the Internal Carotid Artery, so that all the geometries had to be restricted to this region by proper trimming of the surface model. Moreover, following what has been done in [120], we focused our attention on the last tract of the Internal Carotid Artery, prior to its terminal bifurcation. In facts, this location is particularly interesting, since it is a preferential site for aneurysm development [103]. On the other hand, models of ICA reconstructed from Aneurisk dataset of medical images could only be compared by looking at the distal

StL stands for Stereo Lithography, and indicates a triangular representation of a three-dimensional surface geometry. See http://www.ennex.com/~fabbers/StL.asp

63

4 An application of three-dimensional modeling

(a) 97930

(b) 148385I

(c) 179174

(d) 183983

(e) 184480

(f) 184773

(g) 198273

Figure 4.5: Data set for the numerical simulations: ICA geometries which do not belong to either group in the morphological classication. portion of the vessel, which was present in all the images. Indeed, the dimensions of the reconstructed 3D model depend on the size and the spatial position of the volume scanned during the clinical procedure, and this volume is not the same for all the considered patients. According to the surgeons choice, based on the aneurysm location, different specic districts of the cerebral vasculature were captured in medical images. Therefore, it was not possible to reconstruct the ICA to the same extent in all the cases. The hemodynamic quantity of main interest was wall shear stress (WSS): we computed the integral average of WSS on a specic region of the vascular wall, corresponding to an interval of curvilinear abscissas on the vessel centerline spanning the last ICA bend and the last few centimeters prior to the bifurcation (see Sec. 3.5). More precisely, we considered the tract of centerline comprised between the origin of the reference system (located at the bifurcation) and the point of zero curvature delimiting the nearest siphon to the bifurcation [119].

64

4 An application of three-dimensional modeling

(a) 12438

(b) 145573

(c) 146495

(d) 188801

(e) 205752

(f) 209834

(g) 215056

Figure 4.6: Data set for the numerical simulations: ICA geometries classied as belonging to the blue group. The choice of including the bend in the region of interest has two main reasons. On the one hand, it is an easily recognizable landmark and is present in all the geometries, therefore the selected regions are the same in all the data set. On the other side, the ow features are strongly affected by the presence of bends in the vessel geometry (see [37]), especially in ows with high values of the reduced velocity (see Tab. 4.1). The latter is associated to the persistence of ow structures along the streamwise direction, so that mixing effects and vortical patterns induced by the bend are expected to determine the hemodynamics features in all the considered region. It has also to be noted that ow pulsatility, together with the complexity of the overall vascular geometry (a sequence of sharp, non planar bends) induces strong secondary motions resulting in vortical or helical ow patterns. Evidences of this phenomenon have been recently discussed in [48, 104], and on this basis we chose to reconstruct the entire sequence of ICA siphons (to the most possible extent given the images), even if interested only in

65

4 An application of three-dimensional modeling the distal portion. An excessive trimming of the upstream vascular geometry could in fact lead to a non correct evaluation of the patient-specic interplay between vessel morphology and hemodynamics.

(a) The original StL model.

(b) The trimmed model (now mostly representing the ICA).

(c) Flow extensions added to the ICA model.

Figure 4.7: Denition of the computational domain: the model reconstructed from medical images (a) is trimmed (b) and ow extensions are added on the inlet and outlet sections (c). An example of a trimmed geometrical model is depicted in Fig. 4.7 (b). It represents the distal bend of an Internal Carotid Artery and its main bifurcation: the trimming procedure excluded the downstream circulation, but not the upstream part of the artery. Cylindrical prolongations are added to each extremity of the surface, in such a way that the geometrical model features circular inlet and outlet sections (see Fig. 4.7 (c)), corresponding to the proximal and the distal boundaries respectively. The length of these cylindrical extensions is adaptively selected as 10 times the clipped section radius. This technique allows to analytically formulate the boundary conditions, the boundary sections being circular. At the same time, the ow prole is allowed to develop in the cylindrical extensions, prior to entering the vessel domain. For each one of these geometrical models we obtained a tetrahedral grid with an average mesh size of 0.06 cm. The meshing procedure was performed by means of the software Netgen , which offers an implementation of the advancing front method together with several mesh optimization algorithms (both metric optimization and topo

http://www.hpfem.jku.at/netgen/

66

4 An application of three-dimensional modeling logical [33]). The meshes were rened on the basis of the surface curvature: an example is depicted in Fig. 4.8.

Figure 4.8: Mesh renement driven by the surface curvature. The computational domain was assumed to be xed, corresponding to the hypothesis of rigid vascular walls. As pointed out above, we further assumed that blood can be modeled as a continuous incompressible Newtonian uid, so that the blood ow problem can be described by the incompressible Navier-Stokes equations (3.8). For each vascular geometry, three cardiac cyles were simulated, in order to reduce the effects of the initial conditions and obtain the periodic solution in the last simulated heartbeat. The spatial discretization was based on the Galerkin nite element method (see Sec. 3.3.2), and was carried out with a P1 approximation for both the pressure and the velocity. The numerical scheme adopted is based on an edge stabilization technique [18]. The adopted time advancing scheme is a BDF of order 1, with a time step of dt = 103 s. The spatial integral average of WSS was computed on the arterial wall, after the removal of possible branching vessels and aneurysms, as discussed in Sec. 3.5. An example of the considered portion of the ICA surface is shown in Fig. 4.10. All the uid dynamics simulations and the WSS computations were carried out with a software specically realized for Aneurisk project and based on LifeV (see Sec. 6.2), a C++ implementation of algorithms and data structures for the numerical solution of partial differential equations. The treatment of vascular geometries (addition of ow extensions, splitting in branches, identication of regions of interest) has been performed by using the software VMTK .

www.vmtk.org

67

4 An application of three-dimensional modeling

9 8 7 6 Q 5 4 3 2 0

0.2

0.4 t

0.6

0.8

Figure 4.9: Flow rate (in ml/s) in an Internal Carotid Artery. The wave form of this signal reproduces measured in vivo data, the amplitude is scaled to give a time average value of 240 ml/min, in the range of physiological values [79].

Figure 4.10: The portion of the vessel wall over which the integral average of WSS is computed. Boundary conditions In Aneurisk dataset, patient-specic measurements of blood ow rates, velocity or pressures were not available. On the other hand, physiological values for ICA ow rate QICA can be found in the literature, and we had at hand the wave form of the blood ow rate measured in vivo in a single patients ICA. Since our interest was to compare different vascular geometries, and to understand the effect of different morphological features on hemodynamics, starting from the available data we looked for a suitable set of boundary conditions for our geometrical models. We resorted to a non-dimensional

68

4 An application of three-dimensional modeling argument and imposed boundary conditions giving the same ow regime in all the computational domains.

Figure 4.11: Velocity prole (in cm/s) imposed on the inow section: only the axial component un is non zero. This prole corresponds to (4.1) with Qin = 240 ml / min and Rin = 0.2 cm. More precisely, we run a rst set of simulations imposing as inow boundary condition the wave form depicted in Fig. 4.9, scaled to give a time averaged ow rate QICA = 240 ml/min (a reference value for the time averaged ICA ow rate in a cardiac cycle, as found in the literature [79]). The chosen ow rate was obtained by prescribing a velocity prole on the inlet section, more precisely an axial velocity of the following form: 0 r > Rin , 12 Qin 2(Rin r) 1 Rin r Rin , 2 un = (4.1) 7 Rin Rin 2 12 Q 1 in 0 r < Rin , 2 7 Rin 2 where r is the radial coordinate on the inlet section while the values of Rin and Qin are specied in Tab. 4.1. This choice corresponds to the assumption of fully developed axial ow, which can be approximated to a at prole [48, 92] (see Fig. 4.11), and is legitimated by the use of a cylindrical boundary extension on the inlet section. It is indeed proven that the geometrical features of the vessel have a stronger inuence on the solution than the presence of secondary velocities in the inlet prole. Moreover, the effects of these inlet secondary ows, even in case they are present, break down within a few diameters of the inlet [87]. We then computed the Reynolds number on the inow boundary section, in order to classify the ow regime for each geometry. The time average over a cardiac cycle of these values is represented in Fig. 4.12. We found out that, for most of the considered geometries, a time average Reynolds number of Re = 350 describes with a good approximation the ow regime associated to an ICA ow rate in the range of physiological values. Therefore, we chose to scale the amplitude of the inow datum to obtain that value in each geometry (see Tab. 4.1). In two cases (patient ID 183983 and 215056, see Fig. 4.5 and Fig. 4.6) this ow regime was associated to blood ow rates signicantly

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4 An application of three-dimensional modeling

Reynolds number
Patient ID 12438 81256 93817 97930 100170 145573 146495 146842 148385I 149198I 179174 183983 184480 184773 187618 188801 198273 205752 209834 215056 218122

400

350

300

250

Figure 4.12: Boxplot of the time averaged Reynolds numbers, evaluated on the inlet section of each vascular geometry, when the imposed ow rate (averaged over a cardiac cycle) is 240 ml/min

higher than in the others, due to larger ICA radius, found in both cases. Rin (cm) 0.229 0.178 0.215 0.224 0.189 0.21 0.22 0.201 0.181 0.196 0.196 0.284 0.241 0.185 0.203 0.229 0.215 0.223 0.213 0.283 0.17 Qin (ml / min) 263.62 206.88 249.14 258.11 217.51 240.04 253.21 235.37 208.20 224.47 221.93 326.57 273.53 213.76 234.13 264.95 245.02 259.31 245.65 326.36 198.23 Woin 3.072 2.38 2.879 3.002 2.534 2.81 2.95 2.699 2.422 2.628 2.621 3.802 3.23 2.473 2.718 3.075 2.887 2.995 2.848 3.788 2.276 Ured 58 97.897 66.579 60.853 85.336 68.989 62.9 76.403 93.48 78.911 78.608 37.916 51.765 90.16 74.433 58.161 64.964 61.583 67.838 38.323 107.29

Table 4.1: Inow boundary conditions: radius Rin , imposed ow rate Qin (time average over a cardiac cycle), Womersley number Woin and Reduced Velocity Ured evaluated on the inow section.

70

4 An application of three-dimensional modeling A zero-stress condition was prescribed on the outlet sections through homogeneous Neumann boundary conditions. This implies that the same mechanical load was imposed on all the outows, which is clearly not the case in vivo. However, this is a widely accepted assumption, when measures of ow rates or pressures are not available in correspondence of the boundaries of the computational domain. A possible way to avoid this strong assumption is to resort to the so-called geometrical multiscale approach, based on the coupling of detailed models (like the 3D Navier-Stokes equations (3.8)) describing the local uid dynamics, together with reduced models (such as the 1D Euler equations (2.5)) reproducing the remainder of the circulatory system. This approach will be discussed further in Chap. 5.

4.3.1 Discussion

Figure 4.13: Integral average of the wall shear stress (in dyn / cm2 ) over the last portion of ICA, prior to the bifurcation. The values for two different groups are shown (red group with red line, blue group with blue line) Let us consider all the geometries elicited from the red group (see Fig. 4.4), and compute the spatial average WSS in the region of interest as a function of time. This will give seven time patterns, which can be averaged to nd a representative time pattern for the considered quantity. If the same procedure is applied to geometries belonging to the blue group, the resulting representative time patterns can be compared as shown in Fig. 4.13. Moreover, the time average of these curves can be computed, yielding: Time averaged mechanical load (dyn / cm2 ) Red group Blue group 24.097 17.124 where for the sake of brevity we dened mechanical load the spatial average WSS

71

4 An application of three-dimensional modeling in the considered ICA region. This analysis shows that arteries of patients belonging to the red group (that is, with narrower, less tapered and more curved vessels) typically undergo a higher mechanical load, with respect to geometries belonging to the blue group, in the same ow regime. We use this result to dene a simple classication strategy of vascular geometries based on hemodynamics features. More precisely, we identify a threshold value, dened as the mean of the average mechanical load in the two groups: WSS = 20.611 dyn / cm2 . (4.2)

We then classify a vascular geometry as member of the red group if the computed mechanical load is higher than the threshold value. Otherwise, the vascular geometry is classied as member of the blue group. For the sake of clarity, we refer to the results presented in Tab. 4.2: the time average over the cardiac cycle of the mechanical load as previously dened is shown for each simulated case. It is clear from these data that in most cases the classication based on hemodynamics features agrees with the results of the morphological analysis. Indeed, as expected, vessels elicited from the red group and from the blue group are correctly classied by both strategies except for two cases which will be discussed in detail later on. On the other hand, the geometries belonging to the green group (i. e. with geometrical features not clearly associated to the red nor to the blue group, see Fig. 4.5) can now be associated to a typical red-group or blue-group hemodynamics behaviour. More precisely, low values of the spatial average WSS (with respect to the threshold value (4.2)) are found in carotid arteries which do not feature the presence of aneurysms. This means that, from the uid dynamics view point, these cases are similar to the typical representative of the blue group, while the correct classication was not achieved on the basis of their morphological features. The hemodynamics analysis is able to correctly classify also a case of green geometry featuring an aneurysm along the ICA. The case identied as number 184773 (see Fig. 4.5) presents a small aneurysm in the very last part of the ICA, prior to the bifurcation: correspondingly, its time averaged mechanical load is similar to the typical red case value (i. e. higher than the threshold value). One green case (identied as number 184480) is still misclassied on the basis of uid dynamics arguments. It is indeed similar to a blue case, according to the estimated time averaged mechanical load, but it is not a typical blue case in that it has a quite big aneurysm along the Internal Carotid Artery (see Fig. 4.5). The very presence of such a big sac, however, is probably the reason why the proposed uid dynamical analysis is not effective in this case: giant aneurysms with a large neck strongly deform locally the hosting artery, therefore calling for a more specic and detailed study than the evaluation of a spatial average value of WSS. Two cases of wrong hemodynamics classication are the red case 93817, featuring a low mechanical load, and the blue case 205752, featuring high mechanical load. In the former case, however, the anomalous hemodynamic behaviour is due to a pathological condition of the entire vessel, namely a displasia causing the weakening of the

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4 An application of three-dimensional modeling Classication Morphology Hemodynamics R B R R R R R R B B B B B B R B B B B B R B B Patient ID 81256 93817 100170 146842 149198I 187618 218122 12438 145573 146495 188801 204552 205752 215056 148385I 179174 183983 184480 184773 198273 97930 Average WSS (dyn / cm2 ) 20.246 11.003 23.870 24.504 20.096 20.523 48.434 13.260 16.615 16.609 18.997 19.366 25.372 11.556 15.591 16.979 14.791 14.757 20.949 12.956 16.595

Table 4.2: Classication of the considered dataset of ICA. The hemodynamics provides additional information with respect to the morphological analysis, and is able to properly classify uncertain cases.

wall and a non physiological increase of the diameter (see Fig. 4.4). Conversely, the latter case features a particularly marked tapering in the very last tract of the ICA and is unusually tight in the bifurcation zone: this enhances the shear stress exerted by the blood on the wall in that specic region, and makes the spatial average WSS an unsuitable characterizing parameter. Finally, case 218122 deserves a comment, even if it is well classied both from the morphological and uid dynamical point of view. It can be seen in Tab. 4.2 and in Fig. 4.15 that it features an extremely high mechanical load, and again the inspection of the anatomy of the artery provides a reasonable explanation: as can be seen in Fig. 4.4, this vessel is very narrow in the distal part, so that high WSS has to be expected in all the considered area.

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4 An application of three-dimensional modeling

Figure 4.14: Green group: integral average of the wall shear stress (in dyn / cm2 ) over the last section of ICA, prior to the bifurcation.

Figure 4.15: Red group: integral average of the wall shear (in dyn / cm2 ) over the last section of ICA, prior to the bifurcation.

4.3.2 Wall shear stress as a classication parameter

The results of this work suggest that high WSS, beyond the other morphological features discussed in [120], is associated to the presence of aneurysms in the Internal Carotid Artery. Starting from this observation, based on the presented data set, it may be conjectured that a high-WSS environment induced by geometrical features predisposes to the development of the pathology. This conjecture is consistent with the idea of a correlation between geometrical and hemodynamical features of arteries, as assessed

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4 An application of three-dimensional modeling

Figure 4.16: Blue group: integral average of the wall shear stress (in dyn / cm2 ) over the last section of ICA, prior to the bifurcation.

in the literature. More precisely, elevated WSS has been associated to fragmentation of the internal elastic lamina of blood vessels [130], endothelial damage [129] and ultimately to aneurysm initiation (see also Chap. 1). Most brain aneurysms form on the arteries of the circle of Willis or from their main branches. Moreover, most tend to occur in the anterior circulation, preferentially in regions where arteries branch. Indeed brain blood vessels could be naturally weaker in such locations, which are also preferential sites for fatty plaques deposition WSS typically features a complex spatial pattern, corresponding to a non homogeneous mechanical load distribution at the microscopic level. In most cases here considered, however, its spatial average can be a useful and synthetic indicator of the stress exerted by the blood on the arterial wall, whenever the region of interest does not feature abrupt changes in the geometric features, such as localized stenosis or narrowing, or the presence of big aneurysms with large necks. One interesting extension of this analysis technique could be the denition of an index able to discriminate the pattern of the mechanical load along the vessel curvilinear abscissa. To this aim, the approach presented in Sec. 3.5.2 for the mapping of centerline abscissas on the surface can be exploited. Each artery would then be described by a set of geometric and hemodynamics parameters regarded as functions of the curvilinear abscissa of the centerline, and a new classication could be designed following the approach presented by Sangalli et al. [120]. On the other hand, other hemodynamics parameters could be included in the analysis: in particular, vorticity is expected to be a signicant ow feature in the complex ICA geometry, and could help in dening a more robust classication strategy. The in-silico setup here presented, and its further improvements, stand as a candidate tool to give a synthetic description of the mechanical solicitation exerted by blood ow

75

4 An application of three-dimensional modeling on the vascular wall. More than that, our results show that it can be used to characterize cerebral vascular geometries which are associated to the presence of an aneurysm. In this respect, it is worth noting that the additional information provided by CFD could have a prognostic value, helping to assess the evolution trend of the studied vessels: geometries featuring high WSS in the region near to the bifurcation could be more prone to the development of an aneurysm in ICA. Finally, we want to remark that a strong interplay between vascular geometry and blood ow features has been clearly shown from our results. We proposed a way to couple and complement the information coming from two different analysis approaches. Further application and improvement of this twofold approach is likely to give a greater insight and comprehension of cerebral aneurysms.

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5 A geometrical multiscale model of the cerebral circulation

Geometrical multiscale modeling is a strategy advocated in computational hemodynamics for representing dynamics ranging over different space scales in a single numerical model. It allows to couple the description of large vascular districts given by reduced models, with the detailed analysis of blood ow in specic regions of interest. This approach is particularly interesting in the cerebral circulation, whose arteries on the one hand form a complex anastomotic vascular structure (the circle of Willis) with peculiar hemodynamics features (see Chap. 1, Chap. 2) and on the other hand are prone to develop localized diseases such as cerebral aneurysms (see Chap. 1, Chap. 4). The modeling of the entire circulatory system of the brain would be unfeasible by means of 3D models (due to the lack of data and high computational costs), while 1D models are not suitable for the modeling of the microscopic features of the blood ow. A coupled approach can be effectively used in this context, as we discuss in Sec. 5.4. We present a multiscale model of the cerebral circulation where a one-dimensional description of the circle of Willis, relying on the Euler equations, is coupled to a fully three-dimensional model of a carotid artery, based on the solution of the incompressible Navier-Stokes equations. A similar multiscale model has been investigated in [86], where the 3D model includes compliance for avoiding spurious reections induced by a rigid treatment of the 3D geometry in the multiscale model. Even if vascular compliance is often not relevant to the meaningfulness of 3D results (e.g. in large arteries), it is crucial in the multiscale model, since it is the driving mechanism of pressure wave propagation (Sec. 5.1). Unfortunately, 3D simulations in compliant domains still demand computational costs signicantly higher than the rigid case. Appropriate matching conditions between the two models have been devised to concentrate the effects of the compliance at the interfaces and to obtain reliable results still solving a 3D rigid problem (Sec. 5.2).

5.1 The compliant vessel problem

A practical difculty arises when some features, that at a certain scale can be neglected, become relevant in the coupled model, inducing a signicant increase of the overall computational cost. This is the case of the compliance of vessels. In 3D Navier-Stokes stand-alone models compliance is quite often not relevant for bioengineering purposes. However, it is a driving mechanism of pressure wave propagation along the vascular tree. Therefore, when considering 3D/1D geometrical multiscale models in principle compliance should not be neglected in either models.

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5 A geometrical multiscale model of the cerebral circulation

1D Model

3D Model

Figure 5.1: A simple multiscale (3D/1D) model of a cylindrical pipe The coupling between 1D and 3D compliant models has been investigated recently in [86]. The computational cost of a compliant 3D simulation is however by far higher than the rigid case. On the other hand, a naive coupling of 1D (which are intrinsically compliant) and 3D rigid problems, forcing for instance the continuity of pressure and ow rate is problematic, since the different wall modeling in the two subdomains makes the coupled problem ill conditioned and affects the numerical results. We overcome these difculties by resorting to appropriate matching conditions that mimic the presence of the compliance by concentrating it at the interface of the two models. This allows to simulate the overall dyamics still solving a 3D rigid model, getting reliable results with relatively low CPU times.

5.2 Matching conditions in 3D rigid/1D multiscale models

To x the ideas, let us refer to the simple model represented in Fig. 5.1. We assume that a cylindrical pipe has been split at section into two halves. The left one is described in terms of the 1D Euler equations (2.1), while the right hand side is represented by the incompressible Navier-Stokes equations (3.9). Coupling the two models requires appropriate matching conditions. In the case of a rigid 3D model, it is reasonable to prescribe the continuity of pressure and ow rate P1 D = 1 || p3D d,

Q1D =

u3D nd,

(5.1)

where n is the outward normal unit vector on , we added the indexes 1D and 3D for the sake of clarity and denote by || the area of the interface . The negative sign in the second of (5.1) stems from the fact that both Q1D and u3D n are directed outward the 1D and 3D domains respectively. In the sequel, for easiness of notation, we set Q3D =

u3D nd ,

P3D =

1 ||

p3D d .

Other conditions can be considered as well, prescribing the continuity of the total pressure, of the normal stresses or of the characteristic variables (see [112]).

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5 A geometrical multiscale model of the cerebral circulation

5.2.1 Numerical algorithm

When solving multiscale problems numerically it is natural to split the scheme into the iterative sequence of dimensionally homogeneous problems, which we indicate as 1D and 3D, for instance by means of the following algorithm. We assume that standard (Dirichlet or Neumann) conditions are prescribed at the boundaries of the overall 1D/3D model. Moreover, we carry out an appropriate space and time discretization of the problems. In particular, apexes n and n + 1 refer to the approximation of the solution at time steps tn and tn+1 , respectively. Index k will refer to the inner iterations performed at a xed time step, for the fulllment of the matching conditions. For n = 0, 1, . . . we perform the following steps. 1) Inizialization. Set k = 0,
+1 n un 3D,0 = u3D , n+1 n P1 D,0 = P1D , +1 n pn 3D,0 = p3D ,

and
+1 n Qn 1D,0 = Q1D .

n+1 n+1 1 A1 D,0 = (P1D,0 ) ,

2) Loop on k . 2.1) Solve the 1D model with the boundary condition on given by
n+1 n+1 n+1 P1 D,k+1 = P3D,k + (1 )P1D,k ,

(5.2)

where is a relaxation parameter to be set for improving the convergence rate. Solving the 1D model, pressure conditions are recasted in terms of area, thanks to the wall law +1 n+1 1 An 1D,k+1 = (P1D,k+1 ) (see Sec. 2.2). 2.2) Solve the 3D problem with the boundary conditions on
+1 n+1 Qn 3D,k+1 = Q1D,k+1

(5.3)

Set k = k + 1. 3) Test. Different convergence tests can be pursued. A possibility is to check the continuity at the interface, namely terminate the iterations when
n+1 n+1 P1 D,k+1 P3D,k+1

being a user-dened tolerance. Swapping the role of the matching conditions in the set up of the boundary conditions for the iterative scheme, (5.2), (5.3) can be replaced by
+1 n+1 n+1 Qn 1D,k+1 = Q3D,k + (1 )Q1D,k , n+1 n+1 P3 D,k+1 = P1D,k+1 .

(5.4)

The different space dependence of 1D and 3D models leads to unmatched or defective conditions (step 2 of the loop) and in particular (5.3) (or the second condition (5.4)) do not prescribe sufcient conditions for the closure of the Navier-Stokes problem. The latter needs to be solved in the framework of the so-called defective boundary problems, the data being available at the boundary not enough to guarantee the uniqueness of

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5 A geometrical multiscale model of the cerebral circulation

1D Model

Q1D P1D P

R1

R2 C

Q3D =

u3D n 3D Model

P3D =

p3D

Figure 5.2: Representation of a multiscale 3D/1D model with a 0D element representing the compliance of the 3D model at the interface. the solution. This topic has been discussed in [112], Chap. 11, where different mathematically sound techniques for the solution of defective problems are presented. The specic method for solving the 3D problem affects the accuracy of the Navier-Stokes solution and is not relevant for the purpose of the present work, so we do not dwell upon it. Any reasonable technique can be used in the context of our multiscale modeling. The iterative approach given by the previous three steps suffers from numerical problems induced by the different description of the wall mechanics in the two halves of the pipe, which produces some spurious reections at the interface and possible numerical instabilities. One could avoid this kind of problems by resorting to a compliant 3D model. As we have pointed out, this increases the computational costs strongly. More precisely, implicit coupled uid-structure iterative schemes at each time step require to solve the Navier-Stokes and the structural problems several times. In explicit coupled uid-structure iterative schemes, stability concerns typically require to take small time steps. In the next subsection, we present a different strategy based on the set up of an appropriate set of interface conditions.

5.2.2 Matching conditions including compliance

Suppose that we give a simplied representation of the compliance of the 3D vessel in the multiscale model, by gathering its effect at the interface using a special lumped parameter model. Referring for instance to Fig. 5.2, we introduce a RCL network at the interface with the role of representing the effects of the compliance of the artery in the 3D model. In this way, we still use a 3D rigid model, which however behaves like a compliant one with respect to the system dynamics. By denoting with P the pressure associated with the capacitance C , the governing equations read dQ3D P1D R1 Q1D = P = P3D L R2 Q3D dt (5.5) dP C = Q1D + Q3D . dt Taking the derivative of the rst equation and using the third, we can eliminate P and nally obtain the new conditions in the iterative scheme, by replacing (5.2), (5.3) in the

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5 A geometrical multiscale model of the cerebral circulation

Z1D = P1D R1 Q1D 1D Model Z3D = P3D R2 Q3D Q1D P1 D P C R1 L R2 Q3D P3 D 3D Model

Figure 5.3: Alternative representation of the coupled problem: now the unknowns are z 1 D , z 3 D , P1 D , P3 D . algorithm with P1D,k+1 = P3D,k L1 R1 CL dQ3D,k dP3D,k R2 Q3D,k + R1 C1 dt dt + (1 )P1D,k (5.6)

dQ3D,k d2 Q3D,k R1 CR2 R1 Q3D,k 2 dt dt

Q3D,k+1 = Q1D,k+1 + C

dP1D,k+1 dQ1D,k+1 R1 C dt dt

These conditions (hereafter denoted by LP (Lumped Parameter) conditions) involve time derivatives of the matching quantities to be discretized with an appropriate nite difference scheme with the same accuracy of the time advancing methods used for the time discretization of the Navier-Stokes and Euler equations. Remark As was to be expected, for C = 0, R1 = R2 = 0 and L = 0 we recover the coupling given by conditions (5.2), (5.3). This corresponds physically to the case of a rigid portion of artery in a network of compliant vessels, as it is the case of a stented or prosthetic segment (see [45]). Alternative formulation Equations (5.6) involve the second order time derivatives of the interface variables, whose accurate numerical approximation is in general not trivial. This motivates the derivation of an alternative formulation involving only rst order time derivatives. Lets dene z1D (P1D , Q1D ) = P1D R1 Q1D , then system (5.5) becomes L dQ3D = z3 D z1 D dt (5.7) z3D (P3D , Q3D ) = P3D R2 Q3D ,

dz1D C = Q1D + Q3D . dt

81

5 A geometrical multiscale model of the cerebral circulation We remark that the ow rate Q1D at interface is linked to the pressure P1D (consequently to z1D ) through the Euler equations (2.1). We can express this relation in the following form: Q1D = M1D (z1D ) , (5.8) where M1D stands for the set of equations of the 1D model. Similarly, the following relation holds between Q3D and z3D on : z3D = M3D (Q3D ) , (5.9)

where we indicate the 3D Navier-Stokes problem by M3D . Equations (5.7), (5.8) and (5.9) form a non linear system in the four unknowns z1D , z3D , Q1D , Q3D , that can be rewritten in vectorial form as follows: LP (X) = 0 , with z1 D z3 D X= Q1D , Q3D dz 1D (Q1D + Q3D ) C dt z3D M3D (Q3D ) LP (X) = . Q M (z ) 1D 1D 1D dQ3D L (z3D z1D ) dt

Its time discretization can be retrieved for instance by means of a rst order implicit Euler method: LP t (Xn+1 ) = 0 , (5.10) with n+1 n+1 n+1 n C z1 D z1D t Q1D + Q3D n+1 n+1 z3 D M3D (Q3D ) n+1 LP t (X )= +1 n+1 Qn 1D M1D (z1D ) +1 n+1 n+1 n L Qn 3D Q3D t z3D z1D

and with obvious meaning of the symbol Xn+1 . Now the iterative algorithm for the solution of the coupled problem can be formu+1 lated as a Newton scheme applied to system (5.10). Given the approximation Xn of k n+1 n +1 the solution at time t , computed at iteration k , we can recover Xk+1 by solving the +1 +1 n+1 following linear system in the increment Xn = Xn : k k+1 Xk JLP t
+1 +1 Xn = LP (Xn ), k k

(5.11)

+1 Xn k

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5 A geometrical multiscale model of the cerebral circulation JLP t being the Jacobian matrix of function LP t : C 0 t t 0 1 0 M3D n+1 Q3D,k . = JLP t +1 Xn 0 1 0 M k 1D n+1 z1D,k t t 0 L It is quite easy to explicitly compute the inverse of matrix (5.12), which reads:
1 JLP t

(5.12)

=
+1 Xn k

1 det JLP t
+1 Xn k

L + M3D,k t

t2

t(L + M3D,k t)

` M3D,k t t2 + L(C M1D,k t) M3D,k t2 M3D,k tM1D,k C , 2 2 M1D,k (L + M3D,k t) M1D,k t C (L + M3D,k t) + t M1D,k t
t C t M1D,k t2 t2 C M1D,k t

det JLP t

+1 Xn k

= CL + C M3D,k LM1D,k t + (1 M1D,k M3D,k )t2 , and M3D,k = M3D .

where it is understood that M1D,k = M1D Newton iteration (5.11) nally reads:

n+1 z1 D,k

+1 Qn 3D,k

+1 n+1 1 Xn JLP k+1 = Xk t

+1 Xn k

+1 LP (Xn ), k

(5.13)

so that each interface variable at iteration k + 1 is expressed as linear combination of the variables at iteration k . A simplied expression for M1D and M3D can be obtained by considering a 0D representation of the 3D and 1D models, based again on RCL networks. We will describe the 1D model by means of an electric L-network (shown in Fig. 5.4(a)), whose dynamics is represented by the state variables Q1D and P1D,up , while Q1D,up and z1D are prescribed as boundary conditions (we recall that P1D = Z1D + R1 Q1D ): C1D L1D dP1D,up + Q1D = Q1D,up dt (5.14a)

dQ1D + (R1D + R1 ) Q1D = P1D,up z1D , (5.14b) dt where subscript up indicates that the subscripted quantity is evaluated in correspondence of the upstream section of the 1D model.

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5 A geometrical multiscale model of the cerebral circulation

Q1D,up P1D,up C1D L1D R1D Q1D P1D

Q3D P3D

L3D

R3D

Q3D P3D,down

(a) An electric L-network representing the 1D model. The model dynamics is represented by the state variables P1D,up and Q1D .

(b) An electric RL network representing the 3D model. The model dynamics is represented by the state variable Q3D .

Figure 5.4: The electric analogy can be exploited to represent the 1D and 3D models with their 0D counterpart. If we consider the second equation in system (5.14) and approximate the time deriva+1 n+1 tives with an implicit Euler scheme, we can express Qn 1D as a function of z1D (given n+1 P1 D,up ):
+1 Qn 1D =

L1D + R 1D + R 1 t

L1D n n+1 n+1 Q + P1 D,up z1D t 1D

n+1 M(z1 D )

(5.15) ,

and nally we can retrieve an approximation for M1D (z1D ): M1D (z1D )
n+1 z1 D

d M1D n+1 (z ) dz1D 1D 1 . L1D + R 1D + R 1 t

(5.16)

Since we are considering rigid wall 3D models, a simpler 0D network can be used to represent the 3D model (see Fig. 5.4(b)): the electric analogy does not feature a compliance element. Thus, we can resort to an RL network, describing the dynamics of Q3D given z3D and the downstream pressure P3D,down (we recall that P3D = Z3D + R2 Q3D ): L3D dQ3D + (R2 + R3D )Q3D = P3D,down z3D . dt

We discretize in time the previous by means of an implicit Euler scheme, obtaining:

n+1 n+1 z3 D = P3D,down

L3D +1 + R2 + R3D Qn 3D + t

L3D n Q t 3D

+1 M3D (Qn 3D ) ,

and nally we nd M3D (Q3D )

+1 Qn 3D

d M3D n+1 (Q3D ) dQ3D

L3D + R 2 + R 3D t

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5 A geometrical multiscale model of the cerebral circulation name resistance inertia compliance electric analogy R L (inductance) C (capacitance) expression 8l A2 0 l A0
3l 3R0 2Eh0

Table 5.1: Parameter estimation for the electric analog model of a cylindrical vessel (after [112]).

5.2.3 Parameters estimation

The interface lumped parameter model of Fig. 5.2 provides a physical representation to our matching conditions. A major issue in this approach is the tuning of the paramaters featuring the LP model. In particular, we started from a classical RCL network, advocated for representing the capillary circulation (see [2, 134]). We remind that, following classical arguments for the derivation of lumped parameter models (see e.g. [112] Chap. 10, based on a proper average of the Navier-Stokes equations) for a cylindrical vessel with length l, area A0 , with a linear elastic wall with 3/2 A l thickness h0 and Young modulus E , the compliance may be estimated to be C 0 . Eh0 l The resistance induced to the ow by the blood viscosity can be expressed as R 2 , A0 while the inertial term in the momentum equation gives rise in the 0D model to an inl , being the blood density (see Tab. 5.1). ductance L A0 In the case at hand, depicted in Fig. 5.2, we consider a 10 cm long tube, each half measuring l = 5 cm, and we set A0 = 0.785 cm2 . The elastic modulus of the arterial wall is taken E = 106 dyn/cm2 , and the wall thickness is h0 = 0.05 mm. Blood is assumed to be a Newtonian uid of viscosity = 0.035 poise. The electric analogy can be exploited to dene a 0D model of the coupled problem, as depicted in Tab. 5.2. In particular, the lumped parameter representation of 1D and 3D models is useful for the set up of the solution strategy (5.13). The missing capacity element in the 3D model electric analogy is assigned to the interface RCL network. Physiological values of this parameter are of the order of 105 cm5 /dyn. In our computation we set C = 5.89105 cm5 /dyn. The other interface parameters have been properly adjusted in order to reduce spurious effects at the 1D/3D interfaces. More precisely, resistance R1 has been introduced in [3] and, following the proposal of that paper, it is dynamically selected so that an incoming wave from the 1D model is propagated without any reection. For R2 and L, in this paper we have adopted an empirical trial and error approach, so that after some numerical experiments we put R2 = 1 dyn s cm5 and L = 0.01 g cm4 . For more complex models,

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5 A geometrical multiscale model of the cerebral circulation Parameters in the coupled model
L1D R1D R1 L R2 L3D R3D

C1D

R 1D

1D model = 7.1301 dyn s/cm5

L1D = 6.3662 g cm4 C1D = 5.89105 cm5 /dyn

LP interface R1 = (*) R2 = 1 dyn s/cm5 L = 102 g cm4 C1D = 5.89105 cm5 /dyn

R 3D

3D model = 7.1301 dyn s/cm5

L3D = 6.3662 g cm4 -

Table 5.2: A 0D model of the coupled problem depicted in Fig. 5.2. The numerical value for each parameter is reported. (*) R1D is dynamically tuned to a value ensuring the wave propagation from 1D model without spurious reections [3].

these parameters should be adapted accordingly.

5.2.4 Results
The impact of the LP conditions is illustrated in Fig. 5.5 and 5.6. More precisely, in Fig. 5.5 we illustrate results obtained for the model of Fig. 5.2 when a sinusoidal waveform for the ow rate is prescribed at the inlet. We compare the values in time of the ow rate and the area (as function of the pressure) at the interface, denoted by Q1D and A(P1D ) in Fig. 5.2, obtained with a standard multiscale 1D/3D model, using the proposed approach and nally those obtained with a complete 1D model. In Fig. 5.6 we present similar comparisons for the case when a step waveform is prescribed at the inlet of the domain. The impact of interface conditions is evident. In the case based on classical matching, the solution is dramatically affected by reections induced by the different description of the wall mechanics in the 1D and 3D model. These reections change completely the prole of the solution. Observe that the complete reection of the ow rate of Fig. 5.6 can be justied by a linear analysis of the reection coefcient considered e.g. in [89]. For a rigid downstream pipe, this coefcient corresponds to total reection. On the contrary, matching conditions based on the RCL model are able to obtain a behavior similar to that of the complete 1D model, even if we are using a rigid 3D model. The same conclusions hold for the area: the RCL-based conditions allow us to nd a solution signicantly close to that of the complete 1D model. As pointed out, a proper tuning of the parameters is crucial to nd the best RCL model.

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5 A geometrical multiscale model of the cerebral circulation

0.15 1D 1D/3D C=0 1D/3D C 0

0.7858 0.7857 0.7856 1D 1D/3D C=0 1D/3D C 0

0.1

0.05 0.7855
Q1D
A(P )

1D

0.7854 0.7853

0.05 0.7852 0.1 0.7851 0.785 0

0.05

0.1

0.15 time

0.2

0.25

0.05

0.1

0.15 time

0.2

0.25

Figure 5.5: Comparison of dynamics of ow rate (left) and area (right) at x = 5cm of a compliant pipe simulated with a fully 1D model (thick dashed line), a multiscale 1D/3D model with direct coupling (C = 0, solid line) and with the matching conditions obtained by the lumped parameter models (C = 0, thin dashed line). The input waveform of the ow rate at the tube inlet is a sine with amplitude 0.1. (time in [s], volumetric ow rate in [cm3 /s], area in [cm2 ])

0.2 0.15 0.1

0.7858 0.7858 0.7857 0.7857 fully 1D 1D/3D C=0 1D/3D C 0

0.05 0 0.05 0.1 0.15 0.2 0 1D 1D/3D C=0 1D/3D C 0

A(P1D) Q1D

0.7856 0.7856 0.7855 0.7855 0.7854 0.7854 0.15 time 0.2 0.25 0.3 0.7853 0 0.05 0.1 0.15 time 0.2 0.25 0.3

0.5

0.1

Figure 5.6: Comparison of dynamics of ow rate (left) and area (right) at x = 5cm of a compliant pipe simulated with a fully 1D model (thick dashed line), a multiscale 1D/3D model with direct coupling (C = 0, solid line) and with the matching conditions obtained by the lumped parameter models (C = 0, thin dashed line). The input waveform of the ow rate at the tube inlet is a step function with amplitude 0.1 (time in [s], volumetric ow rate in [cm3 /s], area in [cm2 ].)

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5 A geometrical multiscale model of the cerebral circulation

Q1D,l R1 R2

Q3D,l L1

Q3D,r R3 R4 C2

Q1D,r L2 Q1D,end

1D
P1D,l

C1

3D
P3D,l P3D,r

1D
P1D,r

Figure 5.7: Representation of a multiscale model with two 0D buffer elements at the interface.

5.3 A 1D-3D-1D coupling

Let us consider now the case represented in Fig. 5.7, where we show a sequence of 1D3D-1D model with appropriate LP conditions. From the numerical point of view on the left interface we still resort to the iterative scheme with conditions (5.6). On the right interface, we adopt a similar iterative strategy where we prescribe a pressure condition to the 3D problem and ow rate conditions to the 1D Euler system downstream. More precisely, equations corresponding to the downstream interface read dQ1D R4 Q1D P3D R3 Q3D = P1D L2 dt C2 dP3D R3 C2 dQ3D = Q1D + Q3D dt dt Consequently, the coupling conditions used in the iterative scheme are Q1D,k+1 = Q3D,k + C2 dP3D,k R3 C2 dQ3D,k + (1 )Q1D,k dt dt dQ1D,k+1 (5.17) P3D,k+1 = P1D,k+1 L2 R4 Q1D,k+1 + dt 2 R3 C2 dP1D,k+1 R3 C2 L2 d Q1D,k+1 R3 CR4 dQ1D,k+1 R3 Q1D,k+1 dt dt2 dt Alternative formulation We can reformulate the interface problem (5.17) in form (5.13), by setting n+1 n+1 n+1 n C z3D z3D t Q1D + Q3D n +1 n +1 n +1 n L Q Q1D t z1D z3D 1 D LP t (Xn+1 ) = n+1 1 n+1 z1D M1D (Q1D ) +1 1 n+1 Qn M ( z ) 3D 3D 3D

88

5 A geometrical multiscale model of the cerebral circulation where again Xn+1 is dened as
n+1 z1 D z n+1 3 D , = n+1 Q1D +1 Qn 3D

Xn+1

and
1 JLP t

=
+1 Xn k

1 det JLP t
+1 Xn k

1 t M 1D,k 1 L t M 1D,k

1 1 M C t M 1D,k 3D,k t 1 C t M 3D,k 1 M t 3D,k

1 CL + t t L M 3D,k t2 1 t C M t 3D,k 1 M t2 3D,k

1 M t2 1D,k 1 t L t M1D,k
2

t 1 1 M L t M 3D,k 1D,k

t 1 CL + t t M C t 1D,k

det JLP t

+1 Xn k

1 = t2 1 + M 1D,k

1 M 3D,k

1 t C M 1D,k

1 + L M 3D,k

+ CL .

5.3.1 Results
Numerical results are reported in Fig. 5.8. Again, we illustrate the comparison of the solutions obtained with a 1D model, and the multiscale models corresponding to Fig. 5.7, where all the lumped parameters are null (classical conditions) and when they are activated. The inlet waveform is sinusoidal. In the rst picture we present the ow rate at the rst interface (denominated Q1D,l in Fig. 5.7), in the second picture the ow rate Q1D,r at the second interface and nally the ow rate Q1D,end at the outlet of the right pipe. Again, when classical matching conditions are used (corresponding to null values of the parameters) the superposition of the components induced by reections associated to the different wall models are evident. This changes the shape of the propagating wave and affects both the amplitude and the phase at the inlet and at the outlet of the 3D model. Amplitude dissipation in the forward component of the wave is partially compensated by the superposition of the spurious reections. In the case of LP conditions, the shape of the wave is only partially affected. Dispersion errors are remarkably small, whilst dissipation effects are present. More precisely, the dispersion error, evaluated as the difference in the occurrence of the peaks in the 1D and the multiscale LP models, are 20%, 6% and 5% in the three pictures of Fig. 5.8 respectively, while dissipation, evaluated as the difference of the peaks, are 25%, 32% and 32% respectively. The impact of nite difference schemes in the numerical implementation of matching conditions is probably the main responsible of these effects. A more accurate analysis of this aspect is one of the possible future

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5 A geometrical multiscale model of the cerebral circulation

0.15

0.1 0.08

0.1 0.06 0.05 0.04 0.02

Q1D,r

0
Q1D,l

0 0.02 0.04

0.05

0.1 1D 1D/3D C=0 1D/3D C 0 0.05 0.1 time 0.15 0.2 0.25

0.06 0.08 0.1 0 0.05 0.1 time 0.15

0.15

1D 1D/3D C=0 1D/3D C 0

0.2 0

0.2

0.25

(a)
0.1

(b)

0.05
Q1D,end

0 1D 1D/3D C=0 1D/3D C 0

0.05

0.1 0

0.05

0.1

0.15

0.2

0.25 time

0.3

0.35

0.4

0.45

0.5

(c)

Figure 5.8: Comparison of ow rates computed by a 1D model (dash-dot line), a multiscale 1D/3D/1D model with classical matching conditions (dashed line) and with lumped parameter matching conditions (solid line) in correspondence of the rst interface (a), the second (b) and the outlet of the domain (c). (time in [s], volumetric ow rate in [cm3 /s])

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5 A geometrical multiscale model of the cerebral circulation

Middle Cerebral Artery

Basilar Artery

Vertebral Artery Internal Carotid Artery External Carotid Artery

Aorta

Figure 5.9: Left: Anatomical representation of the cerebral vasculature, including the circle of Willis (after [12]). Right: Multiscale representation of the cerebral vasculature: a 3D representation of one of the carotid arteries is embedded in a 1D network of Euler problems developments of this work. Matching conditions guarantee in any case a signicant reduction of spurious reections.

5.4 The 3D carotid model and the multiscale coupling

The proposed model is based on the set-up presented by Alastruey et al. [3] for the description of the cerebral circulation (see Sec. 2.5.4). The multiscale representation is depicted in Fig. 5.9, on the right. Left Internal Carotid geometry adopted is based on the realistic glass model obtained by Liepsch, see [106]. The Navier-Stokes equations in the 3D model have been solved with the code LifeV - see www.lifev.org - based on a P 1P 1 nite element solver stabilized by means of an interior penalty approach. At the interfaces between the 3D and 1D models we prescribe conditions (5.6) at the upstream interface and conditions (5.17) at the downstream interfaces. In Fig. 5.10 and Fig. 5.11 we present the results, in comparison with the ones of a fully 1D model. Results underline that the RCL based conditions can actually obtain good solutions, in particular at the inlet. At the outlets of the carotid arteries the solution is strongly dissipated in the ow rate, while the fully 1D and the LP models are in good agreement for what concerns the phase of both ow rate and area, and the amplitude of the latter. Impact of the time discretisation of the matching conditions and the selection of the parameters on the dissipation error is under investigation. Fig. 5.12 illustrates velocity and pressure elds in the 3D rigid model. On the left we present a detail of the 3D velocity eld, on the right a multiscale perspective coupling local and global dynamics.

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5 A geometrical multiscale model of the cerebral circulation

Flow rate at last node of CCA 14 12 fully 1D lumped parameter interface 0.46 0.44

Area at last node of CCA

velocity flux (cm3/s)

10

area (cm2)

8 6 4 2 0 2 0 0.25 0.5 time (s) 0.75 1

0.42

0.4 0.38 fully 1D lumped parameter interface 0.25 0.5 time (s) 0.75 1

0.36 0

Figure 5.10: Comparison of the results obtained with a fully 1D model (solid line) and the 3D rigid with RCL conditions at the inlet of Common Carotid Artery (dashed line). Left: ow rate, Right: area. (time in [s], volumetric ow rate in [cm3 /s],area in [cm2 ]).

Flow rate at first node of ICA 7 6 fully 1D lumped parameter interface 0.215

Area at first node of ICA

velocity flux (cm3/s)

0.21

3 2 1 0 1 0 0.25 0.5 time (s) 0.75 1

area (cm2)

0.205

0.2 fully 1D lumped parameter interface 0.25 0.5 time (s) 0.75 1

0.195 0

Flow rate at first node of ECA 7 6 fully 1D lumped parameter interface 0.17

Area at first node of ECA

velocity flux (cm3/s)

0.165

3 2 1 0 1 0 0.25 0.5 time (s) 0.75 1

area (cm2)

0.16

0.155 fully 1D lumped parameter interface 0.25 0.5 time (s) 0.75 1

0.15 0

Figure 5.11: Comparison of the results obtained with the fully 1D model (solid line) and the 3D rigid with RCL conditions in the branches (dashed line). Top: Left: ow rate in the Internal Carotid Artery (ICA), Right: area in the ICA. Bottom: Left: ow rate in the External Carotid Artery (ECA), Right: area in the ECA. (time in [s], volumetric ow rate in [cm3 /s], area in [cm2 ]).

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5 A geometrical multiscale model of the cerebral circulation

Figure 5.12: Left: Representation of the 3D solution (velocity and pressure). Right: Coupling of 3D and 1D computations.

5.4.1 Remarks and perspectives

For simple multiscale models, where the parameter quantication for the matching conditions is straightforwardly suggested by the mathematical derivation of the model, numerical results are really promising, showing that the multiscale 3D/0D/1D model can both capture the correct wave propagation (in comparison with a fully 1D model) and compute the local 3D ow. In more complex situations, like the circle of Willis in the cerebral vasculature, when a direct physiological quantication of the parameters is missing, results are only partially good. More precisely, at the inlet of the 3D model results still compare correctly with a fully 1D model, while downstream with respect to the 3D model dissipation effects in the ow rate are dominant. A mathematically sound ne tuning of the parameters is required. This goal can be pursued by a systematic sensitivity analysis or by extensive comparisons with standalone fully 3D models (see e.g. [4, 80]). This subject will be investigated in future works together with a validation of this approach in more complex networks. We nally point out that this approach can be extended to hydraulic networks featuring compliant pipes, beyond the specic medical applications considered here.

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6 Computational tools
The need for effective tools for the numerical solution of differential problems motivates the development of efcient and application-specic algorithms and techniques. In this Chapter we present the LifeV software project (Sec. 6.2) and we mention its many years application to the study of blood ow problems. As an example of its features, we discuss here in particular the implementation of the data structures which allow the representation of the cardiovascular system as a network of vessels represented by 1D models (Sec. 6.3).

6.1 An introductory note on C++

C++ is a statically-typed general-purpose language relying on classes and virtual functions to support object-oriented programming, templates to support generic programming, and providing low-level facilities to support detailed systems programming. Bjarne Stroustrup [135] Although C++ supports different programming paradigms, as pointed out by the words of its very creator, it is usually thought as an object-oriented language. Indeed, this aspect is particularly interesting for software applications dealing with the modeling of physical systems, as we will briey discuss in this introduction. On the other hand, its proximity with C language has not only an historical reason, but also a philosophical motivation. It enhances the language with features allowing the programmer to control the software behaviour at a very low level (near to the machine language). Versatility is perhaps the key to C++ success in the software industry. The object-orented programming paradigm is based on abstract data types, known in C++ as classes. The problem to be solved is modeled by a set of objects, storing privately all the data and providing the algorithms to operate on the data. Objects are considered as independent but can interact by exchanging messages. Moreover, hierarchies of objects can be dened through the concept of inheritance: generic classes can provide the shared behaviour to different specialized classes, which add custom data and algorithms for the fulllment of specic tasks. A typical feature of C++ language allows functions and classes to operate with different data types through a unique interface: they are dened as (function and class) templates. Important examples of the use of templates are the classes provided by the

According to www.langpop.com C++ is the fourth more popular programming language, as of January 2009, based on several indicators including an estimate of the number of job offers requiring C++ knowledge.

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6 Computational tools C++ Standard Template Library (STL), enhancing the language with a set of powerful tools, in particular a framework for the denition of containers (such as vector, list, and map) and algorithms using containers. The generic-programming paradigm is indeed well illustrated by STL containers, which represent the abstract concept of a collection of items, with a set of rules to operate on them. The same general denition and the same policies (such as how to access to the data, how to add or delete elements) can apply for instance to vectors of numerical values, or to vectors of classes (even vectors of vectors). Object-oriented and generic-programming paradigms are particularly attractive for the modeling of complex physical systems: the data structures can be designed to mimic the behaviour of different interacting (physical or logical) components and their relationship can be described in a general and exible way. The same code pattern can be effectively adapted to describe different problems with a similar general structure. In particular, this ideas can be applied to the representation of mathematical objects, such as functions or functional spaces, and to the denition of general sets of rules governing their interaction. Several software projects, indeed, propose the implementation of numerical methods for the solution of mathematical problems: an increasing number of them exploit an object-oriented programming paradigm, and they are often written in C++. We want to mention here some important examples, such as the Trilinos project including a huge set of packages for several different applications (a non-exhaustive list comprehends the solution of linear systems and preconditioning problems, with support to parallel computing) and the OpenFOAM toolbox for the solution of partial differential equations.

6.2 LifeV: a C++ nite element library

LifeV is a software project born from the joint collaboration of three institutions: cole Polytechnique Fdrale de Lausanne (CMCS) in Switzerland, Politecnico di Milano (MOX) in Italy and INRIA (REO) in France. The Department of Mathematics and Computer Science of Emory University in Georgia (USA) started a collaboration since 2008. LifeV consists of the implementation in C++ language of algorithms and data structures for the numerical solution of partial differential equations. More precisely, LifeV provides an abstract framework for the implementation of Galerkin nite element methods, exploiting the object-oriented paradigm supported by the programming language. The development and maintainance of the core of the library are motivated by the research interests of the developers, mostly active in the numerical analysis and computer science elds. Some applications of the library include the the design and testing of efcient numerical techniques for uid-structure interaction problems [42], algorithms for the solution of the Navier-Stokes equations [18, 54], numerical techniques for the coupling of different models in a multiscale perspective [86,95], preconditioning strate

http://trilinos.sandia.gov/ http://www.opencfd.co.uk/openfoam/ www.lifev.org

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6 Computational tools gies for the Bidomain problem (arising in the modeling of the electrical activity of the heart) [55]. Moreover, software based on LifeV has been extensively used in research projects focused on the modeling of blood ow problems, such as the drug release from implantable stents [142], the design of medical procedures in cardiology [27], and the study of cerebral hemodynamics (the Aneurisk project, which motivated this work see Chap. 4).

6.2.1 Code features

The code is hosted on a CVS server, which collects and organizes the contributions of the developers from the four different institutions. Stable releases of the code are published on the web portal www.lifev.org, which also contains the code documentation, and a gallery of applications to different modeling problems. The portability of the library is enhanced by the GNU build system , allowing LifeV to compile on all Unix-like systems (also on Windows systems running Cygwin). Third party required libraries are the standard linear algebra packages BLAS and LAPACK and linear solver packages (such as Aztec, Trilinos, PetSC, UMFPACK). Moreover, LifeV is based on some of the extended C++ functionalities implemented in the Boost libraries, such as smart pointers (helping in effective memory management).

Figure 6.1: LifeV code structure from www.lifev.org A graphical representation of the code organization is presented in Fig. 6.1. The different parts have a hierarchical relationship based on their degree of specialization. More in detail, lifecore contains general components not directly related to scientic computing, such as the denition of the numerical types adopted in the code and a set of assertion macros to help code correctness. lifearray mainly deals with the denition
The Concurrent Versions System (CVS), is a revision control system keeping track of all the work and all the changes in a set of les, managing the concurrent contributions of the developers. also known as Autotools www.boost.org

96

6 Computational tools of array structures used in the code (vector and matrices), while a generic set of algorithms, both inherited from linear solver packages and specically written for LifeV applications, is contained in lifealg. Mesh handling tools (for 1D, 2D or 3D meshes) are implemented in lifemesh. Most part of the data structures designed for the construction of nite element solvers is implemented on the basis of these library components. Classes representing generic nite elements, the denition of the geometrical mapping and the quadrature rules for their characterization are contained in lifefem, together with methods for matrix assembly and boundary conditions management. lifesolver is a collection of several classes, each dealing with the set up and the solution of a specic problem (e. g. the NavierStokes problem or the Darcy problem): these objects take care of the construction of the matrices describing the linear system of equations of the discretized model, and invoke the linear solver for their solution. Methods for the data import and export from and to les are collected in lifelters, in particular enhancing the library with the capabilities of managing different le formats. The testsuite shows examples of software built over the library, and spans the main applications from simple tasks such as mesh import from le and matrix assembly, to more complex problems such as the Navier-Stokes problem on simple geometries and with a small number of unknowns. Finally, we mention that recently the library has been extended with the support for parallel computing, mantaining the same general structure here presented. Preliminary tests show good scalability performances.

6.3 Implementation of networks of 1D models

As discussed in Chap. 2, one-dimensional models offer an effective representation of the wave propagation phenomena in large parts of the circulatory system. This motivates to the design of a robust and exible software tool, able to manage networks of 1D models of general topology in a simple and effective way. A network of one-dimensional models is here regarded as a graph, in which edges stand for the models themselves while vertices represent the interfaces between the models. As shown in Fig. 6.2, an interface can correspond to the center of a branching. Note that when studying vascular networks, it is natural to identify inow and outow sections, describing a reference blood ow path: this induces an orientation (and therefore a reference system) in the graph, and is useful in order to study some aspects of the uid dynamics in the network (in particular energy balance at the interfaces, see Sec. 6.3.2). In this implementation of 1D model network we resorted to the data structures of boost::graph library (BGL), providing a generic interface for traversing graphs. Specic functionalities are added to the graph by associating LifeV 1D model objects with its edges. Moreover, to keep the network independent on the specic implementation of the 1D model, OneDNet has been built as a template class (with the 1D model class as template parameter).

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6 Computational tools
inow section

1D model

interface

1D model outow section outow section 1D model

1D model

inow section

Figure 6.2: 1D model networks can be seen as oriented graphs

template < class SOLVER1D > class OneDNet { public : typedef SOLVER1D SolverType ; / / ! Boost shared p o i n t e r t o 1D s o l v e r c l a s s typedef typename boost : : s h a r e d _ p t r < SolverType > OneDSolverPtr ; };

We expect to work with sparse graphs, in which the number of edges is of the same order of magnitude as the number of vertices: for this case BGL implements an adjacency-list representation . We will adopt this as the underlying data structure for OneDNet, providing it with a private member _M_Network of class Network.
template < class SOLVER1D > class OneDNet { private : / / ! boost : : a d j a c e n c y _ l i s t v a r i a b l e Network _M_network ; };

Network is dened as the template class boost::adjacency_list which stores a list of vertices and a list of out-edges for each vertex, that are edges oriented outwards with respect to a vertex. The rst template parameter (boost:: listS ) determines what kind

http://www.boost.org/libs/graph/doc/index.html

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6 Computational tools of container is used to store the out-edges list: this affects time complexity of adding/removing edge operations. Admitted choices include some of the container objects, as dened in the Standard Template Library (STL): in particular, an STL list turns out to be a better choice compared to an STL vector, since the latter occasionally needs reallocation in adding elements operations [128]. The second template parameter (boost::vecS) concerns vertices list: in this case vector seems to be the good choice since we do not expect the need to add or remove vertices after the initialization of the graph; moreover STL vector has a low per vertex space overhead compared to STL list , which needs to store three extra pointers per vertex [128]. The third template parameter boost:: bidirectionalS selects a directed graph, which provides functions to recover in-edges and out-edges associated to each vertex. The fourth and fth template parameters (OneDVesselsInterface and OneDVessel) are userdened classes containing properties to be attached respectively to vertices and edges. This features of the boost::adjacency_list class are referred to as bundled properties, and allow an easy and exible denition of the attributes of the graph, as we will see later on.
template < class SOLVER1D > class OneDNet { public : typedef boost : : a d j a c e n c y _ l i s t < boost : : l i s t S , boost : : vecS , boost : : b i d i r e c t i o n a l S , OneDVesselsInterface , OneDVessel > Network ; };

In particular, we want each edge to be identied by a numerical index and associated to an object representing a 1D model as implemented in LifeV. Each vertex is instead associated to two numbers (a numerical index and a type) and to a boolean value (internal) whose precise meaning will be explained in Sec. 6.3.1.
template < class SOLVER1D > class OneDNet { public : s t r u c t OneDVesselsInterface { i n t index ; / * ! < numerical l a b e l * / bool i n t e r n a l ; / * ! < i s i t an i n t e r n a l i n t e r f a c e ? * / i n t type ; / * ! < the type of the i n t e r f a c e * / }; s t r u c t OneDVessel { i n t index ; / * ! < numerical l a b e l * / OneDSolverPtr o n e d s o l v e r ; / * ! < p o i n t e r t o 1D s o l v e r c l a s s * / };

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};

The access to edges and vertices of an adjacency_list is performed simply by subscripting the graph with the proper descriptor. Therefore the bundled properties of edges and vertices are easily set and retrieved, as is shown in the example here below:
/ / ! Descriptor type f o r the l i s t of v e r t i c e s typedef typename boost : : g r a p h _ t r a i t s < Network > : : v e r t e x _ d e s c r i p t o r Vertex_Descr ; Vertex_Descr vd ; UInt i ( 0 ) ; / / s e t i n d e x i f o r v e r t e x vd _M_network [ vd ] . i n d e x = i ; / / p r i n t o u t v e r t e x vd s i n d e x s t d : : c o u t << _M_network [ vd ] . i n d e x << s t d : : e n d l ; / / ! D e s c r i p t o r t y p e f o r t h e l i s t o f edges typedef typename boost : : g r a p h _ t r a i t s < Network > : : e d g e _ d e s c r i p t o r Edge_Descr ; Edge_Descr ed ; UInt t ( 0 ) ; / / s e t t y p e t f o r edge ed _M_network [ ed ] . t y p e = t ; / / p r i n t o u t edge ed t y p e s t d : : c o u t << _M_network [ ed ] . t y p e << s t d : : e n d l ;

6.3.1 Building the graph

t1 VII III

t6 II t5 t4 VI

t2

t3

IV

Figure 6.3: A test case: 6 connected tubes. Label ti indicates tube i, while Roman numerals are associated to interfaces

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6 Computational tools Consider the case depicted in Fig. 6.3: its a simple network composed by 6 edges and 7 vertices. Vertex II is internal to the network, meaning that it is connected to more than one edge. Conversely, all the others are terminal vertices. Edges 1, 3, 5 are in-edges with respect to vertex II; edges 2, 4, 5 are out-edges.

1D model

left interface

right interface

Figure 6.4: Left and right interfaces for 1D model. Each oriented edge has intrinsically a local reference system: in this reference system it is possible to unequivocally identify a left and a right interface, as shown in Fig. 6.4. Therefore, the entire Network structure can be built from a list of vertices and a connectivity list whose elements are left-right interface pairs, each one describing an edge. The constructor of the OneDNet class visits the graph and sets the internal bool parameter associated to the vertices, on the basis of the network topology. This information is used to manage the prescription of boundary conditions to the 1D solvers associated to the edges: edges connected to terminal vertices need standard boundary conditions, which are managed by the attached solvers. Edges connected to an internal vertex need instead a set of interface conditions, which are managed by the OneDNet class, as we will discuss later on. The type of an internal vertex is set by the user, and determines how the 1D models interact in the corresponding interface. In other words, according to the interface type, different sets of interface conditions are imposed to the connected models. For the case of blood ow problems, in which networks such as the considered one would represent branching vessels or circulatory anastomosis, reasonable interface conditions would prescribe the conservation of the owing mass and of its kinetic energy. Other possible choices include interface conditions taking into account the energy losses associated to branchings (for example depending on the ow velocity at the interface or on the branching angles of the vessels, see [49]) or the presence of a stenosis or of a valve at the interface between two vessels or two different tracts of the same vessel (which is the case of the venous system, for instance). Visiting the graph In many cases, applying an operation to the network means to recursively apply the same operation to each 1D model in the network. As an example we recall here OneDNet::timeAdvance method:
template < class SOLVER1D > void OneDNet<SOLVER1D> : : timeAdvance ( const Real& t i m e _ v a l ) { / / impose i n t e r f a c e c o n d i t i o n s a t i n t e r n a l v e r t i c e s computeInterfaceTubesValues ( ) ;

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/ / i t e r a t o r s t o v i s i t edge l i s t E d g e _ I t e r e i , ei_end ; f o r ( t i e ( e i , ei_end ) = edges ( _M_network ) ; e i ! = ei_end ; ++ e i ) { / / t e l l me what I am doing Debug ( 6330 ) << " [ OneDNet : : timeAdvance ] 0 Time advancing tube " << _M_network [ * e i ] . i n d e x << " \ n " ; / / c a l l OneDModelSolver method _M_network [ * e i ] . onedsolver >timeAdvance ( t i m e _ v a l ) ; } }

The rst step in this method is the call to computeInterfaceTubesValues function, in order to evaluate the interface conditions in correspondence to internal vertices of the network (see Sec. 6.3.2). Then the edges of the graph are visited through iterators and the timeAdvance method from the attached 1D models is invoked, for the prescription of the boundary conditions at each time step. We remark here that we chose to provide class OneDNet with member functions having the same name and the same parameter list as the corresponding methods in the 1D model class as implemented in LifeV. In this respect, class OneDNet can be regarded as a wrapper of LifeV :: OneDModelSolver class. On the other hand, this can be seen as a precondition on the template parameter SOLVER1D, which needs to share the same public interface as OneDModelSolver in order to work in the network class. One way to achieve this behaviour is by means of inheritance: specialized classes can be dened, providing alternative implementations of 1D models (for instance, exploiting different numerical discretization strategies) and still retaining the same shared public interface.

6.3.2 Interface conditions

As previously mentioned, OneDNet class features the computeInterfaceTubesValues method, visiting the graph vertices and setting up the interface problem, when needed according to vertex type. For the sake of simplicity, we will refer here only to problem (2.25), namely the prescription of the mass conservation and the continuity of the total pressure across the interface. In Listing 6.1, this problem corresponds to vertex type 1. The same approach applies however to different interface problems, for instance involving concentrated energy losses as discussed in Sec. 2.3. Listing 6.1: OneDNet::computeInterfaceTubesValues
template < class SOLVER1D > void OneDNet<SOLVER1D> : : computeInterfaceTubesValues ( ) { / / v e r t e x i t e r a t o r s ( f o r v i s i t i n g t h e graph ) std : : pair < Vertex_Iter , Vertex_Iter > vip ; / / v i s i t vertex l i s t f o r ( v i p = v e r t i c e s ( _M_network ) ; v i p . f i r s t ! = v i p . second ; ++ v i p . f i r s t ) { Debug ( 6330 ) << "0 Computing I n t e r f a c e "

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6 Computational tools
<< _M_network [ * v i p . f i r s t ] . i n d e x << " \ n " ;

/*

I n p r i n c i p l e , i t i s p o s s i b l e t o implement d i f f e r e n t b e h a v i o u r f o r i n t e r f a c e s ( e . g . energy d i s s i p a t i o n due t o b r a n c h i n g angles , v a s c u l a r e v a l v e s e t c ) . ( n o t done y e t )

*/ i f ( _M_network [ * v i p . f i r s t ] . i n t e r n a l ) { / / i n t e r n a l i n t e r f a c e switch ( _M_network [ * v i p . f i r s t ] . t y p e ) { case 0 : /* i n f l o w tube : no " i n t e r f a c e " c o n d i t i o n s ( a c t u a l boundary c o n d i t i o n s i n s t e a d ) */ break ; case 1 : interface_continuity_conditions ( vip . f i r s t ) ; break ; case 9 9 : /* o u t f l o w tube : no " i n t e r f a c e " c o n d i t i o n s ( a c t u a l boundary c o n d i t i o n s i n s t e a d ) */ break ; / / o t h e r cases can be added here ! default : s t d : : c o u t << << << << break ; } / / switch } // if } / / for }

" \ n [ OneDNet : : c o m p u t e I n t e r f a c e V a l u e s ] Unknown t y p e " _M_network [ * v i p . f i r s t ] . t y p e " f o r v e r t e x " << _M_network [ * v i p . f i r s t ] . i n d e x std : : endl ;

Lets consider, for each 1D model in Fig. 6.3, the physical quantities total pressure Pt and mass ow Q: now problem (2.25) reads f =0, having set f = (f (1), . . . , f (6)) and f (1) =
i=1,3,5 Qi

(6.1)

j =2,4,6 Qj )

f (k ) = Pt,k Pt,1 ,

for k = 2, . . . , 6 .

The subscripts in the previous equations indicate that the considered quantity has to be referred to the edge marked by the corresponding numerical label. We remark that f (1) expresses the sum of the mass ows computed by 1D model solvers. In-edges give a positive contribution to the balance equation, while out-edges give a negative contribution. The continuity of mass ow follows from the balance of positive and negative ows. The continuity of total pressure is imposed by taking one edge as a reference and imposing that each one of the others features the same total pressure at the interface

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6 Computational tools node. In this case, for in-edges the interface is located at the right boundary node, while for out-edges its on the left boundary.

in-edge +

out-edge + in-edge

out-edge

Figure 6.5: Edges connected to a vertex have a label and a signum. Method interface_continuity_conditions takes care of setting up system (6.1). In order to do that, two helping structures are built in each vertex. First of all, a map associates a numerical label to 1D solvers associated to both in-edges and out-edges. This label does not necessarily correspond to the edge index, but is rather an ordinal number associated to the edges connected to the considered vertex. A second map is devised to identify the orientation of the edge with respect to the interface: the edge label is associated to a bool ag (true for positive, false for negative orientation). A graphical representation of this approach is presented in Fig. 6.5.
template < class SOLVER1D > void OneDNet<SOLVER1D> : : i n t e r f a c e _ c o n t i n u i t y _ c o n d i t i o n s ( V e r t e x _ I t e r const& v e r t e x ) { / / map t h e edges t o t h e i r n u m e r i c a l l a b e l MapSolver i n t e r f a c e T u b e s ; / / map i d e n t i f y i n g i n edges ( + , t r u e ) and out edges ( , f a l s e ) s t d : : map< i n t , bool > signum ; / / t a k e i n t o account i n t e r f a c e t y p e / / you expect t h i s i n t e r f a c e t o have both i n edges and out edges / / p a i r o f i n edge i t e r a t o r s std : : pair <In_Edge_Iter , In_Edge_Iter > i n _ e d g e _ i t e r _ p a i r ; / / v i s i t t h e l i s t o f i n edges f o r ( i n _ e d g e _ i t e r _ p a i r = in_edges ( * v e r t e x , _M_network ) ; i n _ e d g e _ i t e r _ p a i r . f i r s t ! = i n _ e d g e _ i t e r _ p a i r . second ; ++ i n _ e d g e _ i t e r _ p a i r . f i r s t ) { / / i n s e r t edges i n t o t h e map interfaceTubes . i n s e r t ( MapSolverValueType ( i , _M_network [ * ( i n _ e d g e _ i t e r _ p a i r ) . f i r s t ] . o n e d s o l v e r ) ) ;

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/ / i n edges have " + " signum ( boolean v a l u e t r u e ) signum . i n s e r t ( s t d : : map< i n t , bool > : : v a l u e _ t y p e ( i , t r u e ) ) ; i ++; } / / p a i r o f out edge i t e r a t o r s s t d : : p a i r <Out_Edge_Iter , Out_Edge_Iter > o u t _ e d g e _ i t e r _ p a i r ; / / v i s i t t h e l i s t o f out edges f o r ( o u t _ e d g e _ i t e r _ p a i r = out_edges ( * v e r t e x , _M_network ) ; o u t _ e d g e _ i t e r _ p a i r . f i r s t ! = o u t _ e d g e _ i t e r _ p a i r . second ; ++ o u t _ e d g e _ i t e r _ p a i r . f i r s t ) { / / i n s e r t edges i n t o t h e map interfaceTubes . i n s e r t ( MapSolverValueType ( i , _M_network [ * ( o u t _ e d g e _ i t e r _ p a i r ) . f i r s t ] . o n e d s o l v e r ) ) ; / / i n edges have " " signum ( boolean v a l u e f a l s e ) signum . i n s e r t ( s t d : : map< i n t , bool > : : v a l u e _ t y p e ( i , f a l s e ) ) ; i ++; } }

The non linear problem (6.1) is solved by applying a Newton iterative scheme. The solution at each time step is then obtained as: xk+1 = xk Jf1
xk

f (xk ) ,

Jf1 xk being the jacobian matrix of f while x contains the interface unknowns Ai , Qi , i = 1, . . . , 6. The code invokes the LAPACK routine dgesv, to compute Jf1 xk f through LU decomposition of the jacobian matrix, and then updates the solution at current iteration. Convergence is achieved when mass conservation is ensured by the fulllment of the following request [45]: f (1) < tol tol being a user-dened tolerance.
/ / unknown o f non l i n e a r e q u a t i o n f ( x ) = 0 Vector x ; / / non l i n e a r f u n c t i o n f Vector f ; / / j a c o b i a n o f t h e non l i n e a r f u n c t i o n Matrix jac ; / / t r a n s p o s e o f t h e j a c o b i a n o f t h e non l i n e a r f u n c t i o n Matrix jac_trans ; / / tmp m a t r i x f o r l a p a c k l u i n v e r s i o n boost : : numeric : : u b l a s : : v e c t o r < I n t > i p i v ; / / lapack v a r i a b l e i n t INFO [ 1 ] ; i n t NBRHS [ 1 ] ; / / nb columns o f t h e r h s : = 1 . i n t NBU [ 1 ] ; /* x c o n t a i n s t h e ( unknown ) boundary v a l u e s f o r edges connected to the considered i n t e r f a c e . */ x . resize ( f_size ) ; x . clear ( ) ; /* prepare t h e data s t r u c t u r e s needed f o r s o l v i n g non l i n e a r e q u a t i o n s

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( continuity + compatibility ) */ f . resize ( f_size ) ; f . clear ( ) ; jac . resize ( f_size , f_size ) ; jac . clear ( ) ; jac_trans . resize ( f_size , f_size ) ; jac_trans . clear ( ) ; i p i v . resize ( f_size ) ; i p i v . clear ( ) ; INFO [ 0 ] = 0 ; NBRHS[ 0 ] = 1 ; / / nb columns o f t h e r h s : = 1 . NBU[ 0 ] = f _ s i z e ; i =0; / / newton raphson i t e r a t i o n do { / / f i l l f and i t s j a c o b i a n m a t r i x f _ j a c ( x , f , j a c , i n t e r f a c e T u b e s , signum ) ; / / t r a n s p o s e t o pass t o f o r t r a n s t o r a g e ( l a p a c k ! ) jac_trans = trans ( jac ) ; / / Compute f < ( d f ( x )^{ 1} f ( x ) ) ( l u dcmp ) dgesv_ (NBU, NBRHS, & j a c _ t r a n s ( 0 , 0 ) , NBU , & i p i v ( 0 ) , & f ( 0 ) , NBU, INFO ) ; ASSERT_PRE ( ! INFO [ 0 ] , " Lapack LU r e s o l u t i o n o f y = d f ( x )^{ 1} f ( x ) i s n o t achieved . " ) ; / / x = x d f ( x )^{ 1} f ( x ) x += f ; } / / convergence check while ( ( s t d : : f a b s ( f ( 0 ) ) > 1e 12) && (++ n i t e r < 100) ) ; /* f ( 0 ) c o n t a i n s t h e mass f l o w balance : by m i n i m i z i n g i t s v a l u e we want t o ensure mass c o n s e r v a t i o n . Moreover , we expect a low number o f i t e r a t i o n s , s i n c e t h e i n i t i a l guess i s g i v e n from t h e boundary c o n d i t i o n s a t p r e v i o u s t i m e step , which are l i k e l y t o be a good e s t i m a t i o n o f t h e c u r r e n t s o l u t i o n ( t i m e s t e p i s s m a l l and we expect s o l u t i o n s t o be c o n t i n u o u s i n time ) . */

The f_jac method lls Vector f with the expressions of interface conditions and Matrix jac with the jacobian matrix Jf . For the sake of brevity we omit here the corresponding code, noting that all the computations are straightforward, given the presented data structure.

6.3.3 A simple example

Running a simulation for a network of 1D models is formally the same as running a simulation for a single 1D model, since an object of class OneDNet behaves exactly like an object of class OneDModelSolver, thanks to the wrapping mechanism previously discussed. Consider again the case depicted in Fig. 6.3: the network at hand has only one internal node where we want to impose continuity interface conditions (2.25). Each 1D model is described by the Euler equations (2.1) with the assumption that the vessel wall behaves as a linear elastic solid (see (2.4)). The numerical discretization is based on the Taylor-Galerkin scheme presented in Chap. 2 (2.27).

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6 Computational tools All the physical and numerical discretization parameters are the same for all the six tubes, and are summarized in Tab. 6.1. Moreover tubes 1, 3, 5 feature the same boundary conditions at left boundary, while tubes 2, 4, 6 feature the same boundary conditions at right boundary. More precisely, left boundary conditions for in-edges are managed by each 1D model LifeV class, and prescribe the entering characteristic variable W1 (see [49]). Since W1 (t) = W1 (A(t), Q(t)), it is possible to specify W1 (t) by selecting a function A(t) and a function Q(t). In this simulation we set: A(t) = A0 Q(t) = sin(4t)
(at left boundary for tubes 1, 3, 5)

Absorbing boundary conditions (see [49]) are prescribed at right boundary for outedges: namely, a value for the exiting characteristic variable W2 (t) = W2 (A(t), Q(t)) is imposed, setting: A(t) = A0 Q(t) = 0
(at right boundary for tube 2, 4, 6)

The network class manages the prescription of right boundary conditions for inedges and left boundary conditions for out-edges, as previously illustrated. Length Radius Wall thickness Wall Young modulus Wall Poisson ratio Blood mass density Blood viscosity Mesh spacing Time step 10 cm 0.5 cm 0.05 cm 104 dyn / cm2 0.5 1 g / cm3 0.035 poise 0.1 cm 105 s

Table 6.1: Physical and discretization parameters for the considered numerical set up. We simulate the dynamics of the network in a 2 s time interval, starting from initial conditions A(t = 0) = A0 , Q(t = 0) = 0 in all the tubes. We report snapshots of the solution in Fig. 6.6. The images show that the sinusoidal signals (in terms of ow rate) enter tubes 1, 3, 5, correctly propagate in the network and exit through tubes 2, 4, 6.

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6 Computational tools

(a) t = 1.0 s

(b) t = 1.1 s

(c) t = 1.2 s

(d) t = 1.3 s

(e) t = 1.4 s

(f) t = 1.5 s

Figure 6.6: Solutions of 6 tubes test case.

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7 Conclusions
The study of biological systems offers many different subjects, attaining to different research areas. On the one hand this motivates researchers to devise rened tools for the accurate modeling of the phenomena of interest. On the other hand, it may promote cooperation and stimulate the creation of inter-disciplinary teams and research projects. Of course, these two aspects are bound together, since many different individual skills make a research team stronger and more prompt to fulll its objectives. The experience of Aneurisk project is representative in this respect, since it promoted a balance between the development of the technical knowledge on the side of the personal research interests of each involved researcher, but at the same time forced the exchange of information, a continuous update of the group activities, and a common vision. The present study on the mathematical and numerical modeling of cerebral circulation is mostly beholden to the interactive work environment realized by Aneurisk. Several suggestions from different elds were merged to dene novel methods and research approaches. Indeed, the study of cerebral circulation (as of many other biological systems) is thwarted by the lack of data for the full characterization of the available models or for the validation of new ones. On the other hand, medical knowledge, based on long time experience on the evolution of the pathologies, can suggest the right questions and stimulate the researchers to try to answer them. We experienced this phenomenon through the collaboration with neurosurgeons at Ospedale Niguarda CaGranda in Milan, often discovering that the most interesting issues for a medical doctor were not the most hard to solve, from a technical point of view: they were instead the more intensive to face, requiring all the members of the project to expand their specic professional skills to nd a way to co-operate. In this context, many results here presented do not stand as goals, but rather as milestones, tracking a trail towards a deeper understanding of the physiology and the pathology of the brain circulation. We discussed in Chap. 2 about the exibility of one-dimensional models, suitable for the description of large and complex vascular networks, in different physiological an pathological conditions. In particular, we studied the effects of the mechanical features of the vascular wall on the wave propagation phenomena typical of the circulatory system. The number of potential applications of reduced models, due to their proven effectivity in the study of vascular networks, calls for the design of efcient and robust software tools. In Chap. 6 we addressed this issue, by presenting some excerpts of the software specically written in the context of this work for the simulation of the circulatory system. In Chap. 3 we presented 3D models for blood ow, being aware that in order to

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7 Conclusions understand the deepest mechanisms of vascular pathology initiation and progression, the detailed description of the mechanical action of blood ow on the vessel wall is required. For the application of these models to the study of cerebral aneurysms, discussed in Chap. 4, we resorted to an integrated approach able to exploit at most the expertise of the different members of project Aneurisk and the available data. Starting from medical images, the accurate geometry reconstruction of a large number of cerebral vessels was performed, and some patterns in the location of aneurysms in the data set were observed [103]. Advanced statistical techniques allowed the denition of a classication of the vascular geometries, correlating morphological features to aneurysm position [120]. In the present work, new classication criteria were suggested by the denition of a hemodynamic parameter for the estimation of the mechanical load on the peri-aneurysmal region of the arterial wall. This work could lead to the formulation of a novel risk index for the cerebral aneurysm in the internal carotid artery. Accurate modeling of the blood ow features in specic districts of the vascular system and the understanding of the mechanisms of the wave propagation in the entire network form a prelude to an integrated research on the correlation between the mechanic features of the vascular tree as a whole and the localization of the wall diseases. Chap. 5 describes the two different perspectives embodied in 1D and 3D models and their use in a single, coupled model. This approach has been applied to the description of the blood ow in a complex vascular network, including a 1D model of the circle of Willis and a 3D model of a carotid bifurcation. In the vision of Aneurisk project, and in the intentions of the author, the modeling techniques developed and presented in this thesis are to be regarded as components of a more general stream of information, which connects the medical image to the clinical practice, through added layers of knowledge from different interacting sources.

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Acknowledgements
First of all, I would like to acknowledge the Aneurisk project, for funding my research activity during the period May 2005 - April 2008 with a grant provided by Fondazione Politecnico di Milano and Siemens Medical Solutions Italy. My gratitude goes in particular to prof. Alessandro Veneziani, head of the Aneurisk project and tireless supervisor and guide of my research activity. To all of the other researchers involved in the project, for their friendship, besides their professional skills, which made Aneurisk an exciting and gratifying environment for a young researcher like me. To all the friends and colleagues at MOX, the laboratory of Modeling and Scientic Computing of the Department of Mathematics, Politecnico di Milano, for being the best group in Italy where to enjoy mathematics and numerical modeling. To all the special people I met at the Department of Mathematics and Computer Science of Emory University, Atlanta, for having welcome me last year in an exciting environment and having offered me a gratifying experience abroad. To Conferenza dei Rettori delle Universit Italiane (CRUI) and British Council, for partially supporting my research activity with the grant awarded to the project Numerical Modelling of Cerebral Blood Flow and Auto-regulation, in collaboration with Dr. Jordi Alastruey, Dr. Carlo Dangelo, prof. Joaquim Peir and prof. Luca Formaggia. Special thanks go to Dr. Jordi Alastruey for his professional support and friendly mind in the collaboration on the study of 1D models for the cerebral circulation. To prof. Luca Formaggia for having always kept his door open to visits and questions. To Prof. Spencer Sherwin and Dr. Rod Hose for the detailed review of my thesis and the many stimulating comments on my work.

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