Automated segmentation of atherosclerotic arteries in MR Images Adame Valero, I.M.

Citation

Adame Valero, I. M. (2007, April 4). Automated segmentation of atherosclerotic arteries in MR Images. ASCI dissertation series. ASCI graduate school|Laboratory for Clinical en Experimental Image processing, Faculty of Medicine / Leiden University Medical Center (LUMC), Leiden University. Retrieved from https://hdl.handle.net/1887/11467

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Atherosclerosis

Chapter

2

2 Atherosclerosis

athero

sclerosis

2.1 The disease

ardiovascular disease has long been the leading cause of death in developed countries, and it is rapidly affecting developing countries, too¹. According to the National Center for Health Statistics, cardiovascular disease is the leading cause of death in the United States. Over 70% of these deaths are related to atherosclerosis².

The pathogenesis of atherosclerosis has experienced a remarkable evolution in the 20^th century. However, this disease has a long history: studies of Egyptian mummies have shown traces of atherosclerosis in mummies’ arteries³. Nevertheless, it was not a common disease in antiquity. It started to gain importance as people survived early mortality caused by infectious diseases and, as many societies adopted unhealthy dietary habits which would induce development of atherosclerosis.

Not until the early part of the 20^th century were arteries considered as living, dynamic tissue^4,5, rather than inanimate tubes⁶ as they were formerly viewed. Since then many studies have been carried out, which have led to a better understanding of the nature of the disease.

Figure 2.1 Cut-section of an atherosclerotic artery (http://www.cardiocheck.co.uk)

Chapter

2

C

Atherosclerosis is a systemic disease of the vessel wall that is characterized by accumulation of lipid, protein, and cholesterol esters, leading to the formation of plaques (Figure 2.1). The normal healthy artery contains three layers. The inner layer, the intima, which is the dividing line between lumen and vessel wall, is composed of one layer of endothelial cells. The layer underneath the intima is the media, which is elastic, muscular or an intermediate between these, dependent on the location in the circulatory system. The outer layer of the vessel is the adventitia (Figure 2.2). Atherosclerosis is principally a disease of the intima, although in advanced lesions the media is often affected as well. Atherosclerosis may be present in different sites of the body, including the coronary arteries, the superficial femoral artery, the aorta and the carotid arteries. Aortic, peripheral and carotid artery disease are considered to represent “Coronary Heart Disease (CHD) Equivalents” because the level of CHD risk and CHD event rates associated with these conditions is approximately equivalent to the level of risk seen in stable CHD. Thus, screening for atherosclerosis in various vascular regions has been considered for CHD risk evaluation⁷. Of particular relevance are the carotid arteries, which supply blood to the brain. The most severe consequence of atherosclerotic plaque rupture in the carotid arteries is formation of emboli that lead to obstruction of cerebral vessels. The clinical manifestation of this event sequence is stroke.

Figure 2.2. Segment of an artery showing the different layers of the vessel wall (http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Vascular/Vascular.htm)

The process of initiation and evolution of the atherosclerotic plaque generally takes place over many years, during which the affected person often has no symptoms⁸. When plaque starts to develop, an enlargement of the outer wall occurs (outward remodeling) in order to maintain the lumen dimensions constant (Figure 2.3). When plaque burden exceeds the capacity of the artery to remodel outward, encroachment on the arterial lumen begins.

Eventually the stenoses may occlude the lumen, impeding blood flow. Recent pathophysiologic studies have centered on the identification and understanding of ‘vulnerable plaque’ which poses an increased risk for a thromboembolic event causing ischemia⁹.

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Autopsy studies have shown that thrombosis arises from plaque rupture, erosion, or calcified nodules¹⁰. Of these, plaque rupture is believed to cause the major portion of events and results in exposure of thrombogenic subendothelial material into the blood flow, which may occlude small vessels or embolize into the circulatory system. Cellular and molecular research of the processes leading to arterial plaque development demonstrate that the course of atherosclerotic disease may be altered by administration of lipid lowering drugs –particularly statins. Therefore, accurate methods for identifying vulnerable plaques would enhance the understanding of the disease and result in treatments to regress plaque burden, which would ultimately improve the quality of life.

Figure 2.3. Temporal evolution of atherosclerosis in an artery

2.2 Visualization

As in any imaging situation, the most important consideration lies in adequate spatial resolution to visualize lesion components and in good contrast between different types of tissue. Recently, much research has been focused on the development of different techniques to image atherosclerosis, being currently an active area of study, not only in magnetic resonance, computed tomography, ultrasound and nuclear medicine, but also in novel invasive approaches that exploit the potential of light, heat, and chemistry to distinguish between different tissue types.

X-ray angiography, color Doppler ultrasonography (DUS), computed tomography angiography (CTA), magnetic resonance angiography (MRA) or intra-arterial digital subtraction angiography (IA-DSA), providing location and degree of stenosis, rely on measuring the size of the vessel lumen alone, which often fails to assess the severity of atherosclerosis. One reason is underestimation of plaque burden due to outward remodeling of the vessel wall, in which the vessel increases only its external diameter in response to the development of plaque¹¹. Another reason is that the configuration and composition of plaque components are likely to be much more clinically relevant than lumen size. The histological composition of carotid atheroma is related to a plaque’s vulnerability to rupture¹². Several factors may play a role in triggering plaque rupture, including the size and spatial distribution of various plaque components¹³. Further knowledge about plaque vulnerability relies on studies that track changes in plaque composition over time. Consequently, luminal

arteriography falls short in characterizing atherosclerotic disease. Other modalities capable of imaging plaque components and vessel wall morphology are necessary to complement the information provided by angiographic techniques.

A number of imaging strategies have been investigated to visualize the vessel wall and plaque components by intravascular methods, such as ultrasound (and the related techniques of integrated backscatter and elastography), thermography, near-infrared spectroscopy (NIR), angioscopy and optical coherence tomography (OCT), and by noninvasive means, such as computed tomography (CT) and magnetic resonance imaging (MRI).

2.2.1 Intravascular Ultrasound

Of the invasive approaches, intravascular ultrasound (IVUS) has the longest track record and is often cited as the imaging gold standard for plaque identification, offering tomographic images that visualize many of the characteristics defined by pathologists at autopsy. It has the capability of detecting evidence of plaque remodeling and can identify large ruptures and clots (Figure 2.4). Plaque is characterized according to the degree of echogenicity in comparison with normal adventitia. Soft, lipid-filled plaque is less echogenic, and calcified plaque demonstrates a bright echo and acoustic shadow.

Figure 2.4. Schematic drawing (upper panel) and IVUS images of plaque rupture (lower panel). The ruptured plaque is characterised by a narrow tear in a thin fibrous cap and an emptied echolucent zone (type I). (Courtesy of Dr. J Ge. University Essen)

With the latest advances in radiofrequency signal analysis, integrated backscatter may be able to distinguish areas of hemorrhage from the low-density lipid areas. Nevertheless, heavy calcification in the vessel wall may hinder assessment of lumen patency due to calcium blooming effects. Besides, it is invasive, which makes it unsuitable for screening studies¹⁴. B- mode ultrasound is non-invasive but is limited by the plane of acquisition and the incident angle of the ultrasound¹⁵. Three-dimensional ultrasound may solve those limitations but its ability to characterize plaque components is still being studied¹⁶. Besides, IVUS cannot

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distinguish caps of 0.4 mm thickness from those that are 0.1 mm or less in thickness. This limitation might be solved by elastography.

Elastography (also known as palpography) is a parametric imaging technique based on IVUS that assesses the local mechanical properties of the vessel wall and plaque. It relies on the fact that, when force is applied to a tissue, soft material deforms more than hard tissue. The relative deformability of plaque components can be estimated by measuring the relative displacements of radiofrequency signals, recorded during IVUS acquisition, at two different pressure levels^17,18.

Another limitation of gray-scale IVUS in assessing plaque morphology is its inability to discriminate among adjacent small areas with heterogeneous composition, e.g. fibrous from fatty tissue^19,20. Virtual histology, which is based on frequency-domain and amplitude analyses of the IVUS backscatter signals, has recently been demonstrated to provide information with regard to the size and composition of plaque components, allowing reliable characterization of atherosclerotic plaque into 4 plaque types: fibrous, fibrofatty, dense calcium and necrotic core^14,21.

Despite the fact that IVUS remains the most widely-available technology to interventional cardiologists, an important drawback of IVUS is its inability to gauge plaque inflammation.

Recent studies have shown that proliferation of vasa vasorum (VV) (microvessels that nourish vessel walls) is a preceding or concomitant factor associated with plaque inflammation and instability^22,23. Images are taken during the injection of a microbubble contrast agent and the spatio-temporal changes of the IVUS signal are monitored using enhancement-detection techniques²⁴.

2.2.2 Optical Coherence Tomography

One of the most promising new technologies is optical coherence tomography. OCT is a high-speed technology whose simple fiber optics are incorporated into existing arterial catheters, which, like ultrasound, shows an image from a reflected wave, but it yields much finer spatial resolution (~10 to 20 micrometres), since it uses near-infrared (shorter wave lengths than ultrasound) and interferometry²⁵. This means that, while IVUS may detect plaque, OCT can visualize its makeup in detail, including the layers of intima the plaque has invaded and the thickness of its fibrous cap. Unfortunately, OCT requires inflation of a proximal balloon to obstruct blood flow (to flush the artery to obtain a clear field of view).

This could cause ischemia or injuries in the vessel, and the use of the balloon limits its use in distal segments. Another disadvantage of OCT is that its penetrating power into the vessel wall is very limited.

2.2.3 Angioscopy

Intravascular angioscopy allows direct visualization of the luminal surface. This technique provides information concerning the pathology of lesions and insight into the pathophysiology of acute coronary syndromes, thereby aiding diagnosis and treatment.

However, like OCT, it requires a proximal balloon, which implies inaccessibility to distal lesions²⁶.

2.2.4 Near-infrared Raman Spectroscopy

When the internals of the vessel are illuminated by halogen or laser light from a fiber-optic probe tuned to the near-infrared (NIR) wavelength, some of the light is absorbed by the plaque, but most is scattered back. Once captured by a receptor, scattered photonic energy is dissected into different wavelengths. The spectrum shows absorbent peaks, usually produced by combinations of fundamental bonds, like carbon-hydrogen, carbon-carbon, and carbon- oxygen. These bonds stretch with light inducing the peaks that can be observed in the spectrum.

This technique has demonstrated high sensitivity and specificity for identifying vulnerable plaque in laboratory and animal studies^27,28.

2.2.5 Thermography

Thermography is based on the principle that inflamed tissue has an increased temperature in comparison with healthy tissue. Heat variation in plaque is correlated most closely with the number and activity of inflammatory cells and the thickness of the fibrous cap. A thick cap acts as an insulator, but a thin cap places inflammatory cells close to the lumen, which means that in living atherosclerotic plaques hot spots appear where inflammatory cells are dense or close to the lumen surface, while normal arteries are uniform in temperature. However, blood acts as a cooling mechanism and no large differences in temperature are found²⁹. 2.2.6 Computed Tomography

Computed tomography has become an established method for non-invasive and highly- sensitive detection of artery calcifications³⁰. Only electron-beam computed tomography (EBCT) and multi slice computed tomography (MSCT) can quantify the amount or volume of calcium in blood vessels, although other imaging modalities, such as x-ray angiography, ultrasound or MRI can also identify calcium deposits in vessels. With the introduction of MSCT a high temporal resolution is available. In addition to the faster gantry rotation, the major advantage of this technology compared to conventional mechanical spiral CT scanners is the fact that it consists of 4,16 or 64 detector rows, which allow to generate 4,16 or 64 slices simultaneously. Especially 64-slice CT scanners offer a very high spatial resolution and generate very thin slices allowing the acquisition of isotropic voxels. For soft plaque visualization, contrast agent has to be administered intravenously, and to achieve diagnostic image quality with MSCT it is essential to reduce the heart rate below 65 bpm, by administering oral or intravenous Beta-Blockers. However, a recent study has demonstrated that, despite pharmaceutic beta-blockade, in 15% of patients a sufficient heart rate reduction could not be achieved³¹. Besides, patients with renal insufficiency or an allergy against contrast agents cannot be investigated by MSCT, which means that there is a considerable number of patients for which MSCT is not suitable.

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From studies investigating atherosclerotic plaques of the aorta and the carotid arteries it is known that CT permits to detect and classify atherosclerotic lesions³². MSCT can differentiate lipid-rich plaques in heart tissue specimens from fibrous and calcified lesions on the basis of Hounsfield unit densities (Figure 2.5). Contrast-enhanced MSCT can depict the location and extent of a thrombus that may be treated in patients with acute coronary syndrome or find atheromas that may be susceptible to rupture in asymptomatic individuals.

Newer MSCT scanners can obtain high-quality images, allowing to rule out CHD in patients with atypical chest pain and to detect soft plaques. However, the ability of CT to identify non-calcified plaques is restricted to advanced lesions located in proximal and middle coronary segments, due to limited temporal resolution³¹. Recently, different studies^31,33 have shown that MSCT has the capability of identifying several morphologic features associated with plaque vulnerability like plaque composition, plaque volume and positive vessel remodeling. However, image quality that allows quantitative assessment of vessel and plaque dimensions was only achieved in 50% of patients.

Figure 2.5. CT images of atherosclerotic carotid arteries at two different locations

In conclusion, although expansion of this technology with contrast enhancement for soft plaque imaging is under study the current scope of CT is largely limited to calcium detection³⁴.

2.2.7 Magnetic Resonance Imaging

Noninvasive methods of vessel wall imaging and plaque characterization are especially appealing, and, like CT, MR brings certain advantages. Although its spatial resolution is not as impressive as that of the invasive approaches, cardiovascular magnetic resonance imaging has revolutionized the field of cardiovascular imaging since it provides an impressive range of information: from the dynamics of cardiac function to the smallest details of pathophysiological mechanisms.

MRI has potential as in vivo modality for atherosclerotic imaging and plaque characterization.

In general terms, the pulse sequences designed for vascular imaging can be described as

‘black-blood’ or ‘bright-blood’ techniques, depending on the signal intensity of flowing blood relative to that of surrounding soft tissues. Black-blood techniques refer to MR techniques that suppress the signal from flowing blood³⁵. These sequences are ideal for plaque imaging,

because the conspicuity of the vessel wall is increased when adjacent to a hypointense lumen and the echo and repetition times can be varied to optimize visualization of specific plaque components. The major disadvantage of black-blood techniques are relatively long acquisition times and the fact that these sequences are based on acquisition of two- dimensional data with a section thickness of 2 mm. These techniques typically allow the most accurate quantitative measurements of disease burden and are used to identify soft cores in vivo. Bright-blood techniques refer to the gradient recalled echo (GRE) based imaging sequences that are typically used to acquire MR angiograms. These sequences enhance the signal intensity of flowing blood; thus, the lumen appears hyperintense relative to the adjacent vessel wall. Bright-blood techniques can produce images with shorter repetition and echo time. The lack of a spin echo in these sequences creates T2*-sensitive tissue signal that appears to improve the demonstration of intimal calcifications and a fibrous cap. Faster imaging also allows the acquisition of high-spatial-resolution 3D data sets.

2.2.7.1 Vessel wall MR

Vessel wall MR or ‘black-blood’ techniques’ specific capabilities include the quantification of plaque size^36,37, vessel wall morphology and qualitative analysis of plaque components^38-40. It permits imaging of plaques smaller than 1 mm. It can create both two- and three-dimensional images (Figure 2.6). Besides, it is capable of quickly assessing atherosclerosis throughout the body, an important factor for the assessment of, not only heart attack, but also of stroke, which can result from plaque rupture in the carotids and aorta.

Figure 2.6. Contrast-enhanced T1W MR images of atherosclerotic carotid arteries

MR differentiates plaque components on the basis of biophysical and biochemical parameters: the MR signal is sensitive to the chemical constituents of plaque material. The carotid arteries’ superficial location and relative absence of motion present less of a technical challenge for imaging than the aorta or coronary arteries. Different studies have shown quantification of carotid and aortic plaque by means of multicontrast MR⁴¹ (Figure 2.7). For coronary arteries, atherosclerosis measurements are currently limited by the relatively low spatial and temporal resolution of MR. However, coronary magnetic resonance represents an area of active investigation⁴².

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Figure 2.7. Corresponding T1W and T2W MR images of an atherosclerotic carotid artery

MR reproducibility has proven high⁴³ and is, therefore, suitable to measure progression or regression of plaque burden in serial studies. For example, in a study of lipid-lowering therapy (statins) in asymptomatic untreated hypercholesterolemic patients with carotid and aortic atherosclerosis⁴³, regression of atherosclerotic lesions was observed in the aortic and carotid arteries’ vessel wall at 12 months.

The capability of MR to identify not only the extent but also the characteristics of atherosclerotic plaque is a potential advantage of MR techniques: the major plaque components –lipid core, calcium deposits, fibrous connective tissue, and intraplaque hematomas- can be identified in terms of their signal intensity characteristics on T1-, T2- weighted and TOF images^44,45 (table 2.1). Further improvements in external coils, image acquisition and the use of contrast agents that enhance different tissue types, may improve in vivo atherosclerosis imaging by noninvasive MR.

Plaque Component TOF T1W T2W

Recent hemorrhage High High to moderate Variable

Lipid-rich necrotic core Moderate High Variable

Intimal calcification Low Low Low

Fibrous tissue Moderate to low Moderate Variable

Table 2.1. Contrast at MRI Imaging of Main Components of atherosclerotic plaque (tissue is relative to signal intensity of sternocleidomastoid muscle)

2.2.7.2 Magnetic Resonance Angiography

The basis for phase-contrast MRA⁴⁶ is that the blood flow along a magnetic field gradient causes a shift in the phase of the MR signal. With phase contrast, pairs of images are acquired that have different sensitivities to flow. These are then subtracted to cancel background signal, leaving only signal from flowing blood. The core of MRA is its ability to portray blood vessels in a projective format. Currently, projection images are created by post-processing of images acquired by a 2D or 3D gradient-echo sequence (‘bright-blood’ techniques). The images are processed by use of a maximum-intensity projection (MIP) algorithm⁴⁷. With an MIP algorithm, the brightest pixels along a user-defined direction are extracted to create a projection image (Figure 2.8).

Figure 2.8. MIP of the carotid arteries

Contrast-enhanced MRA (CE-MRA) is advantageous in displaying detailed vessel anatomy and in reducing artifacts. MIP images can be reliably rendered in multiple projections.

Subtraction of a pre-contrast from a post-contrast scan eliminates the signal from background tissue. Additionally, it is possible to perform time-resolved 3D MRA studies to better differentiate arteries and veins.

2.2.7.3 Intravascular Magnetic Resonance Imaging (IVMRI)

Although MRI has yielded acceptable visualization of carotid plaques, current surface MR techniques do not permit visualization of deeper arteries because of poor signal to noise ratio (SNR) associated with the distance between the detector coil and the vessel of interest. A potential solution for acquiring high-quality images comes from placing the intravascular detector coil adjacent to the atherosclerotic plaque⁴⁸. In addition, the location of the MR antenna is relatively stable within the artery in the effective field of view, which reduces motion artifacts. IVMRI has the capability to characterize plaque in vivo, which highlights the inability of IVUS to reliably identify plaque contents and characterize plaque morphology in the presence of calcifications⁴⁹.

Despite being invasive, currently only intravascular MRI can characterize plaque composition in deep arteries. Moreover, IVMRI might be the gate to spectroscopic⁵⁰ and molecular imaging⁵¹ of the vessel wall.

Although IVMRI overcomes many of the limitations of surface MRI, this technique still needs improvement. Higher resolution (currently ~312 micrometers) is needed to visualize fine structural details of the internals of small atherosclerotic vessels.

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2.3 Post-processing in vessel wall MR images

In recent history, all information from medical images was obtained by means of visual inspection or manually segmenting the images, which is labor-intensive and is subjected to inter- and intra-observer variability. Clearly, the development of automated methods to quantitatively measure relevant features would facilitate accurate and reproducible assessment of the severity of atherosclerosis. Those features (morphological and tissue components) should be characterized as ‘lesion markers’, measurements of plaque vulnerability. Potential lesion markers include maximum wall thickness and total plaque volume as well as lipid content and fibrous cap thickness.

The first step toward quantification of plaque morphology is delineation of the inner and outer boundaries of the vessel wall. However, imaging of the artery wall requires sub- millimeter resolution achieved at the expense of signal-to-noise, which makes image segmentation a difficult task. The major challenges inherent to segmentation of arterial wall structures are associated with: (a) contrast variations between lumen and vessel outer wall boundaries, (b) image artifacts due to blood flow and physiologic motion (respiration, cardiac motion), (c) intensity inhomogeneity caused by the nonlinear reception profile of surface coils and (d) low contrast-to-noise ratio leading to fuzzy vessel outer wall boundaries.

Therefore, robust algorithms that combine information from different MR techniques are required to accurately delineate the structures.

A number of segmentation approaches, from manual outlining^52,53 to edge-based^54,55, region- based⁵⁶ or model-based segmentation, have been investigated for different medical applications. Among them, segmentation of arteries from MR images has long been a topic of high interest36,38-40,57-59. Deformable techniques were used^57-59 for carotid lumen and vessel outer wall segmentation. Berr et al.⁵⁷ introduced a balloon-snake based algorithm for segmentation and size estimation of carotid artery lumen, whereas Yuan et al.⁵⁸ used gradient and weighted distance transform to generate the external forces that would lead two initial contours (manually drawn) towards the real lumen and outer wall boundaries, respectively.

Adams et al.⁵⁹ generated the external energy from gradient vector flow field based information. All these approaches need an initial contour to start with and rely on strong defined edges. However, as already indicated, MR images are restricted by low signal-to-noise ratio and diffused boundaries, which may pull the snake towards a strong defined boundary in the vicinity of the vessel, rather than towards the outer arterial wall, resulting in leakages of the snake.

In this thesis we focus on solving some of the segmentation problems reported in the literature^57-59 and improving accuracy, by means of a knowledge-driven approach, incorporating prior information of vessel morphology into the segmentation process. The vessel was represented by a geometrical model (ellipse, cylinder) that constrained the shape to avoid undesirable segmentations. Furthermore, combination of different sources of information (contrast weighted MR, MRA, etc) was also exploited to improve vessel wall segmentation and extraction of relevant parameters (plaque burden, vessel wall thickness, degree of stenosis, etc) to assess the severity of atherosclerosis.

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