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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) UvA-DARE (Digital Academic Repository) Innovative imaging techniques for improved characterization of atherosclerosis and the assessment of novel therapies Duivenvoorden, R. Publication date 2013 Link to publication Citation for published version (APA): Duivenvoorden, R. (2013). Innovative imaging techniques for improved characterization of atherosclerosis and the assessment of novel therapies. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date:25 Apr 2021

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Page 1: UvA-DARE (Digital Academic Repository) Innovative imaging … · Carotid artery 3.0 Tesla magnetic resonance images of the different stages of atherogenesis and the different plaque

UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)

UvA-DARE (Digital Academic Repository)

Innovative imaging techniques for improved characterization of atherosclerosisand the assessment of novel therapies

Duivenvoorden, R.

Publication date2013

Link to publication

Citation for published version (APA):Duivenvoorden, R. (2013). Innovative imaging techniques for improved characterization ofatherosclerosis and the assessment of novel therapies.

General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an opencontent license (like Creative Commons).

Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, pleaselet the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the materialinaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letterto: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. Youwill be contacted as soon as possible.

Download date:25 Apr 2021

Page 2: UvA-DARE (Digital Academic Repository) Innovative imaging … · Carotid artery 3.0 Tesla magnetic resonance images of the different stages of atherogenesis and the different plaque

Chapter 1 GENERAL INTRODUCTION AND OUTLINE OF THE

THESIS

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GENERAL INTRODUCTION AND OUTLINE OF THE THESISAtherosclerosis is a chronic disease, characterized by lipid accumulation, inflammation and calcification of the artery wall.1 Autopsy studies revealed that atherosclerosis starts early in life. In fact, in 3832 United States service members that served in the war in Iraq (mean age 25.9 years), coronary atherosclerosis was present in 8.5%.2 Typically, from the 5th decade of life onward, atherosclerotic disease starts to manifest itself, resulting in atherothrombotic events like myocardial infarction and stroke.Atherosclerosis is commonly assumed to be a disease of modern age, related to our contemporary diet and sedentary lifestyle. However, CT imaging studies showed that 34% of ancient Egyptian and Peruvian mummies also developed atherosclerotic plaques.3

Nowadays, cardiovascular disease represents one of the greatest threats to human health worldwide. In the Netherlands around 38,000 people, and worldwide an estimated 17.3 million people, die annually of cardiovascular diseases.4, 5 The global cardiovascular disease mortality rate is rapidly increasing, especially in middle- and low income countries. The World Health Organization estimates that worldwide more than 23 million people will die annually from cardiovascular disease in 2030.5 Nonetheless, important progress in prevention and treatment has been made in recent years. In most high income countries the implementation of these new prevention and treatment strategies has resulted in a steady decline of cardiovascular mortality. The cardiovascular mortality rate in the Netherlands decreased by 26% in the past decade.4

The current concept of atherogenesisThe healthy artery wall is comprised of three distinct layers, the tunica intima, tunica media and tunica adventitia. The tunica intima is a monolayer of endothelial cells that lines the inner arterial wall. In addition to its barrier function between the blood and the vessel wall, endothelial cells produce a range of factors that regulate vascular tone, cellular adhesion, thrombosis, smooth muscle cell proliferation, and vessel wall inflammation. The tunica media is made up of smooth muscle cells and elastic tissue. By relaxation and contraction of the smooth muscle cells, the artery diameter and blood flow can be regulated. The outer layer is the tunica adventitia, which consists mainly of collagen and is highly vascularised. The early stage of atherogenesis is characterized by changes of the monolayer of endothelial cells. These changes are caused by irritative stimuli such as dyslipidemia, hypertension, diabetes, and pro-inflammatory mediators. Endothelial permeability increases which causes infiltration and retention of cholesterol containing lipoproteins in the artery wall. Furthermore, the endothelium that normally resists attachment of the white blood cells, expresses adhesion molecules on its surface to recruit white blood cells from the circulating blood.6 These endothelial changes occur predominantly in regions of low haemodynamic shear stress, which is the force that flowing blood exerts on the endothelium. This explains the eccentric development and predilection of atherosclerotic lesions at sites of arterial branches.7

At sites of endothelial injury, white blood cells, predominantly monocytes, enter the artery wall and differentiate into tissue macrophages. These macrophages ingest and digest the lipoprotein cholesterol that has infiltrated the artery wall and store it as cholesteryl ester in their cytoplasm as droplets. As a result, atherosclerotic plaques have a unique lipid composition, with a high proportion of cholesteryl ester relative to other lipids.8

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Figure 1. Carotid artery 3.0 Tesla magnetic resonance images of the different stages of atherogenesis and the different plaque phenotypes. A. Carotid artery without atherosclerosis of a young healthy subject. B. Early stage of atherosclerosis, with thickening of the vessel wall in an older healthy subject. C. Calcified plaque. D. Fibrous plaque. E. Plaque with a lipid-rich necrotic core. The left collumn shows the original images, the right shows the analyzed images. Red line = lumen - wall boundary, green line = wall - perivascular tissue boundary, orange = plaque calcification, yellow = lipid-rich necrotic core.

When many lipid-laden macrophages become apoptotic and release their cholesterol cargo in the extracellular space, the cellular debris and extracellular lipids can accumulate and form a lipid-rich necrotic core.1 In addition to macrophages, also lymphocytes, dendritic

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cells, mast cells and T cells can be found in plaque and may have important regulatory functions.1

Another cell type that plays a pivotal role in atherogenesis is the proliferative/synthetic smooth muscle cell. They produce extracellular matrix molecules like collagen and elastin. Smooth muscle cells are responsible for the formation of a fibrous cap that covers the plaque, and causes accumulation of extracellular matrix in the plaque. Until recently, it was believed that proliferative/synthetic smooth muscle cells were de-differentiated mature smooth muscle cells that migrated from the tunica media. However, a recent study disproved this theory, and showed that proliferative/synthetic smooth muscle cells are derived from the differentiation of multipotent vascular stem cells. In response to vascular injuries, these multipotent vascular stem cells become proliferative, and differentiate into smooth muscle cells and chondrogenic cells, thus contributing to vascular remodelling and neointimal hyperplasia.9

Different plaque phenotypes exist, and can coexist within a single vessel. Why and how plaques develop into different phenotypes is poorly understood. In addition to the aforementioned plaques with a lipid-rich necrotic core, also fibrous plaques can develop. Fibrous plaques are characterized by a growing mass of extracellular cholesteryl ester and smooth muscle cell-derived extracellular matrix. In comparison to plaques with a lipid-rich necrotic core, fibrous plaques are less prone to plaque rupture causing atherothrombotic events.10, 11 Another hallmark of atherogenesis is plaque calcification. This is a complex and regulated process that resembles osteogenesis. The mechanism is poorly understood, but multiple stimulators and inhibitors have been identified that control this process. Smooth muscle cells, inflammatory mediators and matrix metalloproteinases are believed to play an important role.12 Calcifications can develop in plaques with lipid-rich necrotic core as well as fibrous plaques, but intima or media calcification can also occur on its own. Figure 1 shows magnetic resonance images of the different stages of atherogenesis and the different plaque phenotypes. A widely used classification of plaque phenotypes is the American Heart Association classification based on the histopathological classification described by Stary et al.10, 11

The rationale for atherosclerosis imagingThis thesis focuses on the development of imaging techniques for improved characterization of atherosclerosis. The rationale for atherosclerosis imaging originates from the fact that autopsy studies revealed that atherosclerosis is present early in life and precedes the occurrence of cardiovascular events. Consequently, detection of atherosclerosis with in vivo imaging holds the potential to predict the risk of future cardiovascular events, can help enhance our understanding of the atherosclerotic disease process, and can be utilized for evaluation of cardiovascular drug efficacy. Chapter 2, as part of the introduction of this thesis, elaborates on the use of atherosclerosis imaging as surrogate endpoints for cardiovascular disease, and discusses the advantages of vascular imaging as compared to soluble biomarkers.

Outline of the thesisPart I of the thesis focuses on the application of ultrasound carotid intima-media thickness (CIMT) measurement in cardiovascular drug efficacy trials. In Chapter 3 we give an overview of how CIMT has been utilized in previous trials that assessed the efficacy of lipid lowering

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drugs. The aim of Chapter 4 was to determine the best CIMT protocol for cardiovascular drug efficacy trials. In Chapter 5, CIMT was used to assess the effect of the serum cholesterol-lowering drug ezetimibe on the progression of atherosclerosis. This trial has received a lot of attention in the international medical community13 as well as the international press14, as the results were rather unexpected. In Chapter 6 CIMT was used to assess the efficacy of the acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibiting drug pactimibe on atherosclerosis progression. Part II of the thesis deals with the development and application of magnetic resonance imaging (MRI) of the vascular wall. Chapter 7 reviews how MRI can be used for vascular wall imaging. In Chapter 8 and 9 we developed a high resolution carotid MRI protocol and compared and validated it against histology and ultrasound CIMT, and assessed the reproducibility of our method. In Chapter 10 and 11 we applied our carotid MRI method to quantify the atherosclerotic burden in patients with low serum HDL-C levels due to either lecithin cholesterol acyltransferase (LCAT) gene mutations or adenosine triphosphate-binding cassette transporter A1 (ABCA1) gene mutations. Chapter 12 describes the development of a 1H-magnetic resonance spectroscopy method for detection of liquid phase cholesteryl ester in carotid atherosclerotic lesions in humans.Part III of the thesis treats novel approaches in investigating haemodynamic shear stress in relation to atherosclerosis development. In Chapter 13 we developed an MRI-based method to derive shear stress data from the spatial velocity gradients. Subsequently we use this method to investigate the relation between haemodynamic shear stress, arterial remodeling and arterial stiffness in humans. Chapter 14 investigates the effect of post prandial hypertriglyceridemia on haemodynamic shear stress.The final section of this thesis, Part IV, concerns target-specific imaging and therapy of vessel wall inflammation in humans and experimental animal studies. In Chapter 15 and 16 [18F] - fluorodeoxyglucose positron emission tomography / computed tomography (FDG-PET/CT) is performed to measure vessel wall inflammation. In Chapter 15 the prevalence and clinical risk factors of carotid vessel wall inflammation are investigated in coronary artery disease patients. Chapter 16 investigates the relation between serum biomarkers of inflammation and carotid and aorta vessel wall inflammation in patients with- or at high risk of coronary artery disease. The final chapter, Chapter 17, is an experimental study in mice. In this chapter we developed a statin-loaded reconstituted HDL nanoparticle and used various in vivo and ex vivo imaging techniques to investigate the atherosclerotic plaque targeting properties and the efficacy of our nanoparticle for the treatment of atherosclerosis.

References1. L u s i s A J . A t h e r o s c l e r o s i s . N a t u r e

2000;407:233-241. 2. Webber BJ, Seguin PG, Burnett DG, et al.

Prevalence of and risk factors for autopsy-determined atherosclerosis among US service members, 2001-2011. JAMA 2012;308:2577-2583.

3. Thompson RC, Allam AH, Lombardi GP et al. Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations. Lancet 2013;381:1211-1222.

4. statline.cbs.nl5. www.who.int/cardiovascular_diseases/en/

6. Libby P, Ridker PM, Hansson GK. Progress and chal lenges in translat ing the biology of atherosclerosis. Nature 2011;473:317-325.

7. Caro CG, Fitz-Gerald JM, Schroter RC. Arterial wall shear and distribution of early atheroma in man. Nature 1969;223:1159-1161.

8. Small DM, Shipley GG. Physical-Chemical Basis of Lipid Deposition in Atherosclerosis. Science 1974;185:222-229.

9. Tang Z, Wang A, Yuan F, et al. Differentiation of multipotent vascular stem cells contributes to vascular diseases. Nat Commun 2012;3:875.

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10. Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. Circulation 1995;92:1355-1374.

11. Stary HC. Natural history and histological classification of atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20:1777-1778.

12. Guzman RJ. Clinical, cellular, and molecular aspects of arterial calcification. J Vasc Surg 2007;45 Suppl A:A57-63.

13. http://www.theheart.org/article/837243.do14. http://www.nytimes.com/2008/04/01/business/

01drug.html

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