The complement system and cardiovascular disease Citation for published version (APA): Hertle, E. (2016). The complement system and cardiovascular disease: the CODAM study. https://doi.org/10.26481/dis.20160401eh Document status and date: Published: 01/01/2016 DOI: 10.26481/dis.20160401eh Document Version: Publisher's PDF, also known as Version of record Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. 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If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.umlib.nl/taverne-license Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 04 Oct. 2021 THE COMPLEMENT SYSTEM AND CARDIOVASCULAR DISEASE: THE CODAM STUDY © Elisabeth Hertle, Maastricht 2016 Cover design: Jean Scheijen │ www.vierdrie.nl Production: Ipskamp Printing B.V., Enschede ISBN: 978-94-028-0085-2 THE COMPLEMENT SYSTEM AND CARDIOVASCULAR DISEASE: THE CODAM STUDY DISSERTATION to obtain the degree of Doctor at the Maastricht University, on the authority of the Rector Magnificus, Prof. dr. L.L.G. Soete, in accordance with the decision of the Board of Deans, to be defended in public on Friday 1st April 2016, at 14.00 hours by Elisabeth Hertle Supervisor: Prof. dr. C.D.A. Stehouwer Co-supervisors: Dr. M.M.J. van Greevenbroek Prof. dr. I.C.W. Arts Assessment Committee: Prof. dr. H. ten Cate (chairman) Prof. dr. N. Marx, University Hospital Aachen, Germany Prof. dr. M.H. Prins Dr. J.C. Sluimer Dr. L.A. Trouw, Leids Universitair Medisch Centrum The research described in this thesis was supported by a grant of the Dutch Heart Foundation (DHF-NHS2010B194) Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged. Financial support from TECOmedical for the printing of this thesis is gratefully acknowledged. Table of contents | 5 Contents Page Chapter 1 General introduction 7 Chapter 2 The complement system in human cardiometabolic disease 21 Chapter 3 Complement C3: an emerging risk factor in cardiometabolic 51 disease Chapter 4 Distinct associations of complement C3a and its precursor C3 59 with atherosclerosis and cardiovascular disease: The CODAM study Chapter 5 Complement activation products C5a and sC5b-9 are associated 81 with low-grade inflammation and endothelial dysfunction, but not with atherosclerosis in a cross-sectional analysis: The CODAM study Chapter 6 The alternative complement pathway is longitudinally associated 103 with adverse cardiovascular outcomes: The CODAM study Chapter 7 Longitudinal associations of factors of the classical complement 127 pathway with cardiovascular outcomes: The CODAM study Chapter 8 Longitudinal associations of MBL, MASP-1, MASP-2, MASP-3 and 153 MAp44 with cardiovascular outcomes: The CODAM study Chapter 9 General discussion 183 Samenvatting 207 Valorisation addendum 211 Dankwoord 217 List of publications 221 Curriculum Vitae 223 6 | Chapter 1 General introduction 8 | C h a p t e r 1 1 Cardiovascular disease Cardiovascular disease (CVD) is a major global health issue. According to the World Health Organization (WHO), CVD is the leading cause of death worldwide [1]. Reduction of cardiovascular mortality was also specified as primary global health target in the latest WHO status report on non-communicable diseases 2014 [2]. CVD denotes malfunction of the heart and/or the blood vessels [1]. Coronary heart disease (CHD) constitutes malfunction of the vessels supplying the heart muscle; and cerebrovascular disease constitutes malfunction of the vessels supplying the brain. CHD can culminate in acute myocardial infarction and cerebrovascular disease in stroke, which together represent the most common causes of death from CVD [2]. Peripheral arterial disease (PAD) constitutes malfunction of the vessels supplying the legs and arms, and can entail amputation of the affected limbs [2]. Myocardial infarction, stroke and limb amputation are advanced clinical endpoints of CVD, but actually, malfunction of the blood vessels is a chronic process that starts early in life and progresses subclinically over many years. 1.1 Aetiology of CVD Endothelial dysfunction, atherosclerosis and atherothrombosis are the pathophysiological processes in the arterial vasculature underlying CVD (figure 1). The endothelium is the inner surface of the blood vessels, which serves as barrier and transfers signals from the blood stream into the outer vessel layers and the surrounding tissue, and vice versa [3]. Endothelial dysfunction is considered the first step in the degeneration of blood vessels, and describes the disturbed interaction of the endothelium with the blood stream and the surrounding tissues [3, 4]. The next stage, atherosclerosis, is characterized by harmful deposition of lipids and immune cells in the vessel wall [5, 6]. Atherosclerotic deposits (plaque) can be present in such a degree that they narrow the arteries and cause a restriction in blood stream. This results in insufficient oxygen delivery to the surrounding tissue (ischaemia). In ischaemic heart disease, the coronary arteries are narrowed, and the heart function is impaired due to ischaemia in the heart muscle [7]. Plaques can additionally destabilize the vessel and as a result, abrupt ruptures along the plaque and the surrounding vessel surface can occur [8]. Figure 1: Aetiology, manifestations and endpoints of cardiovascular disease. Introduction | 9 Plaque rupture activates the coagulation system to seal the injured area, but this repair reaction can escalate into excessive clotting and complete arterial occlusion (atherothrombosis). An acute atherothrombotic event leads to prolonged or severe ischaemia, and can thereby cause tissue death. Myocardial infarction and the main form of stroke, ischaemic stroke, entail irreversible destruction of heart or brain tissue as result of tissue death [9]. 1.2 Current situation and future challenges in cardiovascular research Over the last decades, considerable progress has been made in treatment and also prevention of CVD. As a result, cardiovascular mortality has been continuously decreasing in high-income countries since the widespread use of lipid-modifying, anti-hypertensive and anti-thrombotic medication [10]. However, there are still evident problems that need to be addressed in order to preserve the current state and to potentially further reduce the burden of CVD: First, in Western countries, a large part of patients with CVD would be assigned a relatively low cardiovascular risk based on the current risk prediction strategies [11]. This means that despite efficient control of known cardiovascular risk factors there may be unrecognized, yet crucial processes contributing to CVD. Second, CVD is a comorbidity of several metabolic and degenerative diseases, such as diabetes mellitus, fatty liver disease and rheumatoid arthritis [12-15]. Furthermore, CVD itself stimulates the development of other degenerative diseases such as Alzheimer’s disease [16, 17]. In order to decrease cardiovascular burden not at the expense of other common diseases, treatment of CVD should be improved by intensified targeting of mechanisms that play a role in several chronic diseases. Last, the burden of CVD is at the moment excessively rising in low-income countries [1]. Among other ethnicities, slight variations in aetiology of CVD may exist due to genetic differences and differences in lifestyle [18, 19]. This suggests that identification of further mechanisms contributing to CVD could potentially have a large impact especially on those societies. Together, these three problems illustrate that there is still considerable need to identify novel risk factors for CVD, despite the accomplishments that have already been made in the past. In particular, better understanding of mechanisms is needed that are not yet included in current risk prediction, that may be involved in several chronic diseases, and that may potentially play a great role in CVD among other ethnicities. 1.3 Low-grade inflammation and the immune system in CVD For these reasons, low-grade inflammation and aberrancies in immune function are of particular interest in cardiovascular