Aernoud Fiolet

37 General introduction and thesis outline THESIS OUTLINE The general aim of this thesis is to investigate wheter anti-inflammatory therapy improves outcomes in patients with coronary disease, based on methodology that combines sustainable evidence collection with the highest level of fidelity. This goal is achieved in two ways: firstly, by repurposing a well-known drug to modulate crucial, but formally unaddressed, biological pathways in atherosclerosis and secondly, by showing that such investigator-initiated research can be conducted with scientifically sound methods using pragmatic trial design and innovative data collection methods. PART I: THE ROLE OF CRYSTAL-INDUCED INFLAMMATION IN ATHEROSCLEROSIS In the first part of this thesis, we describe the pathophysiology of atherosclerosis and the concept of crystal-induced inflammation. We will provide evidence of the relationship between cholesterol deposition in an artery wall, its crystallisation, and the perpetuating local inflammatory response that is incited. We will show how this mechanism directly and indirectly leads to traumatic injury, causing plaque disruption or rupture, which precipitates further inflammation and atherothrombotic sequelae. (Chapter 2) By this rationale, therapies that have proven to effectively dampen the inflammatory response in conditions associated with crystal-induced inflammation (such as gout) may be repurposed for the treatment of atherosclerosis. Colchicine is one of such drugs. We describe the currently available observational evidence that suggests a possible atheroprotective effect of the drug. Moreover, we provide data on the safety issues of the drug and an overview of all scientific endeavours focusing on colchicine and cardiovascular outcomes that are currently ongoing. (Chapter 3) PART II: EFFICACY AND SAFETY OF COLCHICINE IN CORONARY DISEASE In the second part of this thesis, we aim to provide the most complete approach to investigate the efficacy of colchicine in coronary disease, using the highest possible levels of scientific evidence. First, we will use a predefined protocol that describes our hypothesis and methods. We will postulate the unmet needs of patients with chronic coronary disease. We will provide the available evidence of the efficacy of