Aernoud Fiolet

383 General summary GENERAL SUMMARY T he general aim of this thesis is to investigatewheter anti-inflammatory therapy improves outcomes in patients with coronary disease, based on a methodology that combines sustainable collection of evidence with the highest level of fidelity. This aim is accomplished using two main approaches. The first approach is clinically and mechanistically orientated and described in parts I, II, and III of this thesis. In these parts, we present the rationale and methods for repurposing a well-known drug, colchicine, to modulate crucial, but to date unaddressed, biological pathways in atherosclerosis. The second approach is methodologically orientated and described in parts II and IV of this thesis. In these parts, we show that investigator-initiated research can be undertaken with scientifically sound methods, by using a pragmatic trial design and innovative data collection methods. PART I: THE ROLE OF CRYSTAL-INDUCED INFLAMMATION IN ATHEROSCLEROSIS In Chapter 2 , we describe the importance of inflammation in the initiation and progression of atherosclerosis. Analogous to other pathophysiologic conditions, we postulate that the concept of crystal-induced inflammation has a pivotal role in atherogenesis, in this particular case caused by cholesterol crystals. Two mechanisms play a role. Firstly, the cholesterol crystals incite a local inflammatory response that activates macrophages, modulated by particular chemokines and inflammatory proteins. This local process can lead to degradation of the fibroatheromataous plaque. Secondly, the sharp edges of the crystals can physically disrupt the structure of the cap, leading to plaque erosion or rupture. We conclude that any drug that dampens crystal-induced inflammation could have the potential to mitigate the inflammatory response in atherosclerotic plaque and reduce the risk of cardiovascular events. In Chapter 3 , we introduce such a drug, colchicine, which is conventionally used to treat gout, familial Mediterranean fever, and pericarditis. To investigate whether there is evidence that colchicine could be repurposed for the treatment of atherosclerosis, we review all available data on colchicine exposure and the course of cardiovascular disease. Based on the current observational evidence and findings from prospective studies we conclude that colchicine has the potential to be successfully repurposed in coronary disease. To evaluate the safety of the drug,