Aernoud Fiolet

13 General introduction and thesis outline GENERAL INTRODUCTION T his general introduction describes the scientific prelude that incited the ideas and hypotheses investigated in this thesis. Firstly, it describes the role of inflammation in medicine and the particular mechanisms of inflammation that contribute to atherogenesis and atherotrombosis. Secondly, it describes the available clinical data on the potential to modulate these processes. Lastly, it discusses the contemporary challenges encountered in drug research and postulates methodological alternatives. INFLAMMATION IN MEDICINE Aulus Cornelius Celsus (c. 25 BC–c. 50 AD) is credited with the first proper description of inflammation, coining the tetrad of calor (warmth), dolor (pain), tumor (swelling), and rubor (redness and hyperaemia). 1 After this first description by Celsus the term inflammation has undergone some form of devaluation to an idle term used by many in widely divergent diseases. Especially in cardiovascular medicine, where it unfruitfully has been announced as the “next clinical breakthrough” for several decades. However, the dissolving of the term inflammation is unjustified, although the term indeed can be considered somewhat undescriptive. No argument has to be made for the quintessential role of inflammation in atherothrombosis. Inflammatory mechanisms play pivotal roles in all stages of atherosclerosis and atherothrombosis. 2,3 (Figure 1) Firstly, we distinguish inflammation in endothelial dysfunction and in response to pathological metabolic states (obesity, hyperglycemia, hyperlipidemia). Secondly, inflammatory mechanisms initiate the formation of a fatty streak and the progression to fibroatheroma. Thirdly, thromboembolic complications may occur after inflammation-initiated plaque destabilisation.And finally, initiated by the ischemic sequelae of the aforementioned processes, many inflammatory responses occur in the damaged cardiomyocytes. 4,5 These various physiological and pathophysiological processes are all described by the term“inflammation.” Inflammation—the biological response to repel pathogens and/or (subsequent) tissue damage—encompasses both our innate and our adaptive immunological response. Both elements play a similarly important role in the