Aernoud Fiolet

28 Chapter 1 immunological response in the development of the atherothrombotic plaque—by initiating the cytokine effects of interleukin – 1 β , mediated by the crystal-induced activation of the NLRP3 inflammasome. Secondly, the biomechanical effect of their crystallised form on the—possibly alreadyweakened—cap of the atheroma may lead to perforation of the endothelium of the cap, leading to erosion or rupture, inevitablydisrupting vascular homeostasis, causing distal thromboembolic complications. THE CLINICAL PERSPECTIVE: TRANSLATING INFLAMMATION FROM CYTOKINES AND CRYSTALS TO CLINICAL CARE The magnitude of inflammation as residual risk To translate the clinical consequences of the inflammatory routes in atherosclerosis, contemporary studies focusing on lowering LDL cholesterol levels are used. Findings from these studies provided insight into the magnitude of the risk that remains after optimal treatment of dyslipidaemia. For example, in the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial, intensive lipid lowering was attained with statins and the proprotein convertase subtilisin/kexin type 9 inhibiting molecular antibody evolocumab. Patients achieved amedian LDLcholesterol level of 0.78mmoles/liter. Even with this state-of-the-art lipid-lowering strategy, 9.8% of patients developed a major adverse cardiovascular event after a median follow-up period of just over 2 years. 97 The most important independent contributors to this risk are hypertriglyceridemia, residual thrombotic risk, diabetes-associated morbidity, and low-grade inflammation. 98 As mentioned above, high-sensitivity C – Reactive Protein (hsCRP) is a robust prognostic risk marker, albeit not causally associated with the disease. Findings from patient-level meta-analyses demonstrated that each standard deviation increment in log-normalised hsCRP is associated with a 37% increase in the relative risk of coronary heart disease. This risk is similar to the risk associated with an increase in systolic blood pressure (35% relative risk increase per every standard deviation increment) and twice as high as the risk associated with an increase in total cholesterol (16% relative risk increase per every standard deviation increment). 63