Aernoud Fiolet

29 General introduction and thesis outline Data on the pleiotropic effects of statins can be used to estimate the proportion of the residual inflammatory risk. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) study and in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE IT), approximately one-third of patients had an hsCRP level equal or above 2 mg/liter after achieving an LDL cholesterol level below 1.8 mmoles/liter. Depending on treatment intensity, statin treatment could reduce median hsCRP by a third, with a greater reduction in hsCRP level associated with a greater relative risk reduction of cardiovascular events. 99,100 In addition, the risk reduction following lowering hsCRP in these patients occurred irrespective of the change in LDL cholesterol, emphasising independence of the inflammatory pathway. 101 The abovementioned findings further shaped the clinical role of the “inflammation hypothesis” in atherosclerotic disease. Subsequently, multiple broad-acting and targetedagentswereintroducedtoinvestigatewhetheranti-inflammatorytreatment would truly translate into beneficial effects for patients with atherosclerosis. A frustrating start looking for therapeutic interventions with anti- inflammatory agents Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used anti- inflammatory drugs. Their anti-inflammatory properties are not suitable for addressing inflammation in atherosclerosis, since they are consistently associated with an increased risk of major coronary events, with the exception of low-dose acetylsalicylic acid. 102 This is a consequence of the dose-dependent pharmacodynamic properties of acetylsalicylic acid. Acetylsalicylic acid inhibits cyclooxygenase 1 (COX-1) and COX-2. COX-1 inhibition reduces thromboxane A2–induced platelet aggregation at low doses, accounting for its atherothrombotic protective effects. At higher doses, the anti-inflammatory properties driven by COX-2 inhibition arise. 103 Many novel NSAIDs are designed to selectively inhibit only COX-2. COX-2 inhibition also leads to undesired cardiovascular effects, such as prostaglandin E2–mediated sodium and water retention, vascular endothelium prostacyclin–mediated platelet activation, and vasoconstriction, increasing the risk of major cardiovascular events. 104 Glucocorticoids play an integral role in the management of many inflammatory conditions. However, many unfavourable side effects, such as hypertension, impaired glucose tolerance, and obesity following long-term treatment with corticosteroids render them unsuitable to dampen the inflammatory component of atherosclerosis. 105