How best to counteract the enemies? By controlling inflammation in the coronary circulation
Gaubius Laboratory, Toegepast natuurwetenschappelijk onderzoek-Preventie en gezondheid (TNO-PG), Leiden, The Netherlands
* Correspondence: C. Kluft, Gaubius Laboratory, TNO-PG, P.O. Box 2215, 2301 CE Leiden, The Netherlands.
Abstract
The function of the heart is jeopardized by a failing coronary circulation. The disease process in the coronary circulation starts at an early age, with progressive atherosclerosis until the arteries become obstructed, and functional myocytes are lost and/or a process of heart failure ensues. Atherosclerosis is characterized by a process of chronic inflammation that is stimulated by numerous noxious and and metabolic factors. In the later stages of the disease coagulation and fibrin formation also contribute as a consequence of inflammation, and reciprocally aggravate inflammation. The various mechanisms that are involved in several stages of the disease are summarized from the perspective of the possibility of intervention. The viewpoint is taken that, primarily, the chronic trigger of the inflammatory process should be considered and tackled, and inflammation should be allowed to fulfil its protective function and rebalance so that proper tissue repair can take place. Nevertheless, advantageous control of inflammation can be instituted temporarily in advanced stages of the process and thus reduce sequelae such as myocardial infarction. Such control of inflammation is also relevant for interventions that are aimed at temporary reduction in inflammation after surgical interventions, and is desirable for local inflammation-modulated coagulation processes. The latter are incompletely understood, which prevents rational intervention. Chronic anti-inflammatory treatments are viewed with caution, and it is acknowledged that the specific processes that are present in patients are poorly understood, resulting in treatment of heterogeneous patient groups. In particular, specific patient groups with a predisposition to hyper-response in inflammation and downstream processes might benefit from a mild, chronic anti-inflammatory regimen. It is recognized that many existing drugs such as statins, fibrates, thiazolidinediones (glitazones), angiotensin-converting enzyme inhibitors and aspirin have anti-inflammatory effects, which might add to their clinical effectiveness in preventing events. The present review focuses on the mechanisms of action of these drugs, as they pertain to processes driven by nuclear factor-kappaB. In monitoring anti-inflammatory effects, it should be recognized that there may be direct effects and indirect effects as a consequence of the improvement achieved by treatment. Direct vascular markers are preferred for assessing vascular inflammation.
Key Words: Atherosclerosis • inflammation • nuclear factor-kappaB • peroxisome proliferator-activated receptor • statins