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Atherosclerotic Plaque Stabilization - Potential Role for Immunomodulatory Therapy

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Abstract:

Acute coronary syndromes (ACS) result from endothelial erosion or rupture of vulnerable atherosclerotic plaques with subsequent thrombus formation and vascular obstruction. The characteristics of a vulnerable plaque include a large lipid pool, reduced smooth muscle cell and collagen content and a thin overlying fibrous cap. Several therapeutic approaches found to achieve plaque stabilization have targeted some of these features and indeed, lipid lowering agents and angiotensin converting enzyme inhibitors have been shown to reduce the incidence of ischemic events in patients with coronary artery disease (CAD). However, despite “state of the art” cardiovascular treatment, ACS are still common manifestations of CAD, suggesting that important pathogenic mechanisms remain active and unmodified by the present treatments. Recent research suggests that persistent immune activation in vulnerable plaques may represent such “unmodified mechanisms”. Thus, vulnerable atherosclerotic plaques show prominent infiltration of inflammatory cells, and activated monocytes / macrophages and T cells may contribute to tissue damage and plaque rupture through promotion of apoptosis and production of inflammatory cytokines, matrix-degrading enzymes and reactive oxygen species. Moreover, inflammatory processes may enhance plaque thrombogenicity through production of tissue factor by monocytes / macrophages. Recently, novel treatment strategies, such as the administration of immunomodulatory agents (i.e. anti-inflammatory cytokines, anti-cytokine antibodies and intravenous immunoglobulin) and immunization have been shown to attenuate atherosclerotic plaque progression and inflammation in experimental models. Interestingly, drugs targeting lipid and carbohydrate metabolism (e.g. statins, fibrates and glitazones) also seem to act as immunomudulators. Furthermore, experimental studies suggest that some of the beneficial effects of these drugs in CAD are due to immunomodulatory effects rather than their action on cholesterol or glucose metabolism. Immunomodulation has therefore, become an attractive therapeutic principle in plaque stabilization acting on key mechanisms in the pathogenesis of atherosclerosis. These issues will be discussed particularly focusing on pathogenic mechanisms in immune-mediated plaque destabilization and potential immunomodulatory treatment regimens that could prevent plaque rupture and ACS.

Keywords: acute coronary syndromes; atherosclerosis; cd40 ligand; chemokines

Document Type: Review Article

DOI: https://doi.org/10.2174/1567270043480832

Affiliations: Research Institute of Internal Medicine, Rikshospitalet University Hospital, Sognsvannsveien 20, 0027 Oslo, Norway.

Publication date: 2004-03-01

More about this publication?
  • Vascular Disease Prevention publishes reviews as well as original papers to update all those concerned with this topic at the clinical or scientific level. In addition to clinically relevant topics, we consider reviews and original papers dealing with the more scientific aspects of vascular disease prevention. This includes the evaluation of emerging vascular risk factors, research dealing with the pathogenesis of atherosclerosis and the investigation of new treatment options both at the clinical and scientific level (e.g. epidemiology, patient-based studies, experimental models, in vitro experiments or molecular research). Therefore, another function of Vascular Disease Prevention is to bridge the gap between clinical practice and ongoing laboratory-based research.

    In particular, we welcome critical reviews and comments on recent trials. This is a topic that requires regular updates because of the large number of trials published every year.

    Debates are encouraged in the correspondence section of this journal.
    The editorial structure of Vascular Disease Prevention is set up with the aim of dealing with the submitted material as rapidly as possible. Specialist editors will provide a more expert and rapid assessment unlike a more centralized editorial structure.
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