Atherosclerotic Plaque Stabilization - Potential Role for Immunomodulatory Therapy

Author(s): Jan Kristian Damas , Torgun Waehre , Arne Yndestad , Lars Gullestad , Pal Aukrust .

Journal Name: Vascular Disease Prevention

Volume 1 , Issue 1 , 2004

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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: atherosclerosis, acute coronary syndromes, cd40 ligand, chemokines

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Article Details

VOLUME: 1
ISSUE: 1
Year: 2004
Page: [17 - 31]
Pages: 15
DOI: 10.2174/1567270010401010017