Elsevier

Progress in Cardiovascular Diseases

Volume 51, Issue 3, November–December 2008, Pages 183-194
Progress in Cardiovascular Diseases

Sudden Cardiac Death Symposium
Atherosclerotic Plaque Stability—What Determines the Fate of a Plaque?

https://doi.org/10.1016/j.pcad.2008.09.001Get rights and content

Although the understanding of the underlying pathology of atherosclerosis has improved in recent years, the disease is still the main cause of death globally. Current evidence has implicated the role of inflammation in atherogenesis and plaque destabilization. Thus, inflammatory cytokines may attenuate interstitial collagen synthesis, increase matrix degradation, and promote apoptosis in several atheroma-associated cell types, and all these cellular events may enhance plaque vulnerability. Several cell types found within the lesion (ie, monocyte/macrophages, T cells, mast cells, platelets) contribute to this immune-mediated plaque destabilization, and a better understanding of these processes is a prerequisite for the development of new treatment strategies in these individuals. Such knowledge could also facilitate a better identification of high-risk individuals. In the present study, these issues will be discussed in more detail, particularly focusing on the interactions between matrix degradation, apoptotic, and inflammatory processes in plaque destabilization.

Section snippets

The Role of Inflammation in Atherogenesis and Plaque Destabilization

Atherosclerosis is a chronic disease characterized by 2 fundamental hallmarks: lipid accumulation and inflammation. The interaction between these 2 processes defines the principal pathogenesis and distinguishes atherosclerosis from other chronic inflammatory disorders. Atherosclerosis is a progressive disease in which lipids, extracellular matrix (ECM), and activated vascular smooth muscle cells (VSMCs) accumulate in the arterial wall resulting in growth of an atherosclerotic plaque. After the

Acute Coronary Syndromes—Shifting Focus from Stenotic Vessels to Plaque Disruption

Our classical view held that acute myocardial infarction (MI) usually occurred because of a critically narrowed coronary arterial lumen, detectable by angiography. However, careful pathologic and angiographic studies in the 1980s determined that fissuring or rupture of the thin fibrous cap of a coronary atheroma with preserved lumen often triggers acute fatal thrombosis. Thus, angiographic studies have shown that the culprit lesion in acute MI may not necessarily cause hemodynamically relevant

Shifting from High-Risk Plaques to High-Risk Patients

The characteristics of atherosclerotic plaques have been extensively studied during the last years, and as listed in Table 1, there are several features characterizing a vulnerable lesion. However, a recent consensus document proposed the term vulnerable patient rather than vulnerable plaque to define patients at risk for ACS, MI, and sudden cardiac death.11, 12 These authors suggest that not only vulnerable plaques but also other factors such as blood (prone to thrombosis) and myocardial

Fibrous Cap Thinning—Imbalance Between Matrix Synthesis and Degradation

The formation of fibrous cap is an important step in atherogenesis. This formation develops as a result of a multifactorial process in which VSMCs play a crucial role. Thus, the mutual activation of T cells and macrophages results in production of various cytokines and growth factors that stimulate VSMC proliferation, migration, as well as their production of ECM. The influx and/or proliferation of VSMCs will be one of the determinants of whether an elastic fibrous cap or thinning of the cap is

Matrix Metalloproteinases: A Complex Role in Atherogenesis and Plaque Destabilization

Matrix metalloproteinases are a group of proteinases consisting of 23 structurally related members that degrade fibrillar collagen type I and III, proteoglycans, collagen, and elastin, which are all substantial constituents of the fibrous atherosclerotic cap.19 Experimental evidence in mouse models suggests that degradation of ECM by MMPs plays an important role not only in plaque destabilization as discussed above, but also in myocardial rupture,22 which is a life-threatening complication of

Apoptosis Decreases Cellularity but Enhances the Vulnerability of Atherosclerotic Plaques

Although the pathologic and clinical significance of apoptosis in atherosclerosis remains unclear, it has recently been proposed that apoptotic cell death may contribute to plaque instability, rupture, and thrombus formation,33, 34 and that the immune system may be involved in this process.35 First, inflammatory mediators may participate in endothelial cell denudation by promoting cytokine-induced endothelial apoptosis.34 Indeed, serum from patients with ACS was recently found to trigger

Macrophages: A Key Regulator of MMP Activity, Apoptosis, and Thrombus Formation

Plaque vulnerability is a primary determinant of thrombus and rupture-mediated complications. In women older than 50 years, 80% of all coronary thrombi occur from plaque rupture.8 In this regard, macrophages play vital roles in vascular remodeling and plaque destabilization through the production of various enzymes, activators, inhibitors, and bioactive mediators, and, importantly, macrophages are more abundant in lesions featuring intense inflammatory responses and vulnerable plaques. Several

Helper Type 1: An Important Inflammatory Actor in Plaque Destabilization

In view of the complexity of T-cell subsets and activities, it has been suggested that only subsets of T cells account for their proatherogenic activity. Recently, Zhou et al showed that the absence of CD4+ cells in apoE–/– mice leads to reduced atherosclerosis, indicating that CD4+ T cells constitute a major proatherogenic cell population.61 There is solid evidence from several independent groups that the T helper type 1 (Th1) subset is a particular proatherogenic subset within the CD4+ T-cell

CD8+ T Cells: Proapoptotic Mediator During Plaque Destabilization

Although several lines of evidence suggest the involvement of CD8+ T cells in tissue destruction in various autoimmune disorders, little data exist regarding the precise role of CD8+ T cells in atherogenesis.4 However, through their ability to release large amount of granzyme B upon activation, these T cells may promote vascular SMC apoptosis and plaque destabilization within an atherosclerotic lesion. Our recent finding of increased serum levels of granzyme B in echolucent as compared with

Platelets and Inflammation—Pathogenic Loop During Plaque Destabilization

Blood platelets play a critical role in hemostasis, providing rapid protection against bleeding and catalyzing the formation of stable blood clots via the coagulation cascade.70 Recently, activated platelets have been implicated not only in thrombosis, but also in inflammatory reactions, immune responses, and in distinct aspects of atherosclerosis.71 Thus, several studies suggest a role for platelets as inflammatory cells.72, 73, 74 First, platelets provide a wide range of growth factors and

Mast Cells: A “New” Mediator in Plaque Destabilization

Mast cells have recently been shown participate in the inflammatory infiltrates of human atherosclerotic lesions.83 These cells contribute importantly to allergic and innate immune responses by releasing a wide range of mediators. Pathologic examinations have revealed that mast cells are located at site rupture.84 Interestingly, MMP-12 is macrophage-specific MMP,55 whereas MMP-1 is produced both by macrophages85, 86 and mast cells,87 and both these MMPs have been found to be located in the

Conclusion

Our understanding of the mechanisms underlying atherosclerosis has evolved beyond the view that this disease reflects progressive collection of lipids and cellular debris in the vascular wall. It is now evident that physical disruption of atherosclerotic plaques (ie, endothelial erosions and fibrous cap rupture) with subsequent thrombus formation and vascular obstruction is a dominant mechanism for acute coronary events. Substantial biological data have implicated the role of inflammatory

Acknowledgments

This work was supported by grants from the Norwegian Council of Cardiovascular Research, The University of Oslo, Rikshospitalet Medical Center, and Helse Sør-Øst.

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