Sudden Cardiac Death SymposiumAtherosclerotic Plaque Stability—What Determines the Fate of a Plaque?
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.
References (95)
Sudden cardiac death in persons with normal (or near normal) hearts
Am J Cardiol
(1997)- et al.
Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study
Lancet
(1997) - et al.
Atherosclerosis. the road ahead
Cell
(2001) - et al.
Pathology of the vulnerable plaque
J Am Coll Cardiol
(2006) Pathogenesis of atherosclerosis
J Am Coll Cardiol
(2006)Metalloproteinases and vulnerable atherosclerotic plaques
Trends Cardiovasc Med
(2007)- et al.
Markers of instability in high-risk carotid plaques are reduced by statins
J Vasc Surg
(2008) - et al.
Interleukin-10 enhances the oxidized LDL-induced foam cell formation of macrophages by antiapoptotic mechanisms
J Lipid Res
(2005) - et al.
TIMP-3 induces cell death by stabilizing TNF-alpha receptors on the surface of human colon carcinoma cells
Cytokine
(1997) - et al.
Increased vulnerability of pre-existing atherosclerosis in ApoE-deficient mice following adenovirus-mediated Fas ligand gene transfer
Atherosclerosis
(2005)
Plasma levels of granzyme B are increased in patients with lipid-rich carotid plaques as determined by echogenicity
Atherosclerosis
Increased levels of neutrophil-activating peptide-2 in acute coronary syndromes: possible role of platelet-mediated vascular inflammation
J Am Coll Cardiol
Platelet-neutrophil-interactions: linking hemostasis and inflammation
Blood Rev
Platelet-derived LIGHT induces inflammatory responses in endothelial cells and monocytes
Blood
Mast cell chymase induces smooth muscle cell apoptosis by disrupting NF-kappaB-mediated survival signaling
Exp Cell Res
Histamine network in atherosclerosis
Trends Cardiovasc Med
The pathogenesis of atherosclerosis
Handb Exp Pharmacol
Inflammation, atherosclerosis, and coronary artery disease
N Engl J Med
Widespread coronary inflammation in unstable angina
N Engl J Med
Stabilization of atherosclerotic plaques: new mechanisms and clinical targets
Nat Med
Multiple complex coronary plaques in patients with acute myocardial infarction
N Engl J Med
From vulnerable plaque to atherothrombosis
J Intern Med
From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II
Circulation
From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I
Circulation
Clinical application of C-reactive protein for cardiovascular disease detection and prevention
Circulation
C-Reactive protein levels and outcomes after statin therapy
N Engl J Med
The molecular mechanisms of the thrombotic complications of atherosclerosis
J Intern Med
Cytokines regulate vascular functions related to stability of the atherosclerotic plaque
J Cardiovasc Pharmacol 25 Suppl
IFN-gamma potentiates atherosclerosis in ApoE knock-out mice
J Clin Invest
Gelatinolytic activity in atherosclerotic plaques is highly localized and is associated with both macrophages and smooth muscle cells in vivo
Circulation
Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice
J Clin Invest
Increased matrix metalloproteinase-8 and -9 activity in patients with infarct rupture after myocardial infarction
Cardiovasc Pathol
Outside-in signals delivered by matrix metalloproteinase-1 regulate platelet function
Circ Res
Localization and translocation of MMP-2 during aggregation of human platelets
Thromb Haemost
Pharmacological characteristics of solid-phase von Willebrand factor in human platelets
Br J Pharmacol
Release of gelatinase A during platelet activation mediates aggregation
Nature
Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease
Circulation
ApoE knockout mice expressing human matrix metalloproteinase-1 in macrophages have less advanced atherosclerosis
J Clin Invest
Matrix metalloproteinase-13/collagenase-3 deletion promotes collagen accumulation and organization in mouse atherosclerotic plaques
Circulation
Effect of MMP-2 deficiency on atherosclerotic lesion formation in apoE-deficient mice
Arterioscler Thromb Vasc Biol
Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, 7, 8, and 13 antagonists: potential role of the macrophage in terminating PMN influx
Blood
Evidence for apoptosis in advanced human atheroma. Colocalization with interleukin-1 beta-converting enzyme
Am J Pathol
Vascular cell apoptosis in remodeling, restenosis, and plaque rupture
Circ Res
The immune response in atherosclerosis: a double-edged sword
Nat Rev Immunol
Serum from patients with acute coronary syndromes displays a proapoptotic effect on human endothelial cells: a possible link to pan-coronary syndromes
Circulation
Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation
J Clin Invest
Apoptosis and efferocytosis in mouse models of atherosclerosis
Curr Drug Targets
Cited by (125)
Liposomal codelivery of inflammation inhibitor and collagen protector to the plaque for effective anti-atherosclerosis
2023, Chinese Chemical LettersThe Unstable Carotid Plaque
2022, Anesthesiology ClinicsGallic acid ameliorates atherosclerosis and vascular senescence and remodels the microbiome in a sex-dependent manner in ApoE<sup>−/−</sup> mice
2022, Journal of Nutritional BiochemistryPhosphatidylserine-containing liposomes: Therapeutic potentials against hypercholesterolemia and atherosclerosis
2021, European Journal of Pharmacology