Inflammation and Atherosclerosis in Acute Coronary Syndromes

Endothelial dysfunction. Vascular endothelial cell dysfunction begins well before any morphologic manifestations of atherosclerosis are visible, and continues throughout the entire course, probably waxing and waning along the way. Well in advance of the development of atherosclerotic lesions, endothelial dysfunction exists as an independent predictor of future cardiovascular events.1 We now know that in fact this dysfunction is characterized by several features typical of inflammation, including expression of numerous cellular adhesion molecules, like vascular cell adhesion molecule (VCAM-1), intercellular adhesion molecule (ICAM-1) and E-selectin. The abnormally functioning endothelial cells also release proinflammatory cytokines such as interleukin (IL-1b), tumor necrosis factor (TNF-a) and c-reactive protein (CRP). Furthermore, the dysfunctional endothelium produces less nitric oxide (NO), a leukocyte and platelet inhibitor and a vasodilator that also helps maintain vascular smooth muscle cells in a nonproliferative state. On the other hand, there are more vasoconstrictor substances like endothelin (ET-1) and angiotensin-produced substances.2–6 Release of these inflammatory substances stimulates blood monocytes to adhere to the endothelium and migrate into the intima, where they develop into macrophages. The macrophages take up oxidized lipoproteins (ox-LDL) and retain them, becoming foam cells.6–11 These foam cells in turn secrete proinflammatory cytokines that sustain the stimulus for more leukocyte adherence, recruit T-lymphocytes to the area and increase the expression of scavenger receptors.12 Traditional cardiovascular risk factors work in part by undermining the endogenous defenses of the vascular endothelium and contributing to its dysfunctional state. Hypercholesterolemia promotes increased formation of oxLDL and foam cells, and reduces intracellular concentrations of NO.13 Angiotensin II, a vasoconstrictor associated with clinical hypertension, opposes NO action, stimulates production of reactive oxygen species, increases the expression of proinflammatory cytokines interleukin (IL-6) and monocyte chemoattractant protein (MCP-1), and upregulates VCAM-1 on endothelial cells.14–16 Other risk factors, such as elevated CRP, decrease production and limit the activity of NO.17 CRP potently upregulates nuclear factor KB (NFKB), a key nuclear factor facilitating transcription of numerous proinflammatory genes.18 Synthesis of many cytokines such as TNF-a, IL-6, IL-8 and IL-1b, is mediated by NF_B, as is the expression of cyclooxygenase.13 Accumulated evidence has established correlative as well as causative links between chronic inflammation and the insulin resistance of diabetes. In obesity, when adiposity reaches a certain threshold, various factors are released from adipocytes that induce widespread macrophage activation and infiltration and that impair adipocyte insulin sensitivity.19 Atherosclerotic plaque growth and degeneration. T-cells, dendritic cells and mast cells are recruited to the developing atheromatous plaque.20 Activated T-cells secrete cytokines that influence macrophage activity. CD40/CD40-ligand binding between activated T-cells and macrophages results in the expression of tissue factor (TF), matrix metalloproteinases (MMPs) and proinflammatory cytokines, which all act to perpetuate and increase the inflammatory response. Mast cells also prompt plaque growth by releasing TNF-a, heparin and serine proteases. If the risk factors for endothelial dysfunction and inflammation persist, the developing atheroma will continue to progress and grow. Proliferation of smooth muscle cells (SMCs), which migrate to the intima and synthesize collagen, causes the arterial fatty streak to evolve to a more complex lesion. Continued release of cytokines (such as MCP-1) by activated endothelial cells, T-cells and foam cells encourages and sustains inflammation and lipid accumulation within the atheroma and also influences further SMC activity.21 Over time, gradual lesion expansion into the coronary lumen can lead to flow reduction, and present clinically as angina. Lipid growth in the central core eventually helps undermine the overlying fibrous cap and leads to destabilization of the upper layers, which may result in its rupture. Activated T-cells in the plaque can produce proinflammatory cytokines such as interferon (INF-8), which inhibits the synthesis of collagen, thus further compromising fibrous cap strength. Continued accumulation of oxLDL is eventually toxic to macrophages and SMCs, leading to islands of necrosis in the lesion core.22 Implicated with oxLDL toxicity is lipoprotein-associated phospholipase A2, an enzyme associated with macrophage death.23 Macrophage foam cell death leads to further inflammation along with overexpression of MMPs, interstitial collagenases and gelatinases, which then further degrade the fibrous cap.24 Once the fibrous capsule is sufficiently weakened, the plaque is susceptible to sudden rupture, thereby exposing an intensely prothrombotic subsurface. Inflammatory mediators as possible markers (Table 1) C-reactive protein (CRP). CRP is the inflammatory marker receiving the most attention to date. It is an acute phase reactant normally present in plasma at low levels, and increases > 100-fold in response to inflammatory stimuli. It is produced by hepatocytes in response to stimulation by IL-6. It is also produced by human coronary artery smooth muscle cells.25 Although initially considered only a “marker” of inflammation, CRP itself has been shown to possess proinflammatory and proatherogenic properties. It stimulates endothelial cells to express adhesion molecules and secrete cytokines26,27 and it decreases the expression of endothelial NO synthase.17,28 CRP accumulates in macrophage-rich regions of nascent atherosclerotic lesions and activates the macrophages to express cytokines and tissue factor, while enhancing macrophage uptake of LDL.29 It also amplifies proinflammatory effects of several other mediators including endotoxin.30,31 In a post mortem study of 302 autopsies of men and women with atherosclerosis, median CRP levels were higher with acute plaque rupture than in stable plaques or controls.32 The levels correlated with the staining intensity for CRP in macrophages and the lipid core of plaques, and it increased with the number of thin cap atheromas found in coronary arteries. Plasma CRP levels at the upper end of the reference range in apparently healthy men and women, in the absence of other sources of inflammation, correlated with increased risk of future cardiovascular events, including myocardial infarction (MI), peripheral vascular disease with claudication and stroke.33 These data support the view that systemic CRP accurately reflects the number of vulnerable atherosclerotic plaques. Unfortunately, many other factors affect CRP. For example, CRP levels are related to abdominal obesity.34 They are elevated in patients with metabolic syndrome and type 2 diabetes, and CRP levels correlate with the severity of the glycemic state and insulin resistance.35–37 In a German health and nutrition survey, there was an almost linear relation between the number of components of the metabolic syndrome and median CRP concentrations.38 Cigarette smoking is the strongest environmental stimulus for CRP production. Current smokers usually have 2-fold higher concentration of both fibrinogen and CRP compared with those who never smoked. Hormone replacement therapy (HRT) raises CRP, and levels were 2 times higher in 493 healthy post-menopausal women in the Women’s Health Study who were taking HRT than among women not taking HRT. The difference was present in all subgroups, including those with no history of hypertension, hyperlipidemia, obesity, diabetes, cigarette consumption or a family history of premature coronary artery disease.39 Renal insufficiency (serum creatinine > 1.3 mg/dl in women and > 1.5 mg/dl in men) was independently associated with elevations in CRP, which may explain in part the increased cardiovascular risk in patients with kidney disease.40 Acute coronary syndromes. Patients with unstable angina and elevated levels of CRP (>= 3 mg/dl) had higher rates of death, acute MI and need for revascularization compared to patients without elevated levels.41 This increased risk may be evident as early as 14 days after presentation.42 The CAPTURE trial found that although only troponin-T was predictive in the first 72-hour period, both CRP and troponin-T were predictors of risk within 6 months.43 The FRISC Investigators reported that the risk associated with elevated CRP levels at the time of an index ACS event continued to increase for several years afterward.44 In ACS patients who are treated with very early revascularization, CRP is a strong independent predictor of both short-term and long-term mortality.45 Clinical testing. General application of CRP testing has many limitations.46 Daily fluctuations in basal CRP levels are significant and are 4–6 times greater than cholesterol fluctuations. CRP levels are transiently elevated for 2–3 weeks following a major infection or trauma. Chronic inflammatory conditions like rheumatoid arthritis or lupus will also confuse interpretation of CRP levels. Minor inflammatory stimuli, such as viral infection, skin lacerations and some noninflammatory states (e.g., a low level of physical activity, aging, chronic fatigue, high protein diets, alcohol consumption and depression), are known to influence CRP. Knowledge of these other causes of CRP fluctuations can help interpret its value for cardiovascular risk assessment. Cytokines. IL-6 (an interleukin) is the major cytokine of the acute phase response and is intimately involved in the pathogenesis of ACS.47 It stimulates production of fibrinogen and CRP, triggers the expression of adhesion molecules and TNF, stimulates macrophages to produce tissue factor and MMPs, and stimulates vascular smooth muscle cell proliferation and platelet aggregation. Data from the FRISC-II study group found that circulating levels of IL-6 are a strong independent marker of increased mortality among patients with unstable angina and may be useful in directing subsequent care.48 As seen with other markers of increased risk, an early invasive strategy led to a 65% relative reduction in 1-year mortality among patients with elevated IL-6 levels. By contrast, among those with low IL-6 levels (i.e., lower risk), an early invasive strategy did not confer any significant benefit over a noninvasive strategy. Furthermore, among patients randomized to the non-invasive arm, the risk associated with elevated IL-6 levels was markedly attenuated if they were assigned to therapy with dalteparin rather than placebo.49 TNF-a is a cytokine produced by a variety of cells, including macrophages, endothelial cells and smooth muscle cells. It has an essential role in the amplification of the inflammatory cascade. High levels of TNF-a identify stable patients with CAD at risk for recurrent cardiovascular events,50 but its short plasma half-life has limited its clinical utility as a screening tool. Cytokine levels are usually undetectable in plasma of stable patients with CAD. While cytokines may be more immediate to the underlying vascular inflammation of ACS than CRP, cytokine measurements are unavailable for routine clinical use. CD40 ligand. CD40L is a transmembrane protein that is structurally related to TNF-a. Soluble CD40L (sCD40L) is released from both stimulated lymphocytes and activated platelets.51–53 Both membrane-bound and soluble forms of this ligand can interact with the CD40 receptor, which is expressed on B-lymphocytes, macrophages, endothelial cells, vascular smooth muscle cells and activated platelets. Binding results in various inflammatory responses. It has been suggested that CD40-CD40L interaction plays a pathogenic role in inflammatory disorders, such as autoimmune disease, multiple sclerosis, cardiac allograft rejection and platelet transfusion reactions. Increasing evidence suggests that CD40L plays an important part in coronary disease progression and plaque destabilization.54,55 Stimulation of endothelial cells by CD40L causes increased expression of adhesion molecules and cytokines and triggers production of IL-12, a potent differentiation factor for naive T-helper cells, which stimulates their clonal expansion. Advanced human atheroma contains numerous T-cells, and relevant to the process of plaque rupture, T-cells account for about 20% of the cells in the highly friable shoulder region of the degenerating plaque.56 Membrane-bound and sCD40L may promote MMP expression in vascular smooth muscle cells and macrophages. The proatherogenic role of CD40 signaling is further supported by experimental animal studies in which atheromatous plaques can be “stabilized” by administering anti-CD40L antibody.52 CD40L also serves as a link between platelets and leukocytes. sCD40L contains a binding motif specific for the major platelet integrin IIb/IIIa.57 In fact, CD40L has been demonstrated to be a glycoprotein IIb/IIIa ligand and a platelet agonist and to be necessary for stabilizing arterial thrombi.58 Because platelets possess in their alpha granules a large array of proinflammatory molecules, a direct link between platelets, inflammation and atherosclerosis exists. The CD40-CD40L interaction induces expression of procoagulant tissue factor from monocytes, endothelial cells and smooth muscle cells.59,60 Clinically, apparently healthy women with increased sCD40L are at increased risk for cardiovascular events.55 Elevation of sCD40L is detectable in the serum of patients with ACS56 and serves as a prognostic marker, with higher levels indicating a significantly increased risk of death or MI. Lipoprotein-associated phospholipase A2 (Lp-PLA2). A2-phospholipase are a family of enzymes that hydrolyze phospholipids to generate lysophospholipids and nonesterified fatty acids (mainly arachidonic acid). Lysophospholipids and products derived from arachidonic acid (prostaglandins and leukotrienes) participate in many vital cellular functions, including signal transduction, inflammation and smooth muscle cell proliferation. Several recent reports link these to atherogenesis and the risk of developing coronary disease.61,62 The West of Scotland study group reported that baseline levels of Lp-PLA2 were a strong independent predictor for incident coronary heart disease in a cohort of high-risk hyperlipidemic men.63 The results showed that those with the highest levels of Lp-PLA2 had twice the risk of an event compared to those with the lowest levels, even after adjustment for traditional risk factors and other inflammatory mediators, including CRP. Elevated PLA2 has also been associated with increased risk of cardiovascular events in women.64 The Atherosclerosis Risk in Communities (ARIC) study showed that elevated levels of Lp-PLA2 are higher in incident coronary disease cases. In individuals without elevated LDL levels (i.e., Matrix metalloproteinases (MMPs). MMPs are a family of enzymes involved in the focal destruction of extracellular matrix. Recent findings have revealed enhanced expression of MMP in the shoulder regions of plaque at sites where fissuring is commonly observed. This renders plaque more susceptible to mechanical stresses and therefore more vulnerable to rupture. Inflammatory mediators, such as TNF-a, CD40L and IL-1, upregulate MMP activity in macrophages and this interaction may represent a link between inflammation and plaque degeneration. Circulating MMP-1, -2 and -9 were elevated on admission in patients with acute MI and unstable angina, and high levels of MMP-9 were identified in atherectomy specimens from patients with recent plaque rupture.66–70 Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase enzyme and a specific activator of insulin-like growth factor, a mediator of atherosclerosis. In a small, case-control study, circulating levels of PAPP-A were higher among patients with unstable angina or acute MI than among patients with stable angina and controls.71 Among patients with ACS, levels of PAPP-A and CRP were highly correlated. Cellular adhesion molecules. Increased surface expression of adhesion molecules, such as E-selectin, ICAM-1 and VCAM-1, is involved in arresting leukocyte rolling and promoting adhesion. Activation of endothelial cells by CRP or IL-1 is associated with a 10-fold increase in ICAM-1 and VCAM-1 expression in human coronary artery endothelial cells. The extracellular portion of these adhesion molecules is cleaved and detected in serum as soluble cell adhesion molecule. In the ARIC study, subjects in the highest quartile for ICAM-1 had more than 5 times the risk for incident coronary heart disease or carotid atherosclerosis compared with subjects in the lowest quartile, even after adjustment for other risk factors.65 The findings from ARIC were confirmed in the Physicians’ Health Study,72 in which relative risk for MI was 1.6 in men with circulating or soluble ICAM-1 in the highest quartile compared with the lowest. This association persisted after adjusting for other risk factors, and in multivariate analyses, the risk for MI was 80% higher in men with sICAM-1 in the highest quartile. A number of studies have shown that soluble forms of adhesion molecules are increased in patients with ACS.73–76 Myeloperoxidase (MPO). MPO is an enzyme secreted by neutrophils, monocytes and certain tissue macrophages, including those found in atherosclerotic plaques. The enzyme is released when leukocyte activation and degranulation occurs. MPO may convert low-density lipoprotein into a form for rapid uptake by macrophages, leading to increased foam cell formation, and it may also help deplete NO. In a recent clinical study, high levels of leukocyte MPO and blood MPO were significant predictors of the risk for coronary disease.77 Leukocytes. Elevated white blood cell count (WBC) in patients with unstable angina and non-ST elevation MI is associated with impaired epicardial and myocardial perfusion, more extensive CAD and higher 6-month mortality.78 Although the ARIC study65 found a clear association between WBC and coronary heart disease, the difference in average values was small (7.2 versus 6.6). Since WBC may vary in patients from day to day and also be influenced by several intercurrent illnesses, such as a common cold, it is doubtful that this marker alone could be used in daily practice. Serum amyloid A (SAA). SAA is an acute phase inflammatory protein that has been linked to adverse cardiovascular outcomes.79 Meta-analysis of 4 studies reporting SAA values and incident coronary disease, following a total of 1,057 patients over 10 years, calculated a risk ratio for the combined data of 1.6 (95% confidence interval, 1.1–2.2). SAA is a non-specific marker that occurs in association with chronic infections, as well as inflammatory disorders such as rheumatoid arthritis and neoplasia. Recently, an SAA-LDL complex has been suggested as a prognostic marker for patients with stable CAD.80 As understanding of the role of inflammation in coronary disease and ACS has become more clear, it is helpful to review the anti-inflammatory aspects of current ACS therapy and consider avenues for potential future treatments (Table 2). Aspirin. Although known for many years to be a platelet anti-aggregating agent through inhibition of the cyclooxygenase-1 (COX-1) enzyme, aspirin is now becoming more recognized for its anti-inflammatory properties. Indeed, the antiplatelet and anti-inflammatory actions are probably linked, now that we know platelets can interact through CD40L with leukocytes and accelerate the inflammatory cascade. In primary prevention, the magnitude of risk reduction attributable to aspirin appears to be greatest among those with elevated CRP, again reemphasizing the importance of the vascular inflammatory state.81 Selective inhibition of cyclooxygenase (COX-2). The isoenzyme COX-2 is a highly inducible enzyme responsible for the generation of inflammatory prostaglandins at sites of inflammation, including the vascular walls. COX-2 messenger ribonucleic acid (mRNA) and protein have been found to be expressed in atherosclerotic, but not in normal, coronary arteries. Recognition of the roles of this enzyme has spurred the development of specific COX-2 inhibitors, which target COX-2 but do not affect the homeostatic activity of COX-1. A potential clinical benefit of COX-2 inhibition in coronary disease has been suggested experimentally82,83 and clinically.84,85 However, other data have raised serious questions about the cardiovascular effects of COX-2 inhibition.86,87 Additional research will be needed to further clarify this issue. Statins (Table 3). While used primarily to reduce levels of LDL cholesterol, statins are becoming more widely appreciated (like aspirin) as inhibitors of inflammation. For example, CRP levels decline 15–25% as early as 6 weeks after initiation of statin therapy, and the reduction in CRP with statin treatment is not related to the magnitude of LDL reduction, suggesting a different mechanism. Clinical risk reduction with statin therapy is particularly large in patients with elevated CRP levels. In the CARE trial of secondary prevention, the risk reduction associated with pravastatin use was nearly 55% for those with elevated CRP levels, compared to 30% reduction for those with low CRP.88 The MIRACL trial89 evaluated the effect of treatment with atorvastatin 80 mg/day, initiated 24–96 hours after hospital admission for ACS. There was a reduction in ischemic events at 16 weeks irrespective of the baseline lipid values. In the AFCAPS/TexCAPS primary prevention trial, lovastatin was highly effective among those with elevated CRP levels, even when LDL levels were only moderately elevated.90 Statin therapy initiated before percutaneous intervention is associated with a marked reduction in mortality among patients with high CRP levels. It has been shown that statins have effects on endothelial function beyond those directly attributable to any lipid lowering. Cerivastatin improves endothelial function of the brachial artery in elderly patients with diabetes in as little as 3 days, well before any appreciable lowering of cholesterol can be detected in serum samples.91 Augmentation of vasodilatation was noted in the human forearm just 24 hours after administration of atorvastatin 80 mg, again before any change in cholesterol level was noted.92 These beneficial effects of statins are believed to involve the Rho-kinase pathway. Rho-kinase has proatherogenic effects, including causing a decrease in NO synthase and plasminogen activator inhibitor-1 (PAI-1). Statins inhibit this pathway. Statins can block integrins93 and decrease MMP secretion.94,95 For all of these reasons involving both lipid reduction as well as inflammation, the clinical use of statins is likely only to increase in the future. Thienopyridines. Pretreatment with clopidogrel prior to PCI has been associated with reduced rates of death and MI, likely by preventing thrombosis, but the benefit was especially pronounced in patients with a high baseline CRP.96 Clopidogrel also attenuates the periprocedural rise of CRP,97 something that does not seem to occur with low-dose aspirin.98 There may be synergistic effects from the combination of aspirin and clopidogrel on other markers of platelet activation, such as P-selectin.99 This helps provide mechanistic support for an anti-inflammatory benefit of combined aspirin and clopidogrel, as was suggested in the CURE trial.100 Thiazolidinediones (TZDs). TZDs are oral insulin sensitizers that enhance glucose uptake by skeletal muscle. TZDs also are ligands for the nuclear receptor, peroxisome proliferator activator receptor gamma (PPAR-gamma). The PPAR-gamma receptor is a member of a nuclear receptor superfamily that functions as a key transcriptional regulator of both lipid metabolism and cell differentiation. All of the major cell types in the vasculature express PPAR-gamma, including intimal macrophages and vascular SMCs in human atheroma.101 TZDs block vascular SMC growth by inducing cell cycle arrest in G1 phase. Migration of monocytes and vascular SMCs is inhibited by TZDs, possibly through decreased MMP production. PPAR-gamma agonists inhibit the expression of VCAM-1 and ICAM-1 in activated endothelial cells and significantly decrease the homing of macrophages and monocytes to atherosclerotic plaques.102 Angiotensin-converting enzyme inhibitors. Studies indicate angiotensin-II enhances synthesis and release of IL-6, an effect that can be blunted by angiotensin-converting enzyme (ACE) inhibition.103 Because IL-6 mediates B-lymphocyte maturation, complement activation and cytokine release, ACE inhibitors may provide anti-inflammatory protection by suppressing these proinflammatory cytokines. ACE has been found in the shoulder region of the atherosclerotic plaque at sites of clustered macrophages, and ACE activity appears enhanced in unstable human plaques compared to stable lesions.104,105 Several clinical trials have reported that ACE inhibition in patients with documented coronary disease (and especially after MI) not only reduces the occurrence of heart failure from left ventricular remodeling, but also lowers the incidence of other cardiovascular acute ischemic events such as stroke, unstable angina and (re)-MI.106–108 Alcohol. Moderate alcohol consumption (5–7 drinks per week), has been associated with lower CRP levels than only occasional or no alcohol intake. In fact, systemic inflammatory markers, including CRP, alpha globulins and leukocyte counts have a J-shaped relationship with alcohol consumption.109,110 That is, light to moderate alcohol intake is associated with lower levels of these markers (and lower cardiovascular mortality) than either heavy or no intake.111–115 Moderate alcohol use has been reported to enhance antioxidant effects, possibly through polyphenolic components of blended spirits. This reportedly may inhibit vascular SMC migration, a critical component of atherosclerosis. Moderate alcohol consumption may also impair IL-6 production, and increase plasminogen activator-1 levels.116–119 Antibiotics. Current research on the infective etiology of coronary disease has focused mainly on the chlamydia pneumonia and helicobacter pylori organisms. Some upper respiratory tract illnesses have been associated with increased risk of ischemic heart disease and stroke. Possible mechanisms include alteration in clotting factors, platelet aggregation, concentration of inflammatory response proteins and alteration in cytokine concentrations. In a 1-year follow-up study of 325 patients admitted with acute MI or unstable angina, patients were randomized to either 1 week of placebo, amoxicillin/metronidazole/omeprazole or azithromycin/metronidazole/omeprazole. CRP decreased in patients with unstable angina receiving amoxicillin, while fibrinogen levels were reduced in both antibiotic groups. Death or readmission with ACS was decreased by 36% at 3 months with antibiotic use, and this difference persisted during a 1-year follow-up.120 Influenza vaccination is associated with reductions in the risk of hospitalization for cardiac and cerebrovascular disease during influenza season.121 Further studies are needed to confirm these findings and elucidate the mechanisms of benefit of antibiotics and vaccinations in coronary disease patients. Miscellaneous. Cigarette smoking has been shown to increase several inflammatory markers, including CRP, IL-6 and soluble ICAM-1. Smoking cessation decreases these markers. Obesity is directly associated with increased CRP, probably via IL-6, which is secreted by adipose tissue. Attenuation of the inflammatory response may represent a mechanism by which diet and weight loss reduce cardiovascular risk. Physical exercise has also been shown to have a beneficial effect in terms of reducing the concentration of several inflammatory markers.122,123 Novel Therapies Antileukotriene drugs. Leukotrienes have vasoconstrictor effects in diseased arteries. They increase vascular permeability and SMC proliferation, facilitate neutrophil adhesion to endothelial cells and regulate angiotensin-II mediated vascular effects. Increased excretion of leukotrienes and increased activation of the 5-lipoxygenase pathway are noted in patients with diabetes mellitus. Leukotriene pathways are fertile potential targets in the search for treatments for vascular disease.124 Toll-like receptor 4 (TLR4) is a receptor for bacterial lipopolysaccharides, and also recognizes cellular fibronectin as well as heat shock protein (HSP-60), which are endogenous peptides that are produced in response to tissue injury. HSP-60 may be a trigger of arterial inflammatory reactions. Recently, the TLR4 receptor has been suggested as another link between infection/inflammation and arteriosclerosis. A functional TLR4 is expressed in human adventitial fibroblasts and macrophages, and activation induces the production of proinflammatory cytokines, which in a mouse model augmented neointima formation. These results provide evidence for a link between the immune receptor TLR4 and intimal lesion formation. The TLR4 receptor may be a potential candidate in the search for new ways to inhibit the development of atherosclerotic vascular disease.125 Conclusion In this review, we have seen how various biochemical reactions that are grouped under the heading of inflammation have been found to be involved in the development and progression of atherosclerotic vascular disease and its clinical consequences, especially the acute coronary syndromes. We have outlined some of the inflammation-related factors and how they fit into the schema of atherosclerosis. Inflammation especially is responsible for the degeneration of plaques that leads to their sudden rupture, producing ACS. When it comes to primary or secondary prevention of heart disease, treating inflammation ultimately may become just as important as, for example, treating lipids. Traditional risk factors allow clinicians to predict only about 50% of the variation in the absolute risk of a cardiovascular event in individual patients. Inflammatory-related risk factors may account for some or perhaps even most of the remaining unexplained variation. Further insight into this important area will come from the inclusion of inflammatory markers into ongoing randomized trials, whereby the level of inflammatory activity and its response to therapy (or lack thereof) may be correlated with clinical outcome. While as yet only a few of the inflammatory-related markers have made their way into clinical use (CRP for example), the current era of research suggests that additional marker substances or perhaps even genetic profiles may in the future be available to help identify individual risks more precisely.

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