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Risk factors in coronary atherosclerosis athero-inflammation: the meeting point
Thrombosis Journal volume 1, Article number: 4 (2003)
Following Russel Ross , there is now general agreement that vessel wall inflammation constitutes a major factor in the development of atherosclerosis, atheroma instability and plaque disruption followed by local thrombosis, that underlies the clinical presentation of acute coronary syndromes [2–4]. Endothelial-cell injury is the main stimulus for development of the atherosclerotic plaque: an inflammatory-fibroproliferative response results from various forms of insult to the endothelium.
Arterial endothelium changes rapidly in response to specific stimuli. Elevated and modified LDL, cigarette smoking, hypertension, diabetes mellitus, genetic alterations, increase of plasma homocysteine, and infectious microorganisms such as herpes virus or Chlamydia pneumoniae, were considered by Ross as possible causes of endothelial dysfunction . In atherosclerosis and other diseases, dysfunctional vascular endothelium leads to leukocyte recruitment. The initial phase of inflammation is usually silent and the atherosclerosis preclinical window is fairly long. In altered arterial endothelium there is increased monocyte adhesion as well as impaired nitric oxide production and vascular relaxation . Adherence of monocytes to the endothelial surface is facilitated by the expression of the adhesion molecules vascular cell adhesion molecule-1 (V-CAM 1) and intercellular adhesion molecule-1 (ICAM-1).
Endothelial function is a balance between vascular cell protectors and risk factors. Under physiological conditions, vascular endothelium has antithrombogenic potential. Activation of endothelia cells by proinflammatory cytokines or infectious agents is associated with a loss of antithrombotic properties. Endothelial dysfunction, injury and inflammation induce cell imbalance and a normal endothelium with anticoagulant properties becomes prothrombotic. Endothelial dysfunction is associated with a decrease of nitric oxide and an increase of oxidative stress, an important promotor of the inflammatory process [6, 7] Risk factors, either acute (infection, immune local reaction) or permanent (hypertension, diabetes, dyslipemia, obesity, hyperhomocysteinemia, smoking, etc) induce endothelial dysfunction, cell injury, and a proinflammatory environment resulting in a local, tissue factor mediated activation of the clotting cascade [6, 8, 9]. In addition, it seems that expression of tissue factor in endothelial cells and monocytes is partly regulated by the proinflammatory cytokines tumor necrosis factor and interleukin-1. Also, interaction of tissue factor and P-selectin accelerates the rate and extent of fibrin formation .
In the presence of cardiovascular risk factors, not all individuals respond with an arterial thrombotic process, suggesting that several additional factors might be involved in coronary events; for instance, behavior of plasmatic coagulation activation, local blood flow conditions (shear stress), circulating progenitor cells, and genetic factors. Inappropriate generation of thrombin may lead to vascular occlusion . In the atheroma environment, procoagulant and anti-coagulant forces together with pro / anti fibrinolytic substances determine a delicate balance.
Hereditary or acquired defects of blood clotting factors, impairment of the anticoagulant system or fibrinolytic mechanism, and inflammation, could promote plasmatic and local hypercoagulation state. Local thrombin generation not only results in a mixed, fibrin/platelets clot but thrombin itself has proinflammatory activity . Plaque in unstable angina possesses elevated levels of tissue factor that could be released during inflammation, precipitating acute clinical syndromes.
Local hemodynamic forces play an important role in thrombogenesis in at least two ways: first, physically, as modulators of endothelial function [13, 14] by decreasing the vasodilator substances prostacyclin and nitric oxide, or by increasing the vasocontrictor endothelin-1; second, as in situ modulators of clotting balance (triggering platelet activation and over-expression of tissue factor), of fibrinolysis, and of thrombin generation.
The role of inflammation in thrombosis probably varies according to the pathogenesis of the syndrome. With the focus on coronary occlusive disease, there are other origins of thrombotic events beside plaque rupture [15, 16]. In atheroma the luminal surface is irregular and sometimes eroded, and the lack of endothelial cells constitutes a vulnerable site, as prone to acute thrombosis as lipid-rich plaques are . The flow zone distal to the apex of the plaque, characterized as a "low shear-stress" region, is prone to fibrinogen deposition  and involves areas of flow recirculation, stagnation points and flow reversal, with changes in the metabolic activities of endothelial cells . Blood turbulence produces platelet and clotting activation, accelerates thrombin formation and promotes a mixed thrombus . In these circumstances, platelets are not only involved in haemostasis but also in initiating the inflammatory response.
CD40 ligand (CD40L, CD154), a transmembrane protein structurally related to the cytokine TNF-alpha, is of paramount importance in the development and function of the humoral immune system. Activated platelets express CD40L and induce endothelial cells to secrete chemokines and to express adhesion molecules, indicating that platelets could initiate an inflammatory response of the vessel wall .
According to a recent report, bone marrow cells give rise to most of the smooth muscle cells that contribute to plaque formation . Circulating endothelial progenitor cells contribute to the repair capacity of endothelium . Whether endothelial injury in the absence of sufficient circulating progenitor cells affects the balance between injury and the repair capacity of endothelium, determining the progression of the lesion and of cardiovascular disease, is a matter of debate  that may provide important insights into the links between inflammation and atherosclerosis.
Genetic predisposition to atherosclerosis was studied in the general population, using carotid artery intima-media thickness as a measure. A positive parental history of myocardial infarction or stroke was associated with increased carotid artery thickness at specific sites in the carotid tree, independently of conventional risk factors [23, 24]. Follow-up studies of coronary stenting provided additional support for the central role of inflammation. Indeed, stent produces a prolonged, intense inflammatory state with recruitment of leukocytes, mainly monocytes. There is strong link between the extent of medial damage, inflammation and restenosis . Additional data were reported by Moreno et al. . These authors found a positive correlation between the number of macrophages present in the tissue at the time of angioplasty and the propensity for restenosis.
Markers of Inflammation
As result of chronic inflammation, numerous markers such as CPR (C-reactive protein), cytokines (interleukin-6 and 18, tumor necrosis factor α), adhesion molecules (ICAM-1), E-selectin and acute-phase reactants related to the clotting system (e.g. fibrinogen) are increased in plasma, possible predictors of further cardiovascular events [27–32]. Interleukin-18 plays a key role in the inflammation cascade and is an important regulator of both innate and acquired immunities . It induces the production of interferon-γ and T-lymphocytes, has been found in human atherosclerotic lesions, and was identified as a strong independent predictor of death from cardiovascular causes in patients with stable as well as unstable angina. Inhibition of interleukin-18 reduced lesion progression with a decrease of inflammatory cells.
Matrix metalloproteinase (MMP-9) (gelatinase B), secreted by macrophages and other inflammatory cells, has been identified in various pathological processes such as general inflammation, tumor metastasis, respiratory diseases, myocardial injury, vascular aneurysms, and remodeling. MMP-9 is elevated in patients with unstable angina . Blankenberg et al.  noted a strong association between baseline MMP-9 levels and future risk of CV death, independent of IL-18. Combined determination of MMP-9 and IL-18 identifies patients at very high risk.
Proinflammatory cytokines derived from monocytes, macrophages and/or adipose tissue trigger CRP in the liver. C-Reactive protein is an acute-phase reactant, a marker of inflammation, and predicts early and late mortality in patients with acute coronary syndromes. It is an independent predictor of future cardiovascular events . CRP itself promotes inflammation  and atherogenesis via effects on monocytes and endothelial cells and increasing the concentration and activity of plasminogen activator inhibitor-1 . CRP in atheroma participates in the pathogenesis of unstable angina and restenosis after coronary intervention . Thus, there is a vicious circle: inflammation releases proinflammatory cytokines, which in turn maintain inflammation. In a subset of healthy men in the Physicians Health study, the benefit of aspirin (325 mg/day every other day) was most significant in patients within the highest quartile of C-reactive protein elevation compared with the lowest quartile. In patients with coronary artery disease, aspirin also seems to reduce C-reactive protein levels . Components of the metabolic syndrome (obesity, hypertension, hypertriglyceridemia, low HDL, abnormal glucose) are associated with increased levels of CRP and add prognostic information on further cardiovascular events . Statin as aspirin therapy was particularly effective among patients with high CRP levels . It seems clear that CRP is a marker for risk for cardiovascular events, but whether it should be used in routine screening is still a matter of debate [42–45].
Inflammation Mediate Risk Factors
Pleiotropic atheroprotective activity of specific treatments involving antiinflammatory properties
Although diabetes mellitus is primarily a metabolic disorder, it is also a vascular disease .
The most important cause of death among diabetic patients is cardiovascular complication. Comparing diabetic patients with non-diabetic patients both with or without prior history of cardiovascular events, Haffner et al.  showed, after a follow-up of 7 years, that mortality in diabetic patients was higher than in non-diabetics and that for diabetic patients with no history of myocardial infarction, the risk of myocardial infarction was similar to that of non-diabetic patients who did have such a history. These data suggest that diabetic patients have already developed vascular disease by the time of clinical diagnosis . Although type 2 diabetes is a state of increased plasma coagulability , it is clear that endothelial dysfunction is the most important factor in thrombotic complications. It is present mainly in type 2 diabetes than type 1 [49, 50]. The so called metabolic syndrome, a concurrence of disturbed glucose and insulin metabolism, overweight and abdominal fat distribution, moderate dyslipemia and hypertension, might be responsible for the vascular endothelial dysfunction. Indeed, cardiovascular disease and all causes of mortality are increased in men with metabolic syndrome .
As indicators that the endothelium is compormised, microalbuminuria and proteinuria are frequently present in diabetic patients and constitute predictors of cardiovascular events and ischemic stroke [52–54]. Hyperglycemia and production of advanced glycation end products (AGE) are probably the most important factors, if not the only factors, in endothelial dysfunction in diabetics. By binding specific receptors (RAGE), AGE induces the expression of different proinflammatory molecules. Endothelial dysfunction could be also consequence of the dyslipidemia frequently present in type 2 diabetes and oxidative stress .
Diabetic patients have impaired endothelium-dependent vasodilatation, hyper-coagulability, increased PAI-1 level in the arterial wall with impaired fibrinolysis, decrease of endothelial nitric oxide synthase, and increase of endothelin-1 . Platelets are larger, with an increased number of glycoprotein IIb-IIIa receptors in the membrane, and are hyper-reactive and show enhanced biosynthesis of thromboxane A2 [57, 58]. Platelets from diabetic subjects behave abnormally, showing increased adhesiveness as well as spontaneous and agonist-induced aggregation, reflected by abnormalities in platelet function tests [59, 60]. Von Willebrand factor, mainly synthesized by endothelial cells and involved in platelet adhesion, is increased, reflecting endothelial activation or damage .
Although diabetic patients presented with thrombophilic profiles, in diabetics with acute coronary syndromes without ST-segment elevation, or following percutaneous coronary intervention, inhibitors of the platelet receptors glycoprotein IIb-IIIa reduced mortality compared with non-diabetics. This remains unexplained at present and is at odds with the hyper-reactivity of platelets seen in these patients [62, 63].
It is known that cytokine release and processes leading to macrophage activation are enhanced in diabetics  and contribute to the development of athero-inflammatory complexes. The blood level of C-RP is generally higher in diabetic patients than in normal populations indicating that inflammation contributes to the development of the disease . Low grade inflammation is involved in the pathogenesis of type-2 diabetes. Results from the MONICA study  showed that men with CRP in the highest quartile (≥ 2.91 mg/L) had a 2.7 times higher risk of developing diabetes than those in the lower quartile (≤ 0.67 mg/L).
Lastly, a novel group of antidiabetic drugs, thiazolidinediones, exhibit anti-inflammatory properties in addition to their plasma glucose lowering effect. Type 2 diabetic patients with coronary artery disease have high levels of inflammatory markers, including serum C-reactive protein, metalloproteinase-9, white cells count, tumor necrosis factor-α and serum amyloid A [67, 68]. Since treatment with rosiglitazone significantly reduces these inflammatory markers it could indicate a link between diabetes, coronary disease and inflammation.
In atherosclerosis, signs of inflammation are accompanied by incipient lipid accumulation in the artery wall . Several factors determine endothelial modifications through a primary inflammatory response followed by a local prothrombotic balance.
LDL oxidation is a main cause of endothelial injury and induces the expression of proinflammatory molecules in endothelial cells. Thus removal of modified LDL is important in the treatment of the inflammatory response.
Several studies have reported high levels of total tissue factor pathway inhibitor (TFPI) antigen in patients with serum elevated cholesterol. Increased TFPI inhibit the extrinsic coagulation system, but the procoagulant system may be activated concurrently. The median levels of total TFPI, free TFPI, FVIIc and prothrombin fragments 1+2 were higher in hyperlipidemic patients than healthy subjects. The increase of fragments 1+2 indicates a global thrombophilic state [70, 71]. These blood changes follow the endothelial inflammatory reaction.
Other lipids have also active inflammatory effects; notably, high plasma levels of VLDL are associated with increased risk of atherosclerosis. In this regard, Dichtl et al  showed that VLDL (75 to 150 μg/mL) activates nuclear factor-κB (NF-κB), a transcription factor known to play a key role in regulation of inflammation, in cultured human endothelial cells. There was also expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, as well as proinflammatory molecules such as the cytokine tumor necrosis factor-α. Injected triglycerides, precursors of LDL, also activate arterial expression of NF-κB. In line with this result, postprandial hypertriglyceridemia is considered a risk factor for cardiovascular disease. It was suggested that postprandial hypertriglyceridemia induces endothelial dysfunction through oxidative stress .
Lipoprotein (a) has a structure similar to that of plaminogen and may reduce plasmin generation and impair fibrinolysis, inducing a prothrombotic state. Elevated levels of lipoprotein (a) might strongly predict endothelial dysfuction in normocholesterolemic and non-diabetic subjects .
Oxidative inactivation of nitric oxide is regarded as an important cause of endothelial lesion. Decreased nitric oxide may favor platelet-adhesion/aggregation and arterial thrombosis. One of the pathophysiological consequences of platelet binding to LOX-1 may be the inactivation of nitric oxide (NO) through increased cellular production of O2 .
Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) reduce cardiovascular disease events and improve outcomes. These benefits have been attributed to their LDL-lowering (and potentially HDL-elevating) effects. However, several trials have suggested that the clinical benefit of statins is greater than expected from the lowering effect on lipids . Analysis of large clinical trials indicates that statin-treated individuals have significantly less cardiovascular disease irrespective of their serum cholesterol levels and the treatment is particularly effective among patients with high CRP levels [77, 78]. Long-term statin therapy has been shown to reduce levels of C-reactive protein in a lipid-independent manner . Additional effects were observed: statins limit tissue factor expression , normalize fibrinolytic activity, reduce plaque inflammation and cause regression of human atheroesclerotic lesions , improve coronary endothelial function  and have antiinflammatory and antiproliferative effects . In this regard, statins are potent upregulators of endothelial cell nitric oxide synthase levels and nitric oxide synthesis. In a rabbit model and in cultured vascular smooth muscle cells, atorvastatin decreased inflammatory mediators in the atherosclerotic lesion and significantly downregulated COX-2 both in vitro and in vivo . Other effects may also be mediated through nonlipid changes: Statins significantly increase circulating endothelial progenitor cells , contributing to the repair capacity of endothelium . Also, statins exert beneficial effects in vascular diseases by inhibition of leukocyte rolling, adherence, and transmigration. All statins are potent reversible inhibitors of the key enzyme in cholesterol synthesis but their pharmacological profiles differ . For instance, it was found that atorvastatin reduced CPR and serum amyloid whilst simvastatin had little or no effect on these variables. Levels of IL-6 and ICAM-1 were also inconsistent and little modified .
Moderate drinking had a lipid lowering effect and alcohol intake, at least three to four days per week, was associated with protection from cardiovascular events. The risk was similar among men who consumed less than 10 g of alcohol per drinking day and those who consumed 30 g or more. No single type of beverage conferred additional benefit . Alcohol intake also lowered the C reactive protein level, independently of effects on lipids, indicating antiinflammatory activity . Thus, there are several effects of statins besides their lipid lowering activity that could be attributed to their antiinflammatory capacity and could be relevant to the improvement of altered local and systemic factors.
It has been consistently reported that increasing degrees of obesity are accompanied by greater rates of cardiovascular disease [90, 91]. Obesity is an independent risk factor for major coronary events although hypercholesterolemia and the metabolic syndrome are often associated with it [92–94]. Obese subjects typically carry a proinflammatory state that may predispose them to acute coronary syndromes. This state is characterized by elevations of serum CRP that reflect high cytokine levels . Excess adipose tissue secretes increased amounts of several inflammatory cytokines. Interestingly, weight loss produces a reduction of CRP levels , and serum concentrations of IL-6, IL-18 and adiponectin levels are increased significantly . This indicates that weight control could diminish the inflammatory state. Adipose tissue present in excess also releases increased amounts of plasminogen activator inhibitor-1 (PAI-1), which imbalances the fibrinolytic system towards prothrombosis [98, 99].
Leptin, a circulating hormone produced by adipose tissue, regulates body weight and food intake and metabolism. It can influence vessel tone and an increase amount of leptin, as in obesity, could contribute to arterial vessel stiffness, impaired vascular function and cardiovascular events. Leptin has angiogenic activity, increases oxidative stress in endothelial cells which could contribute to vascular pathology, and promotes vascular cell calcification and smooth muscle cell proliferation and migration [100, 101]. Although the release of leptin may cause local vasodilation mediated by nitric oxide, with time it increases oxidative stress, followed by a decrease of bioactivity and / or synthesis of nitric oxide and increase of inflammatory mediators .
Inflammation as an immune-mediated disease. Role of infection
Mediators of innate and acquired immunity are involved at various stages of atherosclerosis, as might be anticipated for a chronic inflammatory process . In the chronic state, atheromata contain immune cells: T lymphocytes, activated macrophages and mast cells, which are also present in inflammatory infiltrates. This led to the notion that the inflammatory response is immune-mediated, and the involvement of immune mechanisms in atherosclerosis was postulated . Innate immune reactions against bacteria and viruses have been included in the list of pathogenic factors in atherosclerosis. Toll Like Receptors (TLR), known to play a key role in the innate immune response, are expressed in atherosclerotic plaques and are associated with inflammatory activation of endothelial cells and macrophages. The family of toll like receptors, mainly TLR-1, 2 and 4, expressed at low levels in normal endothelium, are markedly increased in macrophages and endothelial cells of human atherosclerotic lesions. Expression of TLR in cultured vascular endothelial cells was increased by stimulation with proinflammatory cytokine . Lipopolysaccharides released during acute infection might link the immune response, bacterial infection and inflammation through TLR activation in plaque cells, endothelial cells and macrophages. This suggests a mechanism by which microbes may cause inflammatory plaque activation. Chlamydia pneumoniae may signal through TLR to induce the proliferation of human vascular smooth muscle cells .
A recent paper by Kiechl et al  offers an additional and interesting contribution to the potential importance of TLR in the relationship between the inflammatory response to gram-negative pathogens, innate immunity and atherogenesis. These authors found that patients with TLR4 polymorphism have lower levels of proinflammatory cytokines, acute phase reactants, and soluble adhesion molecules. Such subjects are more susceptible to severe bacterial infection, but they have lower risk of atherosclerosis as assessed by high-resolution duplex ultrasonography of the carotid artery.
Some research has suggested that acute respiratory infection may be a risk factor for myocardial infarction. An increase of acute coronary events during winter infections and flu epidemics has been related to seasonal variations in factor VIIa and fibrinogen, probably induced via activation of the acute phase response [107, 108]. In these circumstances an immune response could support an inflammatory process and might be associated with increased trafficking of macrophages into the artery wall . Some studies support the assumption that influenza vaccine reduces the risk of recurrent MI in patients with documented coronary heart disease. Naghavi et al  provided indications that in patients with chronic coronary heart disease, vaccination against influenza was negatively associated with the development of new myocardial infarction during the same influenza season. The beneficial effect of vaccination against influenza in the elderly was indicated in the recent paper of Nichol et al. .
Vaccination was associated with a reduction of 19% in the risk of hospitalization for cardiac disease and cerebrovascular disease (reduction of 16 and 23 percent during the 1998–1999 and the 1999–2000 season respectively). Gurfinkel et al.  evaluated the preventive effect of vaccination on ischemic events in myocardial infarction patients and in subjects undergoing planned percutaneous coronary angioplasty. In a small number of patients suffering from infarction, but not in those recovering from angioplasty, influenza vaccination reduced the risk of death and ischemic events.
The antiphospholipid syndrome considered an autoimmune disease triggering endothelial cellular disturbance, produces arterial and venous thrombosis [113, 114]. The high affinity of antiphospholipid antibody-β2GPI complex for phospholipid membranes seems to be a critical factor in this disease . Activation of endothelial cells and enhanced thrombosis by antiphospholipid seem to be mediated by ICAM-1, P-selectin, or VCAM-1 .
The humoral immune response could be a high risk factor for coronary heart disease, inducing inflammation that links immunity with coronary disease.
Infection and the immune local reaction cause endothelial dysfuction, cell injury, and a proinflammatory environment. Whether infection is the main factor involved in inflammation remains unproved [117–125]. Endotoxins secreted by bacteria are potent activators of different inflammatory reactions, stimulating circulating monocytes and causing production of several cytokines. They may also disturb hemostasis .
Interleukin-18 gene expression is stimulated by proinflammatory cytokines and also by lipopolysaccharides. If infection is also a trigger of interleukin-18 this could explain the relationships between inflammation and infection and the controversial association between previous infection and cardiovascular events. It could also explain the erratic effects of antibiotics on the prevention of coronary artery disease.
Expression of toll like receptors in atheroma is a suggested mechanism for inflammatory plaque activation by microbes .
Many seroepidemiology studies suggest a relationship between infection and the pathophysiology of ischemic heart disease and the severity of atherosclerosis [126, 127]. Chlamydia pneumoniae, cytomegalovirus and Helicobacter pylori have been associated with atherosclerotic lesions. Moreover, viral and bacterial proteins can induce anti-phospholipid antibody production in humans which could be an additional factor attacking endothelium . Of these candidate organisms, Chlamydia pneumoniae appears most likely to be involved in coronary disease through different mechanisms. Chlamydia pneumoniae can be replicated and maintained in human macrophages and in endothelial cells. Thus it can participate in the acute coronary process through a direct effect on atheroma, initiating the inflammatory process, or it can remain latent in the atheroma as a bystander, subsequently being activated during inflammation and acutely exacerbating the response. Alternatively, atheroma might be colonized by Chlamydia pneumoniae during plaque inflammation, contributing to plaque disruption.
The controversial role of Chlamydia pneumoniae in coronary events was also indicated by the effect of antibiotic treatment. Chlamydia pneumoniae is sensitive to macrolides (azithromycin, roxithromycin and clarithromycin) , but besides their anti-infectious activity, an alternative mechanism for macrolides was suggested [130–132]: they could suppress macrophage activity, which means they could have antiinflammatory effects, different for each drug. Controversial results could be related to these different antiinflammatory effects.
Elevated circulating homocysteine (tHcy) level is a risk factor for occlusive disease in the coronary, cerebral, and peripheral vessels and predictive of survival in patients with stable coronary artery disease. Nevertheless a causal relation still remains to be proven [133–136].
The Homocysteine Studies Collaboration concludes that evidence of a link between higher homocysteine levels and the risk of coronary disease is weaker than previously reported . It had been suggested that serum homocysteine level on hospital admission was an independent predictor of long-term survival in patients with acute coronary syndromes, but a meta-analysis of the observational studies suggests only a modest independent prediction of ischemic heart disease and stroke risk in healthy populations. Nurk et al.  provide evidence that plasma homocysteine level is a strong predictor of cardiovascular disease only in elderly patients, and especially among those with preexisting cardiovascular disease. Thus homocysteine interacts with conventional risk factors to provoke the acute event. Klerk et al.  indicate that individuals with the MTHFR 677 TT genotype have a significantly higher risk of coronary heart disease, particularly in the setting of low folate status, and support the hypothesis that impaired folate metabolism, resulting in high homocysteine levels, is causally related to a 16% increased risk of coronary heart disease. Nevertheless, the excess risk was evident only in European studies, not in North American investigations .
The link between homocysteine and coronary disease may be mediated by activation of coagulation and alteration of the vasomotor regulatory and anticoagulant properties of endothelial cells [140–142]. Impaired homocysteine metabolism may result in oxidative stress , which might play a central role in hyperhomocysteinemia-mediated vascular disorders [144, 145]. Homocysteine increases TNF-expression, which enhances oxidative stress and induces a proinflammatory vascular state that may contribute to the development of coronary atherosclerosis .
It has also been suggested that enhanced peroxidation of arachidonic acid to form bioactive F2-isoprostanes could represent the mechanism linking hyperhomocysteinemia to platelet activation in cystathionine β-synthase deficient patients .
A recent report showed that folic acid, vitamin B12, and pyridoxine significantly reduce homocysteine levels, the rate of restenosis and the need for revascularization after coronary angioplasty [148, 149]. But in the paper by Doshi et al., folic acid 5 mg/d for 6 weeks improved endothelial function, as assessed by flow-mediated dilatation in cardiovascular artery disease, by a mechanism independent of homocysteine .
The renin-angiotensin system contributes to the pathogenesis of atherosclerosis. Its effect on blood pressure partially explains this; also, angiotensin II may elicit inflammatory signals in vascular smooth muscle cells. The transcription factor NF-κB participates in most signaling pathways involved in inflammation . Angiotensin II is a regulator of the NF-κB family and may be responsible for activating the expression of cytokine gene networks in vascular smooth muscle cells. It can also promote long-term changes in vascular smooth muscle cell function by its ability to induce cellular hypertrophy, extracellular matrix production, and early gene expression . Angiotensin II also activates inflammatory pathways in human monocytes.
L-Arginine, a nitric oxide precursor that augments endothelium-dependent vasodilatation, acutely improves endothelium-dependent, flow-mediated dilatation of the brachial artery in patients with essential hypertension . As mentioned during the discussion of other risk factors, inflammation may link hypertension and atherosclerosis, and the clinical benefits of treatment with angiotensin-converting enzyme inhibitor may to some extent derive from interrupting inflammation .
Cigarette smoking is a major risk factor for developing coronary artery disease, producing a marked decline in endothelium-dependent vasomotor response [154–156]. It causes endothelial dysfunction, possibly through increased oxidative stress, and this is also true for passive smoking or environmental tobacco smoke. A 30-minute passive smoking exposure was found to affect coronary flow velocity reserve in nonsmokers . Light and heavy smoking have similar detrimental effects on endothelium-dependent vasodilation and the nitric oxide biosynthetic pathway . Significant increases of sICAM-1 and sVCAM-1 were demonstrated in smokers, and nitric oxide metabolites were reduced significantly . Smoking-induced endothelial dysfunction of resistance vessels is rapidly reversed with oral allopurinol. These data suggest that xanthine oxidase contributes importantly to the endothelial dysfunction caused by cigarette smoking . Folic acid significantly improves endothelial function in otherwise healthy cigarette smokers. This provides a potential therapeutic tool for attenuating the atheromatous process in this group .
The new findings add evidence for a close relationship between risk factors, inflammation and atherosclerosis. Inflammation is the common response of endothelial cells to different factors that attack arterial intima. Taking into account this chain of local arterial endothelial cell reactions, the behavior of inflammation markers, and the effects of specific drugs that possess additional anti-inflammatory effects, the concept of athero-inflammation emerges as the meeting point of different morbidities, usually named as risk factors, which include dyslipemia, diabetes, hypertension, obesity, immunity, infection, hyperhomocyteinemia, smoking (Figure).
Ross R: Atherosclerosis: an inflammatory disease. N Engl J Med 1999, 340: 115-126. 10.1056/NEJM199901143400207
Vorchheimer DA, Fuster V: Inflammatory markers in coronary artery disease. Let prevention douse the flames. JAMA 2001, 286: 2154-2156. 10.1001/jama.286.17.2154
Ross R: The pathogenesis of atherosclerosis-a perspective for the 1990s. Nature 1993, 362: 801-809. 10.1038/362801a0
Rosenzweig A: Endothelial Progenitor Cells. N Eng J Med 2003, 348: 581-582. 10.1056/NEJMp020175
Cybulsky MI, Gimbrone MA Jr: Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 1991, 251: 788-791.
Bonetti PO, Lerman LO, Lerman A: Endothelial dysfunction. A marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 2003, 23: 168-175. 10.1161/01.ATV.0000051384.43104.FC
Sela S, Shurtz-Swirski R, Awad J, Shapiro G, Nasser L, Shasha SM, Kristal B: The involvement of peripheral polymorphonuclear leukocytes in the oxidative stress and inflammation among cigarette snokers. Israel Med Ass J 2002, 4: 1015-1019.
Levi M, de Jonge E, van der Poll T, ten Cate H: Disseminated intravascular coagulation. Thromb haemost 1999, 82: 695-705.
Moreno PR, Bernardi VH, Lopez-Cuellar J, et al.: Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syndromes. Circulation 1996, 94: 3090-3097.
Shebuski RJ, Kilgore KS: Role of inflammatory mediators in thrombogenesis. J. Pharmacol Exp Ther 2002, 300: 729-735. 10.1124/jpet.300.3.729
Mann KG, Butenas S, Brummel K: The dynamics of thrombin formatiom. Arterioscler Thromb Vasc Biol 2003, 23: 17-25. 10.1161/01.ATV.0000046238.23903.FC
Matthay MA: Severe sepsis-A new treatment with both anticoagulant and antiinflamatory properties. N Engl J Med 2001, 344: 759-762. 10.1056/NEJM200103083441009
Gimbrone MA Jr, Topper JN, Nagel T, Anderson KM, Garcia Cardeña G: Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann NY Acad Sci 2000, 105: 1567-1572.
Prentice CRM: Platelets and atherosclerosis. Eur Heart J 1999, 1(supplA):A3-A7.
Altman R, Scazziota A: Role of anti-inflammatory drugs in the treatment of acute coronary syndromes. From athero-inflammation to athero-thrombosis. Rev Esp Cardiol 2003, 56: 9-15. 10.1157/13042335
Altman R, Rouvier J, Scazziota A: Secondary prevention of myocardial infarction. Beneficial effect of combining oral anticoagulant plus aspirin: therapy based on evidence. Clin Appl Thromb Hemost 2000, 6: 126-134.
Farb A, Burke AP, Tang AL, Liang Y, Poonam Mannan MS, Smialek J, Virmani R: Coronary plaque erosion without rupture into a lipid core. Circulation 1996, 93: 1354-1363.
Mailhac A, Badimon JJ, Fallon JT, et al.: Effect of an eccentric severe stenosis on fibrin(ogen) deposition on severely damaged vessel wall in arterial thrombosis. Relative contribution of fibrin(ogen) and platelets. Circulation 1994, 90: 988-996.
Gimbrone MA Jr: Endothelial disfunction, hemodynamic forces, and atherosclerosis. Thrombos haemost 1999, 82: 722-726.
Henn V, Slupsky JR, Grafe M, et al.: CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998, 391: 591-594. 10.1038/35393
Sata M, Saiura A, kunusato A, et al.: Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 2002, 8: 403-409. 10.1038/nm0402-403
Hill JM, Zalos G, Halcox JPJ, et al.: Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003, 348: 593-600. 10.1056/NEJMoa022287
Duggirala R, Gonzalez Villalpando C, O'Leary DH, Stern MP, Blangero J: Genetic basis of variation in carotid artery wall thickness. Stroke 1996, 27: 833-837.
Jerrard-Dunne P, Markus HS, Steckel DA, Buehler A, von Kegler S, Sitzer M: Early carotid atherosclerosis and family history of vascular disease. Specific effects on arterial sites have implications for genetic studies. Arteriosscler Thromb Vasc Biol 2003, 23: 302-306. 10.1161/01.ATV.0000051383.75507.60
Welt FGP, Rogers C: Inflammation and restenosis in the stent era. Arterioscler Thromb Vasc Biol 2002, 22: 1769-1776. 10.1161/01.ATV.0000037100.44766.5B
Moreno PR, Bernardi VH, Lopez-Cuellar J, et al.: Macrophages infiltration predicts restenosis after coronary intervention in patients with unstable angina. Circulation 1996, 94: 3098-3102.
Altman R, Rouvier J, Scazziota A, Gonzalez C: No causal association between inflammation and Chlamydia Pneumoniae in patients with chronic ischemic arterial disease. Inflammation 2002, 26: 25-30. 10.1023/A:1014469712395
Liuzzo G, Biasucci LM, Gallimore JL, et al.: The pronostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med 1994, 331: 417-424. 10.1056/NEJM199408183310701
Biasucci LM, Vitelli A, Liuzzo G, et al.: Elevated level of interleukin-6 in ustable angina. Circulation 1996, 94: 874-877.
Blake GJ, Ridker PM: Novel clinical markers of vascular wall inflammation. Circulation Res 2001, 89: 763-771.
Libby P, Ridker PM, Maseri A: Inflammation and Atherosclerosis. Circulation 2002, 105: 1135-1143. 10.1161/hc0902.104353
Wu KK, Aleksic N, Ballantyne Ch M, Ahn Ch, Juneja H, Boerwinkle E: Interaction between soluble thrombomodulin and Intercellular Adhesion Molecule-1 in predicting risk of coronary heart disease. Circulation 2003, 107: 1729-1732. 10.1161/01.CIR.0000064894.97094.4F
Blankenberg S, Tiret L, Bickel Ch, et al.: Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation 2002, 106: 24-30. 10.1161/01.CIR.0000020546.30940.92
Kai H, Ikeda H, Yasukawa H, et al.: Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol 1998, 32: 368-372. 10.1016/S0735-1097(98)00250-2
Blankenberg S, Rupprecht HJ, Odette Poirier O, et al.: Plasma Concentrations and Genetic Variation of Matrix Metalloproteinase 9 and Prognosis of Patients With Cardiovascular Disease. Circulation 2003, 107: 1579-1585. 10.1161/01.CIR.0000058700.41738.12
Ridker PM: Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003, 107: 363-369. 10.1161/01.CIR.0000053730.47739.3C
Pasceri V, Willerson JT, Yeh ET: Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000, 102: 2165-2168.
Devaraj S, Yan Xu D, Jialai I: C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells. Implications for the metabolic syndrome and atherothrombosis. Circulation 2003, 107: 398-404. 10.1161/01.CIR.0000052617.91920.FD
Ishikawa T, Hatakeyama K, Imamura T, et al.: Involvement of C-reactive protein obtained by directional coronary atherotomy in plaque instability and developing restenosis in patients with stable or unstable angina pectoris. Am J Cardiol 2003, 91: 287-292. 10.1016/S0002-9149(02)03156-9
Bhatt DL, Topol EJ: Need to test the arterial inflammation hypothesis. Circulation 2002, 106: 136-140. 10.1161/01.CIR.0000021112.29409.A2
Ridker PM, Buring JE, Cook NR, Rifai N: C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events. An 8-years follow-up of 14719 initially healthy american women. Circulation 2003, 107: 391-397. 10.1161/01.CIR.0000055014.62083.05
Mosca L: C-reactive protein-To screen or not to screen. N Engl J Med 2002, 347: 1615-1617. 10.1056/NEJMe020127
Kereiakes DJ: The fire that burns within. C-reactive protein. Circulation 2003, 107: 373-374. 10.1161/01.CIR.0000053942.27259.BA
Yeh ETH, Willerson JT: Coming of age of C-reactive protein. Using inflammation markers in cardiology. Circulation 2003, 107: 370-372. 10.1161/01.CIR.0000053731.05365.5A
Lloyd-Jones DM, Levy D: C-reactive protein in the prediction of cardiovascular events. N Engl J Med 2003, 348: 1059-1061. 10.1056/NEJM200303133481115
Deedwania PC: Diabetes and vascular disease: Common links in the emerging epidemic of coronary artery disease. Am J Cardiol 2003, 91: 68-71. 10.1016/S0002-9149(02)03000-X
Haffner SM, Lehto S, Ronnemaa T, Pyroala K, Laakso M: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998, 339: 229-234. 10.1056/NEJM199807233390404
Mooradian AD: Cardiovascular disease in type 2 diabetes mellitus. Arch Intern Med 2003, 163: 33-40. 10.1001/archinte.163.1.33
Guerci B, Böhme P, Kearney-Schawartz A, Zannad F, Drouin P: Endothelial dysfuction and type 2 diabetes. Diabetes Metab 2001, 27: 436-447.
Ouvina SM, La Greca RD, Zanaro NL, Palmer L, Sassetti B: Endothelial dysfunction, nitric oxide and platelet activation in hypertensive and diabetic type II patients. Thromb Res 2001, 102: 107-114. 10.1016/S0049-3848(01)00237-7
Lakka HM, Laaksonen DE, Lakka TA, et al.: The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002, 288: 2709-2716. 10.1001/jama.288.21.2709
Neil A, Hawkins M, Potok M, Thorogood M, Cohen D, Mann JA: A prospective population-based study of microalbuminuria as a predictor of mortality in NIDDM. Diabetes Care 1993, 16: 9936-1003.
Marshall SM: Blood control pressure, microalbuminuria and cardiovascular risk in Type 2 diabetes mellitus. Diabet Med 1999, 16: 358-372. 10.1046/j.1464-5491.1999.00045.x
Guerrero-Moreno F, Rodriguez-Moran M: Proteinuria is an independent risk factor for ischemic stroke in non-insulin-dependent diabetes mellitus. Stroke 1999, 30: 1787-1791.
Evans M, Khan N, Rees A: Diabetic dyslipidaemia and coronary heart disease: new perspectives. Curr Opin Lipidol 1999, 10: 387-391. 10.1097/00041433-199910000-00002
Pandolfi A, Cetrullo D, Polishuck R, et al.: Plasminogen activator inhibitor type 1 is increased in the arterial wall of type II diabetic subjects. Arterioscl Thromb Vasc Biol 2001, 21: 1378-1382.
Tschoepe D, Roesen P, Kaufmann L, et al.: Evidence for abnormal platelet glycoprotein expression in diabetes mellitus. Eur J Clin Invest 1990, 20: 166-170.
Davi G, Catalano I, Averna M, et al.: Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med 1990, 322: 1769-1774.
Paton RC, Passa P: Platelet and diabetic vascular disease. Diabete Metab 1983, 4: 306-312.
Knobler H, Savion N, Shenkman B, Kotev-Emeth S, Varon D: Shear-induced platelet adhesion and aggregation on subendothelium are increased in diabetic patients. Thromb Res 1998, 90: 181-190. 10.1016/S0049-3848(98)00050-4
Kessler L, Weisel ML, Attali P, Mossard JM, Cazenave JP, Pinget M: Von Willebrand factor in diabetic angiopathy. Diabetes Metab 1998, 24: 327-336.
Roffi M, Chew DP, Mukherjee D, et al.: Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes. Circulation 2001, 104: 2767-2771.
Bhatt DL, Marso SP, Lincoff AM, Wolski KE, Ellis SG, Topol EJ: Abciximab reduces mortality in diabetics following percutaneous coronary intervention. J Am Coll Cardiol 2000, 15: 922-928. 10.1016/S0735-1097(99)00650-6
Eckel RH, Wassef M, Chait A, Sobel B, Barrett E, King E, Lopes-Virella M, Reusch J, Ruderman N, Steiner G, Vlassara H: Prevention Conference VI: Diabetes and Cardiovascular Disease Writing Group II: Pathogenesis of atherosclerosis in diabetes. Circulation 2002, 105: 138-143. 10.1161/01.CIR.0000013954.65303.C5
Ford ES: Body mass index, diabetes, and C-reactive protein among US adults. Diabetes Care 1999, 22: 1971-1977.
Thorand B, Löwel H, Schneider A, et al.: C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men. Results from the MONICA Augsburg cohort study. 1984–1998. Arch Intern Med 2003, 163: 93-99. 10.1001/archinte.163.1.93
Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI: Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002, 106: 679-684. 10.1161/01.CIR.0000025403.20953.23
Marx N, Froehlich J, Siam L, et al.: Antidiabetic PPARγ-activator rosiglitazone reduces MMP-9 serum levels in type 2 diabetic patients with coronary artery disease. Arterioscler Thromb Vasc Biol 2003, 23: 283-288. 10.1161/01.ATV.0000054195.35121.5E
Libby P, Ridker PM, Maseri A: Inflammation and atherosclerosis. Circulation 2002, 105: 1135-1143. 10.1161/hc0902.104353
Hanson RL, Imperatore G, Bennett PH, Knowler WC: Components of the "metabolic syndrome" and incidence of type 2 diabetes. Diabetes 2002, 51: 3120-3127.
Morishita E, Asakura H, Saito M, et al.: Elevated plasma levels of free-form of TFPI antigen in hypercholesterolemic patients. Atherosclerosis 2001, 154: 203-212. 10.1016/S0021-9150(00)00463-9
Dichtl W, Nilsson L, Goncalves I, et al.: Very low-density lipoprotein activated nuclear factor-kB in endothelial cells. Circ Res 1999, 84: 1085-1094.
Ceriello A, Taboga C, Tonutti L, et al.: Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation. Effects of short- and long-term simvastatin treatment Circulation 2002, 106: 1211-1218. 10.1161/01.CIR.0000027569.76671.A8
Ioka T, Tasaki H, Yashiro A, et al.: Association between plasma lipoprotein(a) and endothelial dysfuction normocholesterolemic and non-diabetic subjects with angiographically normal coronary arteries. Circ J 2002, 66: 267-271. 10.1253/circj.66.267
Cominacini L, Fratta Pasini A, Garbin U, et al.: The platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells. J Am Coll Cardiol 2003, 41: 499-507. 10.1016/S0735-1097(02)02811-5
Blake GJ, Ridker PM: Are statins anti-inflammatory? Curr Control Trials Cardiovasc Med 2000, 1: 161-165. 10.1186/CVM-1-3-161
Simes RJ, Marschner IC, Hunt D, et al.: Relationship Between Lipid Levels and Clinical Outcomes in the Long-Term Intervention With Pravastatin in Ischemic Disease (LIPID) Trial. To What Extent Is the Reduction in Coronary Events With Pravastatin Explained by On-Study Lipid Levels? Circulation 2002, 105: 1162-1169. 10.1161/hc1002.105136
Yeung AC, Tsao P: Statin Therapy. Beyond Cholesterol Lowering and Antiinflammatory Effects. Circulation 2002, 105: 2937-2938. 10.1161/01.CIR.0000023397.12047.03
Ridker PM, Rifai N, Lowenthal SP: Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation 2001, 103: 1191-1193.
Eto M, Kozai T, Cosentino F, et al.: Statin prevent tissue factor expression in human endothelial cells: role of the Rho/Rho-kinase and Akt pathways. Circulation 2002, 105: 1756-1759. 10.1161/01.CIR.0000015465.73933.3B
Corti R, Farkouh ME, Badimon JJ: The vulnerable plaque and acute coronary syndromes. Am J Med 2002, 113: 668-680. 10.1016/S0002-9343(02)01344-X
Blake GJ, Ridker PM: Novel clinical markers of vascular wall inflammation. Circulation Res 2001, 89: 763-771.
Dichtl W, Dulak J, Frick M, et al.: HMG-CoA reductade inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells. Arteroscler Tromb Vasc Biol 2003, 23: 58-63. 10.1161/01.ATV.0000043456.48735.20
Hernandez-Presa MA, Martin-Ventura JL, Ortego M, et al.: Atorvastatin reduces the expression of cyclooxygenase-2 in a rabbit model of atherosclerosis and in cultured vascular smooth muscle cells. Atheroslerosis 2002, 160: 49-58. 10.1016/S0021-9150(01)00547-0
Llevadot J, Murasawa S, Kureishi Y, et al.: HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells. J Clin Invest 2001, 108: 399-405. 10.1172/JCI200113131
Horsmans Y: Differential metabolism of statins: Importance in drug-drug interactions. Eur Heart J Suppl 1999, 1(SupplT):T7-T12.
Wiklund O, Mattsson-Hulten L, Hurt-Camejo E, Oscarsson J: Effects of simvastatin and atorvastatin on inflammation markers in plasma. J Intern Med 2002, 25: 338-347. 10.1046/j.1365-2796.2002.00966.x
Mukamal KJ, Conigrave KM, Mittleman MA, et al.: Roles of drinking pattern and type of alcohol consumed in coronary heart disease in men. N Engl J Med 2003, 348: 163-164. 10.1056/NEJMoa022095
Albert MA, Glynn RJ, Ridker PM: Alcohol consumption and plasma concentration of C-reactive protein. Circulation 2003, 107: 443-447. 10.1161/01.CIR.0000045669.16499.EC
Hubert HB, Fenileib M, McNamara PM, et al.: Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham heart study. Circulation 1983, 67: 968-977.
Kim KS, Owen WL, Williams D, et al.: A comparison between BMI and conicity index on predicting coronary heart disease: the Framingham Heart Study. Ann Epidemiol 2000, 10: 424-431. 10.1016/S1047-2797(00)00065-X
Cooke JP, Oka RK: Does leptin cause vascular disease. Circulation 2002, 106: 1904-1905. 10.1161/01.CIR.0000036864.14101.1B
Eckel RH, Krauss RM: American Heart Association call to action: obesity as a major risk factor for coronary heart disease: AHA Nutrition Committee. Circulation 1998, 97: 2099-2100.
Rimm EB, Stampfer MJ, Giovannucci E, et al.: Body size and fat distribution as predictors of coronary heart disease among middle-aged and older US men. Am J Epidemiol 1995, 141: 1117-1127.
Visser M, Bouter LM, McQuillan GM, et al.: Elevated C-reactive protein levels in overweight and obese adult. JAMA 1999, 282: 2131-2135. 10.1001/jama.282.22.2131
Tchernof A, Nolan A, Sites CK, et al.: Weight loss reduces C-reative protein levels in obese postmenstrual women. Circulation 2002, 105: 564-569. 10.1161/hc0502.103331
Esposito K, Pontillo A, Di Palo C, et al.: Effect of Weight Loss and Lifestyle Changes on Vascular Inflammatory Markers in Obese Women A Randomized Trial. JAMA 2003, 289: 1799-1804. 10.1001/jama.289.14.1799
Grundy SM: Obesity, metabolic syndrome, and coronary atherosclerosis. Circulation 2002, 105: 2696-2698. 10.1161/01.CIR.0000020650.86137.84
Festa A, D'Agostino R Jr, Williams K, et al.: The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord 2001, 25: 1407-1415. 10.1038/sj.ijo.0801792
Fridman JM, Halaas JL: Leptin and the regulation of bodyweight in normals. Nature 1998, 395: 763-770. 10.1038/27376
Singhal A, Farooqi S, Cole TJ, et al.: Influence of leptin on arterial distensibility a novel link between obesity and cardiovascular disease? Circulation 2002, 106: 1919-1924. 10.1161/01.CIR.0000033219.24717.52
Binder Ch J, Chang MK, Shaw PX, et al.: Innate and acquired immunity in atherogenesis. Nature Med 2002, 8: 1218-1226. 10.1038/nm1102-1218
Hanson GK, Libby P, Schönberck U, Yan Z: Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res 2002, 91: 281-291. 10.1161/01.RES.0000029784.15893.10
Edfeldt K, Swedenborg J, Hansson GK, et al.: Expression of toll-like receptors in human atherosclerotic lesions A possible pathway for plaque activation. Circulation 2002, 105: 1158-1161.
Sasu S, LaVerda D, Qureshi N, et al.: Chlamydia pneumoniae and chlamydial heat shock protein 60 stimulate proliferation of human vascular smooth muscle cells via toll-like receptor 4 and p44/p42 mitogen activated protein kinase activation. Circ Res 2001, 89: 244-250.
Kiechl S, Lorenz E, Reindl M, et al.: Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 2002, 347: 185-92. 10.1056/NEJMoa012673
Woodhouse PR, Khaw KT, Plummer M, Foley A, Meade TW: Seasonal variations of plasma fibrinogen and factor VII activity in the elderly: winter infections and death from cardiovascular disease. Lancet 1994, 343: 435-439. 10.1016/S0140-6736(94)92689-1
Tillett HE, Smith JWG, Gooch CD: Excess death attributable to influenza in England and Wales: Age and death and certified cause. Int J Epidemiol 1983, 12: 344-352.
Van Lenten BJ, Wagner AC, Anantharamaiah GM, et al.: Influenza infection promotes macrophage traffic into arteries of mice that is prevented by D-4F, an apolipoprotein A-I mimetic peptide. Circulation 2002, 106: 1127-1132. 10.1161/01.CIR.0000030182.35880.3E
Naghavi M, Barlas Z, Siadaty S, et al.: Association of influenza vaccination and reduced risk of recurrent myocardial infarction. Circulation 2000, 102: 3039-3045.
Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane : Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. N Eng J Med 2003, 348: 1322-1332. 10.1056/NEJMoa025028
Gurfinkel EP, de la Fuente RL, Mendiz O, Mautner B, FESC for the FLUVACS Study Group: Influenza Vaccine Pilot Study in Acute Coronary Syndromes and Planned Percutaneous Coronary Interventions The FLU Vaccination Acute Coronary Syndromes (FLUVACS) Study. Circulation 2002, 105: 2143-2147. 10.1161/01.CIR.0000016182.85461.F4
Galve-de Rochemonteix B, Kobayashi T, Rosnoblet C, et al.: Interaction of anti-phospholipid antibodies with late endosomes of human endothelial cells. Arterioscler Thromb Vasc Biol 2000, 20: 563-574.
Del Papa N, Guidali L, Spatola L, et al.: Relationship between anti-phospholipid and anti-endothelial cell antibodies III: beta 2 glycoprotein I mediates the antibody binding to endothelial membranes and induces the expression of adhesion molecules. Clin Exp Rheumatol 1995, 13: 179-185.
Rand JH: Molecular pathogenesis of the antiphospholipid syndrome. Circulation Research 2002, 90: 29-37. 10.1161/hh0102.102795
Pierangeli SS, Espinola RG, Liu X, Harris EN: Thrombogenic effects of antiphospholipid antibodies are mediated by Intercellular Cell Adhesion Molecule-1, Vascular Cell Adhesion Molecule-1, and P-Selectin. Circ Res 2001, 88: 245-250.
Libby P, Egan D, Skarlatos S: Roles of infectious agents in atherosclerosis and restenosis. Circulation 1997, 96: 4095-4103.
Danesh J, Collins R, Peto R: Chronic infections and coronary heart disease: is there a link? Lancet 1997, 350: 430-436. 10.1016/S0140-6736(97)03079-1
Metha JL, Saldeen TGP, Rand K: Interactive role of infection, inflammation and traditional risk factors in atherosclerosis and coronary artery disease. J Am Coll Cardiol 1998, 31: 1217-1225. 10.1016/S0735-1097(98)00093-X
Gurfinkel E, Bozovich G, Darroca A, et al.: For the ROXIS Study group. Randomized trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS pilot study. Lancet 1997, 350: 404-407. 10.1016/S0140-6736(97)07201-2
Muhlestein JB, Anderson JL, Carlquist JF, et al.: Randomized secondary prevention trial of azithromycin in patients with coronary artery disease. Primary clinical results of the ACADEMIC study. Circulation 2000, 102: 1755-1760.
Sinisalo J, Mattila K, Valtonen V, et al.: Effect of 3 months of antimicrobial treatment with clarithromicin in acute non-Q-wave coronary syndrome. Circulation 2002, 105: 1555-1560. 10.1161/01.CIR.0000012544.07696.1F
Stone AFM, Mendall MA, Kaski JC, et al.: Effect of treatment for Chlamydia pneumoniae and Helicobacter pylori on markers of Inflammation and cardiac events in patients with acute coronary syndromes South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA). Circulation 2002, 106: 1219-1223. 10.1161/01.CIR.0000027820.66786.CF
Smieja M, Gnarpe J, Lonn E, et al.: Multiple infection and subsequent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) study. Circulation 2003, 107: 251-257. 10.1161/01.CIR.0000044940.65226.1F
Cercek B, Shah PK, Noc M, et al.: Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial. Lancet 2003, 361: 809-813. 10.1016/S0140-6736(03)12706-7
Nieminen MS, Mattila K, Valtonen V: Infection and inflammation as risk factors for myocardial infarction. Eur Heart J 1993, 14(Supp K):12-16.
Ericson K, Saldeen GP, Lindquist O, Pahlson C, Mehta JL: Relationship of Chlamydia pneumoniae infection to severity of human coronary atherosclerosis. Circulation 2000, 101: 2568-2571.
Gharavi EE, Chaimovich H, Cucurull E, et al.: Induction of antiphospholipid antibodies by immunization with synthetic viral and bacterial peptides. Lupus 1999, 8: 449-455.
Kuo CC, Jackson LA, Lee A, Grayston JT: In vitro activities of azithromycin, clarithromycin, and other antibiotics against Chlamydia pneumoniae. Antimicrob agents chemother 1996, 40: 2669-2667.
Martin D, Bursill J, Qui MR, Breit SN, Campbell T: Alternative hypothesis for efficacy of macrolides in acute coronary syndromes. Lancet 1998, 351: 1858-1859.
Agen C, Danesi R, Blandizzi C, et al.: Macrolide antibiotics as antiinflammatory agents: Roxithromycin in an unexpected role. Agents Actions 1993, 38: 85-90.
Scaglione F, Rossoni G: Comparative anti-inflammatory effects of roxithromycin, azithromycin and clarithromycin. J Antimicrob Chemother 1998, 41(SupplB):47-50. 10.1093/jac/41.suppl_2.47
Ridker PM, Shih J, Cook TJ, et al.: Plasma Homocysteine Concentration, Statin Therapy, and the Risk of First Acute Coronary Events. Circulation 2002, 105: 1776-1779. 10.1161/01.CIR.0000014447.06099.FB
Kario K, Barton Duell P, Matsuo T, et al.: High plasma homocyst(e)ine levels in elderly Japanese patients are associated with increased cardiovascular disease risk independently from markers of coagulation activation and endothelial cell damage. Atherosclerosis 2001, 157: 441-449. 10.1016/S0021-9150(00)00738-3
Wilson PWF: Homocysteine and coronary heart disease. How great is the hazard? JAMA 2002, 288: 2042-2043. 10.1001/jama.288.16.2042
Omland T, Samuelsson A, Hartford M, et al.: Serum Homocysteine Concentration as an Indicator of Survival in Patients With Acute Coronary Syndromes. Arch Intern Med 2000, 160: 1834-1840. 10.1001/archinte.160.12.1834
xx x: The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002, 288: 2015-2022.
Nurk E, Tell GS, Vollset SE, Nygård O, Refsum H, Ueland PM: Plasma Total Homocysteine and Hospitalizations for Cardiovascular Disease. The Hordaland Homocysteine Study. Arch Intern Med 2002, 162: 1374-1381. 10.1001/archinte.162.12.1374
Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG, and the MTHFR Studies Collaboration Group: MTHFR 677CT polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002, 288: 2023-2031. 10.1001/jama.288.16.2023
Lentz SR, Sobey Ch G, Piegors DJ, Bhopatkar MY, Faraci FM, Malinow MR, Heistad DD: Vascular Dysfunction in Monkeys with Diet-induced Hyperhomocyst(e)inemia. J. Clin. Invest 1996, 98: 24-29.
Stühlinger MC, Tsao PS, Her JS, et al.: Homocysteine Impairs the Nitric Oxide Synthase Pathway Role of Asymmetric Dimethylarginine. Circulation 2001, 104: 25-69.
Key NS, McGlennen RC: Hyperhomocyst(e)inemia and thrombophilia. Arch Pathol Lab Med 2002, 126: 1367-1375.
Cavalca V, Cighetti G, Bamonti F, et al.: Oxidative Stress and Homocysteine in Coronary Artery Disease. Clinical Chemistry 2001, 47: 887-892.
Durand P, Prost M, Loreau N, Lussier-Cacan S, Blache D: Impaired homocysteine metabolism and atherothrombotic disease. Laboratory Investigation 2001, 81: 645-672.
Mujumdar VS, Aru GM, Tyagi SC: Induction of oxidative stress by homocyst(e)ine impairs endothelial function,. J Cellular Biochemistry 2001, 82: 491-500. 10.1002/jcb.1175
Ungvari Z, Csiszar A, Edwards JG, Kaminski PM, Wolin MS, Kaley G, Koller A: Increased superoxide production in coronary arteries in hyperhomocysteinemia. Role of tumor necrosis factor-α, NAD(P)H oxidase, and inducible nitric oxide synthase. Arterioscls Thromb Vasc Biol 2003, 23: 418-424. 10.1161/01.ATV.0000061735.85377.40
Davì G, Di Minno G, Coppola A, et al.: Oxidative stress and platelet activation in homozygous homocystinuria. Circulation 2001, 104: 1124-1128.
Schnyder G, Roffi M, Pin R, et al.: Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001, 345: 1593-1600. 10.1056/NEJMoa011364
Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM: Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6on clinical outcome after percutaneous coronary intervention: the Swiss Heart Study: a randomized controlled trial. JAMA 2002, 288: 973-979. 10.1001/jama.288.8.973
Doshi SN, McDowell IFW, Moat SJ, et al.: Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Circulation 2002, 105: 22-26. 10.1161/hc0102.101388
Kranzhofer R, Browatzki M, Schmidt J, Kubler W: Angiotensin II activates the proinflammatory transcription factor nuclear factor-kappaB in human monocytes. Biochem Biophys Res Commun 1999, 257: 826-828. 10.1006/bbrc.1999.0543
Han Y, Runge MS, Brasier AR: Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-kappa B transcription factors. Circ Res 1999, 84: 695-703.
Lekakis JP, Papathanassiou S, Papaioannou TG, et al.: Oral L-arginine improves endothelial dysfunction in patients with essential hypertension. Int J Cardiol 2002, 86: 317-323. 10.1016/S0167-5273(02)00413-8
Pepine CJ, Schlaifer JD, Mancini GB, Pitt B, O'Neill BJ, Haber HE: Influence of smoking status on progression of endothelial dysfunction. TREND Investigators. Trial on reversing endothelial dysfunction. Clin Cardiol 1998, 21: 331-334.
Iwado Y, Yoshinaga K, Furuyama H, et al.: Decreased endothelium-dependent coronary vasomotion in healthy young smokers. Eur J Nucl Med Mol Imaging 2002, 8: 984-990. 10.1007/s00259-002-0818-1
Neunteufl T, Heher S, Kostner K, et al.: Contribution of nicotine to acute endothelial dysfunction in long-term smokers. J Am Coll Cardiol 2002, 39: 251-256. 10.1016/S0735-1097(01)01732-6
Ahijevych K, Wewers ME: Passive smoking and vascular disease. J Cardiovasc Nurs 2003, 18: 69-74.
Barua RS, Ambrose JA, Eales-Reynolds LJ, DeVoe MC, Zervas JG, Saha DC: Heavy and light cigarette smokers have similar dysfunction of endothelial vasoregulatory activity: an in vivo and in vitro correlation. J Am Coll Cardiol 2002, 39: 1758-1763. 10.1016/S0735-1097(02)01859-4
Mazzone A, Cusa C, Mazzucchelli I, et al.: Cigarette smoking and hypertension influence nitric oxide release and plasma levels of adhesion molecules. Clin Chem Lab Med 2001, 39: 822-826.
Guthikonda S, Sinkey C, Barenz T, Haynes WG: Xanthine oxidase inhibition reverses endothelial dysfunction in heavy smokers. Circulation 2003, 107: 416-421. 10.1161/01.CIR.0000046448.26751.58
O'Grady HL, Leahy A, McCormick PH, Fitzgerald P, Kelly CK, Bouchier-Hayes DJ: Oral folic acid improves endothelial dysfunction in cigarette smokers. J Surg Res 2002, 106: 342-345. 10.1006/jsre.2002.6467
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