doi: 10.1161/hc0902.104353
(Circulation. 2002;105:1135.)
© 2002 American Heart Association, Inc.
Clinical Cardiology: New Frontiers |
Inflammation and Atherosclerosis
From the Leducq Center for Cardiovascular Research (P.L., P.M.R.) and Center for Cardiovascular Disease Prevention (P.M.R.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass, and Department of Cardiovascular Disease (A.M.), University Vita-Salute San Raffaele, Milan, Italy.
Correspondence to Peter Libby, MD, Brigham and Women’s Hospital, 221 Longwood Ave, LMRC 307, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu
 |
Abstract |
|---|
 Top Abstract IntroductionThe Scientific Basis of...Triggers for Inflammation in...Inflammation and the ACSCorrelation of Elevated...Inflammation and Myocardial...Prevalence of Inflammation in...Inflammatory Biomarkers and Risk...ConclusionReferences |
|---|
Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.
Key Words: endothelium • inflammation • atherosclerosis • proteins
|
Introduction |
|---|
|
TopAbstractIntroductionThe Scientific Basis of...Triggers for Inflammation in...Inflammation and the ACSCorrelation of Elevated...Inflammation and Myocardial...Prevalence of Inflammation in...Inflammatory Biomarkers and Risk...ConclusionReferences |
|---|
Over the last dozen years, appreciation of the role of inflammation in atherosclerosis has burgeoned. Although it was formerly considered a bland lipid storage disease, substantial advances in basic and experimental science have illuminated the role of inflammation and the underlying cellular and molecular mechanisms that contribute to atherogenesis. Compelling evidence for the importance of inflammation and atherosclerosis at both the basic and clinical level has evolved in parallel. Accumulating data indicate that insights gained from the link between inflammation and atherosclerosis can yield predictive and prognostic information of considerable clinical utility. This review summarizes the experimental and clinical evidence for inflammation in atherosclerosis, and assesses the current state of knowledge regarding the triggers for inflammation in this disease. We will evaluate the participation of inflammation in the acute coronary syndromes (ACS) and review the data supporting the use of inflammatory markers as prognostic and predictive instruments in the context both of ACS and of prediction of risk for various complications of atherosclerosis. Finally, we will consider how new insights into inflammation in atherosclerosis may identify innovative therapeutic strategies to improve outcomes of individuals at risk for or affected by this scourge of growing worldwide importance.
|
The Scientific Basis of Inflammation in Atherogenesis |
|---|
|
TopAbstractIntroductionThe Scientific Basis of...Triggers for Inflammation in...Inflammation and the ACSCorrelation of Elevated...Inflammation and Myocardial...Prevalence of Inflammation in...Inflammatory Biomarkers and Risk...ConclusionReferences |
|---|
In a variety of animal models of atherosclerosis, signs of inflammation occur hand-in-hand with incipient lipid accumulation in the artery wall. For example, blood leukocytes, mediators of host defenses and inflammation, localize in the earliest lesions of atherosclerosis, not only in experimental animals but in humans as well. The basic science of inflammation biology applied to atherosclerosis has afforded considerable new insight into the mechanisms underlying this recruitment of leukocytes. The normal endothelium does not in general support binding of white blood cells. However, early after initiation of an atherogenic diet, patches of arterial endothelial cells begin to express on their surface selective adhesion molecules that bind to various classes of leukocytes (Figure 1A). In particular, vascular cell adhesion molecule-1 (VCAM-1) binds precisely the types of leukocytes found in early human and experimental atheroma, the monocyte and T lymphocyte. Not only does VCAM-1 expression increase on endothelial cells overlying nascent atheroma,1 but mice genetically engineered to express defective VCAM-1 show interrupted lesion development.2
|
Interestingly, the foci of increased adhesion molecule expression overlap with sites in the arterial tree particularly prone to develop atheroma. Considerable evidence suggests that impaired endogenous atheroprotective mechanisms occur at branch points in arteries, where the endothelial cells experience disturbed flow.3 For example, absence of normal laminar shear stress may reduce local production of endothelium-derived NO. This endogenous vasodilator molecule also has anti-inflammatory properties and can limit expression of VCAM-1.4 In addition to inhibiting natural protective mechanisms, disturbed flow can augment the production of certain leukocyte adhesion molecules (eg, intercellular adhesion molecule-1 [ICAM-1]).5 Augmented wall stresses may also promote the production by arterial smooth muscle cells (SMCs) of proteoglycans that can bind and retain lipoprotein particles, facilitating their oxidative modification and thus promoting an inflammatory response at sites of lesion formation.6
Once adherent to the endothelium, the leukocytes penetrate into the intima (Figure 1A). Recent research has identified candidate chemoattractant molecules responsible for this transmigration. For example, monocyte chemoattractant protein-1 (MCP-1) appears responsible for the direct migration of monocytes into the intima at sites of lesion formation.7,8 A family of T-cell chemoattractants may likewise call lymphocytes into the intima.9 Once resident in the arterial wall, the blood-derived inflammatory cells participate in and perpetuate a local inflammatory response (Figure 1B). The macrophages express scavenger receptors for modified lipoproteins, permitting them to ingest lipid and become foam cells. In addition to MCP-1, macrophage colony-stimulating factor (M-CSF) contributes to the differentiation of the blood monocyte into the macrophage foam cell.10,11 T cells likewise encounter signals that cause them to elaborate inflammatory cytokines such as 
-interferon and lymphotoxin (tumor necrosis factor [TNF]–ß) that in turn can stimulate macrophages as well as vascular endothelial cells and SMCs.12 As this inflammatory process continues, the activated leukocytes and intrinsic arterial cells can release fibrogenic mediators, including a variety of peptide growth factors that can promote replication of SMCs and contribute to elaboration by these cells of a dense extracellular matrix characteristic of the more advanced atherosclerosis lesion.13
Inflammatory processes not only promote initiation and evolution of atheroma, but also contribute decisively to precipitating acute thrombotic complications of atheroma (Figure 1C). Most coronary arterial thrombi that cause fatal acute myocardial infarction arise because of a physical disruption of the atherosclerotic plaque. The activated macrophage abundant in atheroma can produce proteolytic enzymes capable of degrading the collagen that lends strength to the plaque’s protective fibrous cap, rendering that cap thin, weak, and susceptible to rupture. -Interferon arising from the activated T lymphocytes in the plaque can halt collagen synthesis by SMCs, limiting its capacity to renew the collagen that reinforces the plaque.14,15 Macrophages also produce tissue factor, the major procoagulant and trigger to thrombosis found in plaques. Inflammatory mediators regulate tissue factor expression by plaque macrophages, demonstrating an essential link between arterial inflammation and thrombosis.16
|
Triggers for Inflammation in Atherogenesis |
|---|
|
TopAbstractIntroductionThe Scientific Basis of...Triggers for Inflammation in...Inflammation and the ACSCorrelation of Elevated...Inflammation and Myocardial...Prevalence of Inflammation in...Inflammatory Biomarkers and Risk...ConclusionReferences |
|---|
Oxidized Lipoproteins and Inflammation
For almost a century, many have regarded lipids as the sine qua non of atherosclerosis. Over the last few decades, a plausible model linking lipids and inflammation to atherogenesis has emerged. According to the oxidation hypothesis, low-density lipoprotein (LDL) retained in the intima, in part by binding to proteoglycan, undergoes oxidative modification.17,18 Lipid hydroperoxides, lysophospholipids, carbonyl compounds, and other biologically active moieties localize in the lipid fraction of atheroma.19 These modified lipids can induce the expression of adhesion molecules, chemokines, proinflammatory cytokines, and other mediators of inflammation in macrophages and vascular wall cells. The apoprotein moieties of the lipoprotein particles can also undergo modification in the artery wall, rendering them antigenic and capable of inciting T-cell responses, thus activating the antigen-specific adaptive limb of the immune response.20 In some experimental situations, administration of antioxidants can retard the progression of atherosclerotic lesions that develop in the face of hyperlipidemia.
Although attractive, theoretically compelling, and supported by a considerable body of experimental evidence, the relevance of the LDL oxidation hypothesis to human atherosclerosis remains unproven. Chemical analysis of the types of modified lipids and proteins extracted from human atheroma do not necessarily correspond to the compounds derived from lipoproteins oxidized in vitro that have furnished much of the evidence linking oxidized lipoproteins to inflammation. Most cell culture studies of the biological effects of oxidized LDL have used material generated by transition metal–mediated oxidation, conditions that some find of dubious in vivo relevance. Hypochlorous acid–mediated derivation of lipoprotein constituents may bear closer relationship to human atherosclerosis than oxidative modification catalyzed by transition metals.21,22 The leukocyte enzyme myeloperoxidase produces hypochlorous acid within the atheroma. Clinical trials have repeatedly failed to validate the concept that antioxidant vitamin therapy can improve clinical outcomes. Thus, "the jury is still out" on the applicability of the LDL oxidation hypothesis to patients.
Dyslipidemia and Inflammation
Other lipoprotein particles such as very low–density lipoprotein (VLDL) and intermediate-density lipoprotein also have considerable atherogenic potential. These lipoprotein particles can undergo oxidative modification like that of LDL. In addition, some evidence suggests that beta VLDL particles may themselves activate inflammatory functions of vascular endothelial cells.23,24 High-density lipoprotein (HDL) protects against atherosclerosis. Reverse cholesterol transport effected by HDL likely accounts for some its atheroprotective function. However, HDL particles also can transport antioxidant enzymes such as platelet-activating factor acetylhydrolase and paraoxonase, which can break down oxidized lipids and neutralize their proinflammatory effects.
Hypertension and Inflammation
Hypertension follows closely behind lipids on a list of classical risk factors for atherosclerosis. Increasing evidence supports the view that, like atherosclerosis itself, inflammation may participate in hypertension providing a pathophysiological link between these two diseases. Angiotensin II (AII), in addition to its vasoconstrictor properties, can instigate intimal inflammation. For example, AII elicits the production of superoxide anion, a reactive oxygen species, from arterial endothelial cells and SMCs.25 AII can also increase the expression by arterial SMCs of proinflammatory cytokines such as interleukin (IL)–6 and MCP-1 and of the leukocyte adhesion molecule VCAM-1 on endothelial cells.26–28 Some of the clinical benefits of angiotensin-converting enzyme inhibitor therapy may derive from interrupting such proinflammatory pathways.
Diabetes and Inflammation
Diabetes is yet another risk factor for atherosclerosis of growing importance. The hyperglycemia associated with diabetes can lead to modification of macromolecules, for example, by forming advance glycation end products (AGE).29 By binding surface receptors such as RAGE (receptor for AGE), these AGE-modified proteins can augment the production of proinflammatory cytokines and other inflammatory pathways in vascular endothelial cells. Beyond the hyperglycemia, the diabetic state promotes oxidative stress mediated by reactive oxygen species and carbonyl groups.30 As in the case of hypertension, inflammation links diabetes to atherosclerosis.
Obesity and Inflammation
Obesity not only predisposes to insulin resistance and diabetes, but also contributes to atherogenic dyslipidemia. High levels of free fatty acids originating from visceral fat reach the liver through the portal circulation and stimulate synthesis of the triglyceride-rich lipoprotein VLDL by hepatocytes. The resulting elevation in VLDL can lower HDL cholesterol by augmenting exchange from HDL to VLDL by cholesteryl ester transfer protein. Adipose tissue can also synthesize cytokines such as TNF-
and IL-6.31 In this way obesity itself promotes inflammation and potentiates atherogenesis independent of effects on insulin resistance or lipoproteins.
Infection
Infectious agents might also conceivably furnish inflammatory stimuli that accentuate atherogenesis.32,33 Acute infections can alter hemodynamics and the clotting and fibrinolytic systems in ways that can precipitate ischemic events. Chronic extravascular infections (eg, gingivitis, prostatitis, bronchitis, etc) can augment extravascular production of inflammatory cytokines that may accelerate the evolution of remote atherosclerotic lesions. Intravascular infection might also provide a local inflammatory stimulus that could accelerate atherogenesis. Many human plaques show signs of infection by microbial agents such Chlamydia pneumoniae. Chlamydiae, when present in the arterial plaque, may release lipopolysaccharide (endotoxin) and heat shock proteins that can stimulate the production of proinflammatory mediators by vascular endothelial cells and SMCs and infiltrating leukocytes alike.34 Epidemiological studies of infection, however, have yielded mixed results, with little prospective evidence that antibodies directed against Chlamydia pneumoniae, Helicobacter pylori, herpes simplex virus, or cytomegalovirus predict vascular risk.
|
Inflammation and the ACS |
|---|
|
TopAbstractIntroductionThe Scientific Basis of...Triggers for Inflammation in...Inflammation and the ACSCorrelation of Elevated...Inflammation and Myocardial...Prevalence of Inflammation in...Inflammatory Biomarkers and Risk...ConclusionReferences |
|---|
The mechanisms of ACS encompass elements of thrombosis and vasoconstriction superimposed on atherosclerotic lesions. Thrombosis frequently persists, detectable by angiography, by angioscopy, or at autopsy. In contrast, vasospasm presents challenges to quantification because of its transient nature. Reduction of stenoses by administration of nitrates35 or use of provocative maneuvers36,37 provides evidence for arterial spasm. Indeed, thrombosis may beget vasospasm. Local thrombus formation generates serotonin, thromboxane A2, and thrombin. Each of these thrombosis-associated mediators can cause vasoconstriction not only at the site of thrombosis, but also downstream. In this manner, a proximal thrombus in an epicardial conduit coronary artery might propagate spasm to the distal smaller vessels. Thrombi present a more tractable therapeutic target than vasoconstriction, as vasodilator drugs, when given systemically, seldom overcome the effect of locally produced constrictor substances.35
Yet, even with aggressive thrombolytic, anticoagulant, and/or antiplatelet agents or interventional therapy, patients with ACS still have a 12% to 16% incidence of major cardiac events at 4 to 6 months after hospital discharge.38,39 Novel treatments based on increased understanding of the underlying mechanisms of plaque instability should yield further improvements in outcomes. Growing evidence indicates that in ACS, elevated circulating inflammatory markers, in particular C-reactive protein (CRP), predict an unfavorable course, independent of the severity of the atherosclerotic or ischemic burden. Thus, inflammation represents one potential novel pathophysiological mechanism of the ACS that may furnish such a new target for therapy.
|
Correlation of Elevated Inflammatory Markers With Adverse Prognosis |
|---|
|
TopAbstractIntroductionThe Scientific Basis of...Triggers for Inflammation in...Inflammation and the ACSCorrelation of Elevated...Inflammation and Myocardial...Prevalence of Inflammation in...Inflammatory Biomarkers and Risk...ConclusionReferences |
|---|
Elevated values of circulating inflammatory markers such as CRP, serum amyloid A, IL-6, and IL-1 receptor antagonist commonly accompany ACS. Such elevations correlate with in-hospital and short-term adverse prognosis40–47 and may reflect not only a high prevalence of myocardial necrosis, ischemia-reperfusion damage, or severe coronary atherosclerosis but also a primary inflammatory instigator of coronary instability. The contribution of each of the inflammatory processes mentioned above to prognosis may vary in different groups of patients according to the criteria used for their selection. In turn, the short-term prognostic role of elevated CRP values in ACS may correlate at least in part with the long-term prognostic role of CRP values within the normal range in normal individuals48,49 and of elevated values in chronic coronary disease.50,51 Of note, the degree of elevation in CRP discussed here in the context of the ACS exceeds the relative increases within the normal range measured by the high-sensitivity assay discussed below in relation to prospective coronary risk stratification.
|
Inflammation and Myocardial Necrosis and Ischemia |
|---|
|
TopAbstractIntroductionThe Scientific Basis of...Triggers for Inflammation in...Inflammation and the ACSCorrelation of Elevated...Inflammation and Myocardial...Prevalence of Inflammation in...Inflammatory Biomarkers and Risk...ConclusionReferences |
|---|
Liuzzo et al41 demonstrated early on that elevated CRP correlates with adverse short-term prognosis in selected patients with unstable angina, Braunwald class IIIb, who lacked evidence of myocardial necrosis and had an ischemic burden similar to that of patients without CRP elevation. Half of patients with ACS have persistently elevated CRP after discharge, a finding associated with recurrent episodes of instability and infarction.47 Patients with variant angina and large ischemic burden, or stable angina pectoris and severe coronary artery disease, have a very low incidence of elevated CRP, affirming the specificity of systemically detectable inflammation in ACS.52 Indeed, the elevation of CRP in unstable patients does not appear to relate merely to the extent and severity of atherosclerosis, as only about 20% of patients with chronic stable angina and a high prevalence of multivessel disease have elevated CRP values compared with 70% of patients with unstable angina.41 Moreover, CRP values in patients with peripheral vascular disease severe enough to require revascularization do not differ significantly from those observed in unstable angina and single-vessel disease53 (E. Rossi et al, unpublished data, 2001).
Not all patients with unstable angina and elevated CRP develop infarction. But practically all patients with infarctions preceded by unstable angina have elevated CRP on admission. The final sustained coronary occlusion leading to infarction may result from a coexistent prothrombic diathesis or from enhanced coronary vasoreactivity.54 Inflammation might not only mark increased risk of infarction, but also participate in precipitating occlusive events. In addition, aspects of the acute-phase inflammatory response may directly influence thrombosis. Although CRP serves as a convenient marker of inflammation, the other proteins augmented during the acute-phase response include fibrinogen and plasminogen activator inhibitor-1. Thus, inflammation can promote thrombus formation and can enhance clot stability by inhibiting endogenous fibrinolysis.
|
Prevalence of Inflammation in the ACS and Interindividual Variability |
|---|
|
TopAbstractIntroductionThe Scientific Basis of...Triggers for Inflammation in...Inflammation and the ACSCorrelation of Elevated...Inflammation and Myocardial...Prevalence of Inflammation in...Inflammatory Biomarkers and Risk...ConclusionReferences |
|---|
In patients with ACS, the prevalence of a primary inflammatory pathogenic component of coronary instability, as detectable by elevated CRP, varies considerably. Elevated CRP (>3 mg/L) is found in <10% of normals, in <20% of patients with chronic stable or variant angina, but in >65% of patients with unstable angina, Braunwald class IIIb, and in >90% of patients with acute infarction preceded by unstable angina, but in <50% of those in whom the infarction was totally unheralded (in samples taken before elevation of markers of necrosis).41,47,55
The absence of elevated CRP in >30% of patients with severe unstable angina and in >50% of those with acute MI not preceded by unstable angina suggests an important heterogeneity of the role of inflammatory triggers of the clinical syndromes of coronary instability.56 Individuals may vary in their response to inflammatory stimuli. The increase in CRP and IL-6 observed in response to the vascular trauma caused by coronary angioplasty or by uncomplicated cardiac catheterization51 and that observed after acute infarction57 correlates linearly with baseline CRP and IL-6 levels. In vitro, the IL-6 production by isolated monocytes from unstable patients with elevated CRP and IL-6 significantly exceeds that produced by monocytes from patients with normal values.47 These individual differences in the degree of response to given inflammatory stimuli may have a genetic basis. For example, certain haplotypes in the IL-1/IL-1 receptor agonist gene complex correlate with heightened inflammatory responses and incidence of ACS.58
|
Inflammatory Biomarkers and Risk of First Cardiovascular Events: Implications for Prevention |
|---|
|
TopAbstractIntroductionThe Scientific Basis of...Triggers for Inflammation in...Inflammation and the ACSCorrelation of Elevated...Inflammation and Myocardial...Prevalence of Inflammation in...Inflammatory Biomarkers and Risk...ConclusionReferences |
|---|
The above discussion reviewed the role of inflammatory mediators and markers in ACS. However, inflammation contributes across the spectrum of cardiovascular disease, including the earliest steps in atherogenesis. This recognition has had a profound impact on our understanding of atherothrombosis as more than a disease of lipid accumulation, but rather as a disorder characterized by low-grade vascular inflammation. Practically, we can use this concept to predict future cardiovascular risk.
The best human data relating inflammation to the prospective development of vascular events have come from large-scale, population-based studies. To date, elevated levels of several inflammatory mediators among apparently healthy men and women have proven to have predictive value for future vascular events. In particular, prospective epidemiological studies have found increased vascular risk in association with increased basal levels of cytokines such as IL-6 and TNF-49,59–61; cell adhesion molecules such as soluble ICAM-1, P selectin, and E selectin62–64; and downstream acute-phase reactants such as CRP, fibrinogen, and serum amyloid A.48,49,65–70a Several traditional cardiovascular risk factors track with these inflammatory biomarkers, in particular central obesity and body mass index. These observations have considerable importance because, as discussed above, adipocytes can produce inflammatory cytokines, and a common underlying disorder of innate immunity may well link obesity, accelerated atherosclerosis, and insulin resistance.71b In support of this hypothesis, very recent observations show that elevated levels of both IL-6 and CRP associate not only with the subsequent development of atherosclerosis, but also with the development of type II diabetes, even among individuals with no current evidence of insulin resistance.72
For clinical purposes, the most promising inflammatory biomarker appears to be CRP, a classical acute-phase marker and a member of the pentraxin family of innate immune response proteins.73 The clinical appeal of CRP stems from several analytic properties. Unlike upstream cytokines, CRP has a long half-life, affording stability of levels with no observable circadian variation.74 Further, CRP is easily measured in usual outpatient settings, and standardized high-sensitivity assays commercially available provide similar results in fresh, stored, and frozen plasma.75 Functionally, in addition to providing a downstream integration of overall cytokine activation, CRP has several direct effects that may affect vascular disease progression. These reported functions include an ability to bind and activate complement, induce expression of several cell adhesion molecules as well as tissue factor, mediate LDL uptake by endothelial macrophages, induce monocyte recruitment into the arterial wall, and enhance production of MCP-1.76–80
More than a dozen population-based studies have demonstrated that baseline CRP levels predict future cardiovascular events. CRP testing may thus have a major adjunctive role in the global assessment of cardiovascular risk.81 Available prospective epidemiological studies have included elderly as well as middle-aged individuals, and show consistency for the endpoints of first-ever myocardial infarction or stroke as well as for the development of symptomatic peripheral arterial disease53 (Figure 2). In one recent overview analysis that included 2557 cases with an average follow-up of 8 years, individuals with basal CRP levels in the top third exhibited a 2-fold increase in future vascular events even after adjustment for all other available vascular risk factors.69 Perhaps of equal clinical impact, both men and women with elevated levels of CRP consistently show high vascular risk, even in the absence of hyperlidipidemia.49,82 Algorithms that combine CRP and lipid screening to improve risk assessment may have clinical utility for outpatient use81 (Figure 3).
|
|
In addition to providing a simple method to assess low-grade inflammation and improve global risk prediction, CRP screening may also provide a novel method of targeting statin therapy, particularly in the primary prevention of myocardial infarction and stroke. Both experimental and clinical outcome data now support the hypothesis that statins, in addition to being potent LDL-lowering agents, also attenuate plaque inflammation and influence plaque stability. Both pravastatin and cerivastatin can reduce macrophage content within experimental atherosclerotic plaques,83–85 whereas simvastatin, fluvastatin, and atorvastatin appear to reduce intimal inflammation86 and suppress the expression of tissue factor and matrix metalloproteinases both in vivo and in vitro.87,88 Statins may also inhibit expression of adhesion molecules critical for monocyte attachment and adhesion to the vascular endothelium.89
The first data to link the utility of CRP as a marker of inflammation with potential utility in targeting statin therapy emerged from the Cholesterol and Recurrent Events (CARE) trial, a secondary prevention study in which elevated CRP levels correlated with significantly increased risk of recurrent coronary events.50,90 In a series of hypothesis-generating studies, the CARE investigators then demonstrated that the magnitude of risk reduction attributable to pravastatin was substantially greater among those with evidence of inflammation compared with those without evidence of inflammation. The CARE investigators also reported that random allocation to pravastatin lowered CRP levels in a manner unrelated to the effect of pravastatin on LDL or HDL cholesterol, data that provided strong evidence that statins may have important anti-inflammatory effects.90
Although initially controversial, clinical studies with cerivastatin, lovastatin, simvastatin, and atorvastatin have since replicated the reduction in CRP first described in the CARE trial for pravastatin.91–94 Of these confirmatory studies, the Pravastatin Inflammation CRP Evaluation (PRINCE) was by far the largest, enrolling 2884 patients into two parallel study arms: a secondary prevention cohort (N=1182), which received open-label pravastatin 40 mg daily, and a primary prevention cohort (N=1702), which was randomly allocated to either pravastatin 40 mg daily or to matching placebo.93 Forty percent of the PRINCE participants were women, and 28% took prophylactic aspirin, a regimen previously shown to attenuate the effect of CRP on vascular risk.48
Overall, random allocation to pravastatin in PRINCE reduced median CRP levels by 16.9% compared with placebo (P<0.001). This effect was seen as early as 12 weeks (median reduction in CRP with pravastatin 14.7%, P<0.001) and was present among all prespecified subgroups by gender, age, smoking status, body mass index, baseline lipid levels, or the presence of diabetes. This study showed no association between baseline CRP and baseline LDL cholesterol levels or between end-of-study CRP and end-of-study LDL cholesterol levels, such that <2% of the variance in CRP could be explained by lipid levels. As observed in prior hypothesis-generating studies, there was minimal evidence of association between change in LDL cholesterol and change in CRP, data again demonstrating the independent nature of these two effects.93
Although provocative, data describing CRP reduction with statins does not in itself establish a role for CRP testing as an adjunct to lipid screening, or as a tool to improve targeting of statin therapy. However, data from the recently released Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) CRP substudy addresses this issue directly.92 In brief, CRP levels were assessed at baseline among 5742 participants in AFCAPS/TexCAPS, a primary prevention study of lovastatin carried out among low- to moderate-risk individuals. This study showed an overall reduction in primary acute coronary events of 37%.95 In the inflammation analysis, participants were divided into four groups of equal size on the basis of lipid and CRP levels above or below study median (Table).92 As expected, random allocation to lovastatin therapy was highly effective in reducing primary acute coronary events among those with baseline levels of LDL cholesterol above 149 mg/dL, the median LDL value in the cohort as a whole. However, lovastatin therapy also reduced coronary event rates among those with lower levels of LDL cholesterol and above-median levels of CRP. In fact, the event rate in the placebo group (as well as the magnitude of risk reduction associated with lovastatin use) for those with above-median CRP levels and below-median lipid levels was just as high as that observed among those with overt hyperlipidemia. In marked contrast, lovastatin therapy did not benefit participants in the AFCAPS/TexCAPS trial who had below-average LDL levels and below-average CRP levels.92
|
The CRP data from AFCAPS/TexCAPS are important for several reasons. First, they confirm that elevated CRP levels strongly predict future vascular risk and that the addition of CRP to lipid screening helps to predict global risk. Second, the AFCAPS/TexCAPS CRP data raise the possibility that statin therapy may prove highly effective even among apparently healthy individuals who do not have hyperlipidemia, but who have a propensity toward coronary events as detected by elevated levels of CRP. Because half of all heart attacks and strokes in the United States occur among individuals with normal cholesterol levels, these data provide novel biological insights about some patients who may be at higher risk because of elevated CRP levels, although 
50% of patients who develop an infarction not preceded by unstable angina appear to have normal levels of CRP on admission. As nearly 25 000 000 Americans fit within this low-LDL/high-CRP category yet remain outside current preventive guidelines, more specific understanding of the predictive role of elevated CRP in the presence of low LDL is needed.
|
Conclusion |
|---|
|
TopAbstractIntroductionThe Scientific Basis of...Triggers for Inflammation in...Inflammation and the ACSCorrelation of Elevated...Inflammation and Myocardial...Prevalence of Inflammation in...Inflammatory Biomarkers and Risk...ConclusionReferences |
|---|
Our understanding of atherosclerosis has evolved beyond the view that these lesions consist of a lifeless collection of lipid debris. Current evidence supports a central role for inflammation in all phases of the atherosclerotic process. Substantial biological data implicate inflammatory pathways in early atherogenesis, in the progression of lesions, and finally in the thrombotic complications of this disease. Clinical studies affirm correlation of circulating markers of inflammation with propensity to develop ischemic events and with prognosis after ACS. Intralesional or extralesional inflammation may hasten atheroma evolution and precipitate acute events. Circulating acute-phase reactants elicited by inflammation may not only mark increased risk for vascular events, but in some cases may contribute to their pathogenesis. This new insight into the role of inflammation in the pathobiology of atherosclerosis has initiated important new areas of direct clinical relevance. We can use inflammatory markers today for risk stratification. Future studies will gauge their utility as guides to monitor therapy. Finally, the quest to identify proximal stimuli for inflammation, as one pathogenic process in atherogenesis or trigger to lesion complication, may yield novel therapeutic targets in years to come.
|
Acknowledgments |
|---|
This work was supported in part by grants from the National Heart, Lung, and Blood Institute to Drs Libby (HL-34636, HL-48743, and HL-56985) and Ridker (HL-58755 and HL-63293), and by the Leducq Foundation (to Drs Libby and Ridker). Dr Ridker is also supported by a Distinguished Scientist Award from the Doris Duke Foundation. Dr Maseri is supported by a grant from Fondazione Internazionale di Ricerca Per il Cuore onlus.
|
References |
|---|
|
TopAbstractIntroductionThe Scientific Basis of...Triggers for Inflammation in...Inflammation and the ACSCorrelation of Elevated...Inflammation and Myocardial...Prevalence of Inflammation in...Inflammatory Biomarkers and Risk...ConclusionReferences |
|---|
1. Li H, Cybulsky MI, Gimbrone MA Jr, et al. An atherogenic diet rapidly induces VCAM-1, a cytokine regulatable mononuclear leukocyte adhesion molecule, in rabbit endothelium. Arterioscler Thromb. 1993; 13: 197–204.
2. Cybulsky MI, Iiyama K, Li H, et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest. 2001; 107: 1255–1262.[Medline] [Order article via Infotrieve]
3.
Topper JN, Cai J, Falb D, et al. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci U S A. 1996; 93: 10417–10422.
4. De Caterina R, Libby P, Peng HB, et al. Nitric oxide decreases cytokine-induced endothelial activation: nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest. 1995; 96: 60–68.
5. Nagel T, Resnick N, Atkinson WJ, et al. Shear stress selectively upregulates intercellular adhesion molecule-1 expression in cultured human vascular endothelial cells. J Clin Invest. 1994; 94: 885–891.
6.
Lee RT, Yamamoto C, Feng Y, et al. Mechanical strain induces specific changes in the synthesis and organization of proteoglycans by vascular smooth muscle cells. J Biol Chem. 2001; 276: 13847–13851.
7. Gu L, Okada Y, Clinton S, et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low-density lipoprotein-deficient mice. Mol Cell. 1998; 2: 275–281.[CrossRef][Medline] [Order article via Infotrieve]
8. Boring L, Gosling J, Cleary M, et al. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 1998; 394: 894–897.[CrossRef][Medline] [Order article via Infotrieve]
9. Mach F, Sauty A, Iarossi A, et al. Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells. J Clin Invest. 1999; 104: 1041–1050.[Medline] [Order article via Infotrieve]
10.
Smith JD, Trogan E, Ginsberg M, et al. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci U S A. 1995; 92: 8264–8268.
11. Qiao JH, Tripathi J, Mishra NK, et al. Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. Am J Pathol. 1997; 150: 1687–1699.[Abstract]
12. Hansson G, Libby P. The role of the lymphocyte.In: Fuster V, Ross R, Topol E, eds. Atherosclerosis and Coronary Artery Disease. New York, NY: Lippincott-Raven; 1996: 557–568.
13.
Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
14. Libby P, Geng Y-J, Aikawa M, et al. Macrophages and atherosclerotic plaque stability. Curr Opin Lipidol. 1996; 7: 330–335.[Medline] [Order article via Infotrieve]
15.
Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001; 104: 365–372.
16.
Libby P, Simon DI. Inflammation and thrombosis: the clot thickens. Circulation. 2001; 103: 1718–1720.
17. Berliner J, Leitinger N, Watson A, et al. Oxidized lipids in atherogenesis: formation, destruction and action. Thromb Haemost. 1997; 78: 195–199.[Medline] [Order article via Infotrieve]
18. Williams KJ, Tabas I. The response-to-retention hypothesis of atherogenesis reinforced. Curr Opin Lipidol. 1998; 9: 471–474.[CrossRef][Medline] [Order article via Infotrieve]
19. Witztum JL, Berliner JA. Oxidized phospholipids and isoprostanes in atherosclerosis. Curr Opin Lipidol. 1998; 9: 441–448.[CrossRef][Medline] [Order article via Infotrieve]
20.
Stemme S, Faber B, Holm J, et al. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci U S A. 1995; 92: 3893–3897.
21. Hazen SL, Hsu FF, Gaut JP, et al. Modification of proteins and lipids by myeloperoxidase. Methods Enzymol. 1999; 300: 88–105.[Medline] [Order article via Infotrieve]
22.
Sugiyama S, Okada Y, Sukhova GK, et al. Macrophage myeloperoxidase regulation by granulocyte macrophage colony- stimulating factor in human atherosclerosis and implications in acute coronary syndromes. Am J Pathol. 2001; 158: 879–891.
23.
Dichtl W, Nilsson L, Goncalves I, et al. Very low-density lipoprotein activates nuclear factor-
B in endothelial cells. Circ Res. 1999; 84: 1085–1094.
24. Mackness MI, Mackness B, Durrington PN, et al. Paraoxonase and coronary heart disease. Curr Opin Lipidol. 1998; 9: 319–324.[CrossRef][Medline] [Order article via Infotrieve]
25.
Griendling KK, Ushio-Fukai M, Lassegue B, et al. Angiotensin II signaling in vascular smooth muscle: new concepts. Hypertension. 1997; 29: 366–373.
26.
Kranzhofer R, Schmidt J, Pfeiffer CA, et al. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1999; 19: 1623–1629.
27.
Hernandez-Presa M, Bustos C, Ortego M, et al. Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation. 1997; 95: 1532–1541.
28.
Tummala PE, Chen XL, Sundell CL, et al. Angiotensin II induces vascular cell adhesion molecule-1 expression in rat vasculature: a potential link between the renin-angiotensin system and atherosclerosis. Circulation. 1999; 100: 1223–1229.
29.
Schmidt AM, Yan SD, Wautier JL, et al. Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ Res. 1999; 84: 489–497.
30. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes. 1999; 48: 1–9.[Abstract]
31.
Yudkin JS, Stehouwer CD, Emeis JJ, et al. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol. 1999; 19: 972–978.
32.
Libby P, Egan D, Skarlatos S. Roles of infectious agents in atherosclerosis and restenosis: an assessment of the evidence and need for future research. Circulation. 1997; 96: 4095–4103.
33. Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet. 1997; 350: 430–436.[CrossRef][Medline] [Order article via Infotrieve]
34. Kol A, Bourcier T, Lichtman AH, et al. Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages. J Clin Invest. 1999; 103: 571–577.[Medline] [Order article via Infotrieve]
35. Hackett D, Davies G, Chierchia S, et al. Intermittent coronary occlusion in acute myocardial infarction: value of combined thrombolytic and vasodilator therapy. N Engl J Med. 1987; 317: 1055–1059.[Abstract]
36.
Bogaty P, Hackett D, Davies G, et al. Vasoreactivity of the culprit lesion in unstable angina. Circulation. 1994; 90: 5–11.
37.
Pristipino C, Beltrame JF, Finocchiaro ML, et al. Major racial differences in coronary constrictor response between Japanese and Caucasians with recent myocardial infarction. Circulation. 2000; 101: 1102–1108.
38.
Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med. 2001; 344: 1879–1887.
39.
Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. The MIRACL study: a randomized controlled trial. JAMA. 2001; 285: 1711–1718.
40. Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in "active" coronary artery disease. Am J Cardiol. 1990; 65: 168–172.[CrossRef][Medline] [Order article via Infotrieve]
41.
Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med. 1994; 331: 417–424.
42.
Toss H, Lindahl B, Siegbahn A, et al. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. Circulation. 1997; 96: 4204–4210.
43. Rebuzzi AG, Quaranta G, Liuzzo G, et al. Incremental prognostic value of serum levels of troponin T and C-reactive protein on admission in patients with unstable angina pectoris. Am J Cardiol. 1998; 82: 715–719.[CrossRef][Medline] [Order article via Infotrieve]
44.
Biasucci LM, Liuzzo G, Grillo RL, et al. Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability. Circulation. 1999; 99: 855–860.
45.
Morrow DA, Rifai N, Antman EM, et al. Serum amyloid A predicts early mortality in acute coronary syndromes: a TIMI 11A substudy. J Am Coll Cardiol. 2000; 35: 358–362.
46.
Heeschen C, Hamm CW, Bruemmer J, et al. Predictive value of C-reactive protein and troponin T in patients with unstable angina: a comparative analysis. CAPTURE investigators. Chimeric C7E3 Antiplatelet Therapy in Unstable Angina Refractory to Standard Treatment Trial. J Am Coll Cardiol. 2000; 35: 1535–1542.
47. Biasucci LM, Liuzzo G, Colizzi C, et al. Clinical use of C-reactive protein for the prognostic stratification of patients with ischemic heart disease. Ital Heart J. 2001; 2: 164–171.[Medline] [Order article via Infotrieve]
48.
Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336: 973–979.
49.
Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000; 342: 836–843.
50.
Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998; 98: 839–844.
51.
Liuzzo G, Biasucci LM, Rebuzzi AG, et al. Plasma protein acute-phase response in unstable angina is not induced by ischemic injury. Circulation. 1996; 94: 2373–2380.
52.
Horne BD, Muhlestein JB, Carlquist JF, et al. Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease. J Am Coll Cardiol. 2000; 36: 1774–1780.
53.
Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA. 2001; 285: 2481–2485.
54. Maseri A. From syndromes to specific disease mechanisms. The search for the causes of myocardial infarction. Ital Heart J. 2000; 1: 253–257.[Medline] [Order article via Infotrieve]
55. Cianflone D, Ciccirillo F, Buffon A, et al. Comparison of coronary angiographic narrowing in stable angina pectoris, unstable angina pectoris, and in acute myocardial infarction. Am J Cardiol. 1995; 76: 215–219.[CrossRef][Medline] [Order article via Infotrieve]
56.
Solberg LA, Strong JP. Risk factors and atherosclerotic lesions: a review of autopsy studies. Arteriosclerosis. 1983; 3: 187–198.
57. Pepys MB, Hirschfield GM. C-reactive protein and atherothrombosis. Ital Heart J. 2001; 2: 196–199.[Medline] [Order article via Infotrieve]
58.
Francis SE, Camp NJ, Dewberry RM, et al. Interleukin-1 receptor antagonist gene polymorphism and coronary artery disease. Circulation. 1999; 99: 861–866.
59.
Ridker PM, Rifai N, Stampfer MJ, et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000; 101: 1767–1772.
60. Harris TB, Ferrucci L, Tracy RP, et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med. 1999; 106: 506–512.[CrossRef][Medline] [Order article via Infotrieve]
61.
Ridker PM, Rifai N, Pfeffer M, et al. Elevation of tumor necrosis factor- and increased risk of recurrent coronary events after myocardial infarction. Circulation. 2000; 101: 2149–2153.
62.
Hwang SJ, Ballantyne CM, Sharrett AR, et al. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases. The Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1997; 96: 4219–4225.
63. Ridker PM, Hennekens CH, Roitman-Johnson B, et al. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet. 1998; 351: 88–92.[CrossRef][Medline] [Order article via Infotrieve]
64.
Ridker PM, Buring JE, Rifai N. Soluble P-selectin and the risk of future cardiovascular events. Circulation. 2001; 103: 491–495.
65. Haverkate F, Thompson SG, Pyke SD, et al. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet. 1997; 349: 462–466.[CrossRef][Medline] [Order article via Infotrieve]
66.
Kuller LH, Tracy RP, Shaten J, et al. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1996; 144: 537–547.
67.
Tracy RP, Lemaitre RN, Psaty BM, et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol. 1997; 17: 1121–1127.
68.
Ridker PM, Buring JE, Shih J, et al. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation. 1998; 98: 731–733.
69.
Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ. 2000; 321: 199–204.
70.
Koenig W, Sund M, Frohlich M, et al. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation. 1999; 99: 237–242.
70.
Roivanen M, Viik-Kajander M, Paluso T, et al. Infections, inflammation, and the risk of coronary heart disease. Circulation. 2000; 101: 252–257.
71.
Mendall MA, Strachan DP, Butland BK, et al. C-reactive protein: relation to total mortality, cardiovascular mortality, and cardiovascular risk factors in men. Eur Heart J. 2000; 21: 1584–1590.
71. Pickup JC, Crook MA. Is type II diabetes mellitus a disease of the innate immune system? Diabetologia. 1998; 41: 1241–1248.[CrossRef][Medline] [Order article via Infotrieve]
72.
Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001; 286: 327–334.
73. Pepys MB. C-reactive protein fifty years on. Lancet. 1981; 1: 653–657.[Medline] [Order article via Infotrieve]
74.
Meier-Ewert HK, Ridker PM, Rifai N, et al. Absence of diurnal variation of C-reactive protein concentrations in healthy human subjects. Clin Chem. 2001; 47: 426–430.
75.
Rifai N, Tracy RP, Ridker PM. Clinical efficacy of an automated high-sensitivity C-reactive protein assay. Clin Chem. 1999; 45: 2136–2141.
76.
Torzewski M, Rist C, Mortensen RF, et al. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arterioscler Thromb Vasc Biol. 2000; 20: 2094–2099.
77.
Bhakdiz S, Torzewski M, Klouche M, et al. Complement and atherogenesis: binding of CRP to degraded, nonoxidized LDL enhances complement activation. Arterioscler Thromb Vasc Biol. 1999; 19: 2348–2354.
78.
Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000; 102: 2165–2168.
79.
Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation. 2001; 103: 1194–1197.
80.
Pasceri V, Chang J, Willerson JT, et al. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation. 2001; 103: 2531–2534.
81.
Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation. 2001; 103: 1813–1818.
82.
Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation. 1998; 97: 2007–2011.
83.
Fukumoto Y, Libby P, Rabkin E, et al. Statins alter smooth muscle cell accumulation and collagen content in established atheroma of Watanabe heritable hyperlipidemic rabbits. Circulation. 2001; 103: 993–999.
84. Shiomi M, Ito T. Effect of cerivastatin sodium, a new inhibitor of HMG-CoA reductase, on plasma lipid levels, progression of atherosclerosis, and the lesional composition in the plaques of WHHL rabbits. Br J Pharmacol. 1999; 126: 961–968.[CrossRef][Medline] [Order article via Infotrieve]
85.
Williams JK, Sukhova GK, Herrington DM, et al. Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys. J Am Coll Cardiol. 1998; 31: 684–691.
86.
Bustos C, Hernandez-Presa MA, Ortego M, et al. HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in a rabbit model of atherosclerosis. J Am Coll Cardiol. 1998; 32: 2057–2064.
87.
Aikawa M, Rabkin E, Sugiyama S, et al. An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation. 2001; 103: 276–283.
88.
Bellosta S, Via D, Canavesi M, et al. HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol. 1998; 18: 1671–1678.
89. Niwa S, Totsuka T, Hayashi S. Inhibitory effect of fluvastatin, an HMG-CoA reductase inhibitor, on the expression of adhesion molecules on human monocyte cell line. Int J Immunopharmacol. 1996; 18: 669–675.[CrossRef][Medline] [Order article via Infotrieve]
90.
Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of c-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1999; 100: 230–235.
91.
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.
92.
Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001; 344: 1959–1965.
93.
Albert MA, Danielson E, Rifai N, et al. Effect of statin therapy on C-reactive protein levels. The Pravastatin Inflammation/CRP Evaluation (PRINCE): a randomized trial and cohort study. JAMA. 2001; 286: 64–70.
94.
Jialal I, Stein D, Balis D, et al. Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation. 2001; 103: 1933–1935.
95.
Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998; 279: 1615–1622.
This article has been cited by other articles:
 |
|
 |
|
  D. Walcher, K. Hess, R. Berger, M. Aleksic, P. Heinz, H. Bach, R. Durst, A. Hausauer, V. Hombach, and N. Marx Resistin: a newly identified chemokine for human CD4-positive lymphocytes Cardiovasc Res, January 1, 2010; 85(1): 167 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. W. McDade, J. Rutherford, L. Adair, and C. W. Kuzawa Early origins of inflammation: microbial exposures in infancy predict lower levels of C-reactive protein in adulthood Proc R Soc B, December 9, 2009; (2009) rspb.2009.1795v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Leinum, J. M. Dopp, and B. J. Morgan Sleep-Disordered Breathing and Obesity: Pathophysiology, Complications, and Treatment Nutr Clin Pract, December 1, 2009; 24(6): 675 - 687. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Lim, J. Ryu, J.-A. Shin, M.-J. Shin, Y. K. Ahn, J. J. Kim, and K. H. Han Tumor Necrosis Factor-{alpha} Potentiates RhoA-Mediated Monocyte Transmigratory Activity In Vivo at a Picomolar Level Arterioscler Thromb Vasc Biol, December 1, 2009; 29(12): 2138 - 2145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Kucharska-Newton, D. J. Couper, J. S. Pankow, R. J. Prineas, T. D. Rea, N. Sotoodehnia, A. Chakravarti, A. R. Folsom, D. S. Siscovick, and W. D. Rosamond Hemostasis, Inflammation, and Fatal and Nonfatal Coronary Heart Disease: Long-Term Follow-Up of the Atherosclerosis Risk in Communities (ARIC) Cohort Arterioscler Thromb Vasc Biol, December 1, 2009; 29(12): 2182 - 2190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Gaetti-Jardim Jr, S. L. Marcelino, A. C. R. Feitosa, G. A. Romito, and M. J. Avila-Campos Quantitative detection of periodontopathic bacteria in atherosclerotic plaques from coronary arteries J. Med. Microbiol., December 1, 2009; 58(12): 1568 - 1575. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. H. Han, S. Lim, J. Ryu, C.-W. Lee, Y. Kim, J.-H. Kang, S.-S. Kang, Y. K. Ahn, C.-S. Park, and J. J. Kim CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages Cardiovasc Res, December 1, 2009; 84(3): 378 - 386. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L.L. Habets, G. H.M. van Puijvelde, L. M. van Duivenvoorde, E. J.A. van Wanrooij, P. de Vos, J.-W. Cohen Tervaert, T. J.C. van Berkel, R. E.M. Toes, and J. Kuiper Vaccination using oxidized low-density lipoprotein-pulsed dendritic cells reduces atherosclerosis in LDL receptor-deficient mice Cardiovasc Res, November 12, 2009; (2009) cvp338v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Celik C-reactive protein: not only a marker but also a mediator of myocardial damage following acute myocardial infarction Eur. Heart J., November 2, 2009; 30(22): 2813 - 2813. [Full Text] [PDF]
|
|
|
|
 |
|
 J M Noble, L N Borrell, P N Papapanou, M S V Elkind, N Scarmeas, and C B Wright Periodontitis is associated with cognitive impairment among older adults: analysis of NHANES-III J. Neurol. Neurosurg. Psychiatry, November 1, 2009; 80(11): 1206 - 1211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. I. Yilmaz, J. J. Carrero, A. Ortiz, J. L. Martin-Ventura, A. Sonmez, M. Saglam, H. Yaman, M. Yenicesu, J. Egido, and L. M. Blanco-Colio Soluble TWEAK Plasma Levels as a Novel Biomarker of Endothelial Function in Patients with Chronic Kidney Disease Clin. J. Am. Soc. Nephrol., November 1, 2009; 4(11): 1716 - 1723. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wang, M. M. Jacome-Sosa, M. R. Ruth, S. D. Goruk, M. J. Reaney, D. R. Glimm, D. C. Wright, D. F. Vine, C. J. Field, and S. D. Proctor Trans-11 Vaccenic Acid Reduces Hepatic Lipogenesis and Chylomicron Secretion in JCR:LA-cp Rats J. Nutr., November 1, 2009; 139(11): 2049 - 2054. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A Deans, V. Bezlyak, I. Ford, G D. Batty, H. Burns, J. Cavanagh, E. d. Groot, A. McGinty, K. Millar, P. G Shiels, et al. Differences in atherosclerosis according to area level socioeconomic deprivation: cross sectional, population based study BMJ, October 27, 2009; 339(oct27_4): b4170 - b4170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. T. Haren, T. K. Malmstrom, D. K. Miller, P. Patrick, H. M. Perry III, M. M. Herning, W. A. Banks, and J. E. Morley Higher C-Reactive Protein and Soluble Tumor Necrosis Factor Receptor Levels Are Associated With Poor Physical Function and Disability: A Cross-Sectional Analysis of a Cohort of Late Middle-Aged African Americans J Gerontol A Biol Sci Med Sci, October 7, 2009; (2009) glp148v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hogh, S. Vammen, L. Ostergaard, J. B. Joensen, E. W. Henneberg, and J. S. Lindholt Intermittent Roxithromycin for Preventing Progression of Small Abdominal Aortic Aneurysms: Long-Term Results of a Small Clinical Trial Vascular and Endovascular Surgery, October 1, 2009; 43(5): 452 - 456. [Abstract] [PDF]
|
|
|
|
 |
|
 R. E. Marioni, M. C. Stewart, G. D. Murray, I. J. Deary, F. G. R. Fowkes, G. D. O. Lowe, A. Rumley, and J. F. Price Peripheral Levels of Fibrinogen, C-Reactive Protein, and Plasma Viscosity Predict Future Cognitive Decline in Individuals Without Dementia Psychosom Med, October 1, 2009; 71(8): 901 - 906. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. McDermott and D. M. Lloyd-Jones The role of biomarkers and genetics in peripheral arterial disease. J. Am. Coll. Cardiol., September 29, 2009; 54(14): 1228 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Biasucci, G. Liuzzo, S. Giubilato, R. Della Bona, M. Leo, M. Pinnelli, A. Severino, M. Gabriele, S. Brugaletta, M. Piro, et al. Delayed neutrophil apoptosis in patients with unstable angina: relation to C-reactive protein and recurrence of instability Eur. Heart J., September 2, 2009; 30(18): 2220 - 2225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Bagi Mechanisms of coronary microvascular adaptation to obesity Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2009; 297(3): R556 - R567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Recio-Mayoral, J. C. Mason, J. C. Kaski, M. B. Rubens, O. A. Harari, and P. G. Camici Chronic inflammation and coronary microvascular dysfunction in patients without risk factors for coronary artery disease Eur. Heart J., August 1, 2009; 30(15): 1837 - 1843. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Engoren, R. H. Habib, J. Hadaway, A. Zacharias, T. A. Schwann, C. J. Riordan, S. J. Durham, and A. Shah The Effect on Long-Term Survival of Erythrocyte Transfusion Given for Cardiac Valve Operations Ann. Thorac. Surg., July 1, 2009; 88(1): 95 - 100. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Huang, C. Luo, X. Gu, Z. Wu, Z. Wang, Z. Du, C. Hu, and L. Tang Mechanical Strain Induces Expression of C-Reactive Protein in Human Blood Vessels J. Pharmacol. Exp. Ther., July 1, 2009; 330(1): 206 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Yu, X. Ye, J. Wang, Q. Qi, O. H. Franco, K. L. Rennie, A. Pan, H. Li, Y. Liu, F. B. Hu, et al. Associations of Physical Activity With Inflammatory Factors, Adipocytokines, and Metabolic Syndrome in Middle-Aged and Older Chinese People Circulation, June 16, 2009; 119(23): 2969 - 2977. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Dinh, S. Scovell, and A. Veves Review: Peripheral Arterial Disease and Diabetes: A Clinical Update International Journal of Lower Extremity Wounds, June 1, 2009; 8(2): 75 - 81. [Abstract] [PDF]
|
|
|
|
 |
|
 E. W. Kang, H. J. Na, S. M. Hong, S. K. Shin, S.-W. Kang, K. H. Choi, H. Y. Lee, D.-S. Han, and S. H. Han Prognostic value of elevated cardiac troponin I in ESRD patients with sepsis Nephrol. Dial. Transplant., May 1, 2009; 24(5): 1568 - 1573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Luciano, R. E. Marioni, A. J. Gow, J. M. Starr, and I. J. Deary Reverse Causation in the Association Between C-Reactive Protein and Fibrinogen Levels and Cognitive Abilities in an Aging Sample Psychosom Med, May 1, 2009; 71(4): 404 - 409. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ohshima, A. Petrov, S. Fujimoto, J. Zhou, M. Azure, D. S. Edwards, T. Murohara, N. Narula, S. Tsimikas, and J. Narula Molecular Imaging of Matrix Metalloproteinase Expression in Atherosclerotic Plaques of Mice Deficient in Apolipoprotein E or Low-Density-Lipoprotein Receptor J. Nucl. Med., April 1, 2009; 50(4): 612 - 617. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Piconi, D. Trabattoni, C. Luraghi, E. Perilli, M. Borelli, M. Pacei, G. Rizzardini, A. Lattuada, D. H. Bray, M. Catalano, et al. Treatment of periodontal disease results in improvements in endothelial dysfunction and reduction of the carotid intima-media thickness FASEB J, April 1, 2009; 23(4): 1196 - 1204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Pecoits-Filho APPLYING TRANSLATIONAL RESEARCH IN UNDERSTANDING COMPLICATIONS AND DEFINING TARGETS FOR INTERVENTION: INFLAMMATION IN PD AS A MODEL Perit. Dial. Int., March 1, 2009; 29(2): 135 - 141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-i. Chen, S.-L. Kao, M.-H. Tsai, M.-S. Shiao, and C. J. Jen Exercise Training Modulates the Effects of Lipoproteins on Acetylcholine-Induced Endothelial Calcium Signaling in Rat Aortas Experimental Biology and Medicine, March 1, 2009; 234(3): 323 - 331. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sanson, N. Auge, C. Vindis, C. Muller, Y. Bando, J.-C. Thiers, M.-A. Marachet, K. Zarkovic, Y. Sawa, R. Salvayre, et al. Oxidized Low-Density Lipoproteins Trigger Endoplasmic Reticulum Stress in Vascular Cells: Prevention by Oxygen-Regulated Protein 150 Expression Circ. Res., February 13, 2009; 104(3): 328 - 336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. L.C. Chapple Potential Mechanisms Underpinning the Nutritional Modulation of Periodontal Inflammation J Am Dent Assoc, February 1, 2009; 140(2): 178 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Verschuren, J. de Vries-van der Weij, S. Zadelaar, R. Kleemann, and T. Kooistra LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: time course and mechanisms J. Lipid Res., February 1, 2009; 50(2): 301 - 311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. N. Rathcke, F. Persson, L. Tarnow, P. Rossing, and H. Vestergaard YKL-40, a Marker of Inflammation and Endothelial Dysfunction, Is Elevated in Patients With Type 1 Diabetes and Increases With Levels of Albuminuria Diabetes Care, February 1, 2009; 32(2): 323 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Su, A. H. Miller, H. Snieder, J. D. Bremner, J. Ritchie, C. Maisano, L. Jones, N. V. Murrah, J. Goldberg, and V. Vaccarino Common Genetic Contributions to Depressive Symptoms and Inflammatory Markers in Middle-Aged Men: The Twins Heart Study Psychosom Med, February 1, 2009; 71(2): 152 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Mora, K. Musunuru, and R. S. Blumenthal The Clinical Utility of High-Sensitivity C-Reactive Protein in Cardiovascular Disease and the Potential Implication of JUPITER on Current Practice Guidelines Clin. Chem., February 1, 2009; 55(2): 219 - 228. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Nambi, R. C. Hoogeveen, L. Chambless, Y. Hu, H. Bang, J. Coresh, H. Ni, E. Boerwinkle, T. Mosley, R. Sharrett, et al. Lipoprotein-Associated Phospholipase A2 and High-Sensitivity C-Reactive Protein Improve the Stratification of Ischemic Stroke Risk in the Atherosclerosis Risk in Communities (ARIC) Study Stroke, February 1, 2009; 40(2): 376 - 381. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Straat, R. de Klark, S. Gredmark-Russ, P. Eriksson, and C. Soderberg-Naucler Infection with Human Cytomegalovirus Alters the MMP-9/TIMP-1 Balance in Human Macrophages J. Virol., January 15, 2009; 83(2): 830 - 835. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Parish Genetic and Immunologic Aspects of Sleep Disorders ACCP Sleep Med Brd Rev, January 1, 2009; 4(0): 271 - 286. [Full Text] [PDF]
|
|
|
|
 |
|
 P.C. Bennett, S. Silverman, P.S. Gill, and G.Y.H. Lip Ethnicity and peripheral artery disease QJM, January 1, 2009; 102(1): 3 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Sathiyapriya, H. Nandeesha, N. Selvaraj, Z. Bobby, A. Agrawal, and P. Pavithran Association Between Protein-Bound Sialic Acid and High-Sensitivity C-Reactive Protein in Essential Hypertension: A Possible Indication of Underlying Cardiovascular Risk Angiology, January 1, 2009; 59(6): 721 - 726. [Abstract] [PDF]
|
|
|
|
 |
|
 S. De Castro, E. Di Angelantonio, A. Celotto, M. Fiorelli, I. Passaseo, F. Papetti, S. Caselli, A. Marcantonio, A. Cohen, and N. Pandian Short-term evolution (9 months) of aortic atheroma in patients with or without embolic events: a follow-up transoesophageal echocardiographic study Eur J Echocardiogr, January 1, 2009; 10(1): 96 - 102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Pedersen, N. Kupper, and J. Denollet CHAPTER 35 Psychological Factors and Heart Disease ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. MacNee, J. Maclay, and D. McAllister Cardiovascular Injury and Repair in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, December 1, 2008; 5(8): 824 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Siekmeier, T. Grammer, and W. Marz Roles of Oxidants, Nitric Oxide, and Asymmetric Dimethylarginine in Endothelial Function Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2008; 13(4): 279 - 297. [Abstract] [PDF]
|
|
|
|
 |
|
 B. Lamarche Review of the Effect of Dairy Products on Non-Lipid Risk Factors for Cardiovascular Disease J. Am. Coll. Nutr., December 1, 2008; 27(6): 741S - 746S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. W. J. Strachan, R. M. Reynolds, B. M. Frier, R. J. Mitchell, and J. F. Price The relationship between type 2 diabetes and dementia Br. Med. Bull., December 1, 2008; 88(1): 131 - 146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Ammirati, A.-C. Vermi, D. Cianflone, M. Banfi, C. Foglieni, C. Godino, F. Airoldi, L. A. Ferri, C. L. Gorman, A. A. Manfredi, et al. Expansion of T-Cell Receptor {zeta}dim Effector T Cells in Acute Coronary Syndromes Arterioscler Thromb Vasc Biol, December 1, 2008; 28(12): 2305 - 2311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wang, H. Chai, Z. Wang, P. H. Lin, Q. Yao, and C. Chen Serum amyloid A induces endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2399 - H2408. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Shaw, A. Bobik, A. Murphy, P. Kanellakis, P. Blombery, N. Mukhamedova, K. Woollard, S. Lyon, D. Sviridov, and A. M. Dart Infusion of Reconstituted High-Density Lipoprotein Leads to Acute Changes in Human Atherosclerotic Plaque Circ. Res., November 7, 2008; 103(10): 1084 - 1091. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T Lanki, G Hoek, K L Timonen, A Peters, P Tiittanen, E Vanninen, and J Pekkanen Hourly variation in fine particle exposure is associated with transiently increased risk of ST segment depression Occup. Environ. Med., November 1, 2008; 65(11): 782 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sanchez-Quinones, F. Marin, V. Roldan, and G.Y.H. Lip The impact of statin use on atrial fibrillation QJM, November 1, 2008; 101(11): 845 - 861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. S. Retelny, A. Neuendorf, and J. L. Roth Nutrition Protocols for the Prevention of Cardiovascular Disease Nutr Clin Pract, October 1, 2008; 23(5): 468 - 476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Waksman, P. E. McEwan, T. I. Moore, R. Pakala, F. D. Kolodgie, D. G. Hellinga, R. C. Seabron, S. J. Rychnovsky, J. Vasek, R. W. Scott, et al. PhotoPoint Photodynamic Therapy Promotes Stabilization of Atherosclerotic Plaques and Inhibits Plaque Progression J. Am. Coll. Cardiol., September 16, 2008; 52(12): 1024 - 1032. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Mack An Epigenetic Clue to Diabetic Vascular Disease Circ. Res., September 12, 2008; 103(6): 568 - 570. [Full Text] [PDF]
|
|
|
|
|
|
M. A. Reddy, L. M. Villeneuve, M. Wang, L. Lanting, and R. Natarajan Role of the Lysine-Specific Demethylase 1 in the Proinflammatory Phenotype of Vascular Smooth Muscle Cells of Diabetic Mice Circ. Res., September 12, 2008; 103(6): 615 - 623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Gardner, H. Tan, E. L. Hull, J. B. Lisauskas, S. T. Sum, T. M. Meese, C. Jiang, S. P. Madden, J. D. Caplan, A. P. Burke, et al. Detection of lipid core coronary plaques in autopsy specimens with a novel catheter-based near-infrared spectroscopy system. J. Am. Coll. Cardiol. Img., September 1, 2008; 1(5): 638 - 648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Ho, C. D. Owens, T. Longo, X. X. Sui, C. Ifantides, and M. S. Conte C-reactive protein and vein graft disease: evidence for a direct effect on smooth muscle cell phenotype via modulation of PDGF receptor-{beta} Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1132 - H1140. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Steinfeld, R. Navon, D. Ardigo, I. Zavaroni, and Z. Yakhini Clinically driven semi-supervised class discovery in gene expression data Bioinformatics, August 15, 2008; 24(16): i90 - i97. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Steinberg, C. K. Glass, and J. L. Witztum Evidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemia Circulation, August 5, 2008; 118(6): 672 - 677. [Full Text] [PDF]
|
|
|
|
 |
|
 E. Apostolakis and I. Koniari eComment: Statins decelerate the sclerosis progression of senile aortic valves in only selected cases Interactive CardioVascular and Thoracic Surgery, August 1, 2008; 7(4): 689 - 689. [Full Text] [PDF]
|
|
|
|
 |
|
 E. T Fung, A. M Wilson, F. Zhang, N. Harris, K. A Edwards, J. W Olin, and J. P Cooke A biomarker panel for peripheral arterial disease Vascular Medicine, August 1, 2008; 13(3): 217 - 224. [Abstract] [PDF]
|
|
|
|
|
|
M. Zhang, S.-h. Zhou, S.-P. Zhao, Q.-m. Liu, X.-p. Li, and X.-Q. Shen Irbesartan attenuates Ang II-induced BMP-2 expression in human umbilical vein endothelial cells Vascular Medicine, August 1, 2008; 13(3): 239 - 245. [Abstract] [PDF]
|
|
|
|
|
|
A. L. Hogh, J. Joensen, J. S. Lindholt, M. R. Jacobsen, and L. Ostergaard C-Reactive Protein Predicts Future Arterial and Cardiovascular Events in Patients With Symptomatic Peripheral Arterial Disease Vascular and Endovascular Surgery, August 1, 2008; 42(4): 341 - 347. [Abstract] [PDF]
|
|
|
|
 |
|
 F. A. Arain and L. T. Cooper Jr Peripheral Arterial Disease: Diagnosis and Management Mayo Clin. Proc., August 1, 2008; 83(8): 944 - 950. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Jahoor, R. Patel, A. Bryan, C. Do, J. Krier, C. Watters, W. Wahli, G. Li, S. C. Williams, and K. P. Rumbaugh Peroxisome Proliferator-Activated Receptors Mediate Host Cell Proinflammatory Responses to Pseudomonas aeruginosa Autoinducer J. Bacteriol., July 1, 2008; 190(13): 4408 - 4415. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Dumortier, D. N. Streblow, A. V. Moses, J. M. Jacobs, C. N. Kreklywich, D. Camp, R. D. Smith, S. L. Orloff, and J. A. Nelson Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing J. Virol., July 1, 2008; 82(13): 6524 - 6535. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Kintscher, M. Hartge, K. Hess, A. Foryst-Ludwig, M. Clemenz, M. Wabitsch, P. Fischer-Posovszky, T. F.E. Barth, D. Dragun, T. Skurk, et al. T-lymphocyte Infiltration in Visceral Adipose Tissue: A Primary Event in Adipose Tissue Inflammation and the Development of Obesity-Mediated Insulin Resistance Arterioscler Thromb Vasc Biol, July 1, 2008; 28(7): 1304 - 1310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D Tousoulis, M Charakida, and C Stefanadis Endothelial function and inflammation in coronary artery disease Postgrad. Med. J., July 1, 2008; 84(993): 368 - 371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Bogaty, L. Boyer, S. Simard, F. Dauwe, R. Dupuis, B. Verret, T. Huynh, F. Bertrand, G. R. Dagenais, and J. M. Brophy Clinical utility of C-reactive protein measured at admission, hospital discharge, and 1 month later to predict outcome in patients with acute coronary disease. The RISCA (recurrence and inflammation in the acute coronary syndromes) study. J. Am. Coll. Cardiol., June 17, 2008; 51(24): 2339 - 2346. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R A Pollitt, J S Kaufman, K M Rose, A V Diez-Roux, D Zeng, and G Heiss Cumulative life course and adult socioeconomic status and markers of inflammation in adulthood J Epidemiol Community Health, June 1, 2008; 62(6): 484 - 491. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Foglieni, F. Maisano, L. Dreas, A. Giazzon, G. Ruotolo, E. Ferrero, L. Li Volsi, S. Coli, G. Sinagra, B. Zingone, et al. Mild inflammatory activation of mammary arteries in patients with acute coronary syndromes Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2831 - H2837. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Alexanderson, A. Gomez-Leon, A. Vargas, J. L. Romero, C. Sierra Fernandez, M. Rodriguez Valero, L. Garcia-Rojas, A. Meave, and M.-C. Amigo Myocardial ischaemia in patients with primary APS: a 13N-ammonia PET assessment Rheumatology, June 1, 2008; 47(6): 894 - 896. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. S. Sutton, D. R. Crosslin, S. H. Shah, S. C. Nelson, A. Bassil, A. B. Hale, C. Haynes, P. J. Goldschmidt-Clermont, J. M. Vance, D. Seo, et al. Comprehensive genetic analysis of the platelet activating factor acetylhydrolase (PLA2G7) gene and cardiovascular disease in case-control and family datasets Hum. Mol. Genet., May 1, 2008; 17(9): 1318 - 1328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Guldiken, S. Guldiken, B. Turgut, N. Turgut, M. Demir, Y. Celik, E. Arikan, and A. Tugrul The Roles of Oxidized Low-Density Lipoprotein and Interleukin-6 Levels in Acute Atherothrombotic and Lacunar Ischemic Stroke Angiology, May 1, 2008; 59(2): 224 - 229. [Abstract] [PDF]
|
|
|
|
 |
|
 N-E Thomas, J S Baker, M R Graham, S-M Cooper, and B Davies C-reactive protein in schoolchildren and its relation to adiposity, physical activity, aerobic fitness and habitual diet Br. J. Sports Med., May 1, 2008; 42(5): 357 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Arenillas, J. Alvarez-Sabin, C. A. Molina, P. Chacon, I. Fernandez-Cadenas, M. Ribo, P. Delgado, M. Rubiera, A. Penalba, A. Rovira, et al. Progression of Symptomatic Intracranial Large Artery Atherosclerosis Is Associated With a Proinflammatory State and Impaired Fibrinolysis Stroke, May 1, 2008; 39(5): 1456 - 1463. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. T. Fung, S. E. Chiuve, M. L. McCullough, K. M. Rexrode, G. Logroscino, and F. B. Hu Adherence to a DASH-Style Diet and Risk of Coronary Heart Disease and Stroke in Women Arch Intern Med, April 14, 2008; 168(7): 713 - 720. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. L. Bentz and A. D. Yurochko Human CMV infection of endothelial cells induces an angiogenic response through viral binding to EGF receptor and {beta}1 and {beta}3 integrins PNAS, April 8, 2008; 105(14): 5531 - 5536. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Nation, J. A. Gonzales, A. J. Mendez, J. Zaias, A. Szeto, L. G. Brooks, J. Paredes, A. D'Angola, N. Schneiderman, and P. M. McCabe The Effect of Social Environment on Markers of Vascular Oxidative Stress and Inflammation in the Watanabe Heritable Hyperlipidemic Rabbit Psychosom Med, April 1, 2008; 70(3): 269 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Barish, A. R. Atkins, M. Downes, P. Olson, L.-W. Chong, M. Nelson, Y. Zou, H. Hwang, H. Kang, L. Curtiss, et al. PPAR{delta} regulates multiple proinflammatory pathways to suppress atherosclerosis PNAS, March 18, 2008; 105(11): 4271 - 4276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. J. F. Tietge, N. Nijstad, R. Havinga, J. F. W. Baller, F. H. van der Sluijs, V. W. Bloks, T. Gautier, and F. Kuipers Secretory phospholipase A2 increases SR-BI-mediated selective uptake from HDL but not biliary cholesterol secretion J. Lipid Res., March 1, 2008; 49(3): 563 - 571. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Laughlin, S. C. Newcomer, and S. B. Bender Importance of hemodynamic forces as signals for exercise-induced changes in endothelial cell phenotype J Appl Physiol, March 1, 2008; 104(3): 588 - 600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Caballero, K. Bousquet-Santos, L. Robles-Osorio, V. Montagnani, G. Soodini, S. Porramatikul, O. Hamdy, A. C.L. Nobrega, and E. S. Horton Overweight Latino Children and Adolescents Have Marked Endothelial Dysfunction and Subclinical Vascular Inflammation in Association With Excess Body Fat and Insulin Resistance Diabetes Care, March 1, 2008; 31(3): 576 - 582. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||