STATE-OF-THE-ART PAPER
Inflammation and Atherothrombosis
From Population Biology and Bench Research to Clinical Practice
Peter Libby, MD*, ,* and
Paul M. Ridker, MD, MPH*, ,
* Division of Cardiovascular Medicine, Center for Cardiovascular Disease Prevention, Boston, Massachusetts
Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
Harvard Medical School, Boston, Massachusetts.
Manuscript received November 29, 2005;
revised manuscript received June 6, 2006,
accepted June 13, 2006.
*
Reprint requests and correspondence: Dr. Peter Libby, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, NRB 741, Boston, Massachusetts 02115. (Email: plibby{at}rics.bwh.harvard.edu).
 |
Abstract
|
|---|
The concept that inflammation governs atherosclerosis and its complications has provided a new unifying hypothesis of the links between risk factors and the cellular and molecular alterations that underlie this disease. This new mechanistic insight has already begun to translate into changes in clinical practice. The preponderance of available data supports the predictive power of biomarkers of inflammation such as high-sensitivity C-reactive protein (hsCRP) in broad categories of individuals, both those who are apparently well and those with already-manifest atherosclerotic cardiovascular disease. The demonstrated clinical utility of hsCRP and potentially of other inflammatory biomarkers has engendered intense interest in evaluating their cost-effectiveness as predictive tools beyond conventional risk markers and as goals for therapy. The rapid translation of inflammation biology in cardiovascular disease from the laboratory to the clinic serves as a gratifying example of bench-to-bedside research. Ultimately, the insight that inflammation plays a fundamental role in atherosclerosis may lead to novel therapies that target aspects of the inflammatory process smoldering within the atheroma.
|
Abbreviations and Acronyms
| | EC = endothelial cell | | ECM = extracellular matrix | | HDL = high-density lipoprotein | | hsCRP = high-sensitivity C-reactive protein | | IL = interleukin | | LDL-C = low-density lipoprotein cholesterol | | ·NO = nitric oxide | | SMC = smooth muscle cell |
|
Our view of atherosclerosis has evolved strikingly over the last several decades. For over 50 years, the medical community regarded atherosclerosis as a cholesterol storage disease characterized by passive deposition of lipid in the arterial wall. According to this concept, continuing accumulation of fatty debris encrusted the artery, causing progressive stenosis that ultimately provoked occlusive thrombosis. Accumulating data and evolution in our thinking cast doubt on this simple concept of atherothrombosis over the last quarter century. Today, we increasingly understand atherogenesis as an active process that involves altered cellular behavior in response to defined molecular signals. We no longer regard the blood vessel as an inert tube, but rather as a living structure composed of cells such as endothelium and smooth muscle (Fig. 1). We possess increasingly detailed knowledge of the interactions between blood components, including cells, proteins, and small molecules, and the intrinsic cells that populate the normal artery wall as contributors to the pathogenesis of this disease.
View larger version (110K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1 The transition from the normal artery wall to the nascent atherosclerotic lesion. The normal muscular artery has a trilaminar structure. A monolayer of endothelial cells overlies the intimal layer and abuts a basement membrane. In human arteries, the intima normally contains a few resident smooth muscle cells and a layer of extracellular matrix. The internal elastic lamina constitutes the boundary between the intimal layer and the tunica media, normally filled with quiescent smooth muscle cells embedded in an elastin-rich extracellular matrix. When molecules associated with risk factors stimulate oxidative or inflammatory stress, they induce the expression of adhesion molecules for leukocytes and chemoattractants that draw the bound leukocytes into the intimal layer. This diagram does not depict the adventitia, the outermost layer of the blood vessel.
|
|
Current thinking accords a primordial role to inflammation as a common unifying mechanism that links risk factors to lesion formation and their tendency to provoke thrombotic complications. We provide here an overview of the basic and population science that underlies this newfound understanding of this ubiquitous disease. Advances in our understanding of the pathogenesis of atherothrombosis have implications beyond theory and now cross the threshold to clinical practice. This article explores further the translation of basic and population science to clinical practice.
For convenience, we often consider atherogenesis in distinct chronologic phases (Figs. 1 to 4).
In contemporary society, the first phase, initiation, occurs all too frequently in childhood or adolescence (Figs. 1 and 2). The nascent lesion then enters a phase of progression, generally considered to occur during young adulthood through middle life (Fig. 3). Ultimately, atherosclerotic disease becomes manifest with either chronic, stable symptoms or thrombotic complications such as acute myocardial infarction or ischemic stroke (Fig. 4). Traditionally, the latter phase of atherothrombosis, complication, occurs in the middle-age or elderly individual. Clearly, this timeline of atherogenesis greatly oversimplifies a complex process. Indeed, individuals with atherosclerosis have lesions with anatomopathological characteristics of more than one stage that coexist, often close proximity. For example, aortae of individuals with atherosclerotic disease can often harbor within centimeters a fatty streak, a fibrous plaque, a calcified lesion, and an ulcerated plaque with thrombosis in situ. Nonetheless, for pedagogical purposes, separating the discussion of atherosclerosis into the phases of lesion initiation, progression, and complication proves convenient.
View larger version (110K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2 Formation of the fibrofatty plaque. The transition from the fatty streak to the more fibrous lesion involves the migration of smooth muscle cells (SMCs) from the tunica media through the internal elastic lamina into the intima, where they secrete extracellular matrix molecules such as fibrillar collagen and elastin and can divide in response to mitogenic stimuli. The mononuclear phagocytes will imbibe modified lipoproteins such as oxidized low-density lipoprotein (LDL) through scavenger receptors to form foam cells. The activated mononuclear phagocytes in the lesions release chemoattractant cytokines, proinflammatory mediators including cytokines, and small lipid molecules such leukotrienes and prostaglandins, as well as reactive oxygen species (ROS). When SMCs encounter fibrogenic stimuli such as transforming growth factor-beta, they boost their production of extracellular matrix macromolecules, including fibrillar collagen, depicted by the triple helical structures in the diagram and elastin. OxLDL = oxidized low-density lipoprotein.
|
|
View larger version (98K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 4 The thrombotic complications of atherosclerosis. Thrombi complicating atheroma arise by 2 major mechanisms. The first, depicted in the left panel of this diagram, involves a through-and-through rupture of the plaque’s fibrous cap, which has been weakened by the mechanisms described in the text and in the legend to Figure 3. The rent in the fibrous cap permits blood and its coagulation factors to contact tissue factor expressed by macrophages and smooth muscle cell (SMC) and on microparticles elaborated by these cells and endothelial cells (EC). Moreover, the activated cells in the local environment of the plaque, including ECs and SMCs, elaborate large amounts of plasminogen activator inhibitor-1, a potent inhibitor of the endogenous fibrinolytic enzymes also found in the plaque such as urokinase and tissue-type plasminogen activator. A second common mechanism of coronary thrombus formation involves a superficial erosion of the endothelial cells (right panel), perhaps caused by endothelial apoptosis or desquamation.
|
|
View larger version (117K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 3 Maturation of the atherosclerotic plaque. More mature lesions develop a fibrous cap composed of a dense extracellular matrix containing collagen and elastin. Underneath the fibrous cap, a lipid core forms that contains many macrophages, dead or dying macrophages, cellular debris including apoptotic bodies, and extracellular lipid accumulations. Proinflammatory mediators released from activated white cells and endothelial cells and smooth muscle cells (SMC) can potentiate cell death by apoptosis in the advancing lesion. As SMCs die within lesions, fewer remain to renew the extracellular matrix in the plaque’s fibrous cap. In addition, the activated cells in the lesion, notably the macrophages, secrete proteinases that can degrade the macromolecules of the extracellular matrix. In particular, interstitial collagenases can attack the triple helical collagen fragments, weakening the fibrous cap. Elastases can break down elastin required for migration of cells within the lesion, and arterial remodeling occurs during compensatory enlargement, and in the extreme, aneurysm formation. During this phase of atherogenesis neovessels form in the intima, often arising as extensions of vasa vasorum that originate in the adventitial layer. IEL = internal elastic lamina; MFC = macrophage foam cell; ROS = reactive oxygen species.
|
|
|
Inflammation and the initiation of atherosclerosis
|
|---|
Recent research has forged major advances in defining the molecular mediators of classical and emerging risk factors for atherosclerosis. Our knowledge of the links between risk factors and pathobiology remains incomplete. Current concepts will doubtless undergo expansion and revision. Yet, data obtained to date point strongly to inflammation as a final common pathway for transducing the effects of risk factors into changes in the biology of the arterial wall (1–3).
For example, laboratory and population studies conducted over the last century consistently have identified cholesterol as a potent risk factor for atherosclerosis and its complications. Considerable evidence has established the presence of oxidized components of low-density lipoprotein (LDL) in atherosclerotic lesions. Oxidized phospholipids, some with chemically defined structures, can act as proinflammatory stimuli that alter the behavior of intrinsic vascular wall cells and leukocytes alike (4,5). Certain oxidized phospholipids can elicit the expression on the surface of vascular endothelial cells (EC) of well-characterized adhesion molecules that mediate leukocyte adherence to the lumenal surface of these cells (Fig. 1). Likewise, constituents of oxidized LDL can stimulate the expression of chemoattractant molecules, including chemokines such as monocyte chemoattractant protein-1, that beckon the attached leukocyte to migrate through the endothelial monolayer and enter the arterial intima. Angiotensin II can also stimulate the expression of vascular cell adhesion molecule-1 on the endothelial surface (6). Other cytokines regulated by components of oxidized LDL can activate the leukocytes within the intimal layer, provoking their production of further inflammatory mediators (i.e., proinflammatory cytokines and small lipid molecules such as the leukotrienes and prostaglandins). Moreover, these activated leukocytes can generate reactive oxygen species that augment oxidant stress, the constant companion of inflammation in atherosclerosis (6). Concordant population studies support a relationship between hypertension and atherosclerotic cardiovascular disease consistently and convincingly. Considerable evidence now links high blood pressure to inflammation in the artery wall. In particular, angiotensin II, considered a major mediator of hypertension, can act as a proinflammatory stimulus. For example, angiotensin II can stimulate the expression of the proinflammatory cytokine interleukin (IL)-6 and the chemokine monocyte chemoattractant protein-1 from arterial smooth muscle cells (SMC) (7,8). Angiotensin II augments the activity of the adenine dinucleotide phosphate oxidases by vascular wall cells. Such enzymes give rise to superoxide anion, a major contributor to oxidative stress in atherosclerotic lesions (9).
Once resident in the artery wall, mononuclear phagocytes transition from a peripheral blood monocyte to a tissue macrophage (Fig. 2). In the artery wall, macrophages accumulate lipid derived from modified lipoprotein particles internalized through various families of scavenger receptors. However, lipid accumulation in the artery wall depends on a balance between entry and egress. Population studies have consistently established an inverse relationship between high-density lipoprotein (HDL) levels and atherosclerotic cardiovascular disease. One major antiatherosclerotic role of HDL likely results from its ability to accept cholesterol from lipid-engorged macrophages and then ferry it out of the artery wall for catabolism and excretion (10). This process, commonly referred to as reverse cholesterol transport, seems to be only one of the anti-atherosclerotic actions of HDL. Indeed, HDL particles can harbor antioxidant enzymes such as paraoxonase-1, an enzyme that can inactivate potentially proinflammatory phospholipids (11). The HDL particles can mitigate EC expression of cytokine-induced leukocyte adhesion molecules. Thus, low levels of circulating HDL deprive the atheroma’s microenvironment of an endogenous antioxidant and anti-inflammatory particle.
Much recent interest in vascular biology has centered on the endogenous vasodilator molecule nitric oxide (·NO) (12). In addition to its vasorelaxant properties, ·NO can combat thrombosis by inhibiting platelet aggregation. Moreover, ·NO seems to have direct anti-inflammatory actions on EC, in part mediated by antagonism of the proinflammatory transcription regulator nuclear factor-kappa B (13,14). Thus, ·NO exerts a variety of atheroprotective actions. Interestingly shear stress regulates, endothelial nitric oxide synthase, the enzyme that produces ·NO in EC (15,16). Laminar shear stress encountered by EC under normal circumstances augments endothelial nitric oxide synthase expression and local ·NO production by EC. In contrast, the regional release of ·NO likely decreases in regions of disturbed flow (16). Indeed, areas with high probability of initial atherosclerotic lesion formation, notably branch points and flow dividers, display evidence for inflammatory stimulation (17,18). Thus, the balance between local proinflammatory and anti-inflammatory processes probably participates in the preferential formation of atherosclerotic lesions at certain locations in the arterial tree.
Depiction of leukocyte recruitment to early atherosclerotic lesions generally focuses on the mononuclear phagocyte, the precursor of the most numerous white cell in lesions, the lipid-laden macrophage. Indeed, the mononuclear phagocyte constitutes the primary effector of the innate arm of the inflammatory immune response. However, other classes of leukocytes such as T and B lymphocytes and mast cells also congregate in the arterial intima during atherogenesis (19). For a full discussion of roles for these cells, see Kovanen (20) and Hansson and Libby (21).
|
Inflammation and the progression of atherosclerosis
|
|---|
Once established, the atherosclerotic lesion transitions from the fatty streak, composed primarily of macrophage-derived foam cells, to a lesion with a more fibrous character (Figs. 2 and 3). A major cell type involved in the formation of fibrofatty lesions, the arterial SMC, also responds to a myriad of inflammation-associated mediators. Chemoattractants such as platelet-derived growth factor, locally produced by activated leukocytes or elaborated by SMC themselves when appropriately stimulated, can signal SMC to enter the intimal layer from the media, where they reside in a quiescent state in normal arteries (22). The SMC in the intima, some of which may derive from bone marrow as well as from the tunica media, can elaborate extracellular matrix (ECM) molecules that contribute to lesion fibrosis. The arterial SMC manufactures interstitial collagens, elastin, and glycosaminoglycans, principal constituents of the complex ECM characteristic of mature atherosclerotic plaques (23,24). Transforming growth factor-beta, a product of regulatory T cells and other cells associated with atheromata, potently stimulates ECM gene expression by arterial SMC (25). During this phase of atherosclerotic lesion progression, the lesions assume the characteristic architecture of the established atheroma, including the formation of a fibrous cap that surmounts the typical plaque (Fig. 3).
Underneath the fibrous cap, a lipid-rich region forms, often known as the necrotic or lipid core. This central structure in the typical atherosclerotic plaque consists of acellular debris, lipid, and macrophage foam cells. Some cells within and surrounding this region of the plaque bear markers of programmed cell death, or apoptosis (Fig. 3) (26). Proinflammatory cytokines can prime cells for apoptotic death after engagement of receptors such as Fas by death signals such as Fas ligand on activated T cells (27). Inflammation participates in plaque progression, as indicated by in vivo experiments that involve interruption of a central proinflammatory signaling pathway mediated by ligation of CD40 as well as circumstantial evidence based on observations of human and experimental plaques in situ (28).
|
Inflammation and the complications of atherosclerosis
|
|---|
Atherosclerotic plaques typically develop in the arterial intima over a period of many years, even decades. There, these lesions lurk silently until they either produce a flow-limiting obstruction and provoke ischemia or until they trigger thrombosis. The progression of atherosclerotic lesions to occlusive stenoses preoccupied our pathophysiologic concepts and our diagnostic and therapeutic approaches for most of the 20th century. However, we now recognize that occlusive thrombi more frequently complicate noncritically stenotic plaques than those traditionally deemed the culprit of acute myocardial infarction (Fig. 4). Because of positive remodeling or compensatory enlargement, considerable growth of atheroma can occur without substantial lumenal stenosis (29). Such outwardly remodeled plaques may indeed harbor the most intense inflammation and most likely cause acute thrombotic complications (30).
A physical disruption of atherosclerotic plaques predisposes toward thrombus formation. The plaque’s fibrous cap typically stands between the blood and highly thrombogenic material in the plaque’s lipid core. A thinned fibrous cap can break open, exposing the blood and its coagulation factors to thrombogenic stimuli such as tissue factor that concentrates within the lesion’s central core. Endothelial erosion also can precipitate coronary artery thrombosis (Fig. 4) (31). Convergent experimental results and pathological observation support a tight link between inflammation, plaque disruption, and thrombosis (32). Interferon gamma, a prominent product of the activated T lymphocyte, can limit severely the ability of the SMC to produce new collagen required to repair and maintain the ECM of the plaque’s fibrous cap and hence resist rupture (25). Multiple inflammatory cytokines can augment, alone or in concert, the expression within the plaque of proteinases specialized in degrading the ECM macromolecules that lend strength to the plaque’s fibrous cap (33). Members of the matrix metalloproteinase family, including interstitial collagenases, likely participate in this process. Cysteinyl proteinases such as cathepsin S also can catabolize elastin, a prominent constituent of the arterial ECM in plaques (34). Additionally, serine proteinases, including neutrophil elastase and plasminogen activators, may participate in arterial ECM remodeling and potentially predispose toward plaque disruption and thrombosis (35). Mediators related to inflammation regulate all of these proteolytic enzyme categories.
The plaque’s predominant procoagulant, tissue factor, also undergoes regulation by proinflammatory cytokines, notably CD40 ligand or CD154. In situ studies have colocalized CD40 ligand-positive cells in the vicinity of tissue factor–bearing macrophages in human atherosclerotic lesions (36). Thus, inflammation tightly regulates the procoagulant potential of the atherosclerotic plaque.
Atherothrombotic events, however, depend on not only the "solid state" of procoagulants in the plaque itself but also on the "fluid phase" of the blood (30). Individuals with a systemic proinflammatory burden such as the metabolic syndrome or the diabetic state have elevated levels of fibrinogen, the immediate precursor to fibrin, the major component of thrombi (37). Moreover, the major inhibitor of endogenous fibrinolytic enzymes, plasminogen activator inhibitor-1, also increases in systemic inflammatory states such as those mentioned above (38,39). Thus, in the setting of local inflammation in the plaque or systemic inflammation as reflected by the acute-phase response, inflammatory pathways conspire to promote thrombosis and combat fibrinolysis. Consequently, inflammation promotes clot formation and instability and underlies the thrombotic aspects of atherothrombosis as well as lesion initiation and progression.
|
Clinical implications of inflammation biology in atherosclerosis
|
|---|
The inflammatory hypothesis of atherothrombosis has major implications for clinical practice. First, inflammatory biomarkers possess substantial clinical utility for improving vascular risk detection beyond that achieved with hyperlipidemia and traditional risk factors (40). Second, the recognition of atherosclerosis as an inflammatory disease provides impetus to seek novel anti-inflammatory therapies with the potential to treat and prevent acute thrombosis (41).
|
Risk prediction
|
|---|
Multiple studies in primary and secondary prevention as well as acute coronary ischemia have determined that a diverse set of proinflammatory biomarkers can furnish prognostic information beyond that available from traditional risk factors. Current analyses of fibrinogen (37); the cytokines IL-1, IL-6, and IL-18 (42–44); myeloperoxidase (45); metalloproteinase-9 (46); sCD40L (47,48); lipoprotein-associated phospholipase A2 (49); the adhesion molecules soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and P-selectin (50–52); and the adipokines leptin and adiponectin (53,54) have determined an association between each of these biomarkers and the risk of initial or recurrent vascular events; similar observations pertain to incident hypertension, even among currently normotensive individuals (55). However, clinical application of these findings largely focuses on high-sensitivity C-reactive protein (hsCRP), a pentraxin biomarker of innate immunity with analytical chemistry characteristics favorable to standard outpatient clinical settings. As outlined below, such effects prove relevant in primary and secondary prevention and acute coronary ischemia; they also enhance our understanding of the mechanisms and underlying agents commonly used to treat vascular disease (Fig. 5).
View larger version (55K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 5 An inflammatory pathway links risk factors to altered cellular behavior and elevated inflammatory markers in peripheral blood. The primary proinflammatory risk factors depicted on the top of this diagram activate the various cell types prominent in the atherosclerotic plaque, including the macrophage, endothelial cells (EC), smooth muscle cells (SMC), and in complicated lesions, the activated platelet. These various cell types in turn can secrete inflammatory mediators and reactive oxygen species (ROS). The ECs will express leukocyte adhesion molecules that can be shed and recovered in a soluble form in the peripheral blood. The primary proinflammatory cytokines, including interleukin-1 (IL-1) and tumor necrosis factor-alpha, can stimulate large amounts of IL-6 production by intrinsic vascular wall cells. This heightened IL-6 production represents an amplification loop, because 1 molecule of a primary proinflammatory cytokine can beget the expression of many more molecules of IL-6. The IL-6 can function as a messenger, traveling through the peripheral blood to the liver, where it alters the program of gene expression to elicit the acute-phase response. The acute-phase reactants include C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, and plasminogen activator inhibitor-1. Among these acute-phase reactants, CRP has proved to be a robust prospective indicator of cardiovascular events in a wide spectrum of individuals. Activated platelets release a number of inflammatory mediators, including CD40 ligand, which is also shed in a soluble form. The CD40 ligand can activate tissue factor gene expression, providing a positive feedback reinforcement of thrombosis in an inflammatory milieu. AGE = advanced glycation end products; Ang II = angiotensin II; MMPs = matrix metalloproteinases; OxLDL = oxidized low-density lipoprotein; PAI-1 = plasminogen activator inhibitor-1; RANTES = Regulated on Activation, Normal T Cell Expressed and Secreted (also known as chemokine ligand 5, CCL5).
|
|
|
The use of hsCRP in primary and secondary prevention
|
|---|
More than 24 prospective epidemiologic studies of initially healthy individuals have evaluated the role of hsCRP as a determinant of vascular risk, and all reported positive findings. Of these studies, 10 were adequately powered to evaluate the risk prediction role of hsCRP beyond that associated with traditional factors included in global assessment algorithms such as the Framingham Risk Score (49,56–64). When evaluated as a group and despite highly diverse patient populations, each study showed the importance of inflammation beyond traditional approaches to risk prediction (Fig. 6); as shown, these studies consistently find that the risk for subjects in the top tertile of hsCRP is approximately twice that of those in the lowest tertile. On this basis, the U.S. Centers for Disease Control and Prevention and the American Heart Association endorsed hsCRP as an adjunct to risk prediction in primary prevention, particularly among individuals at "intermediate" risk (65). Broadly, blood levels of hsCRP <1, 1 to 3, and >3 mg/l correspond to low, moderate, and high vascular risk across all levels of LDL cholesterol (LDL-C), the Framingham Risk Score, and the metabolic syndrome. More recent analyses show that these clinical cut points for hsCRP add relevant prognostic information across all levels of the total/HDL cholesterol and apolipoprotein B/apolipoprotein A ratios, not only after adjustment for traditional covariates but also after controlling for diabetes and obesity (66) (Fig. 7). Contrary to prior assumptions, the rare individuals who chronically show markedly elevated levels of hsCRP (>10 mg/l) do not seem to represent false-positive cases. Rather, such individuals likely have markedly increased vascular risk, suggesting that inflammation from several sources can be pathogenic in the vascular endothelium (67). Despite the frequent citation of a few studies as not showing independent predictive value, the data they report actually agree with the overall effect estimates seen in larger studies. For example, the Rotterdam Study reported an age-adjusted relative risk for those in the highest compared with the lowest quartile of hsCRP of 2.0 (95% confidence interval 1.1 to 3.4), fully consistent with other data (68). Similarly, data from the Framingham Heart Study regarding CRP show strong positivity for stroke (69).
View larger version (28K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 6 Framingham-adjusted relative risks of future cardiovascular events according to baseline levels of high-sensitivity C-reactive protein <1, 1 to 3, and >3 mg/l in 10 major prospective cohort studies. Data from references 56–61,65. *Data from the Reykjavik study are shown in tertiles. ARIC = Atherosclerosis Risk in Communities Study; CHS = Cardiovascular Health Study; EPIC-Norfolk = Evaluation c7E3 for Prevention of Ischemic Complications–Norfolk Study; HPFS = Health Professionals Follow-Up Study; MONICA = Monitoring Trends and Developments in Cardiovascular Disease Study; NHS = National Health Study; PHS = Physicians Health Study; PIMA = Pima Indian Study; WHS = Women’s Health Study.
|
|
View larger version (23K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 7 Additive value of high-sensitivity C-reactive protein (hsCRP) over and above the total cholesterol (TC):high-density lipoprotein cholesterol (HDLC) ratio (left) and the apolipoprotein (Apo) B:Apo A ratio (right), after adjustment for age, smoking, hypertension, body mass index, and diabetes. Adapted with permission from Ridker et al. (66).
|
|
Clinical interest in hsCRP also links in part to the observation that its baseline levels associate with increased risk of developing type 2 diabetes mellitus, even after adjustment for obesity and other population-based determinants of diabetogenesis (70). Multiple studies show that hsCRP levels predict vascular events beyond the components of the metabolic syndrome (as defined by Adult Treatment Panel III criteria) or the presence of frank diabetes (71–73). Although partly caused by associations between CRP and insulin resistance, such effects are consistent across patient groups with and without overt evidence of altered glucose homeostasis (74) (Fig. 8). Although the American Diabetes Association recently challenged the existence of the metabolic syndrome (75), the concerns largely addressed the controversy surrounding syndrome definition. If the definition of patients with metabolic syndrome aims to identify those with the highest risk of developing both vascular events and type 2 diabetes, and given the practical difficulty of measurement of insulin resistance and hypofibrinolysis in clinical settings, we and others suggest that inclusion of hsCRP in formal definitions of metabolic syndrome may help achieve this goal (76).
View larger version (30K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 8 Odds ratios of cardiovascular disease (CVD) in U.S. patients with diabetes mellitus, metabolic syndrome, and elevated high-sensitivity C-reactive protein (hsCRP) in NHANES (National Health and Nutrition Evaluation Survey). Adapted with permission from Malik et al. (74).
|
|
Beyond primary prevention, multiple studies have found that hsCRP levels in stable patients after myocardial infarction can predict recurrent infarction and cardiovascular death (77,78), a finding consistent with data from patients undergoing elective percutaneous intervention (79) or surgical revascularization (80). However, inflammatory mechanisms of atherothrombosis occur in multiple vascular beds, and hsCRP levels predict incident peripheral arterial disease (81) as well as incident and recurrent stroke (69,82). Such predictive ability may reach beyond large-vessel disease. The Rotterdam Scan Study recently reported that higher CRP levels are associated with the presence and progression of cerebral white matter lesions in the periventricular and subcortical regions, data with implications for small-vessel disease progression (83). Supporting the selectivity for CRP as a predictor of cardiovascular disease, this marker does not correlate with either the development of cancer (84) or with noncardiovascular disease events (85).
|
hsCRP in acute coronary ischemia
|
|---|
The role of hsCRP in cardiovascular events emerged initially from observations on patients with acute ischemia and unstable angina (86–88). Multiple studies have determined that hsCRP levels at the time of presentation or at hospital discharge provide prognostic information on both short-term and long-term risk, even in the absence of troponin elevation (89,90). As such, a component of plaque vulnerability may not depend on myocardial cell death, an issue likely relevant for the development of targeted anti-inflammatory agents for acute myocardial ischemia.
When used in conjunction with other biomarkers, including brain natriuretic peptide and myeloperoxidase, hsCRP levels also provide incremental evidence of vulnerability to acute ischemia. Compared with any 1 biomarker used in isolation, investigators for the TIMI (Thrombolysis In Myocardial Infarction) 16 and TIMI 18 trials showed that combinations of these emerging biomarkers may provide a superior method for the detection of vascular risk, at least in the setting of acute ischemia (91) (Fig. 9).
View larger version (18K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 9 Prognostic utility of combining high-sensitivity C-reactive protein, troponin, and brain natriuretic peptide in the setting of acute coronary ischemia in the TIMI 16 and TIMI 18 clinical trials. Adapted with permission from Sabatine et al. (91). OPUS-TIMI = Orbofiban in Patients With Unstable Coronary Syndromes–Thrombolysis In Myocardial Infarction Trial; TACTICS = Treat Angina With Aggrastat and Determine Costs of Therapy With Invasive or Conservative Strategies.
|
|
|
hsCRP and therapeutic interventions
|
|---|
Although hsCRP is clearly an effective clinical tool for risk stratification in multiple clinical settings, currently no data directly link hsCRP reduction to lower rates of vascular events. Nonetheless, diet and exercise—therapies proven to lower the risk of both heart disease and diabetes—are associated with decreased hsCRP in obese and modestly overweight patients (92,93). Interestingly, insulin resistance is associated not only with elevated baseline levels of hsCRP but also with greater hsCRP reduction during weight loss. Although patients have sustained hsCRP reductions after gastric bypass surgery, intensive lifestyle modifications that combine both caloric restriction and moderate-intensity physical exercise produce reductions of approximately 30% (94). Agents commonly used to treat diabetes, including insulin, metformin, and the peroxisome proliferator activated receptor-gamma agonists rosiglitazone and pioglitazone, also lower CRP (95). Whether these effects result from improvements in insulin resistance and/or do not depend on improved glycemic control remains controversial.
The use of hsCRP to improve patient selection for cardiovascular therapies is best shown with regard to 3-hydroxyl-3-methylglutaryl reduction with statins. Originally developed solely as a means to lower LDL-C, statin agents may possess additional anti-inflammatory properties. As recently reviewed, statins may be directly immunomodulatory, may inhibit expression of cell adhesion molecules, can induce thrombomodulin and tissue plasminogen activator and thus favorably alter hemostatic balance, and may have direct beneficial effects on platelets and smooth muscle proliferation (96,97).
Initial observations from the CARE (Cholesterol and Recurrent Events) trial showed clinically that statins lower CRP levels (98); additionally, the benefit of statin therapy seemed greater among individuals with higher levels of the inflammatory biomarkers hsCRP or serum amyloid A protein (77). We now recognize that statins as a class lower hsCRP levels. However, the mechanisms of this effect remain uncertain, because IL-6 levels do not decline consistently with statin therapy. Indeed, statins can reduce the production of CRP by isolated hepatocytes (99,100). Further, the magnitude of hsCRP reduction expected from the initiation of statin therapy cannot be gleaned from the magnitude of LDL reduction in individual patients (101).
Provocative data now suggest the utility of hsCRP in monitoring the effectiveness of statins in primary prevention, after stent placement, and in high-risk acute coronary syndromes. Data regarding apparently healthy patients in the AFCAPS-TexCAPS (Air Force Coronary Atherosclerosis Prevention Study–Texas Coronary Atherosclerosis Prevention Study) primary prevention trial showed that lovastatin decreases hsCRP levels, and suggested that individuals with low levels of LDL-C and concomitant elevations of hsCRP might benefit substantially from statin treatment (102). By contrast, the AFCAPS-TexCAPS trial found no evidence of statin efficacy among individuals with low levels of both LDL-C and hsCRP. These analyses led to the initiation of the ongoing large-scale JUPITER (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) of primary prevention with rosuvastatin among individuals with native LDL-C levels <130 mg/dl, who thus do not qualify for statin therapy but are at increased risk because of CRP levels >2 mg/l (103). The hard end points of the JUPITER trial will make its results important not only regarding the inflammatory hypothesis of atherosclerosis but also for the conceptual basis of extending beyond LDL-C as the sole method for determining those likely to benefit from statin therapy. With regard to coronary stent placement in patients with stable angina, statins reduce the increased risk of recurrent events associated with elevated CRP levels, independent again of underlying levels of LDL-C (104,105).
Recent data from the PROVE IT (Pravastatin or Atorvastatin Evaluation and Infections Therapy)–TIMI 22 and the REVERSAL (Reversal of Atherosclerosis with Lipitor) trials further suggest that hsCRP levels achieved by statin therapy may rival LDL-C levels achieved with these agents. Specifically, in the PROVE IT–TIMI 22 trial of patients with acute coronary syndrome treated with either atorvastatin (80 mg) or pravastatin (40 mg), the survival rate of individuals who achieved LDL-C levels below the study median (70 mg/dl) improved significantly, data consistent with clinical recommendations to aggressively lower lipid levels in high-risk patients (106) (Fig. 10, left). However, that same trial determined that the survival rate of individuals with hsCRP levels below the median (2 mg/l) improved significantly as well, regardless of the LDL-C level achieved (Fig. 10, right). Perhaps more importantly, the magnitude of benefit associated with low levels of hsCRP equaled that of low LDL, even though the effect was almost entirely independent of lipid lowering. Thus, the greatest clinical benefit of statin therapy within the PROVE IT–TIMI 22 trial occurred among patients who lowered both LDL-C (<70 mg/dl) and hsCRP (<2 mg/l) (Fig. 11). Post-hoc analyses of these data showed even greater risk reductions at hsCRP levels <1 mg/l.
View larger version (18K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 10 Cumulative rate of recurrent myocardial infarction or death from cardiac causes among statin-treated patients according to levels of low-density lipoprotein cholesterol (LDL-C) (left) and levels of C-reactive protein (CRP) (right) both achieved after 30 days in the TIMI 22 trial. Adapted with permission from Ridker et al. (106). TIMI = Thrombolysis In Myocardial Infarction.
|
|
View larger version (19K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 11 Cumulative rate of recurrent myocardial infarction or death from cardiac causes among statin-treated patients according to achieved levels of both low-density lipoprotein (LDL) cholesterol and high-sensitivity C-reactive protein (CRP) in the TIMI 22 trial. Adapted with permission from Ridker et al. (106). TIMI = Thrombolysis In Myocardial Infarction.
|
|
The REVERSAL trial treated coronary disease patients with the same statin agents and doses as PROVE IT. Atherosclerotic progression, as measured by intravascular ultrasound, slowed primarily among individuals who lowered both LDL-C and hsCRP (107). Similar to the PROVE IT trial, individuals who achieved aggressive reductions in both LDL-C and hsCRP experienced the highest degree of disease regression. Taken together, these clinical data strongly suggest that dual goals of therapy for high-risk patients treated with statins should include LDL-C <70 mg/dl as well as hsCRP <2 mg/l. On this basis, clinicians may need to measure and monitor hsCRP in a manner analogous to the methods currently used to measure and monitor LDL-C, at least if the goal is to maximize patient benefit with statin therapy.
|
Is CRP more than a clinical marker of disease?
|
|---|
For a biomarker to be clinically useful, it need only improve the clinician’s ability to detect disease risk and assist in therapeutic decision making. As previously outlined, hsCRP has overwhelmingly proven to have these characteristics. Whether or not a biomarker is in the causal pathway of disease and can formally fulfill the Koch postulates is ultimately not relevant for decisions regarding these important clinical applications. Nonetheless, it has been of interest to examine the possibility that CRP might play a direct role in the atherothrombotic process.
Commonly, CRP localizes in atherosclerotic plaques, where it can bind to modified LDL, contribute to complement activation, increase monocyte recruitment, and lead to lesion progression (108,109); CRP also reduces ·NO synthesis, increases the release of endothelin-1, and augments the function of adhesion molecules and chemokines within vascular SMC and EC (110,111). In transgenic mice, CRP may heighten thrombosis after arterial injury (112). Yet, overexpression of CRP in atherosclerosis-prone mice has little effect on lesion progression. Additionally, controversy remains regarding any direct pathogenic effects mediated by monomeric rather than pentameric CRP (113).
Based on currently available data, we believe that CRP has potential as a relevant target for therapy, but also recognize that evidence to date is both controversial and incomplete. Indeed, research on the possible pathogenic mechanisms of CRP must proceed carefully to answer questions regarding the potential role of CRP as a target for therapy. Recently released studies indicate at least 7 common single-nucleotide polymorphisms in the CRP gene, including one tri-alleleic single-nucleotide polymorphism; haplotypes based on these single-nucleotide polymorphisms, however, are responsible for only a tiny fraction of the population variance in CRP, confirming the major importance of environmental factors on inflammatory processes (114,115). Recently completed human CRP infusion studies suggest induction of a substantial proinflammatory and prothrombotic state, albeit with limitations (116). The development of agents that specifically lower CRP without effecting platelet function or lipid levels will assist in understanding these issues.
As previously described, the clinical application of hsCRP is a mature practice, and abundant evidence shows that hsCRP can assist physicians as they evaluate cardiovascular risk and monitor therapeutic interventions. Whether or not hsCRP ultimately proves to be a direct mediator of vascular disease will not alter its role as a useful clinical tool.
Conclusions.
The concept that inflammation governs atherosclerosis and its complications has provided a new unifying hypothesis regarding the links between risk factors and the cellular and molecular alterations that underlie this disease. This construct not only furnishes new mechanistic insight into the disease process but also has begun to translate into changes in clinical practice. The preponderance of present data support the predictive power of biomarkers of inflammation in broad categories of individuals, both those who are apparently well and those with already-manifest atherosclerotic cardiovascular disease. The clinical utility of inflammatory biomarkers has engendered intense interest and ongoing investigation to evaluate cost-effectiveness as a predictive tool beyond conventional risk markers. The proposition that hsCRP levels should become a guide for and/or a goal of therapy has received support from large-scale clinical trials.
The rapid translation of inflammation biology in cardiovascular disease from the laboratory to the clinic serves as a gratifying example of bench-to-bedside research. Yet, many questions remain unsettled in this regard, and we can look forward to considerable excitement in the future as experimental and clinical studies emerge to help settle the unresolved and/or controversial issues. The application of inflammation biology to atherosclerosis has already afforded new insight into how current interventions, both pharmacologic and lifestyle, may reduce cardiovascular risk. Ultimately, the insight that inflammation plays a fundamental role in atherosclerosis may lead to novel therapies that target aspects of the inflammatory process smoldering within the atheroma.
|
Footnotes
|
|---|
Supported by a grant from the Fondation Leducq, Paris, France (to Drs. Libby and Ridker). Drs. Libby and Ridker are listed as co-inventors on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease.
|
References
|
|---|
1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease N Engl J Med 2005;352:1685-1695.[CrossRef][Web of Science][Medline]2. Lucas AR, Korol R, Pepine CJ. Inflammation in atherosclerosis: some thoughts about acute coronary syndromes Circulation 2006;113:e728-e732.[Free Full Text] 3. Tsimikas S, Brilakis ES, Miller ER, et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease N Engl J Med 2005;353:46-57.[CrossRef][Web of Science][Medline] 4. Watson AD, Leitinger N, Navab M, et al. Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo J Biol Chem 1997;272:13597-13607.[Abstract/Free Full Text] 5. Berliner JA, Watson AD. A role for oxidized phospholipids in atherosclerosis N Engl J Med 2005;353:9-11.[CrossRef][Web of Science][Medline] 6. 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.[Abstract/Free Full Text] 7. Kranzhofer R, Schmidt J, Pfeiffer CA, Hagl S, Libby P, Kubler W. Angiotensin induces inflammatory activation of human vascular smooth muscle cells Arterioscler Thromb Vasc Biol 1999;19:1623-1629.[Abstract/Free Full Text] 8. Chen XL, Tummala PE, Olbrych MT, Alexander RW, Medford RM. Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells Circ Res 1998;83:952-959.[Abstract/Free Full Text] 9. Mollnau H, Wendt M, Szocs K, et al. Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling Circ Res 2002;90:E58-E65. 10. Tall AR, Jiang X, Luo Y, Silver D. 1999 George Lyman Duff memorial lecture: lipid transfer proteins, HDL metabolism, and atherogenesis Arterioscler Thromb Vasc Biol 2000;20:1185-1188.[Abstract/Free Full Text] 11. Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL Circ Res 2004;95:764-772.[Abstract/Free Full Text] 12. Ignarro LJ, Napoli C. Novel features of nitric oxide, endothelial nitric oxide synthase, and atherosclerosis Curr Diab Rep 2005;5:17-23.[Medline] 13. DeCaterina R, Libby P, Peng HB, et al. Nitric oxide decreases cytokine-induced endothelial activationNitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 1995;96:60-68.[Web of Science][Medline] 14. Peng HB, Libby P, Liao JK. Induction and stabilization of I kappa B alpha by nitric oxide mediates inhibition of NF-kappa B J Biol Chem 1995;270:14214-14219.[Abstract/Free Full Text] 15. Dudzinski DM, Igarashi J, Greif D, Michel T. The regulation and pharmacology of endothelial nitric oxide synthase Annu Rev Pharmacol Toxicol 2006;46:235-276.[CrossRef][Web of Science][Medline] 16. Garcia-Cardena G, Comander J, Anderson KR, Blackman BR, Gimbrone Jr MA. Biomechanical activation of vascular endothelium as a determinant of its functional phenotype Proc Natl Acad Sci U S A 2001;98:4478-4485.[Abstract/Free Full Text] 17. Collins T, Cybulsky MI. NF-kappaB: pivotal mediator or innocent bystander in atherogenesis? J Clin Invest 2001;107:255-264.[Web of Science][Medline] 18. Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI. The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation Proc Natl Acad Sci U S A 2000;97:9052-9057.[Abstract/Free Full Text] 19. Hansson GK, Libby P, Schonbeck U, Yan ZQ. Innate and adaptive immunity in the pathogenesis of atherosclerosis Circ Res 2002;91:281-291.[Abstract/Free Full Text] 20. Kovanen PT. Role of mast cells in atherosclerosis Chem Immunol 1995;62:132-170.[Web of Science][Medline] 21. Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword Nat Rev Immunol 2006;6:508-519.[CrossRef][Web of Science][Medline] 22. Libby P, Warner SJC, Salomon RN, Birinyi LK. Production of platelet-derived growth factor-like mitogen by smooth-muscle cells from human atheromata N Engl J Med 1988;318:1493-1498.[Web of Science][Medline] 23. Lafont A, Libby P. The smooth muscle cell: sinner or saint in restenosis and the acute coronary syndromes? J Am Coll Cardiol 1998;32:283-285.[Free Full Text] 24. Schwartz SM, Virmani R, Rosenfeld ME. The good smooth muscle cells in atherosclerosis Curr Atheroscler Rep 2000;2:422-429.[Medline] 25. Amento EP, Ehsani N, Palmer H, Libby P. Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells Arterioscler Thromb Vasc Biol 1991;11:1223-1230.[Abstract/Free Full Text] 26. Geng YJ, Libby P. Progression of atheroma: a struggle between death and procreation Arterioscler Thromb Vasc Biol 2002;22:1370-1380.[Abstract/Free Full Text] 27. Henderson EL, Geng YJ, Sukhova GK, Whittemore AD, Knox J, Libby P. Death of smooth muscle cells and expression of mediators of apoptosis by T lymphocytes in human abdominal aortic aneurysms Circulation 1999;99:96-104.[Abstract/Free Full Text] 28. Schonbeck U, Libby P. CD40 signaling and plaque instability Circ Res 2001;89:1092-1103.[Abstract/Free Full Text] 29. Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultrasound study Circulation 2000;101:598-603.[Abstract/Free Full Text] 30. Libby P, Theroux P. Pathophysiology of coronary artery disease Circulation 2005;111:3481-3488.[Abstract/Free Full Text] 31. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque J Am Coll Cardiol 2006;47:C13-C18.[Abstract/Free Full Text] 32. Davies MJ. Stability and instability: the two faces of coronary atherosclerosisThe Paul Dudley White Lecture, 1995. Circulation 1996;94:2013-2020.[Free Full Text] 33. Dollery CM, Libby P. Atherosclerosis and protease activation Cardiovasc Res 2006;69:625-635.[Abstract/Free Full Text] 34. Sukhova GK, Shi GP, Simon DI, Chapman HA, Libby P. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells J Clin Invest 1998;102:576-583.[Web of Science][Medline] 35. Dollery CM, Owen CA, Sukhova GK, Krettek A, Shapiro SD, Libby P. Neutrophil elastase in human atherosclerotic plaques: production by macrophages Circulation 2003;107:2829-2836.[Abstract/Free Full Text] 36. Mach F, Schoenbeck U, Bonnefoy J-Y, Pober J, Libby P. Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40Induction of collagenase, stromelysin, and tissue factor. Circulation 1997;96:396-399.[Abstract/Free Full Text] 37. Danesh J, Lewington S, Thompson SG, et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis JAMA 2005;294:1799-1809.[Abstract/Free Full Text] 38. Vaughan DE. Plasminogen activator inhibitor-1 and the calculus of mortality after myocardial infarction Circulation 2003;108:376-377.[Free Full Text] 39. Vaughan DE. PAI-1 and atherothrombosis J Thromb Haemost 2005;3:1879-1883.[CrossRef][Web of Science][Medline] 40. Ridker PM, Brown NJ, Vaughan DE, Harrison DG, Mehta JL. Established and emerging plasma biomarkers in the prediction of first atherothrombotic events Circulation 2004;109:IV6-IV19. 41. Libby P, Ridker PM. Novel inflammatory markers of coronary risk: theory versus practice Circulation 1999;100:1148-1150.[Free Full Text] 42. Biasucci LM, Liuzzo G, Fantuzzi G, et al. Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events Circulation 1999;99:2079-2084.[Abstract/Free Full Text] 43. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men Circulation 2000;101:1767-1772.[Abstract/Free Full Text] 44. Tiret L, Godefroy T, Lubos E, et al. Genetic analysis of the interleukin-18 system highlights the role of the interleukin-18 gene in cardiovascular disease Circulation 2005;112:643-650.[Abstract/Free Full Text] 45. Baldus S, Heeschen C, Meinertz T, et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes Circulation 2003;108:1440-1445.[Abstract/Free Full Text] 46. Blankenberg S, Rupprecht HJ, 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.[Abstract/Free Full Text] 47. Schonbeck U, Varo N, Libby P, Buring J, Ridker PM. Soluble CD40L and cardiovascular risk in women Circulation 2001;104:2266-2268.[Abstract/Free Full Text] 48. Varo N, deLemos JA, Libby P, et al. Soluble CD40L: risk prediction after acute coronary syndromes Circulation 2003;108:1049-1052.[Abstract/Free Full Text] 49. Ballantyne CM, Hoogeveen RC, Bang H, et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study Circulation 2004;109:837-842.[Abstract/Free Full Text] 50. Ridker PM, Hennekens CH, Roitman-Johnson B, Stampfer MJ, Allen J. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men Lancet 1998;351:88-92.[CrossRef][Web of Science][Medline] 51. Malik I, Danesh J, Whincup P, et al. Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis Lancet 2001;358:971-976.[CrossRef][Web of Science][Medline] 52. Ridker PM, Buring JE, Rifai N. Soluble P-selectin and the risk of future cardiovascular events Circulation 2001;103:491-495.[Abstract/Free Full Text] 53. Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men JAMA 2004;291:1730-1737.[Abstract/Free Full Text] 54. Okamoto Y, Kihara S, Funahashi T, Matsuzawa Y, Libby P. Adiponectin, a key adipocytokine in metabolic syndrome Clin Sci (Lond) 2006;110:267-278.[Medline] 55. Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM. C-reactive protein and the risk of developing hypertension JAMA 2003;290:2945-2951.[Abstract/Free Full Text] 56. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men N Engl J Med 1997;336:973-979.[CrossRef][Web of Science][Medline] 57. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events N Engl J Med 2002;347:1557-1565.[CrossRef][Web of Science][Medline] 58. Koenig W, Lowel H, Baumert J, Meisinger C. C-reactive protein modulates risk prediction based on the Framingham Score: implications for future risk assessment: results from a large cohort study in southern Germany Circulation 2004;109:1349-1353.[Abstract/Free Full Text] 59. Pai JK, Pischon T, Ma J, et al. Inflammatory markers and the risk of coronary heart disease in men and women N Engl J Med 2004;351:2599-2610.[CrossRef][Web of Science][Medline] 60. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease N Engl J Med 2004;350:1387-1397.[CrossRef][Web of Science][Medline] 61. Best LG, Zhang Y, Lee ET, et al. C-reactive protein as a predictor of cardiovascular risk in a population with a high prevalence of diabetes: the Strong Heart Study Circulation 2005;112:1289-1295.[Abstract/Free Full Text] 62. Cushman M, Arnold AM, Psaty BM, et al. C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study Circulation 2005;112:25-31.[Abstract/Free Full Text] 63. Laaksonen DE, Niskanen L, Nyyssonen K, Punnonen K, Tuomainen TP, Salonen JT. C-reactive protein in the prediction of cardiovascular and overall mortality in middle-aged men: a population-based cohort study Eur Heart J 2005;26:1783-1789.[Abstract/Free Full Text] 64. Boekholdt SM, Hack CE, Sandhu MS, et al. C-reactive protein levels and coronary artery disease incidence and mortality in apparently healthy men and women: the EPIC-Norfolk prospective population study 1993–2003 Atherosclerosis 2006;187:415-422.[CrossRef][Web of Science][Medline] 65. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practiceA statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-511.[Free Full Text] 66. Ridker PM, Rifai N, Cook NR, Bradwin G, Buring JE. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women JAMA 2005;294:326-333.[Abstract/Free Full Text] 67. Ridker PM, Cook N. Clinical usefulness of very high and very low levels of C-reactive protein across the full range of Framingham Risk Scores Circulation 2004;109:1955-1959.[Abstract/Free Full Text] 68. van der Meer IM, de Maat MP, Kiliaan AJ, van der Kuip DA, Hofman A, Witteman JC. The value of C-reactive protein in cardiovascular risk prediction: the Rotterdam Study Arch Intern Med 2003;163:1323-1328.[Abstract/Free Full Text] 69. Rost NS, Wolf PA, Kase CS, et al. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham Study Stroke 2001;32:2575-2579.[Abstract/Free Full Text] 70. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin-6, and risk of developing type 2 diabetes mellitus JAMA 2001;286:327-334.[Abstract/Free Full Text] 71. Festa A, D’Agostino Jr. R, Tracy RP, Haffner SM. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study Diabetes 2002;51:1131-1137.[Abstract/Free Full Text] 72. Han TS, Sattar N, Williams K, Gonzalez-Villalpando C, Lean ME, Haffner SM. Prospective study of C-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City Diabetes Study Diabetes Care 2002;25:2016-2021.[Abstract/Free Full Text] 73. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14,719 initially healthy American women Circulation 2003;107:391-397.[Abstract/Free Full Text] 74. Malik S, Wong ND, Franklin S, Pio J, Fairchild C, Chen R. Cardiovascular disease in U.S. patients with metabolic syndrome, diabetes, and elevated C-reactive protein Diabetes Care 2005;28:690-693.[Abstract/Free Full Text] 75. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes Diabetes Care 2005;28:2289-2304.[Abstract/Free Full Text] 76. Ridker PM, Wilson PW, Grundy SM. Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk? Circulation 2004;109:2818-2825.[Abstract/Free Full Text] 77. Ridker PM, Rifai N, Pfeffer MA, et al. Cholesterol and Recurrent Events (CARE) Investigators Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels Circulation 1998;98:839-844.[Abstract/Free Full Text] 78. Retterstol L, Eikvar L, Bohn M, Bakken A, Erikssen J, Berg K. C-reactive protein predicts death in patients with previous premature myocardial infarction—a 10 year follow-up study Atherosclerosis 2002;160:433-440.[CrossRef][Web of Science][Medline] 79. de Winter RJ, Koch KT, van Straalen JP, et al. C-reactive protein and coronary events following percutaneous coronary angioplasty Am J Med 2003;115:85-90.[CrossRef][Web of Science][Medline] 80. Milazzo D, Biasucci LM, Luciani N, et al. Elevated levels of C-reactive protein before coronary artery bypass grafting predict recurrence of ischemic events Am J Cardiol 1999;84:459-461A9.[CrossRef][Web of Science][Medline] 81. 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.[Abstract/Free Full Text] 82. Di Napoli M, Papa F. Inflammation, hemostatic markers, and antithrombotic agents in relation to long-term risk of new cardiovascular events in first-ever ischemic stroke patients Stroke 2002;33:1763-1771.[Abstract/Free Full Text] 83. van Dijk EJ, Prins ND, Vermeer SE, et al. C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study Circulation 2005;112:900-905.[Abstract/Free Full Text] 84. Zhang SM, Buring JE, Lee IM, Cook NR, Ridker PM. C-reactive protein levels are not associated with increased risk for colorectal cancer in women Ann Intern Med 2005;142:425-432.[Abstract/Free Full Text] 85. Tice JA, Browner W, Tracy RP, Cummings SR. The relation of C-reactive protein levels to total and cardiovascular mortality in older U.S. women Am J Med 2003;114:199-205.[CrossRef][Web of Science][Medline] 86. Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in "active" coronary artery disease Am J Cardiol 1990;65:168-172.[CrossRef][Web of Science][Medline] 87. 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.[CrossRef][Web of Science][Medline] 88. Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB, European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group Production of C-reactive protein and risk of coronary events in stable and unstable angina Lancet 1997;349:462-466.[CrossRef][Web of Science][Medline] 89. Morrow DA, Rifai N, Antman EM, et al. C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudyThrombolysis in Myocardial Infarction. J Am Coll Cardiol 1998;31:1460-1465.[Abstract/Free Full Text] 90. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery diseaseFRISC Study Group. Fragmin During Instability in Coronary Artery Disease. N Engl J Med 2000;343:1139-1147.[CrossRef][Web of Science][Medline] 91. Sabatine MS, Morrow DA, deLemos JA, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide Circulation 2002;105:1760-1763.[Abstract/Free Full Text] 92. McLaughlin T, Abbasi F, Lamendola C, et al. Differentiation between obesity and insulin resistance in the association with C-reactive protein Circulation 2002;106:2908-2912.[Abstract/Free Full Text] 93. Tchernof A, Nolan A, Sites CK, Ades PA, Poehlman ET. Weight loss reduces C-reactive protein levels in obese postmenopausal women Circulation 2002;105:564-569.[Abstract/Free Full Text] 94. Haffner S, Temprosa M, Crandall J, et al. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance Diabetes 2005;54:1566-1572.[Abstract/Free Full Text] 95. 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.[Abstract/Free Full Text] 96. Schonbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents? Circulation 2004;109:II18-II26. 97. Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms Nat Rev Drug Discov 2005;4:977-987.[CrossRef][Web of Science][Medline] 98. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E, The Cholesterol and Recurrent Events (CARE) Investigators Long-term effects of pravastatin on plasma concentration of C-reactive protein Circulation 1999;100:230-235.[Abstract/Free Full Text] 99. Kleemann R, Verschuren L, deRooij BJ, et al. Evidence for anti-inflammatory activity of statins and PPARalpha activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro Blood 2004;103:4188-4194.[Abstract/Free Full Text] 100. Arnaud C, Burger F, Steffens S, et al. Statins reduce interleukin-6-induced C-reactive protein in human hepatocytes: new evidence for direct antiinflammatory effects of statins Arterioscler Thromb Vasc Biol 2005;25:1231-1236.[Abstract/Free Full Text] 101. Albert MA, Danielson E, Rifai N, Ridker PM. 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.[Abstract/Free Full Text] 102. 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.[CrossRef][Web of Science][Medline] 103. Ridker PM. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial Circulation 2003;108:2292-2297.[Free Full Text] 104. Walter DH, Fichtlscherer S, Sellwig M, Auch-Schwelk W, Schachinger V, Zeiher AM. Preprocedural C-reactive protein levels and cardiovascular events after coronary stent implantation J Am Coll Cardiol 2001;37:839-846.[Abstract/Free Full Text] 105. Walter DH, Fichtlscherer S, Britten MB, et al. Statin therapy, inflammation and recurrent coronary events in patients following coronary stent implantation J Am Coll Cardiol 2001;38:2006-2012.[Abstract/Free Full Text] 106. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy N Engl J Med 2005;352:20-28.[CrossRef][Web of Science][Medline] 107. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease N Engl J Med 2005;352:29-38.[CrossRef][Web of Science][Medline] 108. Torzewski J, Torzewski M, Bowyer DE, et al. C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries Arterioscler Thromb Vasc Biol 1998;18:1386-1392.[Abstract/Free Full Text] 109. Han KH, Hong KH, Park JH, et al. C-reactive protein promotes monocyte chemoattractant protein-1–mediated chemotaxis through upregulating CC chemokine receptor 2 expression in human monocytes Circulation 2004;109:2566-2571.[Abstract/Free Full Text] 110. Venugopal SK, Devaraj S, Yuhanna I, Shaul P, Jialal I. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells Circulation 2002;106:1439-1441.[Abstract/Free Full Text] 111. Verma S, Wang CH, Li SH, et al. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis Circulation 2002;106:913-919.[Abstract/Free Full Text] 112. Danenberg HD, Szalai AJ, Swaminathan RV, et al. Increased thrombosis after arterial injury in human C-reactive protein-transgenic mice Circulation 2003;108:512-515.[Abstract/Free Full Text] 113. Khreiss T, Jozsef L, Potempa LA, Filep JG. Conformational rearrangement in C-reactive protein is required for proinflammatory actions on human endothelial cells Circulation 2004;109:2016-2022.[Abstract/Free Full Text] 114. Miller DT, Zee RY, Suk Danik J, et al. Association of common CRP gene variants with CRP levels and cardiovascular events Ann Hum Genet 2005;69:623-638.[CrossRef][Web of Science][Medline] 115. Carlson CS, Aldred SF, Lee PK, et al. Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels Am J Hum Genet 2005;77:64-77.[CrossRef][Web of Science][Medline] 116. Bisoendial RJ, Kastelein JJ, Levels JH, et al. Activation of inflammation and coagulation after infusion of C-reactive protein in humans Circ Res 2005;96:714-716.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
W. Q. Gan, H. W. Davies, and P. A. Demers
Exposure to occupational noise and cardiovascular disease in the United States: the National Health and Nutrition Examination Survey 1999-2004
Occup. Environ. Med.,
March 1, 2011;
68(3):
183 - 190.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. B. Goldstein, C. D. Bushnell, R. J. Adams, L. J. Appel, L. T. Braun, S. Chaturvedi, M. A. Creager, A. Culebras, R. H. Eckel, R. G. Hart, et al.
Guidelines for the Primary Prevention of Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association
Stroke,
February 1, 2011;
42(2):
517 - 584.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Van Heyningen and M. T. Obafemi
Familial dysbetalipoproteinaemia, chronic inflammatory arthropathy and diabetes mellitus causing premature peripheral vascular atherosclerosis
The British Journal of Diabetes & Vascular Disease,
May 1, 2010;
10(3):
153 - 154.
[PDF]
|
|
|
|
|
|
|
A. T. Yan, R. T. Yan, M. Cushman, A. Redheuil, R. P. Tracy, D. K. Arnett, B. D. Rosen, R. L. McClelland, D. A. Bluemke, and J. A.C. Lima
Relationship of interleukin-6 with regional and global left-ventricular function in asymptomatic individuals without clinical cardiovascular disease: insights from the Multi-Ethnic Study of Atherosclerosis
Eur. Heart J.,
April 1, 2010;
31(7):
875 - 882.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Libby and F. Crea
Clinical implications of inflammation for cardiovascular primary prevention
Eur. Heart J.,
April 1, 2010;
31(7):
777 - 783.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Libby, P. M. Ridker, G. K. Hansson, and for the Leducq Transatlantic Network on Atherothro
Inflammation in Atherosclerosis: From Pathophysiology to Practice
J. Am. Coll. Cardiol.,
December 1, 2009;
54(23):
2129 - 2138.
[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]
|
|
|
|
|
|
|
A. S. Leon and U. G. Bronas
Pathophysiology of Coronary Heart Disease and Biological Mechanisms for the Cardioprotective Effects of Regular Aerobic Exercise
American Journal of Lifestyle Medicine,
September 1, 2009;
3(5):
379 - 385.
[Abstract]
[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]
|
|
|
|
|
|
|
P. M Ridker
C-Reactive Protein: Eighty Years from Discovery to Emergence as a Major Risk Marker for Cardiovascular Disease
Clin. Chem.,
February 1, 2009;
55(2):
209 - 215.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Osto, C. M. Matter, A. Kouroedov, T. Malinski, M. Bachschmid, G. G. Camici, U. Kilic, T. Stallmach, J. Boren, S. Iliceto, et al.
c-Jun N-Terminal Kinase 2 Deficiency Protects Against Hypercholesterolemia-Induced Endothelial Dysfunction and Oxidative Stress
Circulation,
November 11, 2008;
118(20):
2073 - 2080.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Waldeck, F. Hager, C. Holtke, C. Lanckohr, A. von Wallbrunn, G. Torsello, W. Heindel, G. Theilmeier, M. Schafers, and C. Bremer
Fluorescence Reflectance Imaging of Macrophage-Rich Atherosclerotic Plaques Using an {alpha}v{beta}3 Integrin-Targeted Fluorochrome
J. Nucl. Med.,
November 1, 2008;
49(11):
1845 - 1851.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Apovian, S. Bigornia, M. Mott, M. R. Meyers, J. Ulloor, M. Gagua, M. McDonnell, D. Hess, L. Joseph, and N. Gokce
Adipose Macrophage Infiltration Is Associated With Insulin Resistance and Vascular Endothelial Dysfunction in Obese Subjects
Arterioscler Thromb Vasc Biol,
September 1, 2008;
28(9):
1654 - 1659.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Bobik
Apolipoprotein CIII and Atherosclerosis: Beyond Effects on Lipid Metabolism
Circulation,
August 12, 2008;
118(7):
702 - 704.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. B Panagiotakos, C. Pitsavos, C. Chrysohoou, I. Skoumas, and C. Stefanadis
Five-year incidence of cardiovascular disease and its predictors in Greece: the ATTICA study
Vascular Medicine,
May 1, 2008;
13(2):
113 - 121.
[Abstract]
[PDF]
|
|
|
|
|
|
|
R. Clarke, J. R. Emberson, E. Breeze, J. P. Casas, S. Parish, A. D. Hingorani, A. Fletcher, R. Collins, and L. Smeeth
Biomarkers of inflammation predict both vascular and non-vascular mortality in older men
Eur. Heart J.,
March 2, 2008;
29(6):
800 - 809.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D Conen, B M Everett, R J Glynn, and P M Ridker
Effect of valsartan compared with valsartan/hydrochlorothiazide on plasma levels of cellular adhesion molecules: the Val-MARC trial
Heart,
March 1, 2008;
94(3):
e13 - e13.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. R. S. Packard and P. Libby
Inflammation in Atherosclerosis: From Vascular Biology to Biomarker Discovery and Risk Prediction
Clin. Chem.,
January 1, 2008;
54(1):
24 - 38.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. M. Punjabi, B. A. Beamer, A. Jain, M. E. Spencer, and N. Fedarko
Elevated Levels of Neopterin in Sleep-Disordered Breathing
Chest,
October 1, 2007;
132(4):
1124 - 1130.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. M. Ridker
C-Reactive Protein and the Prediction of Cardiovascular Events Among Those at Intermediate Risk: Moving an Inflammatory Hypothesis Toward Consensus
J. Am. Coll. Cardiol.,
May 29, 2007;
49(21):
2129 - 2138.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. A. Jaffer, D.-E. Kim, L. Quinti, C.-H. Tung, E. Aikawa, A. N. Pande, R. H. Kohler, G.-P. Shi, P. Libby, and R. Weissleder
Optical Visualization of Cathepsin K Activity in Atherosclerosis With a Novel, Protease-Activatable Fluorescence Sensor
Circulation,
May 1, 2007;
115(17):
2292 - 2298.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Libby
Fat Fuels the Flame: Triglyceride-Rich Lipoproteins and Arterial Inflammation
Circ. Res.,
February 16, 2007;
100(3):
299 - 301.
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Inflammation and the initiation...