C-reactive protein is not only an inflammatory marker but also a direct cause of cardiovascular diseases

Inflammatory processes play a pivotal role in the pathogenesis of atherosclerosis and mediate many of the stages of atheroma development from initial leukocyte recruitment to eventual rupture of the unstable atherosclerotic plaque. C-reactive protein (CRP), an acute phase reactant that reflects different degree of inflammation, has been indicated an independent risk factor in a variety of cardiovascular disease (CVD), especially in unstable coronary syndrome. Our data have showed that increased level of CRP in patients with unstable angina was associated with short-term clinical outcomes, response for conventional therapy, and activation of nuclear factor-kappa B (NF-kappaB), but it is not correlated to coronary artery stenosis as well as lipid profile. Traditionally, CRP has been thought of as a bystander marker of vascular inflammation, without playing a direct role in the CVD. More recently, accumulating evidence suggest that CRP may have direct proinflammatory effects, which is associated with all stages of atherosclerosis. In our recent study, the results demonstrate that monocytes exhibit an enhanced production of interleukin-6 (IL-6) in response to CRP, and this response is significantly inhibited by simvastatin in a dose-dependent manner. This may be of important interest in the connection between CVD and CRP. Based on those evidence, we hypothesis that CRP is not only an inflammatory marker but also a direct cause of CVD, and treatments that reduce CRP should be benefit for primary and secondary prevention of CVD. Administration of several agents, especially statin has been showed to modify CRP concentrations with a concurrent fall in cardiovascular events. Our clinical investigation suggested that treatment with a single high-dose or a short-term common dose of simvastatin could rapidly reduce CRP level. Those data indicated that the benefit to the vascular endothelium might occur quickly in patients with CVD, which is critical issue for high-risk subgroup. Other interventions, such as lifestyle changes, weight loss, and stop smoking are also warrant attention.     

CRP and the risk of atherosclerotic events

A large body of literature supports the idea that inflammation plays a pivotal role in all phases of atherosclerosis, from the fatty streak lesion formation to the acute coronary event due to vulnerable plaque rupture. Indeed, vascular inflammation contributes to the pathogenesis of atherosclerosis, and later in the disease process, it is a major determinant for the acute coronary syndromes. There are various inflammatory markers that have been shown to predict cardiovascular events. These include high-sensitivity C-reactive protein (hs-CRP), a simple downstream marker of inflammation, recently emerged as a major cardiovascular risk factor. Elevated baseline concentrations of hs-CRP are associated with the risk of atherosclerotic events in general populations and show a predictive value even in terms of secondary prevention, both in patients with chronic stable angina and acute coronary syndromes. In recent year, a lot of concerns have emerged about the experimental models used to study the role of CRP in atherosclerosis; moreover, the results of trials evaluating the clinical association between this molecules and outcome are still controversial. In this paper, we attempt to review the pathophysiological evidences about the link between CRP and atherosclerosis and, most notably, about its utility as a marker and risk predictor in various clinical settings. The identification of specific triggers and mechanisms of underlying inflammation and a better understanding of each step involved in this complex process might lead to new ways to manage patients with atherosclerosis, both in terms of primary and secondary prevention, and CRP still appears to be a suitable candidate for this purpose.     

C-reactive protein (CRP) in the cardiovascular system

CRP (C-reactive protein) is an acute-phase reactant, the levels of which increase dramatically in response to severe bacterial infection, physical trauma, and other inflammatory conditions. CRP is found in human atherosclerotic lesions. Atherosclerosis is clearly multifactorial in origin, and chronic inflammation is an important component in its pathogenesis. Focus on inflammation is critical in research on atherosclerosis. Elevated levels of CRP have been associated with increased risk of future coronary artery disease (CAD) events. I have summarized the recent literature on CRP studies in CAD. Both coronary heart disease and dilated cardiomyopathy(DCM) result in congestive heart failure due to myocardial damage. The inflammatory state produced by myocarditis of viral or other origin may induce advanced myocardial damage, resulting in heart failure with a poor prognosis. Routine CRP measurement proved to be valuable for identifying high-risk patients with DCM and lymphocytic myocarditis. I suggest that measurement of circulating CRP would be useful for the diagnosis of and for selecting therapeutic strategies for cardiovascular disorders.     

Anti-atherogenic properties of fibrates may be largely due to their anti-inflammatory effects

Current understanding of the pathophysiology of atherosclerosis has undergone a remarkable evolution. Compelling evidence has evolved at both the basic science and clinical level for the importance of inflammation in the pathogenesis of atherosclerosis and its complications. Recent research has shown that both systemic and local inflammation plays a central role in all phases of the atherosclerotic process. Inflammatory cells dominate early atherosclerotic lesions, inflammatory cytokines accelerate progression of the lesions, and activation of inflammation can elicit acute coronary syndromes. Robust clinical studies have affirmed that fibrates are anti-atherogenic and can improve the cardiovascular risk profile. Fibrates not only modulate the serum concentrations of triglyceride and cholesterol, but also inhibit systemic inflammatory statue and inflammatory response in vascular cells. Fibrates act anti-inflammatory effects in monocyte/macrophage, T lymphocyte, endothelial cells, vascular smooth muscle cells and adipocytes. Since atherosclerosis is now regarded as an inflammatory disease and those inflammatory cells play critical important roles in the initiation and development of atherosclerosis, we hypothesize that anti-atherogenic properties of fibrates may be largely due to their anti-inflammatory effects.     

Inflammation: a pivotal link between autoimmune diseases and atherosclerosis

Premature coronary heart disease has emerged as a major cause of morbidity and mortality in systemic autoimmune diseases. Recent epidemiologic and pathogenesis studies have suggested a great deal in common between the pathogenesis of prototypic autoimmune disease such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and that of atherosclerosis. Some of the most remarkable data in support of a link between autoimmunity and atherosclerosis comes from epidemiological studies of patients with autoimmune disorders (RA and SLE). Many epidemiologic observations have linked systemic inflammation with the cardiovascular events in autoimmune disease such as RA and SLE. Inflammation is increasingly being considered central to the pathogenesis of atherosclerosis and an important risk factor for vascular disease. Systemic inflammation may be regarded as accelerating the atherosclerotic process. Systemic levels of soluble inflammatory mediators such as C-reactive protein (CRP) have been associated with cardiovascular risk in the general population. CRP, or more specifically high sensitivity-hsCRP, is a marker of systemic inflammation that has been identified as a valid biomarker of cardiovascular risk. Furthermore, the immunomodulatory and anti-inflammatory actions of statins may affect their utility in the context of chronic inflammatory autoimmune disease. Thus, effective control or dampening of inflammation, with such agents, should be included in the therapeutic armamentarium of autoimmune diseases with the aim of protecting against cardiovascular disease.     

Inflammatory markers and cytokines in cardiovascular disease

Inflammatory processes play a pivotal role in the pathogenesis of atherosclerosis and mediate the stages of atheroma development from initial leukocyte recruitment to eventual rupture of the unstable atherosclerotic plaque. Recent investigations demonstrated that several inflammatory markers are considered as new predictable risk factors for atherosclerosis and cardiac events. Among these markers, C-reactive protein (CRP) has been most widely studied. CRP is produced in the liver in response to interleukin-6 (IL-6), it is an acute phase reactant and used as a general inflammatory marker. High-sensitivity-CRP (hs-CRP) which could detect a small amount of CRP was recently developed, and numerous large-scale, prospective studies have found that elevated baseline levels of hs-CRP are independent predictor of cardiovascular events. Inflammatory cytokines such as IL-6 and tumor necrosis factor-alpha (TNF-alpha) have also been evaluated as potential tools for prediction of the cardiovascular events. In this review, we focused on the recent reports and potential use of the inflammatory markers and cytokines as a predictable tool for the cardiovascular events.     

Silent myocardial ischemia may be related to inflammatory response

Silent myocardial ischemia (SMI) is a common phenomenon in patients with coronary artery diseases, which frequently occurs at rest, during daily life activities or after physical or emotional exertion. Although individual differences in pain threshold may partially explain the variability in pain perception, the mechanisms responsible for SMI are not well understood. A defective warning mechanism was proposed by some investigators as the reason for the absence of pain, stressing that sensibility to pain differs from patient to patient. A central nervous system as well as peripheral nerve endings alteration was also posited. There is increasing evidence that the development of atherosclerosis is associated with inflammation, and increased levels of inflammatory markers have been documented in various settings of coronary artery disease. Patients with chronic and stable coronary artery disease have clear evidence of a low-grade inflammation, which is independent of traditional cardiovascular risk factors. A systemic inflammatory response to coronary angioplasty has also been reported after balloon angioplasty and after stent implantation. More recently, intriguing observations have shown that there is a particular biochemical pattern of inflammatory system activation (an increased production of inflammatory cytokines) that explains the lack of anginal symptoms in patients with silent myocardial ischemia. That is, pain perception may result from microenviromental balance between proinflammatory and anti-inflammatory cytokines.     

Periodontal disease as a risk factor for cardiovascular disease: suggestion of a further link in systemic lupus erythematosus

Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Due to either infection or disease activity, elevated levels of inflammatory markers and up-regulation of the autoimmune process can contribute to the development of atherosclerosis in SLE patients. Periodontal diseases are among the most prevalent chronic infections in humans and are characterized by pathogen-induced oral inflammatory disease affecting the supporting tissues of teeth. Several cytokines capable of inducing systemic effects are produced during the course of this infection. The presence of these cytokines can be verified by changes in the levels of C-reactive protein (CRP). Periodontal disease is a well-known risk factor for atherosclerosis. The potential for beneficial prevention of CVD events through the use of periodontal treatment has been previously recommended. This review reinforces the hypothesis that periodontal infection could be a risk factor for CVD in patients diagnosed with SLE, and suggests that by reducing the progression of this oral infection, levels of inflammatory markers common to both diseases (SLE and periodontal disease) would likely decrease.     

Genetic and environmental contributions to plasma C-reactive protein and interleukin-6 levels--a study in twins

Elevated baseline levels of acute-phase proteins such as C-reactive protein (CRP) or cytokines like interleukin-6 (IL-6) are known risk factors for atherosclerosis and cardiovascular disease (CVD) events. However, until today, there is only controversial information about the contribution of genetic and environmental factors. Therefore, we performed an open prospective study in 108 monozygotic (MZ) and 60 same-sex dizygotic (DZ) twin pairs to analyse the genetic and environmental contributions to plasma CRP and IL-6 levels. Heritability of IL-6 was 0.61, indicating that plasma IL-6 levels are to a major part influenced by genetic determinants; however, for CRP, heritability was only 0.22, pointing to a moderate genetic influence. Plasma CRP levels were strongly influenced by female gender, older age and especially the body mass index. Our data underline the central role of IL-6 in low-grade inflammation contributing to atherosclerosis and CVD.     

Definitions of and contributions to cardiovascular disease in systemic lupus erythematosus

Abstract

Patients with systemic lupus erythematosus (SLE) have a significantly increased risk of cardiovascular disease (CVD). Increased prevalence of atherosclerosis may explain part of this enhanced risk, but SLE related CVD can also result from other mechanisms. Vascular events may be the result of several pathophysiologic mechanisms; some can be caused by atherosclerosis, others may be primarily thrombotic, and some may be due to ongoing inflammation. The traditional risk factors are of importance for the development of CVD in lupus. However, lupus-related factors, such as endothelial dysfunction and inflammation, renal impairment and disease activity, lupus phenotype, autoantibodies and genetic predisposition are equally or even more important. Risk factors may also contribute separately or in combination to increase the risk of atherosclerosis and clinical CVD in SLE. Studies investigating risk factors for CVD in SLE vary with respect to definition of outcome, it is, e.g. common that the terms atherosclerosis and clinical CVD are used interchangeably. Varying definitions and outcomes may thus explain divergent results of different studies and make comparisons difficult. This review summarizes some of the current knowledge regarding risk factors and mechanisms for atherosclerosis and clinical CVD in SLE. Aspects on the importance of CVD definitions and outcomes are briefly discussed.     

Pathogenic Mechanisms Shared between Psoriasis and Cardiovascular Disease

Psoriasis is associated with an increased risk of cardiovascular disease, a hallmark of which is atherosclerosis. The objective of this study was to review the pertinent literature and highlight pathogenic mechanisms shared between psoriasis and atherosclerosis in an effort to advocate early therapeutic or preventive measures. We conducted a review of the current literature available from several biomedical search databases focusing on the developmental processes common between psoriasis and atherosclerosis. Our results revealed that the pathogenic mechanisms shared between the two diseases converged onto “inflammation” phenomenon. Within the lymph nodes, antigen-presenting cells activate naive T-cells to increase expression of LFA-1 following which activated T-cells migrate to blood vessel and adhere to endothelium. Extravasation occurs mediated by LFA-1 and ICAM-1 (or CD2 and LFA-3) and activated T-cells interact with dendritic cells (and macrophages and keratinocytes in psoriasis or smooth muscle cells in atherosclerosis). These cells further secrete chemokines and cytokines that contribute to the inflammatory environment, resulting in the formation of psoriatic plaque or atherosclerotic plaque. Additionally, some studies indicated clinical improvement in psoriasis condition with treatment of associated hyperlipidemia. In conclusion, therapeutic or preventive strategies that both reduce hyperlipidemia and suppress inflammation provide potentially useful approaches in the management of both diseases.     

Autoimmunity,oxidized LDL and cardiovascular disease

Atherosclerosis is the major cause of cardiovascular disease (CVD) and in addition to established risk factors as smoking, hypertension, diabetes and dyslipidemia, inflammation and autoimmune reactions have been much discussed recently. Several lines of evidence indicate that also inflammation and autoimmune reactions are highly relevant in atherosclerosis and CVD. Inflammatory cells and cytokines are present in lesions, already at an early stage; animal experiments suggest that immune reactions, though not necessary for development of atherosclerosis, can modulate disease development and systemic inflammation is associated with an enhanced risk of CVD. The enhanced risk of CVD in a major autoimmune disease, systemic lupus erythematosus (SLE), is therefore highly relevant, and in addition to being an important clinical problem, SLE-related CVD could give insights into the nature of autoimmunity in atherosclerosis and CVD in general. We recently defined traditional and non-traditional risk factors for CVD in SLE. These include increased atherosclerosis (as determined by intima-media thickness of carotid artery); raised oxidized low density lipoprotein (OxLDL) and autoantibodies to OxLDL; dyslipidemia with raised triglycerides and Lp(a) and decreased HDL-cholesterol concentrations; raised systemic inflammation; presence of anti-phospholipid antibodies including lupus anticoagulant, homocysteine-levels and more frequent osteoporosis. Disease duration, smoking, blood pressure or diabetes mellitus did not differ significantly between the groups. Taken together, immune reactions are highly relevant in atherosclerosis, and patients with autoimmune disease like SLE are at high-risk of CVD. If confirmed prospectively, non-traditional risk factors like OxLDL in the circulation, autoantibodies against OxLDL and phospholipids and inflammation could lead to new therapeutic strategies and insight into disease mechanisms.     

Atherosclerosis and systemic lupus erythematosus: mechanistic basis of the association

As patients with Systemic Lupus Erythematosus (SLE) live longer due to improved therapies and preventive measures, death and disability from cardiovascular events are increasing. Patients with SLE have an increased risk of atherosclerosis that persists even after accounting for traditional cardiac risk factors. Recent studies strongly suggest that the mechanism is due in part to a combination of inflammatory and immune mechanisms. Contributory factors include increased levels of oxidized lipids (such as oxidized LDL and pro-inflammatory HDL), upregulation of adhesion molecules, and upregulation of cytokines such as MCP-1, TNF-alpha, IFN-gamma, IL-1, and IL-12. Autoanitbodies to oxidized lipids and immune complexes may also play a role in the development of atherosclerosis in SLE. As in the pathogenesis of many lupus disease processes, the increased risk of atherosclerosis seen in SLE is likely due to the complex interplay of many of these inflammatory and immune mediators.     

Genetic polymorphisms of inflammatory cytokines and myocardial infarction in the elderly

Cardiovascular diseases (CVD), such as myocardial infarction (MI), are major causes of disability and mortality in the elderly. The increasing burden of CVD in ageing industrialized populations requires intensive research in order to improve preventive and therapeutic strategies especially in old people and if possible slow the processes of cardiovascular disease generation and progression. Ageing is accompanied by an age-dependent up-regulation of the inflammatory response, due to chronic antigenic stress stimulation, which potentially triggers the onset of inflammatory diseases, especially CVD. However, the exact mechanisms are still poorly understood. Since CVD are caused by interactions between genetic and environmental factors, a possible approach to their prevention is to identify the potential genetic component of inflammatory cardiovascular risk factors, providing the basis for personalized lifestyle modification and improved pharmacological therapy. Some common gene polymorphisms associated with high production of inflammatory molecules have been associated with atherosclerosis. Therefore, controlling inflammation might play a protective role against CVD, especially in ageing. Although a large number of studies of pro- and anti-inflammatory gene variants in association with CVD and MI exists, the emerging data are quite conflicting and do not provide definitive evidence for a role of these polymorphisms in the pathogenesis of MI. In this paper we review the evidence for a possible role of genetic polymorphisms of the most important inflammatory cytokines (IL-6, TNF-alpha, IL-10) and immune receptors (CD14 receptor and TLR-4) in modulating the incidence or the prognosis of MI, with a special focus in ageing population.     

Inflammation and atherosclerosis: Cardiovascular evaluation in patients with autoimmune diseases

Evidence now indicates that inflammation contributes considerably to the initiation and progression of atherosclerosis and active inflammatory processes may trigger plaque rupture and enhance the risk of coronary thrombosis leading to a clinical ischemic event. Interest in characterizing inflammatory markers that predict clinical events have dominated clinical investigation. Such markers include C-reactive protein, Fibrinogen and a number of interleukins.Human macrophages avidly phagocytize cholesterol crystals. These cholesterol crystals induce a dose-dependent secretion of mature Interleukin 1-beta (IL-1β) from human monocytes and macrophages (an NLRP3 inflammasome-mediated pathway). Since IL-1β production leads to increased levels of IL-6 and C-reactive protein, this could be a mechanistic link between early deposition of cholesterol crystals within the vessel wall to the macrophage–monocyte interactions that initiate fatty streaks and promote local atherosclerotic progression. We have entered a time where a pure anti-inflammatory drug without significant effects on lipids or any other traditional cardiovascular risk factor decreased cardiovascular events. Patients with autoimmune diseases are at increase cardiovascular risk. In this review we describe the link between inflammation and atherosclerosis. Furthermore we explore the data regarding primary prevention, cardiac imaging for risk stratification and the implications of targeting inflammation in patients with autoimmune disease.     

Chronic inflammation in psoriasis and obesity: implications for therapy

A recent study has shown an indisputable relationship between psoriasis and obesity. Obesity leads to a higher risk in developing psoriasis and a poorer long-term clinical outcome of psoriasis. Furthermore, loosing weight may improve the psoriasis. A network of pro-inflammatory cytokines (especially tumour necrosis factor alpha (TNF-alpha)) is believed to play an important role in the pathophysiology of both obesity and psoriasis. The chronic low-level inflammation- as seen in obesity--may contribute to the extent of psoriatic lesions in obese patients. TNF-alpha in obesity is presumed to be derived from inflammatory cells (macrophages) in the adipose tissue and in psoriasis from activated T cells. Several drugs, such as peroxisome proliferator activated receptor (PPAR)-gamma agonists and TNF-alpha blocking agents, that target the pro-inflammatory pathways involved in both psoriasis and obesity have proven their benefit in the treatment of these entities. Furthermore, changes in levels of metabolic hormones as ghrelin and leptin in obesity may also play a role in the pathogenesis of deterioration of psoriasis by their potency to release pro-inflammatory mediators (e.g. interleukin (IL) 6 and TNF-alpha). We hypothesize that the treatment of obese psoriasis patient could be focused on reducing the obesity-induced inflammation. Reducing this obesity-induced inflammation may finally lead to a better clinical outcome. Weight loss could lead to a less inflammatory state by reducing concentrations of TNF-alpha, IL-6, leptin and improving insulin sensitivity.     

Briakinumab for the Treatment of Plaque Psoriasis

Psoriasis is a chronic inflammatory skin disorder affecting approximately 2% of individuals worldwide. An improved understanding of the pathogenesis of psoriasis has led to the development of targeted biologic therapies. Briakinumab (ABT-874) is a recombinant human antibody that blocks the biological activity of the cytokines interleukin (IL)-12 and IL-23 through their shared subunit p40. IL-12 and IL-23 are key mediators in T-cell differentiation and have been shown to play a significant role in maintaining inflammation and abnormal keratinocyte function in psoriasis patients through development and stimulation of Th1 and Th17 subsets, respectively. In one phase II and four phase III studies (including two 52-week trials), the Psoriasis Area and Severity Index (PASI)-75 score at weeks 12 and 52 was achieved by at least 80.6% and 66.2% (p?相似文献   

C-reactive protein: a nontraditional serum marker of cardiovascular risk.

Cardiovascular disease (CVD) is multifactorial in etiology. Traditional cardiovascular risk factors, such as increased cholesterol concentrations and blood pressure, are used to assess CVD risk. Recently, better understanding of the role of inflammation in atherosclerosis has prompted many to propose the measurement of various inflammatory markers to better identify those who are at increased risk. C-reactive protein (CRP) is found in endothelial atherosclerotic lesions, and evidence suggests that it may play a role in atherogenesis. Of candidate serum markers that might add information to clinical risk assessment, high-sensitivity C-reactive protein (hsCRP) measurement has the most potential for clinical use for multiple reasons: (a) high hsCRP is associated with a twofold to a threefold increase in the prevalence of myocardial infarction, stroke, and peripheral vascular disease, and it predicts incident cardiovascular events in those with and without preexisting CVD; (b) the increased risk associated with high hsCRP is independent of other established risk factors; (c) hsCRP augments the predictive capacity of the Framingham Risk Score; (d) hsCRP assays are standardized, and this analyte is biologically stable over time; (e) various risk-reducing interventions also reduce hsCRP, and research is underway to assess whether specifically targeting hsCRP reduces CVD risk. National guidelines regarding the clinical utility of hsCRP in primary and secondary prevention settings have been recently issued.     

The role of inflammation in coronary artery calcification

Vascular calcification is an age-dependent, common finding in human coronary arteries and begins as early as the second decade of life, just after fatty streak formation. Previous studies have showed that the severity of coronary calcification is closely related to atherosclerotic plaque burden and cardiac event rate. In the past few decades, coronary calcification has been considered passive and degenerative. With recent clinical and basic research, however, there is increasing recognition that coronary calcification is an active, regulated process. Current diagnostic methods for coronary artery calcification (CAC) are usually traditional coronary angiography, intravascular ultrasound (IVUS), electron beam computed tomography (EBCT) and multi-slice computed tomography (MSCT) while treatment for patients with calcified coronary arteries is troublesome. Several lines of evidence suggest that inflammation plays a major role in the development of atherosclerosis as well as its clinical manifestations. Recent study showed that inflammatory process might be also involved in coronary calcification. Accordingly, measurements of inflammatory markers such as C-reactive protein (CRP) may in part reflect indices of atherosclerosis, such as coronary calcification, and are likely to provide distinct information regarding cardiovascular risk. In this article, we review the current evidence of relationship between coronary calcification and inflammation for purpose of drawing the more attention on the inflammatory mechanism of coronary calcification, which may change our research as well as therapeutic strategies for coronary calcification in the future.     

C-reactive protein: ligands, receptors and role in inflammation

C-reactive protein (CRP) is the prototypical acute phase serum protein, rising rapidly in response to inflammation. CRP binds to phosphocholine (PC) and related molecules on microorganisms and plays an important role in host defense. However, a more important role may be the binding of CRP to PC in damaged membranes. CRP increases clearance of apoptotic cells, binds to nuclear antigens and by masking autoantigens from the immune system or enhancing their clearance, CRP may prevent autoimmunity. CRP binds to both the stimulatory receptors, FcgammaRI and FcgammaRIIa, increasing phagocytosis and the release of inflammatory cytokines; and to the inhibitory receptor, FcgammaRIIb, blocking activating signals. We have shown that, in two animal models of systemic lupus erythematosus (SLE), the (NZB x NZW)F1 mouse and the MRL/lpr mouse, a single injection of CRP before onset of proteinuria delayed disease development and late treatment reversed proteinuria. Thus, in these models, CRP plays an anti-inflammatory role.