Immune System In Atherosclerosis Research Articles

Antibodies against Phosphorylcholine-Implications for Chronic Inflammatory Diseases.

Atherosclerosis and its main consequence, cardiovascular disease (CVD) are nowadays regarded as chronic inflammatory disease conditions, and CVD is the main cause of death in the world. Other examples of chronic inflammation are rheumatic and other autoimmune conditions, but also diabetes, obesity, and even osteoarthritis among others. In addition, infectious diseases can have traits in common with these conditions. Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease, where atherosclerosis is increased and the risk of CVD is very high. This is a clinical problem but could also shed light on the role of the immune system in atherosclerosis and CVD. Underlying mechanisms are of major interest and these are only partially known. Phosphorylcholine (PC) is a small lipid-related antigen, which is both a danger associated molecular pattern (DAMP), and a pathogen associated molecular pattern (PAMP). Antibodies against PC are ubiquitous and 5-10% of circulating IgM is IgM anti-PC. Anti-PC, especially IgM and IgG1 anti-PC, has been associated with protection in the chronic inflammatory conditions mentioned above, and develops during the first years of life, while being present at very low levels at birth. Animal experiments with immunization to raise anti-PC ameliorate atherosclerosis and other chronic inflammatory conditions. Potential mechanisms include anti-inflammatory, immune modulatory, clearance of dead cells and protection against infectious agents. An intriguing possibility is to raise anti-PC levels through immunization, to prevent and/or ameliorate chronic inflammation.

Insight into the Role of the Immune System in Atherosclerosis and Related Immune Therapy Strategies

Atherosclerosis is identified as the most common reason of numerous cardiovascular diseases (CVD), which is a chronic disease caused by the low-density lipoprotein (LDL) accumulate together and form a plaque. One of the factors contributing to that is the inflammatory response which is related to various signaling pathways. Both innate immune cells and adaptive immune cells participate in inflammatory responses, which lead to atherosclerosis. Their specific roles in the disease are explained in detail respectively in this project. In order to mitigate overactivated inflammatory responses in atherosclerosis, lots of research and studies have been made to find the potential treatment. Various antagonists which target interleukin 6 (IL-6) or interleukin-1 (IL-1) have been evaluated and applied in clinical treatment for atherosclerosis. In addition, monoclonal antibodies are also developed to target oxidized LDL. Despite the progress on the current therapy for atherosclerosis, more research on the field is needed due to the limit efficiency and adverse effects.

Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed?

Atherosclerosis is a chronic inflammatory disease of the arterial wall, characterized by the formation of plaques containing lipid, connective tissue and immune cells in the intima of large and medium-sized arteries. Over the past three decades, a substantial reduction in cardiovascular mortality has been achieved largely through LDL-cholesterol-lowering regimes and therapies targeting other traditional risk factors for cardiovascular disease, such as hypertension, smoking, diabetes mellitus and obesity. However, the overall benefits of targeting these risk factors have stagnated, and a huge global burden of cardiovascular disease remains. The indispensable role of immunological components in the establishment and chronicity of atherosclerosis has come to the forefront as a clinical target, with proof-of-principle studies demonstrating the benefit and challenges of targeting inflammation and the immune system in cardiovascular disease. In this Review, we provide an overview of the role of the immune system in atherosclerosis by discussing findings from preclinical research and clinical trials. We also identify important challenges that need to be addressed to advance the field and for successful clinical translation, including patient selection, identification of responders and non-responders to immunotherapies, implementation of patient immunophenotyping and potential surrogate end points for vascular inflammation. Finally, we provide strategic guidance for the translation of novel targets of immunotherapy into improvements in patient outcomes.

Red Blood Cell Released ATP Regulates Systemic Immune Response in Atherosclerosis

Our studies demonstrated that disturbed flow-induced ATP release from red blood cells (RBCs) via pannexin 1 (Panx1) channels plays a significant role in site-specific vascular inflammation and atherosclerosis. This is supported by a 40-60% reduction of atherosclerotic plaque observed in high fat diet (HFD)-fed ApoE-/- mice with RBC panx1 deletion that nearly abolished the release of ATP. Given the interplay of the immune system in atherosclerosis, we hypothesize that disturbed blood flow-induced release of ATP from RBCs at micromolar concentration is a major source of extracellular ATP (orders of magnitude higher than other ATP sources), which plays a crucial role in purinergic signaling-mediated local and systemic immune cell activation, cytokine production, and phenotypic transformation, serving as an important mediator in immune system-mediated initiation and progression of atherosclerosis. To test this hypothesis, we conducted experiments in 3 mouse groups (n = 4 to 12 per group): chow diet-fed wild type control, and 16 weeks HFD-fed ApoE-/- and ApoE-/-/RBC Panx1-/- mice. Plasma inflammatory cytokines were measured via ELISA. Subpopulations of peripheral blood monocytes (PBMCs) were characterized by flow cytometry, and the cytokine secretion capacity of T cells was examined by intracellular interferon-gamma (IFN-γ) staining in isolated splenocytes. Results showed that plasma IFN-γ and interleukin 1 beta (IL-1β) increased 10 and 8 fold, respectively, in HFD ApoE-/- mice when compared to the control group. These increases were reduced to levels close to the control in HFD ApoE-/-/RBC Panx1-/- mice. PBMCs analysis showed a significantly increased pro-inflammatory Ly6Chigh monocytes in HFD ApoE-/- mice from 2.9 ± 0.5% (control) to 19.2 ± 2.0%, while only 7.6 ± 1.0% was found in HFD ApoE-/-/RBC Panx1-/- mice. Intracellular IFN-γ staining of isolated splenocytes from HFD ApoE-/- mice showed a 5-fold increase in IFN-γ+ T cells (%) when compared to the control. In contrast, ApoE-/-/RBC Panx1-/- mice had significantly reduced percentage of IFN-γ+ T cells when compared with ApoE-/- mice (0.12 ± 0.03% vs 1.5 ± 0.48%, p < 0.05), especially in CD4+ T cells (0.06 ± 0.01% vs 0.79 ± 0.21%, p < 0.05). These cells further demonstrated their increased inflammatory potential, as stimulation with phorbol 12-myristate 13-acetate and Ionomycin yielded a markedly higher percentage of IFN-γ+ T cells in the HFD ApoE-/- group (40.4 ± 3.3%) than control (22.7 ± 1.8%) and ApoE-/-/RBC Panx1-/- group (26.6 ± 3.2%), and more prominent differences were found in CD4+ subgroup with values at 29.0 ± 2.5%, 11.1 ± 1.7%, and 14.5 ± 2.9%, respectively (p<0.05). In conclusion, our results indicate that shear stress-induced release of ATP from RBCs via Panx1 channels plays important roles in the immune cell recruitment, activation, and cytokine production, contributing to immune system-mediated vascular inflammation and the initiation and progression of atherosclerosis. Our findings provide novel mechanistic insight into local hemodynamics and systemic risk factor-mediated vascular pathogenesis and disease progression, directly benefiting clinical diagnosis and the prediction of atherosclerosis development.

An overview of the innate and adaptive immune system in atherosclerosis

AbstractCardiovascular disease is the leading cause of death globally. Coronary artery disease (CAD) is a chronic inflammatory disease usually caused by atherosclerosis, in which the coronary arteries become narrowed by atheromatous plaque. Plaques in atherosclerosis are formed through the accumulation of lipids and various immune cells. Both adaptive and innate immune systems are involved in the pathogenesis of atherosclerosis and facilitate plaque formation and disease progression. Almost all immune system cells, including neutrophils, B cells, T cells monocytes, macrophages, foam cells, and dendritic cells (DCs), play a vital role in atherosclerotic plaque. Atherogenesis, the normal function of the endothelium, is initially disrupted and, then, cells of the immune system are recruited to the endothelium following increased expression of cell adhesion molecules. Accumulation of immune cells and lipids leads to the formation of a necrotic nucleus. As the disease progresses, smooth muscle cells form fibrous layers, whose rupture results in exposing the necrotic nucleus and thrombosis. Accordingly, the present review was conducted to determine the role of different cells in innate and adaptive immune systems in inhibition and progression of atherosclerosis.

Role of the adaptive immune system in atherosclerosis.

Atherosclerosis, the pathology underlying heart attacks, strokes and peripheral artery disease, is a chronic inflammatory disease of the artery wall initiated by elevated low-density lipoprotein (LDL) cholesterol levels. LDL accumulates in the artery wall, where it can become oxidized to oxLDL. T cell responses to ApoB, a core protein found in LDL and other lipoproteins, are detectable in healthy mice and people. Most of the ApoB-specific CD4T cells are FoxP3+ regulatory T cells (Treg). In the course of atherosclerosis development, the number of ApoB-reactive T cells expands. At the same time, their phenotype changes, showing cell surface markers, transcription factors and transcriptomes resembling other T-helper lineages like Th17, Th1 and follicular helper (TFH) cells. TFH cells enter germinal centers and provide T cell help to B cells, enabling antibody isotype switch from IgM to IgG and supporting affinity maturation. In people and mice with atherosclerosis, IgG and IgM antibodies to oxLDL are detectable. Higher IgM antibody titers to oxLDL are associated with less, IgG antibodies with more atherosclerosis. Thus, both T and B cells play critical roles in atherosclerosis. Modifying the adaptive immune response to ApoB holds promise for preventing atherosclerosis and reducing disease burden.

Tofacitinib inhibits ox-LDL-induced adhesion of THP-1 monocytes to endothelial cells

Atherosclerosis is a chronic inflammatory disease of the blood vasculature. Endothelial dysfunction is an early event in the development of atherosclerosis and the endothelium plays an important role in the innate immune defense in the pathology of cardiovascular diseases. New therapies are being developed based on the involvement of the immune system in atherosclerosis. In this study, we demonstrate that a commonly used anti-rheumatic drug, tofacitinib, possesses vascular protective properties in cultured primary human aortic endothelial cells (HAECs). Tofacitinib ameliorates oxidized low-density lipoprotein (ox-LDL)-induced adhesion of THP-1 cells to HAECs, suppresses the expression of vascular adhesion molecules and production of cytokines, including vascular cell adhesion molecule 1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Moreover, tofacitinib inhibits elevation of endothelial lectin-like ox-LDL receptor-1 (LOX-1) and production of reactive oxygen species (ROS) triggered by ox-LDL. As a result, the presence of tofacitinib reduces ox-LDL-induced cytotoxicity and improves endothelial viability. Mechanistically, we demonstrate that tofacitinib suppresses ox-LDL-mediated activation of NF-κB inhibitor α (IκB-α), accumulation of nuclear p65 and activation of nuclear factor κB (NF-κB) promoter, indicating that tofacitinib inhibits NF-κB activation. Collectively, our data support that tofacitinib possesses a novel protective function in endothelial cells, implying that tofacitinib could have the therapeutic potential to modulate inflammation in cardiovascular diseases.

A potent multivalent vaccine for modulation of immune system in atherosclerosis: an in silico approach

PurposeAtherosclerosis is classically defined as an immune-mediated disease characterized by accumulation of low-density lipoprotein cholesterol over intima in medium sized and large arteries. Recent studies have demonstrated that both innate and adaptive immune responses are involved in atherosclerosis. In addition, experimental and human models have recognized many autoantigens in pathophysiology of this disease. Oxidized low-density lipoproteins, β2 glycoprotein I (β-2-GPI), and heat shock protein 60 (HSP60) are the best studied of them which can represent promising approach to design worthwhile vaccines for modulation of atherosclerosis.Materials and MethodsIn silico approaches are the best tools for design and evaluation of the vaccines before initiating the experimental study. In this study, we identified immunogenic epitopes of HSP60, ApoB-100, and β-2-GPI as major antigens to construct a chimeric protein through bioinformatics tools. Additionally, we have evaluated physico-chemical properties, structures, stability, MHC binding properties, humoral and cellular immune responses, and allergenicity of this chimeric protein by means of bioinformatics tools and servers.ResultsValidation results indicated that 89.1% residues locate in favorite or additional allowed region of Ramachandran plot. Also, based on Ramachandran plot analysis this protein could be classified as a stable fusion protein. In addition, the epitopes in the chimeric protein had strong potential to induce both the B-cell and T-cell mediated immune responses.ConclusionOur results supported that this chimeric vaccine could be effectively utilized as a multivalent vaccine for prevention and modulation of atherosclerosis.

Accelerated atherosclerosis in patients with chronic inflammatory rheumatologic conditions.

Atherosclerosis is a complex inflammatory disease involving aberrant immune and tissue healing responses, which begins with endothelial dysfunction and ends with plaque development, instability and rupture. The increased risk for coronary artery disease in patients with rheumatologic diseases highlights how aberrancy in the innate and adaptive immune system may be central to development of both disease states and that atherosclerosis may be on a spectrum of immune-mediated conditions. Recognition of the tight association between chronic inflammatory disease and complications of atherosclerosis will impact the understanding of underlying pathogenic mechanisms and change diagnostic and therapeutic approaches in patients with rheumatologic syndromes as well as patients with coronary artery disease. In this review, we provide a summary of the role of the immune system in atherosclerosis, discuss the proposed mechanisms of accelerated atherosclerosis seen in association with rheumatologic diseases, evaluate the effect of immunosuppression on atherosclerosis and provide updates on available risk assessment tools, biomarkers and imaging modalities.

Once Upon a Time: The Adaptive Immune Response in Atherosclerosis--a Fairy Tale No More.

Extensive research has been carried out to decipher the function of the adaptive immune response in atherosclerosis, with the expectation that it will pave the road for the design of immunomodulatory therapies that will prevent or reverse the progression of the disease. All this work has led to the concept that some T- and B-cell subsets are proatherogenic, whereas others are atheroprotective. In addition to the immune response occurring in the spleen and lymph nodes, it has been shown that lymphoid neo-genesis takes place in the adventitia of atherosclerotic vessels, leading to the formation of tertiary lymphoid organs where an adaptive immune response can be mounted. Whereas the mechanisms orchestrating the formation of these organs are becoming better understood, their impact on atherosclerosis progression remains unclear. Several potential therapeutic strategies against atherosclerosis, such as protective vaccination against atherosclerosis antigens or inhibiting the activation of proatherogenic B cells, have been proposed based on our improving knowledge of the role of the immune system in atherosclerosis. These strategies have shown success in preclinical studies, giving hope that they will lead to clinical applications.

Absence of L-selectin accelerates atherosclerosis via the modulation of B cell subsets and local immune response within the aortas of L-selectin-deficient Apoe-/- mice. (CAM1P.236)

Abstract To date, a significant body of evidence implicates the immune system in atherosclerosis. Studies report that follicular B cells are pro-atherogenic whereas B1a cells play a protective role; yet the role of other B cell subsets is unclear. The mechanisms behind the regulation of cell subset specific homing into aortas are not well understood. To determine the role of L-selectin in atherosclerosis, we bred L-selectin deficient (Sell-/-) and Apoe-/- mice and generated Sell-/-Apoe-/- mice. L-selectin deficiency resulted in accelerated atherosclerosis that was accompanied by a 1.3-fold increase in the number of leukocytes within aortas of Sell-/-Apoe-/- mice. However, Sell-/-Apoe-/- aortas displayed a 2-fold reduction in aortic B cells. Importantly, L-selectin deficiency significantly reduced the percentage and number of B1a and regulatory B (Breg) cells within Sell-/-Apoe-/- compared to Apoe-/- aortas and spleens. We found more B1a expressing L-selectin compared with splenic FO B cells, suggesting a potentially high dependence of B1a cells from L-selectin. With the reduction of aortic B1a and Breg, there were reduced IL-10 levels in Sell-/-Apoe-/- aortas. In line with the increased aortic leukocyte cellularity, there was a 1.5-fold increase in aortic CD68hi macrophages. These data provide evidence for a functional role of L-selectin in atherosclerosis via the regulation of the content of aortic B1a and Breg cells and the modulation of the local immune response within the aorta.

Immunological aspects of atherosclerosis

Cardiovascular disease is the leading cause of death in several countries. The underlying process is atherosclerosis, a slowly progressing chronic disorder that can lead to intravascular thrombosis. There is overwhelming evidence for the underlying importance of our immune system in atherosclerosis. Monocytes, which comprise part of the innate immune system, can be recruited to inflamed endothelium and this recruitment has been shown to be proportional to the extent of atherosclerotic disease. Monocytes undergo migration into the vasculature, they differentiate into macrophage phenotypes, which are highly phagocytic and can scavenge modified lipids, leading to foam cell formation and development of the lipid-rich atheroma core. This increased influx leads to a highly inflammatory environment and along with other immune cells can increase the risk in the development of the unstable atherosclerotic plaque phenotype. The present review provides an overview and description of the immunological aspect of innate and adaptive immune cell subsets in atherosclerosis, by defining their interaction with the vascular environment, modified lipids and other cellular exchanges. There is a particular focus on monocytes and macrophages, but shorter descriptions of dendritic cells, lymphocyte populations, neutrophils, mast cells and platelets are also included.

Abstract 50: Absence of L-selectin Affects the Distribution of B Cell Subsets and Local Immune Response in Apoe-/- Aortas

To date, a significant body of evidence implicates the immune system in atherosclerosis. Multiple cell subsets provide a fine tuning of pro-inflammatory and suppressive arms of the immunological response. Studies report that follicular B cells are pro-atherogenic whereas B1a cells play a protective role via T15/E06 antibody production; yet the other B cell subsets have to be explored in atherosclerosis. Thus far, little information is available on the mechanisms behind the regulation of cell subset specific homing during atherogenesis. L-selectin is a homing receptor modulating leukocyte tethering and rolling. To investigate the role of L-selectin in atherosclerosis, we generated 50 week old L-selectin deficient Apoe -/- ( Sell -/- Apoe -/- ) mice fed a chow diet. A L-selectin deficiency resulted in accelerated atherosclerosis that was accompanied by a 1.3-fold increase in the number of leukocytes within aortas of Sell -/- Apoe -/- mice. In contrast to the elevated total leukocyte cellularity in aortas, Sell -/- Apoe -/- aortas had a 2-fold reduction in B cell content. Importantly, an L-selectin deficiency significantly reduced the percentage and number of B1a and regulatory B (B reg ) cells within Sell -/- Apoe -/- compared to Apoe -/- aortas and spleens. Despite reduced numbers of B1a cells we detected a 3.2-fold increase in the splenic mRNA expression of T15/E06 suggesting that B1a cells are hyperactive, but are still unable to reduce atherogenesis in Sell -/- Apoe -/- mice. To further examine the effects of L-selectin deficiency on aortic wall inflammation, we analyzed lymphocyte activation and found elevated mRNA expression of B and T cell activation markers in Sell -/- Apoe -/- aortas. In line with the increased leukocyte cellularity of the aorta, there was a 1.5-fold increase in aortic CD68 hi macrophages. These data provide evidence for a functional role of L-selectin in atherosclerosis via the regulation of the content of aortic B1a and B reg cells and the modulation of the local immune response within the aorta. However, it also suggests the functions of B1a and B reg cells can be suppressed by additional factors contributing to accelerated atherosclerosis.

Role of Peroxisome Proliferator-Activated Receptor-γin Vascular Inflammation

Vascular inflammation plays a crucial role in atherosclerosis, and its regulation is important to prevent cerebrovascular and coronary artery disease. The inflammatory process in atherogenesis involves a variety of immune cells including monocytes/macrophages, lymphocytes, dendritic cells, and neutrophils, which all express peroxisome proliferator-activated receptor-γ (PPAR-γ). PPAR-γ is a nuclear receptor and transcription factor in the steroid superfamily and is known to be a key regulator of adipocyte differentiation. Increasing evidence from mainly experimental studies has demonstrated that PPAR-γ activation by endogenous and synthetic ligands is involved in lipid metabolism and anti-inflammatory activity. In addition, recent clinical studies have shown a beneficial effect of thiazolidinediones, synthetic PPAR-γ ligands, on cardiovascular disease beyond glycemic control. These results suggest that PPAR-γ activation is an important regulator in vascular inflammation and is expected to be a therapeutic target in the treatment of atherosclerotic complications. This paper reviews the recent findings of PPAR-γ involvement in vascular inflammation and the therapeutic potential of regulating the immune system in atherosclerosis.

Atherosclerosis: A Classic Inflammatory Disease

Atherosclerosis is an inflammatory disease due to a diet high in saturated fat, hypercholesterolemia, obesity, hypoglycemia, etc. mainly mediated by the infiltration of macrophage and T cells into the vascular wall. Once the endothelial is damaged monocytes penetrate the tissue and are transformed in scavenger cells. Upon stimulation of Th1 cells, a group of cytokines is released and contributes to the inflammatory response of atherosclerotic tissue. When macrophages proliferate they amplify inflammatory response through the secretion of growth factors and cytokines such as TNF and IL-1. In addition, chemokines such as RANTES and other C-C chemokines are generated, and matrix metalloprotinease 9 (MMP-9) are produced by activated monocytes. However, the immune system in atherosclerosis still remains unclear. Here, in this study we revisited the inter-relationship between atherosclerosis and inflammation.

The immune system in atherosclerosis

Cardiovascular disease, a leading cause of mortality worldwide, is caused mainly by atherosclerosis, a chronic inflammatory disease of blood vessels. Lesions of atherosclerosis contain macrophages, T cells and other cells of the immune response, together with cholesterol that infiltrates from the blood. Targeted deletion of genes encoding costimulatory factors and proinflammatory cytokines results in less disease in mouse models, whereas interference with regulatory immunity accelerates it. Innate as well as adaptive immune responses have been identified in atherosclerosis, with components of cholesterol-carrying low-density lipoprotein triggering inflammation, T cell activation and antibody production during the course of disease. Studies are now under way to develop new therapies based on these concepts of the involvement of the immune system in atherosclerosis.

Vaccines modulating lipoprotein autoimmunity as a possible future therapy for cardiovascular disease

Current strategies for prevention of cardiovascular disease focus on risk factor intervention. Although these have been proven both safe and effective results from randomized clinical trials suggest that it is difficult to achieve relative risk reductions exceeding 40% with this approach. To further improve efficacy future therapies must aim at targeting the actual disease process in the arterial wall. Emerging evidence have identified an important role of the immune system in atherosclerosis and suggest that modulation of autoimmune responses against oxidized LDL and other antigens in the atherosclerotic plaque represent one possible new approach to disease prevention. Oxidized LDL is targeted by both antibody-mediated and cellular immune responses and as much as 10% of the T cells in atherosclerotic plaques are oxidized LDL-specific. Immune activation in the atherosclerotic plaque is primarily of the pro-inflammatory Th1-type and inhibition Th1 immunity reduces atherosclerosis in experimental animals. Atherosclerosis vaccines based on antigens derived from LDL have been developed to modulate these processes. Their mechanisms of action remain to be full characterized but may involve expression of protective antibodies that facilitate the removal of oxidized LDL and antigen-specific regulatory T cells that counteract Th1 autoimmunity against oxidized LDL. In this review we will discuss the possibilities and challenges encountering the translation of immune-modulatory therapy for atherosclerosis from the experimental stage into the clinic.

The immune system in atherosclerosis and in acute myocardial infarction

Acute myocardial infarction (AMI) occurs when the atheromatous process prevents total blood flow through the coronary artery. It was previously thought that progressive luminal narrowing from the continued growth of smooth muscle cells (SMCs) in the plaque was the main cause of infarction, however, angiographic studies, have identified culprit lesions that do not cause marked stenosis.

The Immune System in Atherosclerosis and in Acute Myocardial Infarction

The Immune System in Atherosclerosis and in Acute Myocardial Infarction

CRP—Marker or Maker of Cardiovascular Disease?

C-reactive protein (CRP) has emerged as an interesting novel and potentially clinically useful marker for increased cardiovascular risk.1,2 This is an attractive concept because atherosclerosis is a disease characterized by chronic arterial inflammation3,4 and suggests the possibility that subclinical states of atherosclerosis can be identified by an increase in circulating markers of inflammation before acute events occur. Based on data obtained primarily from in vitro studies it has also been proposed that CRP in itself is actively contributing to disease progression and that it should be considered as true risk factor and consequently as a target for intervention. However, in the present issue of Arteriosclerosis, Thrombosis, and Vascular Biology , two independent reports demonstrate that transgenic overexpression of CRP does not affect the development of atherosclerosis in mice, suggesting that this is not the case. See pages 1635 and 1641 The association between moderately elevated CRP levels and an increased risk for development of cardiovascular disease is well established. Although the increase in risk may have been overestimated in initial studies, recent meta-analysis comprising >7000 patients with coronary events shows that subjects with CRP in the upper tertile have a 50% increased risk for development of acute cardiovascular events.2 There are several possible explanations for this association (Figure). (1) The inflammatory process in arterial tissue affected by atherosclerosis results in release of cytokines into the circulation that subsequently activates expression of CRP in the liver. Plasma CRP levels would then reflect the severity of atherosclerosis and, as a consequence, the risk for development of clinical events. If CRP in addition …