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Anti-inflammatory Therapies for Cardiovascular Disease: Signaling Pathways and Mechanisms.
Martínez-Hervás, S, González-Navarro, H
Revista espanola de cardiologia (English ed.). 2019;(9):767-773
Abstract
Cardiovascular diseases (CVD) are the clinical manifestation of atherosclerosis, a chronic inflammatory disease promoted by several risk factors such as dyslipidemia, type 2 diabetes mellitus, hypertension, and smoking. Acute CVD events are the result of an unresolved inflammatory chronic state that promotes the rupture of unstable plaque lesions. Of note, the existing intensive therapies modify risk factors but do not prevent life-threatening recurrent ischemic events in high-risk patients, who have a residual inflammatory risk displayed by increased C-reactive protein (CRP) levels. Better understanding of the role of innate and adaptive immunity in plaque development and rupture has led to intensive investigation of anti-inflammatory strategies for CVD. Some of them are being tested in specific clinical trials and use lower doses of existing medications originally developed for other inflammatory diseases such as rheumatoid arthritis and psoriasis, which have high CVD risk. Other investigations are retrospective and meta-analyses of existing clinical trials that evaluate the incidence of CVD in these inflammatory diseases. Others are based on preclinical testing such as vaccines. In this article, we summarize the main anti-inflammatory strategies and associated molecular mechanisms that are being evaluated in preclinical or clinical CVD studies.
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2.
Biomarkers for rheumatoid arthritis: From molecular processes to diagnostic applications-current concepts and future perspectives.
Nakken, B, Papp, G, Bosnes, V, Zeher, M, Nagy, G, Szodoray, P
Immunology letters. 2017;:13-18
Abstract
Early diagnosis and immediately started appropriate treatment are mandatory for the prevention of radiographic progression, functional disability and unfavourable disease outcome in rheumatoid arthritis (RA). The current classification criteria for RA include two different types of biomarkers representing inflammatory processes, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) or immune processes including autoantibodies, such as rheumatoid factor (RF) and antibodies against citrullinated proteins (ACPA). After the discovery of RF, the recent recognition of various autoantibodies against post-translationally modified proteins opened new avenues to diagnosing RA and predicting the course of the disease. Citrullination and carbamylation of amino acids generate new epitopes that can potentially promote the production of novel autoantibodies. In spite of growing knowledge, the pathogenic role of these autoantibodies is still not fully elucidated in RA. In this paper, we review the currently available and novel promising immune biomarkers, which may help in early diagnosis and estimating prognosis in RA.
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3.
C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis.
Fernandes, BS, Steiner, J, Molendijk, ML, Dodd, S, Nardin, P, Gonçalves, CA, Jacka, F, Köhler, CA, Karmakar, C, Carvalho, AF, et al
The lancet. Psychiatry. 2016;(12):1147-1156
Abstract
BACKGROUND Inflammatory processes and neural-immune interactions have been implicated in the pathogenesis of psychiatric conditions, but studies in bipolar disorder are inconclusive so far. We aimed to investigate whether peripheral concentrations of C-reactive protein (CRP), an acute-phase response protein of inflammatory activity, are increased in bipolar disorder across the mood spectrum. METHODS In this systematic review and meta-analysis, we searched MEDLINE, the Cochrane Library, Scopus, and Web of Knowledge from database inception to Aug 14, 2016, for studies that measured serum and plasma CRP concentrations in adult patients with bipolar disorder (as defined by DSM-IV-TR) and healthy controls. We extracted data from published reports. We did three between-group meta-analyses comparing CRP concentrations in patients in mania, depression, or euthymia, with those in healthy controls (cross-sectional studies), and two within-group meta-analyses comparing changes in CRP concentrations before and after treatment of an index manic or depressive episode (longitudinal studies). We used Hedges' adjusted g to calculate effect sizes and pooled results using random-effect models. We also did meta-regression analyses by mood state to investigate possible moderators of CRP concentrations. FINDINGS We identified 27 studies representing 2161 patients with bipolar disorder and 81 932 healthy controls. Compared with healthy individuals, CRP concentrations were moderately increased in people with bipolar disorder during depression (g 0·67, 95% CI 0·23 to 1·11; p=0·003) and euthymia (0·65, 0·40 to 0·90; p<0·0001) and more substantially increased during mania (0·87, 0·58 to 1·15; p<0·0001). The extent of the increases in CRP concentrations in mania and depression was not related to symptom severity (p=0·256 for mania and p=0·626 for depression). CRP concentrations were moderately decreased after resolution of an index manic episode (-0·36, -0·66 to -0·05; p=0·022) and slightly decreased after resolution of an index depressive episode (-0·18, -0·30 to -0·07; p=0·002). INTERPRETATION CRP concentrations are increased in bipolar disorder regardless of mood state, but are higher during mania than in depression and euthymia, suggesting an increased inflammatory burden in mania. FUNDING None.
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4.
Inflammation, C-reactive protein, and atherothrombosis.
Ridker, PM, Silvertown, JD
Journal of periodontology. 2008;(8 Suppl):1544-51
Abstract
Atherothrombosis of the coronary and cerebral vessels is understood to be a disorder of inflammation and innate immunity, as well as a disorder of lipid accumulation. From a vascular biology perspective, the processes of cellular adhesion, monocyte and macrophage attachment, and transmigration of immune cells across the endothelium are crucial steps in early atherogenesis and in the later stages of mature plaque rupture, particularly the transition of unstable plaque at the time of acute thrombosis. There is abundant clinical evidence demonstrating that many biomarkers of inflammation are elevated years in advance of first ever myocardial infarction (MI) or thrombotic stroke and that these same biomarkers are highly predictive of recurrent MI, recurrent stroke, diabetes, and cardiovascular death. In daily practice, the inflammatory biomarker in widest use is high-sensitivity C-reactive protein (hsCRP); when interpreted within the context of usual risk factors, levels of hsCRP <1, 1 to 3, and >3 mg/l denote lower, average, and higher relative risk for future vascular events. Risk-prediction models that incorporate hsCRP, such as the Reynolds Risk Score, have been developed that improve risk classification and the accuracy for global risk prediction, particularly for those deemed at "intermediate risk" by usual algorithms, such as the Framingham Risk Score. With regard to cerebral vessels, increased biomarkers of inflammation, including hsCRP, have been associated with increased stroke risk as well as an increased rate of atherosclerosis progression in the carotid vessels. Although the proportion of variation in hsCRP explained by genetic factors may be as large as 20% to 40%, diet, exercise, and smoking cessation remain critical tools for risk reduction and CRP reduction. Statin therapy reduces hsCRP in a largely low-density lipoprotein (LDL)-independent manner, and the "anti-inflammatory" properties of these agents have been suggested as a potential mechanism beyond LDL reduction for the efficacy of these agents. The ongoing multinational Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial of 17,802 initially healthy men and women with low levels of LDL cholesterol but increased levels of hsCRP will help to define whether vascular protection can be achieved with statin therapy, even in the absence of hyperlipidemia. Targeted anti-inflammatory therapies are being developed that may provide a direct method of translating the biology of inflammation into new clinical treatments across multiple vascular beds. This article summarizes data supporting a role for inflammation in cardiovascular disease and offers the possibility that other disorders characterized by inflammation, such as periodontal disease, may have an indirect role by influencing the risk, manifestation, and progression of vascular events.
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5.
[Pharmacogenetics and anti-inflammatory effect of HMG-CoA reductase inhibitors].
Rosendo, AB, Dal-Pizzol, F, Fiegenbaum, M, Almeida, Sd
Arquivos brasileiros de endocrinologia e metabologia. 2007;(4):520-5
Abstract
Atherosclerosis is a result from the association of lipid deposition in the arterial wall and inflammatory process. This inflammatory process may be detected by clinical markers of systemic inflammation, such as ultrasensible C-reactive protein, which is associated with cardiovascular risk, independently of lipid levels. Statins reduce the inflammation associated to atherosclerosis, which may be verified by a reduction of the C-reactive protein levels. It seems that statins alter immune function by modulating post-translational protein prenylation. Individual genetic variations are associated with modulation of statins lipid-lowering effect; however, few studies have related the effect of the genetic variants with anti-inflammatory effect of statins. In addition to the genes involved in the cholesterol metabolism, genetic factors affecting statins pharmacodynamics and/or pharmacokinetics are potentially responsible for lipid and anti-inflammatory effects.
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6.
[High sensitivity of C-reactive protein in primary prevention].
Corrado, E, Novo, S
Giornale italiano di cardiologia (2006). 2007;(6):327-34
Abstract
In an attempt to improve global cardiovascular risk prediction, considerable interest has focused on C-reactive protein (CRP), that has been shown in multiple prospective epidemiological studies to predict incident myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death. CRP is a hepatically-derived pentraxin that plays a key role in the innate immune response. Standard CRP tests determine levels which are increased up to 1000-fold in response to infection or tissue destruction, but cannot adequately assess the normal range. High-sensitive CRP detects levels of CRP within the normal range as well as higher levels proven to predict future cardiovascular events. The relationship between a patient's baseline plasma level of CRP and future vascular risk has been consistent in several studies, and in most cases has proven independent of major "traditional" risk factors such as age, smoking, cholesterol levels, blood pressure and diabetes. Several pharmacological agents proven to reduce vascular risk influence CRP levels. Other lipid-lowering agents reported to reduce CRP include niacin, fibrates, and gemfibrozil. Aspirin also has an intriguing interaction with CRP in that the magnitude of relative risk reduction attributable to aspirin in primary prevention appears to be greatest among those with elevated CRP and declines proportionately in direct relation to CRP levels. Observational data, moreover, suggest possible differential benefits for clopidogrel and abciximab on the basis of CRP levels before percutaneous coronary interventions. As documented above for primary prevention, CRP is an independent predictor of future cardiovascular events that adds prognostic information to lipid screening, to the metabolic syndrome, and to the Framingham risk score. An approach in primary prevention is to measure CRP only among those at intermediate risk as defined by the Framingham risk score. In secondary prevention, the potential utility of CRP is less certain, as aggressive therapies should already be instituted and low-density lipoprotein evaluation provides an excellent method to assess statin efficacy.
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7.
Potential inflammatory biomarkers in Alzheimer's disease.
Mrak, RE, Griffin, WS
Journal of Alzheimer's disease : JAD. 2005;(4):369-75
Abstract
The role of the brain's innate immune system in Alzheimer pathogenesis is now well established. Proinflammatory cytokines elaborated by this system, in particular activated microglia-derived interleukin-1 (IL-1), drive a cascade of neurotoxic changes that are important for the development and progression of both the neuritic plaques and neurofibrillary tangles characteristic of Alzheimer's disease. Cytokine expression may also be modulated by variants of genes. For instance, inheritance of certain IL-1 gene variants is associated with Alzheimer's disease. The potential for using blood levels of proinflammatory cytokines as biomarkers of disease progression, however, remains unrealized. The interpretation of cytokine levels in the blood is complicated by the fact, for example, that the overexpression of IL-1 in Alzheimer brain may act to increase adrenal cortisol production through the hypothalamic-pituitary-adrenal axis, which acts to limit macrophage activation and peripheral cytokine production.
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8.
High sensitivity C-reactive protein in clinical practice.
Torres, JL, Ridker, PM
The American heart hospital journal. 2003;(3):207-11
Abstract
As a growing number of patients with low low-density lipoprotein cholesterol levels are diagnosed with atherosclerosis, research has shifted toward markers of inflammation in an attempt to improve global cardiovascular risk prediction. These markers include cytokines, cell adhesion molecules, and acute phase reactants like high sensitivity C-reactive protein, an innate immune response protein. When measured with new high-sensitivity assays, levels of high sensitivity C-reactive protein have proven to predict future cardiovascular risk at all levels of low-density lipoprotein cholesterol, at all levels of the Framingham Risk Score, and at all levels of the metabolic syndrome. Among apparently healthy men and women, levels of high sensitivity C-reactive protein of <1, 1-3, and >3 mg/L distinguish between those at low, moderate, and high risk for future cardiovascular disease, respectively. In clinical practice, high sensitivity C-reactive protein should be used along with lipid evaluation as part of global risk assessment. Improved knowledge of cardiovascular risk should lead to improved compliance with both lifestyle and pharmacologic interventions designed to prevent future cardiovascular events.
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9.
Cardiovascular disease: C-reactive protein and the inflammatory disease paradigm: HMG-CoA reductase inhibitors, alpha-tocopherol, red yeast rice, and olive oil polyphenols. A review of the literature.
Patrick, L, Uzick, M
Alternative medicine review : a journal of clinical therapeutic. 2001;(3):248-71
Abstract
The current understanding of the origin of atherosclerosis is that of an inflammatory process that involves the acute phase response -an innate biological response to a disturbance in homeostasis -infection, inflammation, tissue injury, neoplasm, or immune disturbance. The activation of the acute phase response, signaled by interleukin-6, produces proteins (fibrinogen, C-reactive protein (CRP), serum amyloid A) that lead to inflammatory reactions. The tissues themselves contain elevated levels of acute phase proteins and cytokines resulting in a localized inflammatory effect. Localized inflammatory responses in the intimal layer of the arterial wall have been shown to be responsible for many of the aspects of intimal thickening and plaque disruption, leading to acute cardiovascular events. The predictive value of plasma C-reactive protein as a risk factor for cardiovascular events has led some researchers to support the use of CRP as a main cardiovascular risk assessment tool, along with total cholesterol:HDL ratios and homocysteine levels. The ability of HMG-CoA reductase inhibitors to lower C-reactive protein levels has recently brought into question the mechanisms of action of the statin drugs. Because these medications lower incidences of acute cardiovascular events as well as decreasing morbidity and mortality well before the effects of lowered LDL cholesterol can be expected to occur, questions have been asked about whether they may work independently of LDL-lowering mechanisms. Red yeast rice contains a naturally-occurring statin (lovastatin) as well as other cholesterol-lowering compounds, some with antioxidant effects. Alpha-tocopherol also significantly lowers CRP levels in diabetics and nondiabetics, and minimizes other aspects of the acute phase response and inflammatory damage involved in atherosclerosis. This may account for alpha-tocopherol's positive effect on cardiovascular morbidity and mortality. Finally, polyphenolic compounds present in virgin olive oil also have anti-inflammatory and antioxidative effects in cardiovascular disease. The phenolic compounds in virgin olive oil may explain some of the protective effects found in epidemiological studies.