Selected Articles by Category
Cardiovascular Disease
General Biomarker Research
Cardiovascular Disease
Cancer
High-sensitivity C-reactive protein and cardiovascular risk: rationale for screening and primary prevention
Author: Ridker PM;
Inflammation is a major factor in atherothrombotic disease. Levels of high-sensitivity C-reactive protein (hs-CRP), a marker of systemic inflammation and a mediator of atherothrombotic disease, have been shown to correlate with cardiovascular disease risk. Recent findings in 27,939 healthy women in the Women's Health Study indicate that hs-CRP (1) is a stronger predictor of risk than low-density lipoprotein (LDL) cholesterol, (2) predicts elevated risk in subjects without overt hyperlipidemia, and (3) adds prognostic information to risk scoring and LDL cholesterol categories. Other data from this cohort show that hs-CRP level adds prognostic information to the diagnosis of the metabolic syndrome. Taken together with other data in men on the association of hs-CRP with vascular risk, a strong argument is provided for screening in the primary prevention population. With regard to potential treatment, statins have been found to reduce hs-CRP levels, and data from statin treatment trials raise the possibility that subjects with elevated hs-CRP levels may derive greater benefit from treatment than do patients without elevated hs-CRP. The Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial is planned to examine the effects of rosuvastatin treatment in preventing cardiovascular events in 15,000 healthy subjects with elevated hs-CRP levels in the absence of overt hyperlipidemia
An association between coronary artery calcification score, lipid profile, and selected markers of chronic inflammation in ESRD patients treated with peritoneal dialysis
Author: Stompor T;Pasowicz M;Sullowicz W;mbinska-Kiec A;Janda K;Wojcik K;Tracz W;Zdzienicka A;Klimeczek P;Janusz-Grzybowska E;
BACKGROUND: Chronic uremia is considered a proinflammatory state associated with high cardiovascular morbidity and mortality. The aim of the present study is to evaluate the potential relationship between the prevalence of coronary artery calcification (CAC) and selected factors that may be involved in the process of atherogenesis (lipid profile, acute-phase reactants, growth factors, and cytokines). METHODS: The study group consisted of 43 patients (19 women, 24 men) with a mean age of 50.6 +/- 13.4 years treated with peritoneal dialysis (PD) for a median period of 15 months (range, 2 to 96 months). Only patients with sinus rhythm were included. CAC score (CaSc) was measured using multirow spiral computed tomography (MSCT). As parameters of lipid profile, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were assayed. C-reactive protein (CRP) and fibrinogen represented the level of acute-phase activation. Proinflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-alpha]), leptin, and basic fibroblast growth factor (bFGF) also were measured. RESULTS: Median CaSc equaled 17.9 Agatston units (range, 0 to 5,502 Agatston units). No calcification was detected in 20 subjects (46.5%; CaSc < 10 Agatston units). CaSc correlated with age (R = 0.57; P < 0.0001), body mass index (R = 0.42; P < 0.005), and serum leptin (R = 0.3; P < 0.05) and CRP levels (R = 0.38; P < 0.05). The correlation with PD therapy duration was borderline statistically significant (P = 0.063). Patients with the greatest values for CaSc (> 400 Agatston units) were characterized by significantly greater levels of IL-6, bFGF, and CRP compared with subjects with a CaSc less than 10 Agatston units (P < 0.05 for all). Patients with history of coronary artery disease (CAD) had significantly greater CaSc values (median, 778.6 versus 3.3 Agatston units; P < 0.001) compared with those without CAD. Serum triglyceride levels were significantly greater and HDL cholesterol levels were significantly lower in patients with CAD. The first group also was characterized by significantly greater serum TNF-alpha (P < 0.01) and CRP levels (P < 0.005). In multiple regression analysis, only age was independently associated with CaSc (beta = 0.45; P = 0.002). CONCLUSION: Our results may suggest an association between CAC and chronic inflammation activity in the mentioned group of patients. To our knowledge, this is the first study reporting the prevalence of CAC in PD patients using the MSCT method. The association between CaSc results and classic, as well as inflammatory, risk factors for CAD found in this study should be interpreted with caution because of its method limitations (cross-sectional design, heterogeneity of study population, and small number of studied patients)
Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?
Author: Yudkin JS;Kumari M;Humphries SE;Mohamed-Ali V;
There is mounting evidence that inflammation plays a role in the development of coronary heart disease (CHD). Observations have been made linking the presence of infections in the vessel wall with atherosclerosis, and epidemiological data also implicate infection in remote sites in the aetiology of CHD. In this article we propose a key role for the proinflammatory cytokine interleukin-6 (IL-6) in several mechanisms that contribute to the development of CHD. IL-6 is a powerful inducer of the hepatic acute phase response. Elevated concentrations of acute phase reactants, such as C-reactive protein (CRP), are found in patients with acute coronary syndromes, and predict future risk in apparently healthy subjects. The acute phase reaction is associated with elevated levels of fibrinogen, a strong risk factor for CHD, with autocrine and paracrine activation of monocytes by IL-6 in the vessel wall contributing to the deposition of fibrinogen. The acute phase response is associated with increased blood viscosity, platelet number and activity. Furthermore, raised serum amyloid A lowers HDL-cholesterol levels. IL-6 decreases lipoprotein lipase (LPL) activity and monomeric LPL levels in plasma, which increases macrophage uptake of lipids. In fatty streaks and in the atheromatous 'cap' and 'shoulder' regions, macrophage foam cells and smooth muscle cells (SMC) express IL-6, suggesting a role for this cytokine along with interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha), in the progression of atherosclerosis. Both these cytokines induce the release of IL-6 from several cell types, including SMC. During vascular injury SMC are exposed to platelets or their products, and cytokine production by SMC further contributes to vascular damage. Furthermore, circulating IL-6 stimulates the hypothalamic-pituitary-adrenal (HPA) axis, activation of which is associated with central obesity, hypertension and insulin resistance. Thus we propose a role for IL-6 in the pathogenesis of CHD through a combination of autocrine, paracrine and endocrine mechanisms. This hypothesis lends itself to testing using interventions to influence IL-6 secretion and actions
Cytokines in the rheumatic diseases
Author: Arend WP;Gabay C;
Extensive data has accumulated over the last 10 to 15 years to implicate various cytokines in pathways of pathophysiology in rheumatic diseases. Abnormalities in cytokine production are not the cause of these diseases, but reflect continual production by immune and inflammatory cells. Cytokines are heterogeneous and function in an overlapping and redundant network. An important principle to emerge is that the net biologic response in a diseased organ or tissue reflects a balance between the local levels of proinflammatory and anti-inflammatory cytokines and factors. Thus, a chronic disease may result from the excess production of proinflammatory cytokines or the inadequate production of anti-inflammatory cytokines. This article summarizes the role of cytokines in rheumatic diseases by focusing on each disease and the involved pathways of pathophysiology
Adhesion molecules as therapeutic targets
Author: Bochner BS;
This article focuses on the importance of cell-adhesion molecules in the process of allergic inflammation. After reviewing the contribution of different families of adhesion molecules to the cellular recruitment cascade, phenotypic characteristics of leukocyte subtypes are discussed to illustrate how expression of differing patterns of adhesion molecules and their counterligands within tissues influence the type of inflammatory response that occurs. The involvement of adhesion molecules in allergic inflammation in animal models and human studies is described. Examples of specific adhesion-molecule antagonists are provided, and results of their use in human studies of allergic and other inflammatory conditions are discussed
Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes
Author: de Lemos JA;Morrow DA;Sabatine MS;Murphy SA;Gibson CM;Antman EM;McCabe CH;Cannon CP;Braunwald E;
BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is a chemokine responsible for the recruitment of monocytes to sites of inflammation. MCP-1 appears to play a critical role at multiple stages in atherosclerosis, including the initiation of the fatty streak, promotion of plaque instability, and remodeling after myocardial infarction. METHODS AND RESULTS: MCP-1 was measured from frozen plasma specimens in 279 healthy volunteers and 2270 patients with acute coronary syndromes enrolled in the Oral Glycoprotein IIb/IIIa Inhibition with Orbofiban in Patients with Unstable Coronary Syndromes (OPUS-TIMI) 16 trial. Median [25th, 75th percentiles] MCP-1 levels were 157 [124, 196] pg/mL in healthy volunteers and 178 [128, 238] pg/mL in the OPUS-TIMI 16 population (P<0.001). In OPUS-TIMI 16, baseline MCP-1 levels were associated with older age, female sex, hypertension, diabetes, prior coronary disease, and renal insufficiency (P<0.01 for each) but not with smoking status, body mass index, ejection fraction, troponin I or C-reactive protein. After adjustment for differences in baseline characteristics, ECG changes, troponin I, and C-reactive protein, an MCP-1 level >75th percentile (corresponding to the 90th percentile in the healthy volunteers) was associated with an increased risk of death or myocardial infarction through 10 months of follow-up (adjusted hazard ratio, 1.53; 95% CI, 1.09 to 2.14; P=0.01). CONCLUSIONS: In a large cohort of patients with acute coronary syndromes, an elevated baseline level of MCP-1 was associated both with traditional risk factors for atherosclerosis as well as an increased risk for death or myocardial infarction, independent of baseline variables. Because it appears to play a crucial role at multiple stages of atherosclerosis, MCP-1 is attractive as a surrogate biomarker and merits further study as a potential therapeutic target
Antiphospholipid syndrome
Author: Gezer S;
Antiphospholipid syndrome has received considerable attention from the medical community because of its association with a number of serious clinical disorders, including arterial and venous thromboembolism, acute ischemic encephalopathy, recurrent pregnancy loss, thrombocytopenia, and livido reticularis. It can occur within the context of several diseases, mainly autoimmune disorders, and is then called secondary antiphospholipid syndrome. However, it may be also be present without any recognizable disease, or so-called primary antiphospholipid syndrome. There is no defined racial predominance for primary antiphospholipid syndrome, although a higher prevalence of systemic lupus erythematosus (SLE) occurs in African Americans and the Hispanic population. Multiple terms exist for this syndrome, some of which can be confusing. Lupus anticoagulant syndrome, for example, is a misleading term, because patients may not necessarily have SLE, and it is associated with thrombotic rather than hemorrhagic complications. To avoid further confusion, antiphospholipid syndrome is currently the preferred term for this clinical syndrome. Antiphospholipid antibodies are found in 1% to 5% of young healthy control subjects; however, the incidence increases with age and coexistent chronic disease. The syndrome occurs most commonly in young to middle-aged adults; however, it also can occur in children and the elderly. Among patients with SLE, the prevalence of antiphospholipid antibodies is high, ranging from 12% to 30% for anticardiolipin antibodies, and 15% to 34% for lupus anticoagulant antibodies. In general, anticardiolipin antibodies occur approximately five times more often then lupus anticoagulant in patients with antiphospholipid syndrome. This syndrome is the most common cause of acquired thrombophilia, associated with either venous or arterial thrombosis or both. It is characterized by the presence of antiphospholipid antibodies, recurrent arterial and venous thrombosis, and spontaneous abortion. Rarely, patients with antiphospholipid syndrome may have fulminate multiple organ failure, or catastrophic antiphospholipid syndrome. This is caused by widespread microthrombi in multiple vascular beds, and can be devastating. Patients with catastrophic antiphospholipid syndrome may have massive venous thromboembolism, along with respiratory failure, stroke, abnormal liver enzyme concentrations, renal impairment, adrenal insufficiency, and areas of cutaneous infarction. According to the international consensus statement, at least one clinical criterion (vascular thrombosis, pregnancy complications) and one laboratory criterion (lupus anticoagulant, antipcardiolipin antibodies) should be present for a diagnosis of antiphospholipid syndrome. The hallmark result from laboratory tests that defines antiphospholipid syndrome is the presence of antibodies or abnormalities in phospholipid-dependent tests of coagulation, such as dilute Russell viper venom time. There is no consensus for treatment among physicians. Overall, there is general agreement that patients with recurrent thrombotic episodes require life-long anticoagulation therapy and that those with recurrent spontaneous abortion require anticoagulation therapy and low- dose aspirin therapy during most of gestation. Prophylactic anticoagulation therapy is not justified in patients with high titer anticardiolipin antibodies with no history of thrombosis. However, if a history of recurrent deep vein thrombosis or pulmonary embolism is established, long-term anticoagulant therapy with international normalized ratio (INR) of approximately 3 is needed
Inflammation and atherosclerosis: role of C-reactive protein in risk assessment
Author: Libby P;Ridker PM;
Inflammation participates critically in atherosclerosis. Circulating levels of several inflammatory markers rise in individuals at risk for atherosclerotic events. In particular, elevation of plasma C-reactive protein (CRP), a nonspecific acute-phase reactant that is easily and reliably measured, has strong predictive power for cardiovascular events. Indeed, measurements of high-sensitivity CRP (hs-CRP) plasma levels add to both the prognostic information gleaned from assay of plasma lipid risk factors and the risk levels estimated by means of Framingham study-based criteria. Retrospective data suggest the hypothesis that hs-CRP plasma levels may be useful for guiding use of lipid-lowering therapy in individuals who appear to be at low risk according to traditional risk assessment. A large-scale, randomized clinical trial-Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)-will test whether rosuvastatin therapy will reduce incident cardiovascular disease in subjects with elevated plasma hs-CRP concentrations who do not meet current criteria for initiation of lipid-lowering drug therapy. Such clinical trial data may provide an evidence base for the use of plasma CRP assay as an adjuvant guide to therapy to complement the established traditional risk factors such as plasma lipid levels. Thus, medical practitioners are ushering in an era in which the biology of inflammation in atherosclerosis will find its way into clinical application
Lipoprotein-associated phospholipase A2 independently predicts the angiographic diagnosis of coronary artery disease and coronary death
Author: May HT;Horne BD;Anderson JL;Wolfert RL;Muhlestein JB;Renlund DG;Clarke JL;Kolek MJ;Bair TL;Pearson RR;Sudhir K;Carlquist JF;
BACKGROUND: Whereas C-reactive protein (CRP) is a nonspecific marker of coronary artery disease (CAD) and cardiovascular (CV) events, Lp-PLA2 may be a nonvariable inflammatory biomarker. We evaluated the independent association of lipoprotein-associated phospholipase A2 (Lp-PLA2) to angiographic CAD and CV events adjusting for standard factors, lipids, and CRP. METHODS: Lipoprotein-associated phospholipase A2 (PLAC test, diaDexus, Inc, San Francisco, CA) and CRP were measured from samples donated by consecutive consenting patients (N = 1493) enrolled in the registry of the Intermountain Heart Collaborative Study. All patients underwent coronary angiography (1996-1998) for CAD determination and were followed for 6.7 +/- 0.5 years (range 5.7-7.9 years) for CV events (death [including all-cause, CAD, and non-CAD CV death], myocardial infarction, and cerebrovascular accident). RESULTS: Lipoprotein-associated phospholipase A2 weakly correlated with lipids (low-density lipoprotein: r = 0.22, P < .001; high-density lipoprotein: r = -0.13, P < .001), but not CRP (r = 0.03, P = .26). Increasing quartile (Q) of Lp-PLA2 predicted greater the presence of CAD (vs Q1) for Q2 (adjusted odds ratio [OR] 1.15, 95% CI 0.78-1.71, P = .48), for Q3 (OR 1.53, 95% CI 1.02-2.31, P = .042), and for Q4 (OR 2.44, 95% CI 1.58-3.79, P < .001), although CRP was also predictive (vs Q1, Q2: OR 1.47, P = .057; Q3: OR 1.93, P = .002; Q4: OR 3.43, P < .001). In Cox regression, Lp-PLA2 predicted CAD death (vs Q1; Q2: adjusted hazard ratio [HR] 1.27, 95% CI 0.58-2.78, P = .55; Q3: HR 2.18, 95% CI 1.04-4.57, P = .04; Q4: HR 1.73, 95% CI 0.84-3.61, P = .14). CONCLUSION: Lipoprotein-associated phospholipase A2 was confirmed to predict the presence of CAD, even among patients undergoing coronary angiography. Uniquely, Lp-PLA2 predicted the risk of CAD death, but not all-cause death, myocardial infarction, or cerebrovascular accident