Complement component C5a predicts future cardiovascular events in patients with advanced atherosclerosis.
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AIMS: Complement activation occurs in atherosclerotic lesions, and particularly complement component C5a exerts potent chemotactic and proinflammatory effects. However, it is yet unknown, whether plasma levels of C5a may predict cardiovascular risk. The aim of this study was to examine whether plasma levels of the complement component C5a may predict cardiovascular risk in patients with advanced atherosclerosis. METHODS AND RESULTS: We studied 173 patients with symptomatic peripheral artery disease (median age 72, 82 male). Cardiovascular risk profile, levels of the complement factor C5a, and other non-specific inflammatory parameters [high sensitivity C-reactive protein, serum amyloid A (SAA), and fibrinogen] were obtained at baseline, and patients were followed for median 22 months [interquartile range (IQR) 13-27] for the occurrence of major adverse cardiovascular events (MACE: myocardial infarction, percutaneous coronary interventions, coronary artery bypass graft, carotid revascularization, stroke, and death). We observed 65 MACE in 49 patients (28%). Cumulative event rates (95% confidence interval (CI)) within quartiles of C5a at 24 months were 16 (5-27), 26 (13-39), 36 (21-51), and 37% (23-51), respectively (P=0.0077). Adjusted hazard ratios for the occurrence of a first MACE according to increasing quartiles of C5a were 1.81, 2.23, and 2.66, respectively, as compared to the lowest quartile (P=0.038), irrespective of the level of other inflammatory parameters. CONCLUSION: Complement activation, indicated by the elevation of C5a, seems to be associated with increased cardiovascular risk in patients with advanced atherosclerosis. Clinically, determination of C5a may add to the predictive value of other non-specific inflammatory parameters. (+info)
Effect of sexual steroids on the calcium content of aortic atherosclerotic plaque of oophorectomized rabbits.
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We determined the effect of conjugated equine estrogen plus medroxyprogesterone acetate on calcium content of aortic atherosclerotic lesions in oophorectomized adult New Zealand rabbits submitted to a cholesterol rich diet. Five groups of 10 animals each were studied: G1 = control, G2 = cholesterol diet only, G3 = diet plus conjugated equine estrogen (0.625 mg/day); G4 and G5 = diet, conjugated equine estrogen (0.625 mg/day) plus medroxyprogesterone acetate (5 and 10 mg/day, respectively). Mean weight varied from 2.7 +/- 0.27 to 3.1 +/- 0.20 kg (P = 0.38) between groups at the beginning and 3.1 +/- 0.27 to 3.5 +/- 0.20 kg (P = 0.35) at the end of the experiment. Cholesterol and triglyceride levels were determined at the time of oophorectomy, 21 days after surgery (time 0), and at the end of follow-up of 90 days. The planimetric method was used to measure plaque and caryometric method for histopathologic examination of the aorta. Calcium content was determined by the method of von Kossa. A similar increase in cholesterol occurred in all treated groups without differences between them at the end of the study. Groups G4 and G5 had smaller areas of atherosclerotic lesions (2.33 +/- 2.8 and 2.45 +/- 2.1 cm(2), respectively) than the groups receiving no progestogens (G2: 5.6 +/- 4 and G3: 4.6 +/- 2.8 cm(2); P = 0.02). The relation between lesion area and total aorta area was smaller in groups treated with combined drugs compared to the groups receiving no progesterone (G4: 14.9 +/- 13 and G5: 14.2 +/- 13.4 vs G2: 35.8 +/- 26 and G3: 25 +/- 8 cm(2), respectively; P = 0.017). Oral conjugated equine estrogen (0.625 mg/day) plus medroxyprogesterone acetate (5 or 10 mg/day) provoked a greater reduction in atherosclerotic plaque area and calcium content in treated groups, suggesting a dose-dependent effect. (+info)
Atherosclerotic renovascular disease in chronic heart failure: should we intervene?
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Renal artery stenosis (RAS) is most commonly caused by atherosclerosis, which is also the most common cause of chronic heart failure (CHF). One-third of patients with CHF are reported to have significant renovascular disease. The presence of RAS confers a worse outcome in studies of hypertension and coronary disease, though data are lacking for patients with CHF. As the kidney is intricately involved in the fluid retention that occurs in CHF, an adverse effect of RAS on outcome would be expected. Presentations of RAS in CHF include flash pulmonary oedema, hypertension, worsening of CHF, and worsening renal function. RAS commonly progresses and may cause worsening of renal function in patients with CHF and previously stable renal function. A variety of investigations that can safely and accurately identify RAS in CHF are available, although none is recommended in current guidelines for the management of CHF. Treatment for RAS, whether for hypertension, for renal dysfunction, or for pulmonary oedema, is at the discretion of the physician due to the lack of adequate randomized controlled trials demonstrating the efficacy and safety of intervention. As it is not clear how RAS should be managed in CHF, screening cannot be advocated. Currently, a multicentre randomized outcome trial, which includes a cohort of patients with RAS and CHF, is in progress to provide answers in this area of uncertainty. (+info)
Role of C-reactive protein in atherogenesis: can the apolipoprotein E knockout mouse provide the answer?
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OBJECTIVE: Human C-reactive protein (CRP) was reported to accelerate atherosclerotic lesion development in male but not in female apolipoprotein E (apoE) knockout mice. Here, mice expressing rabbit CRP (rbCRP) were crossbred onto apoE knockout animals, and the effect on atherogenesis was studied. METHODS AND RESULTS: Hemolytic complement activity could not be detected in apoE knockout mice. Furthermore, in contrast to human complement, neither rabbit nor human CRP complexed to modified low-density lipoprotein-activated murine complement. At 52 weeks, rbCRP levels were similar in male and female transgenic animals. Serum cholesterol levels were equivalent in female animals irrespective of rbCRP expression, whereas rbCRP-positive males had significantly higher serum cholesterol levels than the rbCRP-negative counterparts. All mice exhibited extensive atherosclerotic lesions, as studied en face, and no differences were noted between rbCRP-negative and rbCRP-positive animals. Atherosclerotic luminal obstruction of aortic arch and first-order neck branches did not differ significantly between rbCRP-positive and rbCRP-negative mice. There was no correlation between rbCRP levels and atherosclerotic lesion formation. CONCLUSIONS: No marked effect of rbCRP on the formation of moderately advanced atherosclerotic lesions could be discerned in the apoE knockout mouse. Because of the oddities of the mouse complement system, however, this may not be a good model to investigate the role of CRP in human atherosclerosis. (+info)
Quantification of calcification in atherosclerotic lesions.
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Calcification can be deposited throughout the vasculature in several forms of calcium phosphate, including calcium hydroxyapatite (CHA). Calcium accumulation in arteries by mineralization and calcium loss from bone by osteoporosis often coexist, and vascular calcification may share common mechanisms with bone remodeling. Deposition of calcification in valves and arteries diminishes the valvular or arterial wall elasticity, a major cause of aneurysm and stenosis. Obstruction of arteries by calcification and other components can lead to heart attack and stroke. Mineralization in the femoral arteries can cause intermittent claudication in the legs, causing decreased mobility. Accurate measurement of calcification is essential for identifying other factors associated with this process and ultimately for elucidating the mechanism(s) of calcification. A wide range of methods for visualizing and measuring calcification for diagnosis and treatment in vivo and for studying the calcification process ex vivo are available. This review provides a critical comparison of older established methods and newer evolving technologies for quantifying calcification. (+info)
Role of the intrinsic coagulation pathway in atherogenesis assessed in hemophilic apolipoprotein E knockout mice.
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OBJECTIVE: The contribution of thrombosis and coagulation in atherogenesis is largely unknown. We investigated the contribution of the coagulation intrinsic factor VIII (FVIII)-dependent pathway in atherogenesis. METHODS AND RESULTS: Apolipoprotein E and FVIII double-deficient mice (E degrees/FVIII degrees) were generated. Aortic root lesions were analyzed in 14-week-old and 22-week-old female mice maintained for 8 or 16 weeks, respectively, on a normal chow diet or a hypercholesterolemic diet. CONCLUSIONS: Despite a higher plasma total cholesterol concentration compared with E degrees mice, E degrees/FVIII degrees mice developed dramatically less early-stage atherosclerotic lesions. Whereas early lesions in E degrees mice contained abundant fibrin(ogen) deposits on which few platelets adhered, lesions in E degrees/FVIII degrees were almost devoid of fibrin(ogen), and no platelets could be detected. The genotype effect on development and composition of lesions tended to decrease with time. This study demonstrates that the activation of the intrinsic pathway of coagulation is potently proatherogenic at the early stage of atherogenesis. (+info)
No effect of C-reactive protein on early atherosclerosis development in apolipoprotein E*3-leiden/human C-reactive protein transgenic mice.
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OBJECTIVE: C-reactive protein (CRP) has been associated with risk of cardiovascular disease. It is not clear whether CRP is causally involved in the development of atherosclerosis. Mouse CRP is not expressed at high levels under normal conditions and increases in concentration only several-fold during an acute phase response. Because the dynamic range of human CRP is much larger, apolipoprotein E*3-Leiden (E3L) transgenic mice carrying the human CRP gene offer a unique model to study the role(s) of CRP in atherosclerosis development. METHODS AND RESULTS: Atherosclerosis development was studied in 15 male and 15 female E3L/CRP mice; E3L transgenic littermates were used as controls. The mice were fed a hypercholesterolemic diet to induce atherosclerosis development. Cholesterol exposure did not differ between E3L/CRP and E3L mice. Plasma CRP levels were on average 10.2+/-6.5 mg/L in male E3L/CRP mice, 0.2+/-0.1 mg/L in female E3L/CRP mice, and undetectable in E3L mice. Quantification of atherosclerosis showed that lesion area in E3L/CRP mice was not different from that in E3L mice. CONCLUSIONS: This study demonstrates that mildly elevated levels of CRP in plasma do not contribute to the development of early atherosclerosis in hypercholesterolemic E3L/CRP mice. (+info)
Human atheromatous plaques stimulate thrombus formation by activating platelet glycoprotein VI.
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Lipid-rich atherosclerotic plaques are vulnerable, and their rupture can cause the formation of a platelet- and fibrin-rich thrombus leading to myocardial infarction and ischemic stroke. Although the role of plaque-based tissue factor as stimulator of blood coagulation has been recognized, it is not known whether plaques can cause thrombus formation through direct activation of platelets. We isolated lipid-rich atheromatous plaques from 60 patients with carotid stenosis and identified morphologically diverse collagen type I- and type III-positive structures in the plaques that directly stimulated adhesion, dense granule secretion, and aggregation of platelets in buffer, plasma, and blood. This material also elicited platelet-monocyte aggregation and platelet-dependent blood coagulation. Plaques exposed to flowing blood at arterial wall shear rate induced platelets to adhere to and spread on the collagenous structures, triggering subsequent thrombus formation. Plaque-induced platelet thrombus formation was observed in fully anticoagulated blood (i.e., in the absence of tissue factor-mediated coagulation). Mice platelets lacking glycoprotein VI (GPVI) were unable to adhere to atheromatous plaque or form thrombi. Human platelet thrombus formation onto plaques in flowing blood was completely blocked by GPVI inhibition with the antibody 10B12 but not affected by integrin alpha2beta1 inhibition with 6F1 mAb. Moreover, the initial platelet response, shape change, induced by plaque was blocked by GPVI inhibition but not with alpha2beta1 antagonists (6F1 mAb or GFOGER-GPP peptide). Pretreatment of plaques with collagenase or anti-collagen type I and anti-collagen type III antibodies abolished plaque-induced platelet activation. Our results indicate that morphologically diverse collagen type I- and collagen type III-containing structures in lipid-rich atherosclerotic plaques stimulate thrombus formation by activating platelet GPVI. This platelet collagen receptor, essential for plaque-induced thrombus formation, presents a promising new anti-thrombotic target for the prevention of ischemic cardiovascular diseases. (+info)