1.
Anti-inflammatory therapies for cardiovascular disease.
Ridker, PM, Lüscher, TF
European heart journal. 2014;(27):1782-91
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Abstract
Atherothrombosis is no longer considered solely a disorder of lipoprotein accumulation in the arterial wall. Rather, the initiation and progression of atherosclerotic lesions is currently understood to have major inflammatory influences that encompass components of both the innate and acquired immune systems. Promising clinical data for 'upstream' biomarkers of inflammation such as interleukin-6 (IL-6) as well as 'downstream' biomarkers such as C-reactive protein, observations regarding cholesterol crystals as an activator of the IL-1β generating inflammasome, and recent Mendelian randomization data for the IL-6 receptor support the hypothesis that inflammatory mediators of atherosclerosis may converge on the central IL-1, tumour necrosis factor (TNF-α), IL-6 signalling pathway. On this basis, emerging anti-inflammatory approaches to vascular protection can be categorized into two broad groups, those that target the central IL-6 inflammatory signalling pathway and those that do not. Large-scale Phase III trials are now underway with agents that lead to marked reductions in IL-6 and C-reactive protein (such as canakinumab and methotrexate) as well as with agents that impact on diverse non-IL-6-dependent pathways (such as varespladib and darapladib). Both approaches have the potential to benefit patients and reduce vascular events. However, care should be taken when interpreting these trials as outcomes for agents that target IL-6 signalling are unlikely to be informative for therapies that target alternative pathways, and vice versa. As the inflammatory system is redundant, compensatory, and crucial for survival, evaluation of risks as well as benefits must drive the development of agents in this class.
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How do elevated triglycerides and low HDL-cholesterol affect inflammation and atherothrombosis?
Welty, FK
Current cardiology reports. 2013;(9):400
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Abstract
This review article summarizes recent research into the mechanisms as to how elevated levels of triglyceride (TG) and low levels of high- density- lipoprotein cholesterol (HDL-C) contribute to inflammation and atherosclerosis. Evidence supports the role of TG-rich lipoproteins in signaling mechanisms via apolipoproteins C-III and free fatty acids leading to activation of NFKβ, VCAM-1 and other inflammatory mediators which lead to fatty streak formation and advanced atherosclerosis. Moreover, the cholesterol content in TG-rich lipoproteins has been shown to predict CAD risk better than LDL-C. In addition to reverse cholesterol transport, HDL has many other cardioprotective effects which include regulating immune function. The "functionality" of HDL appears more important than the level of HDL-C. Insulin resistance and central obesity underlie the pathophysiology of elevated TG and low HDL-C in metabolic syndrome and type 2 diabetes. Lifestyle recommendations including exercise and weight loss remain first line therapy in ameliorating insulin resistance and the adverse signaling processes from elevated levels of TG-rich lipoproteins and low HDL-C.
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Towards a superior streptokinase for fibrinolytic therapy of vascular thrombosis.
Keramati, M, Mianroodi, RA, Memarnejadian, A, Mirzaie, A, Sazvari, S, Aslani, MM, Roohvand, F
Cardiovascular & hematological agents in medicinal chemistry. 2013;(3):218-29
Abstract
Medical intervention with fibrinolytic drugs such as tissue plasminogen activator (tPA) and streptokinase (SK) is the principal treatment for life-treating thromboembolic disorders. Contrary to tPA, SK is a heterogenic and non-human (bacterial) protein produced by streptococci and its medical application may elicit sever immune and anaphylactic responses that restrict its utilization. Besides, human plasminogen (HPG) activation by SK is not blood-clot specific and associated with a risk of hemorrhage. Despite these limitations, comparative clinical trials on various thrombolytic agents suggested that SK is the most cost-effective fibrinolytic drug and almost as safe as its other counterparts such as tPA. Therefore, a number of studies were conducted to provide structurally modified SK with reduced immunogenicity, higher blood-clot specificity and half-lives. Although there are extensive overlaps in SK structural domains responsible for functionality, immunogenicity and stability that may limit its modifications, various strategies such as genetic manipulations (amino acid substitution /addition /deletion or domain fusions through production of chimeric SK proteins linked to HPG or hirudin) and chemical modification such as (homogenous/site-specific) PEGylation have been employed to develop a superior SK. In addition, data of the latest studies on SK screened from different streptococcal sources indicated the possibility of retrieving naturally occurring SKs with higher activities, less antigenicity and/or more fibrinspecificity. In the present review, after a survey on structure function relationships of SK domains and different strategies for SK improvement, recent advances and potential application of computer and matrix-based analyses for design and introduction of superior SKs will be presented.
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The use of low-molecular-weight heparins in pregnancy--how safe are they?
Deruelle, P, Coulon, C
Current opinion in obstetrics & gynecology. 2007;(6):573-7
Abstract
PURPOSE OF REVIEW Low-molecular-weight heparins are in widespread use during pregnancy. As with every treatment in pregnant patients, concerns have been raised about the safety of Low-molecular-weight heparins. The purpose of the present article is to review recent advances, published during the past year, that have studied the maternal, fetal, and neonatal safety of Low-molecular-weight heparins in pregnant women. RECENT FINDINGS Low-molecular-weight heparins do not increase the risk of maternal bleeding during pregnancy. Closed management is needed during the peripartum period, and discontinuing Low-molecular-weight heparins at least 12 h before delivery seems sufficient to prevent post-partum haemorrhage. The incidence of Low-molecular-weight heparins-induced immune reaction is low. Fondaparinux or danaparoid may be used as an alternative option in pregnant women with heparin-induced thrombocytopenia. Long-term Low-molecular-weight heparins therapy may be associated with osteopenia. Calcium vitamin D supplementation during pregnancy may reduce the risk of Low-molecular-weight heparins-induced osteoporosis. As Low-molecular-weight heparins do not cross the placenta, no fetal or neonatal complication has been reported. Beyond the safety question, Low-molecular-weight heparins have the potential to improve the live-birth rate in high-risk pregnancies (antiphospholipid syndrome, thrombophilia, or recurrent fetal loss). SUMMARY Recent studies have confirmed the safety of Low-molecular-weight heparins therapy during pregnancy. The risk of potential side effects is low for both the mother and the neonate.
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New aspects in the pathogenesis of diabetic atherothrombosis.
Moreno, PR, Fuster, V
Journal of the American College of Cardiology. 2004;(12):2293-300
Abstract
Diabetes mellitus is increasing worldwide, resulting from the interaction of obesity, inflammation, and hyperglycemia. Activated immunity and cytokine production lead to insulin resistance and other components of the metabolic syndrome, establishing the link between diabetes and atherosclerosis. Hyperglycemia-induced endothelial dysfunction is mediated by increased oxidative stress, a promoter of adventitial inflammation and vasa vasorum neovascularization in experimental models of diabetic atherosclerosis. Recent studies have documented increased inflammation, neovascularization, and intraplaque hemorrhage in human diabetic atherosclerosis. This inflammatory microangiopathic process is independently associated with plaque rupture, leading to coronary thrombosis. Tissue factor, the most potent trigger of the coagulation cascade, is increased in diabetic patients with poor glycemic control. Circulating tissue factor microparticles are also associated with apoptosis of plaque macrophages, closing the link among inflammation, plaque rupture, and blood thrombogenicity. High-density lipoproteins, responsible for free cholesterol removal, are reduced in patients with insulin resistance and diabetes. High-density lipoprotein therapy leads to a significant decrease in plaque macrophages and increase in smooth-muscle cells. These beneficial effects may be responsible for coronary plaque stabilization in patients treated with recombinant Apolipoprotein A-I Milano/phospholipid complex. Finally, peroxisomal proliferator-activated receptors (PPARs) are now considered the nuclear transcriptional regulators of atherosclerosis. Three subfamilies, including PPAR-alpha, -delta, and -gamma, have been identified with crucial roles in lipid metabolism, plaque inflammation, expression of adhesion molecules and cytokines, and regulation of matrix metalloproteinases. Multiple experimental studies have documented plaque stabilization with PPAR-gamma agonists, a group of medications holding great promise in the treatment of diabetes atherosclerosis.