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Vascular Disease in Patients with Nonalcoholic Fatty Liver Disease.
Potze, W, Siddiqui, MS, Sanyal, AJ
Seminars in thrombosis and hemostasis. 2015;(5):488-93
Abstract
Nonalcoholic fatty liver disease (NAFLD) is increasingly being diagnosed and is considered to be the most frequent chronic liver disorder in Western countries. It represents a histopathological spectrum ranging from simple hepatic steatosis to steatohepatitis and finally cirrhosis. NAFLD is considered as the hepatic manifestation of the metabolic syndrome and is associated with increased mortality. Increasing evidence now suggests that NAFLD is also associated with higher cardiovascular disease (CVD) morbidity and mortality independent of conventional cardiometabolic risk factors (such as obesity, insulin resistance, and diabetes mellitus). The exact mechanisms linking NAFLD to increased CVD risk are still incompletely understood and likely reflect multiple coexisting pathways. Recent evidence suggests a contributive effect of an altered hemostasis in patients with NAFLD. For example, patients with NAFLD have higher levels of prothrombotic factors (e.g., von Willebrand factor, fibrinogen, factor VII activity, and plasminogen activator inhibitor-1), which correlate with underlying histological severity of the disease. The current review focuses on these hemostatic abnormalities in NAFLD and the link with increased CVD risk.
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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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The metabolic syndrome as a risk factor for venous and arterial thrombosis.
Dentali, F, Squizzato, A, Ageno, W
Seminars in thrombosis and hemostasis. 2009;(5):451-7
Abstract
The metabolic syndrome is a cluster of risk factors for atherosclerosis. Although a universally accepted definition is still lacking because available classifications present slightly different diagnostic criteria, the metabolic syndrome is now recognized as a serious public health problem that affects up to 45% of the population >50 years of age in the United States and approximately 20 to 25% of the adult population in Europe. To diagnose the metabolic syndrome, the concomitant presence of at least three components, among them visceral obesity defined by the measurement of the waist circumference, elevated blood pressure, hyperglycemia, hypertriglyceridemia, or reduced high-density lipoprotein cholesterol levels, is required. The concomitant presence of these risk factors, and thus the presence of the metabolic syndrome, is associated with inflammatory and hypercoagulable states that through increased levels of coagulation factors, reduction in fibrinolysis, endothelial dysfunction, and platelet hyperreactivity may predispose patients to develop cardiovascular events. Several studies have consistently shown that patients with the metabolic syndrome are at significantly increased risk of diabetes, coronary artery disease, and ischemic stroke. A few recent studies suggest that the metabolic syndrome may also play a role in the pathogenesis of venous thromboembolism, but this latter finding needs confirmation by large clinical studies.
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Oxidative stress and platelets.
Freedman, JE
Arteriosclerosis, thrombosis, and vascular biology. 2008;(3):s11-6
Abstract
Platelet-dependent thrombus formation may be influenced by alteration of platelet or vascular redox state, the presence of endogenous or exogenous antioxidants, as well as the formation of reactive oxygen and nitrogen species. Specifically, settings and pathways that influence the formation of superoxide and nitric oxide, as well as their metabolism, may influence platelet function and thrombus formation. Although some antioxidant regimens have been associated with bleeding and hemorrhagic stroke, the therapeutic value of antioxidants in clinical syndromes that lead to platelet-dependent thrombosis is not clear, as supplemental antioxidants have not been generally associated with better cardiovascular outcome.
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Emerging risk factors for cerebrovascular disease.
Solenski, NJ
Current drug targets. 2007;(7):802-16
Abstract
Nontraditional risk factors for cerebrovascular disease are rapidly emerging. The categories are expanding, and include those related to infection, inflammation, sleep disorders, hemostasis, nutrition, endocrine, and one's individual genotype. Many of the promising factors lack large randomized prospective population studies confirming direct cause and effect. However there have been strong evidence supporting increased stroke risk factor for infection, obstructive sleep disorders, the metabolic syndrome and impaired glucose tolerance in particular. Unique drug targets have already been identified in some of these emerging risk factors. The complexity of the pathophysiology of this disease remains a challenge. For example despite repeated evidence of estrogen-related neuroprotection, large population-based studies in postmenopausal women receiving estrogen replacement did not demonstrate the expected neuroprotection. This suggests that aggressive research both at the basic science and transitional level needs to evolve, to ensure targeted successful stroke therapy. The advent of nanotechnology including the development of targeted therapeutic nanospheres, and of revolutionary molecular technology resulting in the synthesis of specific peptide mimetics, bodes well for the future development of cerebrovascular drug treatment.
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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.