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The metabolic syndrome has received increased attention in the past few years. This statement from the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) is intended to provide up-to-date guidance for professionals on the diagnosis and management of the metabolic syndrome in adults.

The metabolic syndrome is a constellation of interrelated risk factors of metabolic origin— metabolic risk factors —that appear to directly promote the development of atherosclerotic cardiovascular disease (ASCVD).1 Patients with the metabolic syndrome also are at increased risk for developing type 2 diabetes mellitus. Another set of conditions, the underlying risk factors , give rise to the metabolic risk factors. In the past few years, several expert groups have attempted to set forth simple diagnostic criteria to be used in clinical practice to identify patients who manifest the multiple components of the metabolic syndrome. These criteria have varied somewhat in specific elements, but in general they include a combination of both underlying and metabolic risk factors.

The most widely recognized of the metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose. Individuals with these characteristics commonly manifest a prothrombotic state and a pro-inflammatory state as well. Atherogenic dyslipidemia consists of an aggregation of lipoprotein abnormalities including elevated serum triglyceride and apolipoprotein B (apoB), increased small LDL particles, and a reduced level of HDL cholesterol (HDL-C). The metabolic syndrome is often referred to as if it were a discrete entity with a single cause. Available data suggest that it truly is a syndrome, ie, a grouping of ASCVD risk factors, but one that probably has more than one cause. Regardless of cause, the syndrome identifies individuals at an elevated risk for ASCVD. The magnitude of the increased risk can vary according to which components of the syndrome are …

https://www.lipidcenter.com/pdf/metabolic.pdf

Diagnosis and Management of the Metabolic Syndrome An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement

Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.

/pdf/inflammation-and-atherosclerosis-1q9qkglell.pdf

Inflammation and Atherosclerosis

Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement.

The metabolic syndrome

PURPOSE OF REVIEW C-reactive protein (CRP) is the prototypic downstream marker of inflammation High levels of CRP predict future cardiovascular risk in apparently healthy men and women Recent evidence from different cell types suggests that CRP is not only a risk marker but may also be a participant in atherogenesis This review will focus on the effects of CRP on different cells involved in atherosclerosis RECENT FINDINGS CRP is shown to induce matrix metalloproteinase-1 (MMP-1) expression through the Fc gamma RII and extracellular signal-related kinase pathway in U937 cells MMPs are implicated in plaque instability A recent report shows that CRP does not induce tissue factor in human monocytes directly, disputing the previous concept that CRP induces tissue factor in monocytes CRP is shown to upregulate interleukin-8 in human aortic endothelial cells via nuclear factor-kappa B CRP promotes monocyte chemoattractant protein-1-mediated chemotaxis by upregulating CC-chemokine receptor 2 expression in human monocytes Also CRP is shown to attenuate endothelial progenitor cell survival, differentiation, and function via inhibiting nitric oxide Human CRP transgenic animal models show that CRP promotes atherothrombosis and increases plasminogen activator inhibitor-1 Also, the classic dogma that CRP is produced exclusively in liver is challenged by recent data on the extrahepatic production of CRP in different cells including atherosclerotic lesions SUMMARY All this recent evidence along with earlier reports support a role for CRP in atherosclerosis

Effect of C-reactive protein on vascular cells: evidence for a proinflammatory, proatherogenic role.

C-reactive protein (CRP) is a risk marker for cardiovascular events in apparently healthy persons. Cogent data show that, aside from the liver, CRP is produced in atherosclerotic lesions, kidney, neurons, and alveolar macrophages. Because several proatherogenic effects of CRP have been documented in endothelial cells, we examined human aortic endothelial cells (HAEC) for CRP production. We detected the presence of CRP mRNA by RT-PCR and in situ hybridization, intracellular protein by Western blot and secreted protein by ELISA. Coincubation with the cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor alone and in combination showed that the most potent agonist for CRP production from HAEC is the combination of IL-1 and IL-6 (P < 0.05). To mimic the in vivo situation, we examined whether vascular smooth muscle cell (VSMC) and/or macrophage conditioned media (MCM) could augment CRP production by HAEC. While VSMC-conditioned media had no effect, incubation with MCM resulted in a significant twofold increase in the synthesis of both intracellular and secreted CRP (P < 0.05). The effect of MCM could be reversed by inhibiting both IL-1 and IL-6. Thus, stimulated synthesis and secretion of CRP by cells in the atherosclerotic lesion by paracrine/autocrine loops could result in local concentrations of CRP far in excess of plasma concentrations and could contribute to proinflammatory, proatherogenic effects.

Macrophage Conditioned Medium Induces the Expression of C-Reactive Protein in Human Aortic Endothelial Cells : Potential for Paracrine/Autocrine Effects

Context: The metabolic syndrome (MetS) is associated with increased risk of diabetes and cardiovascular disease (CVD). Numerous groups have shown increased circulating biomarkers of inflammation in MetS. However, there are scanty data on the cellular sources contributing to this low-grade inflammation. Objective: The aim of this study was to determine the role of sc adipose tissue (SAT) biology in nascent MetS without concomitant diabetes or CVD. Patients and Methods: Subjects with MetS and controls were recruited after informed consent. Fasting blood was collected, and SAT was obtained by biopsy. Results: Circulating biomarkers of inflammation and insulin resistance, high-sensitivity C-reactive protein (hsCRP), IL-6, IL-1β, leptin, serum amyloid A, and retinol-binding protein-4 (RBP-4) concentrations were significantly higher in the MetS subjects than controls, whereas adiponectin concentrations were lower. In SAT, leptin, RBP-4, CRP, serum amyloid A, plasminogen activator inhibitor-1, IL-1, IL-6, IL-8, ...

/pdf/adipose-tissue-dysregulation-in-patients-with-metabolic-4xi658511p.pdf

Adipose tissue dysregulation in patients with metabolic syndrome.

Previously, IL-1β secretion from Type 2 diabetic patients has been shown to be increased compared with controls. In this study, we aimed to delineate the mechanism of IL-1β induction under high-glu...

/pdf/high-glucose-induces-il-1b-expression-in-human-monocytes-3zuwoznv68.pdf

High glucose induces IL-1β expression in human monocytes: mechanistic insights

OBJECTIVE The metabolic syndrome (MetS) is highly prevalent and confers an increased risk for diabetes and cardiovascular disease (CVD). While MetS is a proinflammatory state, there is a paucity of data on cellular inflammation in MetS. Toll-like receptors (TLRs) are classical pattern recognition receptors of the innate immune response. RESEARCH DESIGN AND METHODS The aim of this study was to examine monocyte TLR2, and TLR4 in MetS patients without diabetes or CVD and control subjects since both of the receptors have been implicated in atherosclerosis and insulin resistance. Fasting blood was obtained for TLR expression and activity. RESULTS Circulating levels of high-sensitivity C-reactive protein, interleukin (IL)-1β, IL-6, IL-8, and soluble tumor necrosis factor receptor-1 were significantly increased in MetS versus control subjects following adjustment for waist circumference. There was a significant increase in both TLR2 and TLR4 surface expression and mRNA on monocytes after adjustment for waist circumference. In addition to increased nuclear factor-κB nuclear binding, there was significantly increased release of IL-1β, IL-6, and IL-8 in MetS versus control subjects following priming of the monocytes with lipopolysaccharides. While both plasma free fatty acids and endotoxin were increased in MetS, they correlated significantly with TLR4 only. CONCLUSIONS In conclusion, we make the novel observation that both TLR2 and TLR4 expression and activity are increased in the monocytes of patients with MetS and could contribute to increased risk for diabetes and CVD.

/pdf/increased-toll-like-receptor-activity-in-patients-with-4m7ta5tbco.pdf

Sridevi Devaraj

Papers

Effect of C-reactive protein on vascular cells: evidence for a proinflammatory, proatherogenic role.

Macrophage Conditioned Medium Induces the Expression of C-Reactive Protein in Human Aortic Endothelial Cells : Potential for Paracrine/Autocrine Effects

Adipose tissue dysregulation in patients with metabolic syndrome.

High glucose induces IL-1β expression in human monocytes: mechanistic insights

Increased Toll-Like Receptor Activity in Patients With Metabolic Syndrome