Search

Background: The number of circulating LDL particles is a strong indicator of future cardiovascular disease (CVD) events, even superior to the concentration of LDL cholesterol. Atherogenic (primarily LDL) particle number is typically determined either directly by the serum concentration of apolipoprotein B (apo B) or indirectly by nuclear magnetic resonance (NMR) spectroscopy of serum to obtain NMR-derived LDL particle number (LDL-P)., Content: To assess the comparability of apo B and LDL-P, we reviewed 25 clinical studies containing 85 outcomes for which both biomarkers were determined. In 21 of 25 (84.0%) studies, both apo B and LDL-P were significant for at least 1 outcome. Neither was significant for any outcome in only 1 study (4.0%). In 50 of 85 comparisons (58.8%), both apo B and LDL-P had statistically significant associations with the clinical outcome, whereas in 17 comparisons (20.0%) neither was significantly associated with the outcome. In 18 comparisons (21.1%) there was discordance between apo B and LDL-P., Conclusions: In most studies, both apo B and LDL-P were comparable in association with clinical outcomes. The biomarkers were nearly equivalent in their ability to assess risk for CVD and both have consistently been shown to be stronger risk factors than LDL-C. We support the adoption of apo B and/or LDL-P as indicators of atherogenic particle numbers into CVD risk screening and treatment guidelines. Currently, in the opinion of this Working Group on Best Practices, apo B appears to be the preferable biomarker for guideline adoption because of its availability, scalability, standardization, and relatively low cost., (© 2013 American Association for Clinical Chemistry.)

Background: Obesity, metabolic syndrome, and type 2 diabetes are major public health challenges. Recently, interest has surged regarding the possible role of the intestinal microbiota as potential novel contributors to the increased prevalence of these 3 disorders., Content: Recent advances in microbial DNA sequencing technologies have resulted in the widespread application of whole-genome sequencing technologies for metagenomic DNA analysis of complex ecosystems such as the human gut. Current evidence suggests that the gut microbiota affect nutrient acquisition, energy harvest, and a myriad of host metabolic pathways., Conclusion: Advances in the Human Microbiome Project and human metagenomics research will lead the way toward a greater understanding of the importance and role of the gut microbiome in metabolic disorders such as obesity, metabolic syndrome, and diabetes., (© 2013 American Association for Clinical Chemistry)

Background: Inflammation is pivotal in atherosclerosis. A key early event in atherosclerosis is endothelial dysfunction. C-reactive protein (CRP), the prototypic marker of inflammation in humans, is a risk marker for cardiovascular disease, and there is mounting evidence to support its role in atherothrombosis. CRP has been shown to promote endothelial dysfunction both in vitro and in vivo. Emerging biomarkers of endothelial dysfunction include circulating endothelial cells (CECs) and endothelial microparticles (EMPs). However, there is a paucity of data examining the effect of CRP on CEC and EMP production in vitro and in vivo., Methods: In this report, we treated human aortic endothelial cells (HAECs) with increasing concentrations of CRP (0-50 μg/mL) or boiled CRP. We counted CECs and EMPs by flow cytometry., Results: Although CRP treatment resulted in a significant increase in release of both CECs and EMPs, boiled CRP failed to have an effect. Pretreatment of HAECs with sepiapterin or diethylenetriamine NONOate, both of which preserve nitric oxide (NO), resulted in attenuation of CRP's effects on CECs and EMPs. CD32 and CD64 blocking antibodies but not CD16 antibody or lectin-like oxidized LDL receptor 1 small interfering RNA (LOX-1 siRNA) prevented CRP-induced production of CECs and EMPs. Furthermore, delivery of human CRP to Wistar rats compared with human serum albumin resulted in significantly increased CECs and EMPs, corroborating the in vitro findings., Conclusions: We provide novel data that CRP, via NO deficiency, promotes endothelial dysfunction by inducing release of CECs and EMPs, which are biomarkers of endothelial dysfunction.

Background: C-reactive protein (CRP) inhibits the activity of the endothelial isoform of nitric oxide synthase (eNOS) via uncoupling of the enzyme both in vitro and in vivo. eNOS activity appears to be related in part to its interaction with other cellular proteins, including heat shock protein 90 (Hsp90), caveolin-1, and porin. In this study, we examined the effect of CRP treatment of human aortic endothelial cells (HAECs) on eNOS interaction with caveolin-1, Hsp90, and porin., Methods: We incubated HAECs with CRP (0, 12.5, and 25 mg/L) for 1, 6, or 24 h and assessed the interaction of these proteins with eNOS by immunoprecipitation and western blotting., Results: CRP treatment (12.5 and 25 mg/L) of HAECs for 24 h significantly increased eNOS binding to caveolin-1 (40% and 54% increase, respectively; P < 0.05) and decreased binding to Hsp90 (33% and 66% decrease, respectively; P < 0.05). CRP (25 mg/L) also significantly decreased the binding of porin to eNOS (11% decrease, P < 0.05). Similar results were seen when HAECs were treated with CRP for 6 h., Conclusions: These negative protein-protein interactions of eNOS were able to partly explain the CRP-induced decreases in the activity of this critical enzyme, which caused endothelial dysfunction.

Background: Low-density lipoprotein cholesterol (LDL-C) has been the cornerstone measurement for assessing cardiovascular risk for nearly 20 years., Content: Recent data demonstrate that apolipoprotein B (apo B) is a better measure of circulating LDL particle number (LDL-P) concentration and is a more reliable indicator of risk than LDL-C, and there is growing support for the idea that addition of apo B measurement to the routine lipid panel for assessing and monitoring patients at risk for cardiovascular disease (CVD) would enhance patient management. In this report, we review the studies of apo B and LDL-P reported to date, discuss potential advantages of their measurement over that of LDL-C, and present information related to standardization., Conclusions: In line with recently adopted Canadian guidelines, the addition of apo B represents a logical next step to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) and other guidelines in the US. Considering that it has taken years to educate physicians and patients regarding the use of LDL-C, changing perceptions and practices will not be easy. Thus, it appears prudent to consider using apo B along with LDL-C to assess LDL-related risk for an interim period until the superiority of apo B is generally recognized.

Background: C-reactive protein (CRP), the prototypic marker of inflammation, is present in atherosclerotic plaques and appears to promote atherogenesis. Also, CRP has been localized to monocytes and tissue macrophages, which are present in the necrotic core of lesions prone to plaque rupture. Leukocyte-derived myeloperoxidase (MPO), primarily hosted in human polymorphonuclear cells (PMNs), has also been shown to be present in human atherosclerotic lesions. Because MPO and CRP concentrations are increased in acute coronary syndrome (ACS) patients and predict poor outcomes, we tested the effect of CRP on MPO release from PMNs and monocytes., Methods: We treated human PMNs and monocytes with CRP (25 and 50 mg/L for 6 h) and measured MPO release as total mass and activity in culture supernatants. We also measured nitro-tyrosinylation (NO(2)-Tyr) of LDL as an indicator of biological activity of CRP-mediated MPO release. Furthermore, we explored the effect of human CRP on MPO release in the rat sterile pouch model., Results: CRP treatment significantly increased release of MPO (both mass and activity) from human PMNs as well as monocytes (P < 0.05) and caused NO(2)-Tyr of LDL. Human CRP injection in rats resulted in increased concentrations of MPO in pouch exudates (P < 0.05), thus confirming our in vitro data., Conclusions: CRP stimulates MPO release both in vitro and in vivo, providing further cogent data for the proinflammatory effect of CRP. These results might further support the role of CRP in ACS.

Background: Inflammation is pivotal in all phases of atherosclerosis. Among the numerous inflammatory biomarkers, the largest amount of published data supports a role for C-reactive protein (CRP) as a robust and independent risk marker in the prediction of primary and secondary adverse cardiovascular events. In addition to being a risk marker, there is much evidence indicating that CRP may indeed participate in atherogenesis., Content: In this review, we focus on the role of CRP in promoting atherothrombosis by discussing its effects on endothelial cells, endothelial progenitor cells, monocyte-macrophages, and smooth muscle cells., Conclusions: CRP is clearly a risk marker for cardiovascular disease and is recommended for use in primary prevention. In addition, CRP appears also to contribute to atherogenesis. However, much further research is needed, especially in appropriate animal models, to confirm the possible role of CRP in promoting atherothrombosis.

Background: Subfractions of HDL, particularly large HDL (HDL2), are inversely correlated with the severity of coronary artery disease (CAD). alpha-Tocopherol (AT) is the main lipid-soluble antioxidant in plasma. Results of a previous small study (n = 44) suggested that either a combination of an antioxidant cocktail [800 IU/day 2R,4'R,8'R-(RRR)-AT plus 1 g vitamin C, 25 mg beta-carotene, and 100 microg selenium] or individual antioxidant vitamins combined with simvastatin-niacin (S-N) therapy attenuated the protective increase in HDL2 seen with S-N alone. Few data are available on the effect of AT therapy alone on HDL subfractions, which we addressed in this study., Methods: In a prospective placebo-controlled study, we randomized 127 patients with stable CAD to receive high-dose RRR-AT (1200 IU/day for 2 years) or placebo. HDL subfractions (small, medium, and large HDL particles) were analyzed by nuclear magnetic resonance spectroscopy., Results: AT concentrations significantly increased in the AT arm but not with placebo. No differences were noted between AT and placebo groups in concentrations of total cholesterol, triglyceride, LDL-cholesterol, or HDL-cholesterol. AT therapy did not affect total, small, medium, or large HDL particles compared with baseline or placebo. Furthermore, serum apolipoprotein A1 concentrations did not change after 2 years AT therapy as compared with baseline., Conclusions: High-dose AT therapy administered for a 2-year period does not negatively affect either HDL subfractions or apolipoprotein A1 in patients with CAD on statin therapy. Thus the negative interaction previously proposed between antioxidant cocktail and statin therapy cannot be attributed to AT.

Background: Monocytes and macrophages are critical in atherosclerosis and on stimulation secrete proinflammatory, proatherogenic cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, which have been shown to be present in atherosclerotic lesions. The aim of this study was to develop a rapid in vitro screening assay to test the antiinflammatory effects of different compounds., Methods and Results: THP-1 cells (human monocytic cell line) were stimulated with different concentrations of lipopolysaccharide (LPS; 0 to 1000 microg/L) and for different times (4, 12, and 24 h), and the secretion of proinflammatory cytokines (IL-1, IL-6, and TNF-alpha) was assessed. TNF-alpha secretion was maximum at the lowest LPS concentration (100 microg/L) and at shortest duration of incubation (4 h). Maximum secretion of IL-1beta and IL-6 was achieved at 24 h with higher doses of LPS. Treatment of THP-1 with various test compounds such as dietary supplements (alpha-tocopherol, N-acetylcysteine, catechin and epigallocatechin gallate) as well as pharmacologic agents (statins, peroxisome proliferator-activated receptor-gamma agonists, and an angiotensin II receptor blocker) significantly inhibited LPS-stimulated TNF-alpha release., Conclusions: The release of TNF-alpha after stimulation of THP-1 cells with LPS is a valid model system to test novel compounds for potential antiinflammatory effects.