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Showing 1101–1120 of 2058 publications.
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Ong, Kwok Leung; Wu, Ben Jing; Cheung, Bernard Man Yung; Barter, Philip J.; Rye, Kerry AnneObjective: Arthritis is associated with cardiovascular diseases (CVDs). However, there are limited epidemiologic studies on arthritis in a national survey study. We therefore investigated the prevalence of self-reported arthritis and its association with CVDs. Methods: Data from 15,888 subjects aged 40 years or older in the United States National Health and Nutrition Examination Survey 1999 through 2008 were analyzed. CVD was defined as a self-reported history of heart attack, congestive heart failure, coronary heart disease, angina, or stroke. Results: The overall prevalence of self-reported arthritis in subjects aged 40 years or older increased from 33.5% in 1999 through 2000 to 37.0% in 2007 through 2008 (P for trend = 0.017). Among subjects with arthritis in 1999 through 2008, 35.3% had osteoarthritis (OA), 17.9% had rheumatoid arthritis (RA), and 10.2% had other types of arthritis, but 36.6% were unaware of their type of arthritis. Compared with subjects without OA, subjects with OA had higher odds for CVDs (odds ratio [OR], 1.53; P < .001), especially angina (OR, 2.18: P < .001). Compared with subjects without RA, subjects with RA had higher odds for CVDs (adjusted OR, 2.39; P < .001), especially congestive heart failure (OR, 3.59; P < .001). Conclusions: Both RA and OA are strongly associated with CVDs in the general population. Further studies are needed to investigate their causal relationship. 2013 Elsevier Inc.
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Davidson, Michael H.; Liu, Sherry Xueyu; Barter, Philip J.; Brinton, Eliot A.; Cannon, Christopher Paul; Gotto, Antonio M.; Leary, Elizabeth Teng; Shah, Sukrut; Stepanavage, Michael E.; Mitchel, Yale B.; Dansky, Hayes M.Estimation of low-density lipoprotein cholesterol (LDL-C) using the Friedewald (FR) formula is often inaccurate when triglycerides are elevated or VLDL particle composition is altered. We hypothesized that LDL-C estimation by the FR formula and other measurement methods might also be inaccurate in individuals treated with a cholesteryl ester transfer protein (CETP) inhibitor. An assay comparison study was conducted using pre and posttreatment serum samples from 280 of the 811 patients treated with the CETP inhibitor anacetrapib in the DEFINE study (determining the efficacy and tolerability of CETP inhibition with anacetrapib). After 24 weeks of treatment with anacetrapib, mean LDL-C values by FR formula, Roche direct method (RDM) and Genzyme direct method (GDM) deviated from that measured by the ?-quantification (BQ) reference method by -12.2 7.5, -10.2 6.6, -10.8 8.8 mg/dl, respectively. After treatment with anacetrapib, the FR formula and detergent-based direct methods provided lower LDL-C values than those obtained by the BQ reference method. The bias by the FR formula appeared to be due to an overestimation of VLDL-C by the TG/5 component of the formula. Evaluation of the clinical significance of these findings awaits comprehensive lipid and cardiovascular outcome data from ongoing Phase III clinical studies of anacetrapib. Copyright 2013 by the American Society for Biochemistry and Molecular Biology, Inc.
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Rahmanto, Aldwin Suryo; Pattison, David I.; Davies, Michael J.Singlet oxygen (1O<inf>2</inf>) is a reactive oxygen species generated during photo-oxidation, inflammation, and via peroxidase-catalyzed reactions (e.g., myeloperoxidase and eosinophil peroxidase). 1O <inf>2</inf> oxidizes the free amino acids Trp, Tyr, His, Cys, and Met, and those species present on peptides/proteins, with this resulting in modulation of protein structure and function. Impairment of the activity of antioxidant enzymes may be of relevance to the oxidative stress observed in a number of pathologies involving either light exposure or inflammation. In this study, the effects of 1O<inf>2</inf> on glutathione peroxidase (GPx) and thioredoxin reductase (TrxR) activity, including the mechanisms of their inactivation, were investigated. Exposure of GPx or TrxR, either as purified proteins or in cell lysates, to Rose Bengal and visible light (an established source of 1O<inf>2</inf>) resulted in significant, photolysis time-dependent reductions in enzyme activity (10-40%, P<0.05). More extensive inhibition (ca. 2-fold) was detected when the reactions were carried out in D<inf>2</inf>O, consistent with the intermediacy of 1O<inf>2</inf>. No additional inhibition was detected after the cessation of photolysis, eliminating a role for photo-products. Methionine, which reacts rapidly with 1O<inf>2</inf> (k?107 M-1 s -1)<inf>,</inf> significantly reduced photo-inactivation at large molar excesses, presumably by acting as an alternative target. Reductants (NaBH<inf>4</inf>, DTT, GSH, or NADPH) added after the cessation of 1O<inf>2</inf> formation were unable to reverse enzyme inactivation, consistent with irreversible enzyme oxidation. Formation of nonreducible protein aggregates and/or fragments was detected for both photo-oxidized GPx and TrxR by SDS-PAGE. An oxidant concentration-dependent increase in protein carbonyls was detected with TrxR but not GPx. These studies thus demonstrate that the antioxidant enzymes GPx and TrxR can be irreversibly inactivated by 1O<inf>2</inf>. 2012 Elsevier Inc.
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Pattison, David I.; Lam, Magdalena A.; Shinde, Sujata S.; Anderson, Robert F.; Davies, Michael J.Protein oxidation occurs during multiple human pathologies, and protein radicals are known to induce damage to other cell components. Such damage may be modulated by agents that scavenge protein radicals. In this study, the potential protective reactions of the nitroxide TEMPO (2,2,6,6-tetramethyl-1- piperidinyloxyl radical) against Tyr- and Trp-derived radicals (TyrO/TrpN) have been investigated. Pretreatment of macrophage cells with TEMPO provided protection against photo-oxidation-induced loss of cell viability and Tyr oxidation, with the nitroxide more effective than the hydroxylamine or parent amine. Pulse radiolysis was employed to determine rate constants, k, for the reaction of TEMPO with TyrO and TrpN generated on N-Ac-Tyr-amide and N-Ac-Trp-amide, with values of k?108 and 706 M-1 s-1, respectively, determined. Analogous studies with lysozyme, chymotrypsin, and pepsin yielded k for TEMPO reacting with TrpN ranging from 1.507 (lysozyme) to 1.108 (pepsin) M-1 s-1. Pepsin-derived TyrO reacted with TEMPO with k?407 M-1 s-1; analogous reactions for lysozyme and chymotrypsin TyrO were much slower. These data indicate that TEMPO can inhibit secondary reactions of both TyrO and TrpN, though this is protein dependent. Such protein radical scavenging may contribute to the positive biological effects of nitroxides. 2012 Elsevier Inc. All rights reserved.
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Waterhouse, Anna; Wise, Steven G.; Yin, Yongbai; Wu, Buchu; James, Barbara; Zreiqat, Hala H.; McKenzie, David R.; Bao, Shishan San; Weiss, Anthony Steven; Ng, Martin K.C.; Bilek, Marcela M.M.Bare metal and drug-eluting coronary stents suffer an inherent lack of vascular cell and blood compatibility resulting in adverse patient responses. We have developed a plasma-activated coating (PAC) for metallic coronary stents that is durable, withstands crimping and expansion, has low thrombogenicity and can covalently bind proteins, linker-free. This has been shown to enhance endothelial cell interactions in vitro and has the potential to promote biointegration of stents. Using the rabbit denuded iliac artery model, we show for the first time that PAC is a feasible coating for coronary stents in vivo. The coating integrity of PAC was maintained following implantation and expansion. The rate of endothelialization, strut coverage, neointimal response and the initial immune response were equivalent to bare metal stents. Furthermore, the initial thrombogenicity caused by the PAC stents showed a reduced trend compared to bare metal stents. This work demonstrates a robust, durable, non-cytotoxic plasma-based coating technology that has the ability to covalently immobilize bioactive molecules for surface modification of coronary stents. Improvements in the clinical performance of implantable cardiovascular devices could be achieved by the immobilization of proteins or peptides that trigger desirable cellular responses. 2012 Elsevier Ltd.
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Chan, Sandra W.; Dunlop, Rachael Anne; Rowe, Anthony; Double, Kay L.; Rodgers, Kenneth JohnLevodopa (l-dopa), a close structural analogue of the protein amino acid l-tyrosine, can substitute for l-tyrosine in protein synthesis and be mistakenly incorporated into newly synthesised proteins in vitro. We show that l- dopa-containing proteins are present in the brain in l-DOPA-treated Parkinson's disease patients and accumulate in specific brain regions. In vitro studies demonstrate that substitution of l-tyrosine residues in proteins with l-DOPA causes protein misfolding and promotes protein aggregation in SH-SY5Y neuroblastoma cells resulting in the appearance of autofluorescent bodies. We show that the presence of l-DOPA-containing proteins causes profound changes in mitochondria and stimulates the formation of autophagic vacuoles in cells. Unlike l-DOPA, which is toxic to cells through its ability to generate radicals, proteins containing incorporated l-DOPA are toxic to SH-SY5Y cells by a mechanism independent of oxidative stress and resistant to antioxidants. These data suggest that the accumulation of l-DOPA-containing proteins in vulnerable cells might negatively impact on cell function. 2011 Elsevier Inc.
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Barter, Philip J.; Rye, Kerry Anne; Beltangady, Mohan S.; Ports, William C.; Duggan, William T.; Boekholdt, S. M.; DeMicco, David A.; Kastelein, Johannes Jacob Pieter; Shear, Charles L.Development of the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, was halted after the ILLUMINATE trial revealed an increase in both all-cause mortality (ACM) and major cardiovascular events (MCVEs) associated with its use. We now report that the harm caused by torcetrapib was confined to those in the 10 mg atorvastatin subgroup for both ACM [hazard ratio (HR) = 2.68, 95% CI (1.58, 4.54), P < 0.0001] and MCVEs [HR = 1.41, 95% CI (1.14, 1.74), P = 0.002], with no evidence of harm when torcetrapib was coadministered with higher doses of atorvastatin. In the atorvastatin 10 mg subgroup, age, prior heart failure and stroke were significantly associated with ACM, independent of torcetrapib treatment, whereas low apoA-I, smoking, hypertension, heart failure, myocardial infarction, and stroke were independently associated with MCVEs. After adjusting for these factors, the HR associated with torcetrapib treatment in the 10 mg atorvastatin subgroup remained elevated for both ACM [HR = 2.67, 95% CI (1.57, 4.54), P < 0.001] and MCVE [HR = 1.36, 95% CI (1.10, 1.69), P = 0.005]. Thus, the harm caused by torcetrapib was confined to individuals taking atorvastatin 10 mg. The harm could not be explained by torcetrapib-induced changes in lipid levels, blood pressure, or electrolytes. It is conceivable that higher doses of atorvastatin protected against the harm caused by torcetrapib. Copyright 2012 by the American Society for Biochemistry and Molecular Biology, Inc.
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Rahmanto, Aldwin Suryo; Davies, Michael J.Selenium is a trace element essential for normal physiological processes. Organic selenium-containing amino acids, such as selenocysteine (Sec) / selenocystine and selenomethionine (SeMet, the major dietary form), can provide antioxidant benefits by acting both as direct antioxidants as well as a source of selenium for synthesis of selenium-dependent antioxidant and repair proteins (e.g., glutathione peroxidases, thioredoxin reductases, methionine sulfoxide reductases). The direct antioxidant actions of these amino acids arise from the nucleophilic properties of the ionized selenol (RSe-, which predominates over the neutral form at physiological pH values) and the ease of oxidation of Sec and SeMet. This results in higher rate constants for reaction with multiple oxidants, than for the corresponding thiols/thioethers. Furthermore, the resulting oxidation products are more readily and rapidly reversed by both enzyme and nonenzymatic reactions. The antioxidant effects of these seleno species can therefore be catalytic. Seleno amino acids may also chelate redox-active metal ions. The presence of Sec in the catalytic site of selenium-dependent antioxidant enzymes enhances the kinetic properties and broadens the catalytic activity of antioxidant enzymes against biological oxidants when compared with sulfur-containing species. However, while normal physiological selenium levels afford protection, when compared with deficiency, excessive selenium may induce damage and adverse effects, with this being manifest, for example, as an increased incidence of type 2 diabetes. Further studies examining the availability of redox-active selenium species and their mechanisms and kinetics of action are therefore of critical importance in the potential development of seleno species as a therapeutic strategy. Copyright 2012 International Union of Biochemistry and Molecular Biology, Inc.
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Morton, Jamie; Zoungas, Sophia; Li, Qiang; Patel, Anushka A.; Chalmers, J. P.; Woodward, Mark A.; Celermajer, David S.; Beulens, J. W.J.; Stolk, Ronald P.; Glasziou, Paul P.; Ng, Martin K.C.OBJECTIVE - Although low HDL cholesterol (HDL-C) is an established risk factor for atherosclerosis, data on HDL-C and the risk ofmicrovascular disease are limited.We tested the association between HDL-C and microvascular disease in a cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS - A total of 11,140 patients with type 2 diabetes and at least one additional vascular risk factor were followed a median of 5 years. Cox proportional hazardsmodelswere used to assess the association between baselineHDL-C and the development of new or worsening microvascular disease, defined prospectively as a composite of renal and retinal events. RESULTS - The mean baseline HDL-C level was 1.3 mmol/L (SD 0.45mmol/L [range 0.1-4.0]). During follow-up, 32% of patients developed new or worsening microvascular disease, with 28% experiencing a renal event and 6%a retinal event. Compared with patients in the highest third, those in the lowest third had a 17% higher risk of microvascular disease (adjusted hazard ratio 1.17 [95% CI 1.06-1.28], P = 0.001) after adjustment for potential confounders and regression dilution. Thiswas driven by a 19%higher risk of renal events (1.19 [1.08-1.32], P = 0.0005). There was no association between thirds of HDL-C and retinal events (1.01 [0.82-1.25], P = 0.9). CONCLUSIONS - In patients with type 2 diabetes, HDL-C level is an independent risk factor for the development of microvascular disease affecting the kidney but not the retina. 2012 by the American Diabetes Association. Readers.
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Johnen, Heiko; Kuffner, Tamara A.; Brown, David Alexander; Wu, Ben Jing; Stocker, Roland; Breit, Samuel N.Aim: MIC-1/GDF15 is a member of the TGF-b superfamily, which is thought to have pleiotropic roles in stress responses, inflammation, tissue injury and repair, energy homeostasis, and malignancy. MIC-1/GDF15 was recently identified as a new biomarker for the development of cardiovascular events and the outcome of atherosclerotic disease therapy. The aim of our study was to determine if MIC-1 also directly exerts pro- or antiatherogenic properties during the development of atherosclerosis. Methods and results: We investigated the effect of transgenic overexpression of MIC-1 in macrophages in the ApoE-/- mouse model of atherosclerosis. After 6 months of high-fat diet, MIC-1/GDF15 transgenic ApoE-/- mice had smaller atherosclerotic lesions; however, no differences in lesion composition, pro- or anti-inflammatory cytokine production, or serum levels of lipids or cytokines were detected. Conclusions: Our results suggest that MIC-1 has an overall protective effect on the disease process, but further studies will be required to define its mechanism of action. 2012 Elsevier Inc.
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Storkey, Corin M.; Pattison, David I.; White, Jonathan M.L.; Schiesser, Cart H.; Davies, Michael J.Heme peroxidases including myeloperoxidase (MPO) are released at sites of inflammation by activated leukocytes. MPO generates hypohalous acids (HOX, X = Cl, Br, SCN) from H<inf>2</inf>O<inf>2</inf>; these oxidants are bactericidal and are key components of the inflammatory response. However, excessive, misplaced or mistimed production can result in host tissue damage, with this implicated in multiple inflammatory diseases. We report here methods for the conversion of simple monosaccharide sugars into selenium- and sulfur-containing species that may act as potent water-soluble scavengers of HOX. Competition kinetic studies show that the seleno species react with HOCl with rate constants in the range 0.8-1.0 108 M-1 s-1, only marginally slower than those for the most susceptible biological targets including the endogenous antioxidant, glutathione. The rate constants for the corresponding sulfur-sugars are considerably slower (1.4-1.9 10 6 M-1 s-1). Rate constants for reaction of the seleno-sugars with HOBr are ?8 times lower than those for HOCl (1.0-1.5 107 M-1 s-1). These values show little variation with differing sugar structures. Reaction with HOSCN is slower (?102 M-1 s-1). The seleno-sugars decreased the extent of HOCl-mediated oxidation of Met, His, Trp, Lys, and Tyr residues, and 3-chlorotyrosine formation, on both isolated bovine serum albumin and human plasma proteins, at concentrations as low as 50 ?M. These studies demonstrate that novel selenium (and to a lesser extent, sulfur) derivatives of monosaccharides could be potent modulators of peroxidase-mediated damage at sites of acute and chronic inflammation, and in multiple human pathologies. 2012 American Chemical Society.
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Karton, Amir; O'Reilly, Robert J.; Pattison, David I.; Davies, Michael J.; Radom, LeoThe enzyme myeloperoxidase generates significant amounts of hypochlorous acid (HOCl) at sites of inflammation to inflict oxidative damage upon invading pathogens. However, excessive production of this potent oxidant is associated with numerous inflammatory diseases. Recent kinetic measurements suggest that the endogenous antioxidant carnosine is an effective HOCl scavenger. On the basis of computational modeling, we suggest a possible mechanism for this antioxidant activity. We find that a unique structural relationship between three adjacent functional groups (imidazole, carboxylic acid, and terminal amine) enables an intramolecular chlorine transfer to occur. In particular, two sequential proton shifts are coupled with a Cl+ shift converting the kinetically favored product (chlorinated at the imidazole nitrogen) into the thermodynamically favored product (chlorinated at the terminal amine) effectively trapping the chlorine. We proceed to design systems that share similar structural features to those of carnosine but with even greater HOCl-scavenging capabilities. 2012 American Chemical Society.
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Schwartz, Gregory G.; Olsson, Anders G.; Abt, Markus; Ballantyne, Christie Mitchell; Barter, Philip J.; Brumm, Jochen; Chaitman, Bernard R.; Holme, Ingar Morten K.; Kallend, David G.; Leiter, Lawrence Alan; Leitersdorf, Eran; McMurray, John JV; Mundl, Hardi; Nicholls, Stephen J.; Shah, Prediman Krishan; Tardif, Jean Claude; Wright, R. ScottBACKGROUND:In observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes. METHODS:We randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. RESULTS:At the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P = 0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (P<0.001 for both comparisons). CONCLUSIONS:In patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events. (Funded by F. Hoffmann-La Roche; dal-OUTCOMES ClinicalTrials.gov number, NCT00658515.) Copyright 2012 Massachusetts Medical Society.
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Cook, Naomi L.; Pattison, David I.; Davies, Michael J.Zinc is an abundant cellular transition metal ion, which binds avidly to protein cysteine (Cys) and histidine (His) residues to form zinc-Cys/His clusters; these play a key role in the function of many proteins (e.g., DNA binding and repair enzymes, transcription factors, nitric oxide synthase). Leukocyte-derived myeloperoxidase generates powerful oxidants including hypochlorous (HOCl), hypobromous (HOBr), and hypothiocyanous (HOSCN) acids from H<inf>2</inf>O<inf>2</inf> and (pseudo)halide ions. Excessive or misplaced formation of these species is associated with cellular dysfunction, apoptosis and necrosis, and multiple inflammatory diseases. HOCl and HOBr react rapidly with sulfur-containing compounds, and HOSCN reacts specifically with thiols. Consequently, we hypothesized that zinc-Cys/His clusters would be targets for these oxidants, and the activity of such enzymes would be perturbed. This hypothesis has been tested using yeast alcohol dehydrogenase (YADH), which contains a well-characterized Zn<inf>1</inf>Cys<inf>2</inf>His<inf>1</inf> cluster. Incubation of YADH with pathologically relevant concentrations of HOSCN, HOCl, and HOBr resulted in rapid oxidation of the protein (rate constants, determined by competition kinetics, for reaction of HOCl and HOSCN with YADH being (3.30.9)08 and (2.90.4) 04 M-1 s-1 per YADH monomer, respectively), loss of enzyme activity, Zn2+ release, changes in protein structure (particularly formation of disulfide cross-links), and oxidation of Cys residues. The loss of enzyme activity correlated with Zn 2+ release, loss of thiols, and changes in protein structure. We conclude that exposure of zinc-Cys/His clusters to inflammatory oxidants can result in impaired protein activity, thiol oxidation, and Zn2+ release. These reactions may contribute to inflammation-induced tissue damage. 2012 Elsevier Inc.
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Lambert, Gilles; Sjouke, B.; Choque, Benjamin; Kastelein, Johannes Jacob Pieter; Hovingh, Gerard KeesPCSK9 proprotein convertase subtilisin/kexin type (PCSK9) is a crucial protein in LDL cholesterol (LDL-C) metabolism by virtue of its pivotal role in the degradation of the LDL receptor. In recent years, both in vitro and in vivo studies have greatly supplemented our understanding of the (patho)physiological role of PCSK9 in human biology. In the current review, we summarize studies published or in print before May 2012 concerning the physiological role of PCSK9 in cholesterol metabolism. Moreover, we briefly describe the clinical phenotypes encountered in carriers of mutations in the gene encoding PCSK9. As PCSK9 has emerged as a novel target for LDL-C lowering therapy, methods to inhibit PCSK9 will also be reviewed. Initial data from investigations of PCSK9 inhibition in humans are promising and indicate that PCSK9 inhibition may be a viable new therapeutic option for the treatment of dyslipidemia and associated cardiovascular diseases. Copyright 2012 by the American Society for Biochemistry and Molecular Biology, Inc.
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Marais, David A.; Blom, Dirk J.; Petrides, Francine; Goufic, Yann; Lambert, GillesPURPOSE OF REVIEW: There are now ample data that demonstrate that inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) can safely lower LDL cholesterol synergistically with statins. Considering that PCSK9 was first identified less than a decade ago, the last few years have shown rapid and remarkable advancements in our understanding and knowledge of the structure and function of PCSK9. RECENT FINDINGS: Therapeutic developments have not lagged far behind with some monoclonal antibodies currently entering phase III trials. Of the many approaches to PCSK9 inhibition, these compounds are the furthest advanced in their clinical development while small molecule oral inhibitors seem a distant prospect. SUMMARY: This review summarizes the discovery and history of PCSK9 and in particular its mode of action as an inhibitor of the LDL receptor. It also recapitulates key studies that have demonstrated the potential of inhibiting PCSK9 to further decrease LDL-cholesterol levels safely and synergistically with statins. Finally, we review the strategies that are currently in development to inhibit PCSK9, with a special emphasis on the spectacular results from recent phase-I and phase-II clinical trials. 2012 Wolters Kluwer Health|Lippincott Williams & Wilkins.
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Katzenellenbogen, Judith Masha; Sanfilippo, Frank Mario; Hobbs, Michael S.T.; Briffa, Tom G.; Knuiman, Matthew William; Dimer, Lyn A.; Thompson, Peter Lindsay; Thompson, Sandra ClaireObjective: To determine the impact of remoteness on Aboriginal and non-Aboriginal myocardial infarction incidence rates in men and women of different ages. Design: Descriptive study. Setting: Western Australia. Participants: Incident cases of myocardial infarction in Western Australia from 2000-2004 identified from person-linked files of hospital and mortality records. Analysis was undertaken for Aboriginal and non-Aboriginal populations, separately and combined, by broad age group, sex and remoteness. Main outcome measure: Incidence of myocardial infarction. Results: In the combined analysis, age-standardised incidence was significantly higher for men in very remote areas (rate ratio 1.31: 95% confidence interval (CI), 1.19-1.45) and in women in both regional (rate ratio 1.12: 95% CI, 1.01-1.20) and very remote (rate ratio 2.05: 95% CI, 1.75-2.41) areas. Aboriginal rates were substantially higher than non-Aboriginal rates in all substrata. Compared with metropolitan people, regional Aboriginal men and very remote non-Aboriginal men aged 25-54 years had significantly higher incidence rates. For the remaining rural strata, there was either no geographical disadvantage or inconclusive findings. Conclusions: Non-metropolitan disadvantage in myocardial infarction rates is confirmed in regional areas and women in very remote areas. This disadvantage is partly explained by the high rates in Aboriginal people. Non-metropolitan dwellers are not uniformly disadvantaged, reflecting the interplay of the many factors contributing to the complex relationship between myocardial infarction incidence and sex, age, Aboriginality and residence. Aboriginal Western Australians in all regions and young non-Aboriginal men living in very remote areas need to be targeted to reduce disparities in myocardial infarction. 2012 The Authors. Australian Journal of Rural Health National Rural Health Alliance Inc.
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Ong, Kwok Leung; Rye, Kerry Anne; O'Connell, Rachel L.; Jenkins, Alicia J.; Brown, Christopher S.B.; Xu, Aimin; Sullivan, David R.; Barter, Philip J.; Keech, Anthony C.Context: Fenofibrate is a peroxisome proliferator-activated receptor (PPAR)-? agonist that showed beneficial effects on total cardiovascular risk in patients with type 2 diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Objective: This study aimed to investigate the long-term effect of fenofibrate therapy on three novel biomarkers of cardiovascular risk, namely adipocyte-fatty acid-binding protein (A-FABP), fibroblast growth factor 21 (FGF21), and retinol-binding protein 4 (RBP4), which are all down-stream targets of PPAR-? or PPAR-?, in patients with type 2 diabetes. Design, Setting, and Patients: A total of 216 patients (108 in the fenofibrate group and 108 in the placebo group) were randomly selected from the FIELD study cohort. A-FABP, FGF21, and RBP4 levels were measured in serum samples at both baseline and the fifth year of the study. Results: Relative to the placebo group, the changes of serum FGF21 and RBP4 levels were 85% (P < 0.001) and 10% (P = 0.032) higher in the fenofibrate group, respectively, over 5 yr. Fenofibrate treatment had no detectable effect on serum A-FABP level (P > 0.05). The effect of fenofibrate treatment on serum FGF21, but not RBP4, remained significant after adjusting for fenofibrate-induced changes in glycosylated hemoglobin, total cholesterol, triglycerides, apolipoprotein A-II, fibrinogen, plasma creatinine, and homocysteine (P = 0.002). Conclusions: Long-term fenofibrate treatment could increase serum FGF21 levels over 5 yr in patients with type 2 diabetes. Additional studies are needed to investigate the potential role of FGF21 in the fenofibrate-mediated reduction of cardiovascular risk. Copyright 2012 by The Endocrine Society.
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Wise, Steven G.; Waterhouse, Anna; Kondyurin, Alexey V.; Bilek, Marcela M.M.; Weiss, Anthony StevenPolymeric and metallic materials are used extensively in permanently implanted cardiovascular devices and devices that make temporary but often prolonged contact with body fluids and tissues. Foreign body responses are typically triggered by host interactions at the implant surface, making surface modifications to increase biointegration desirable. Plasma-based treatments are extensively used to modify diverse substrates; modulating surface chemistry, wettability and surface roughness, as well as facilitating covalent biomolecule binding. Each aspect impacts on facets of vascular compatibility including endothelialization and blood contact. These modifications can be readily applied to polymers such as Dacron and expanded polytetrafluoroethylene, which are widely used in bypass grafting and the metallic substrates of stents, valves and pacemaker components. Plasma modification of metals is more challenging given the need for coating deposition in addition to surface activation, adding the necessity for robust interface adhesion. This review examines the evolving plasma treatment technology facilitating the biofunctionalization of polymeric and metallic implantable cardiovascular materials. 2012 Future Medicine Ltd.
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Morales-Villegas, Enrique Cuitluac; Moreno-Virgen, Gualberto; Barter, Philip J.Manipulating the action of the Cholesteryl Ester Transfer Protein -CETP- and transforming the human lipid phenotype into one resembling the mouse lipid phenotype, in order to reduce susceptibility to atherosclerosis, is a hypothesis based on at least three lines of scientific evidence summarized within the introduction of this article. The following aspects related to the pharmacological manipulation of the CETP are discussed within the present article: a) CETP as a controversial protein involved in heterotypic and homotypic transport of neutral lipids between different lipoproteins; b) CETP as a protein involved in atherogenic dyslipidemia associated with the insulin resistance syndrome and c) pharmacological manipulation of the CETP by using "second generation" drugs -dalcetrapib, anacetrapib and evacetrapib- focusing on the results of Phase IIb and Phase III studies published up to May 2012. The article concludes with a review of the strengths, weaknesses, opportunities and current controversy on the HDL-centric versus LDL-centric theories. 2012 Bentham Science Publishers.
