Plasma visfatin levels are increased in overweight and obese subjects with MetS compared with those individuals who do not fulfil the criteria for the diagnosis of MetS.
Eur J Clin Invest 2008; 38 (1): 71-72Editor -The presence of the metabolic syndrome (MetS) increases the risk for cardiovascular disease (CVD) and type 2 diabetes mellitus [1]. A 'new' adipocytokine named 'visfatin' (pre-B cell colony-enhancing factor) is a cytokine highly expressed in visceral fat that exhibits insulin-mimetic properties [2]. We investigated the possible differences in plasma visfatin levels between subjects with and without MetS.Consecutive patients (n = 186, 81 men/105 women) without known CVD or diabetes mellitus attending the Outpatient Lipid Clinic of the University Hospital of Ioannina participated in the present study. Ninety of them fulfilled the National Cholesterol Educational Program Adult Treatment Panel III (NCEP ATP III) criteria for the diagnosis of MetS [3] and the remaining 96 subjects served as a control group (non-MetS). Plasma visfatin concentrations were measured using an enzyme-linked immunoabsorbent assay (EIA) kit (Phoenix Pharmaceuticals, Belmont, California, USA).Plasma visfatin concentrations were higher in MetS subjects compared with non-MetS individuals [24·6 (9·1-56·6) ng mL -1 vs. 16·1 (6·7-48·7) ng mL -1 , P < 0·01], even after adjustment for age, sex and body mass index. Visfatin levels increased proportionally to the number of MetS components (P for trend < 0·01) (Fig. 1). Plasma visfatin concentrations were correlated with waist circumference (rho = 0·3, P < 0·001), triglycerides (rho = 0·35, P < 0·001), systolic (rho = 0·28, P < 0·001) and diastolic (rho = 0·27, P < 0·001) blood pressure but not with high-density lipoprotein cholesterol levels. Plasma visfatin levels were marginally correlated with fasting glucose (rho = 0·144, P = 0·055) and insulin levels (rho 0·165, P = 0·035), as well as with the homeostasis model assessment (HOMA) index (rho = 0·16, P = 0·041).In conclusion, plasma visfatin levels are increased in patients with MetS compared with individuals that do not fulfil the criteria for this syndrome. Visfatin concentrations elevate in parallel with the number of MetS components. Gene expression of visfatin was recently found to be enhanced in macrophages of human unstable carotid and coronary atherosclerotic lesions; this finding suggests a potential role for visfatin as an inflammatory mediator and in plaque destabilisation process [4]. Larger clinical studies are needed in order to assess if the observed increase in visfatin levels in MetS subjects is a consequence of the involvement of the molecule in the pathogenesis of this syndrome, or it is just an epiphenomenon that might be a useful marker of abdominal fat deposition and cardiovascular risk. Figure 1 Plasma visfatin concentrations (logarithmically transformed) in subjects with a different number of components of the metabolic syndrome (MetS). The groups consist of: MetS components = 0 n = 34 patients MetS components = 1 n = 29 patients MetS components = 2 n = 38 patients MetS components = 3 n = 50 patients MetS components = 4 n = 24 patients MetS components = 5 n = 11 patients.
Patients with heterozygous familial hypercholesterolaemia (FH) have elevated plasma concentrations of low-density lipoprotein (LDL) and develop premature atherosclerosis. There is increasing evidence that oxidative modification of LDL is important for the pathogenesis of atherosclerosis, and the LDL-associated platelet-activating factor acetylhydrolase (PAF-AH) seems to play a key role in LDL oxidation by hydrolysing the oxidized phospholipids of phosphatidylcholine (PC) and producing lysophosphatidylcholine (lyso-PC). We measured the total serum and high-density lipoprotein (HDL) levels of PAF-AH activity and studied the distribution of PAF-AH activity among three LDL subfractions isolated by gradient ultracentrifugation in 15 patients with heterozygous FH and 13 normolipidaemic control subjects. We also determined the lyso-PC production in each LDL subfraction during Cu2(+)-induced oxidation in vitro. The total serum PAF-AH activity in heterozygous FH patients was significantly higher than in control subjects, whereas the HDL-associated PAF-AH activity, expressed as a percentage of total serum PAF-AH activity, was significantly lower in the FH patients than in control subjects (13.9 +/- 6.6% vs. 30.6 +/- 4.4%, P < 0.001). Among the LDL subfractions, the PAF-AH activity in both normolipidaemic control subjects and FH patients, expressed as nmol mg-1 protein min-1, was significantly higher in the LDL3 subfraction (33.1 +/- 4.8 and 53.4 +/- 11.5 respectively) than in the LDL2 (18.6 +/- 5.3 and 26.8 +/- 10.4 respectively, P < 0.0001 for both comparisons) and LDL1 subfractions (5.1 +/- 1.5 and 7.8 +/- 2.6, respectively, P < 0.0001 for both comparisons). Additionally, the enzyme activity in each LDL subfraction of the heterozygous FH patients was significantly higher than in control subjects (P < 0.02 for LDL1, P < 0.03 for LDL2 and P < 0.0001 for LDL3). No difference was observed in the susceptibility to oxidation of each LDL subfraction among the heterozygous FH patients and the normolipidaemic control subjects. During oxidation, the PAF-AH activity decreased, whereas the lyso-PC levels significantly increased in all subfractions of both groups. The lyso-PC/sphingomyelin molar ratio in each LDL subfraction of the FH patients 3 h after the onset of the oxidation was significantly higher than in control subjects [0.38 +/- 0.05 and 0.27 +/- 0.04, respectively, for LDL1 (P < 0.006), 0.47 +/- 0.08 and 0.39 +/- 0.03, respectively, for LDL2 (P < 0.04), 0.55 +/- 0.11 and 0.42 +/- 0.06, respectively, for LDL3 (P < 0.02)]. Our results show that heterozygous FH patients exhibit higher PAF-AH activity than control subjects in all LDL subfractions, resulting in higher lyso-PC production during oxidation, which confers on these subfractions higher biological potency. This phenomenon, in combination with the diminished anti-atherogenic and antioxidant capability of HDL in these patients due to the relatively low HDL-cholesterol levels compared with LDL-cholesterol levels and, consequently, the relatively low HDL-associated PAF-AH...
This article is available online at http://www.jlr.org herpes simplex virus, helicobacter pylori, as well as periodontitis have been studied ( 2-4 ). On the contrary, other studies have disputed the causal role of infectious agents in atherogenesis ( 5-7 ).Current evidence suggests that atherosclerosis develops as a response to infl ammatory stimulus. Therefore, common or uncommon infections could represent a risk factor. Mechanisms that may be implicated in the atherogenesis caused by infectious agents include local increase of proinfl ammatory cells, local effusion of endotoxins, autoimmune reaction, systemic cytokine release, and changes in lipid metabolism ( 8 ).Infection and infl ammation cause similar cytokineinduced changes in lipid and lipoprotein metabolism ( 9 ). These include reductions in serum levels of total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), apolipoproteins (Apo) AI and B, and lipoprotein (a) [Lp(a)] and increases in triglyceride (TG) and ApoE concentrations ( 9-14 ).Current evidence suggests that the host response to infection and infl ammation increases oxidized lipids in serum and induces LDL oxidation in vivo. Oxidative modifi cation of LDL is an important event in the development of atherosclerosis ( 15 ). In addition, the cholesterol ester transfer protein (CETP) plays a central role in HDL metabolism and the regulation of HDL-C levels in serum. High levels of CETP activity lead to a reduction in HDL-C levels and an atherogenic lipoprotein profi le ( 16 ).Platelet-activating factor (PAF) is a potent pro-infl ammatory phospholipid produced by activated platelets, -C), ApoB, ApoAI, and ApoCIII and higher LDL-C/HDL-C and ApoB/ApoAI ratios; 2 ) higher levels of IL-1b, IL-6, and TNFa; 3 ) similar ApoCII and oxLDL levels and Lp-PLA 2 activity, lower PON1, and higher CETP activity; and 4 ) higher small dense LDL-C concentration. Four months later, increases in TC, HDL-C, LDL-C, ApoB, ApoAI, and ApoCIII levels, ApoB/ApoAI ratio, and PON1 activity were noticed compared with baseline, whereas CETP activity decreased. LDL-C/HDL-C ratio, ApoCII, and oxLDL levels, Lp-PLA 2 activity, and small dense LDL-C concentration were not altered. Brucella infection is associated with an atherogenic lipid profi le that is not fully restored 4 months following treatment. There is increasing evidence that a link exists between infection/infl ammation and atherosclerosis ( 1 ). Infections with chlamydia pneumoniae, cytomegalovirus,
To cite this article: Tselepis AD, Tsoumani ME, Kalantzi KI, Dimitriou AA, Tellis CC, Goudevenos IA. Influence of high-density lipoprotein and paraoxonase-1 on platelet reactivity in patients with acute coronary syndromes receiving clopidogrel therapy. J Thromb Haemost 2011; 9: 2371-8.Summary. Background: The paraoxonase activity of the enzyme paraoxonase-1 (PON-1) associated with high-density lipoprotein (HDL) may significantly influence clopidogrelÕs antiplatelet and clinical efficacy as a result of its involvement in the clopidogrel biotransformation to the pharmacologically active thiol metabolite. We evaluated the possible relationships of HDL levels as well as PON-1 activities and the Q192R genotype with clopidogrelÕs antiplatelet efficacy in acute coronary syndrome (ACS) patients. Methods and results: The platelet aggregation, P-selectin expression and platelet/leukocyte conjugates as well as the clopidogrel response variability (evaluated by the VASP phosphorylation test and expressed as platelet reactivity index, PRI) were assessed in 74 ACS patients undergoing percutaneous coronary intervention (PCI) in relation to the PON-1 Q192R genotype and to serum HDLcholesterol levels, and PON-1 (paraoxonase and arylesterase) activities. Patients were loaded with 600 mg of clopidogrel followed by 75 mg per day. HDL-cholesterol levels and PON-1 activities at baseline (before clopidogrel loading) were not altered at 5-and 30-day post-clopidogrel loading, whereas baseline platelet activation parameters were significantly attenuated. At 5 days, 17 patients were clopidogrel non-responders (PRI: 64.2 ± 11.1%). HDL-cholesterol was inversely associated with platelet activation parameters independently on platelet response variability to clopidogrel whereas a negative association between platelet activation parameters and paraoxonase activity was observed in patients adequately responding to clopidogrel but not in clopidogrel non-responders. Similarly, the platelet activation markers were significantly higher in PON-1 Q192Q genotype carriers compared with those having one or two R alleles only in patients adequately responding to clopidogrel. Conclusions: PON-1 is an important determinant of clopidogrel antiplatelet efficacy only in patients adequately responding to clopidogrel. These findings may be clinically important in ACS patients receiving clopidogrel therapy, especially the first days after the episode.
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