Large-scale distribution of tuna species in a warming ocean.

Tuna are globally distributed species of major commercial importance and some tuna species are a major source of protein in many countries. Tuna are characterized by dynamic distribution patterns that respond to climate variability and long-term change. Here, we investigated the effect of environmental conditions on the worldwide distribution and relative abundance of six tuna species between 1958 and 2004 and estimated the expected end-of-the-century changes based on a high-greenhouse gas concentration scenario (RCP8.5). We created species distribution models using a long-term Japanese longline fishery dataset and two-step generalized additive models. Over the historical period, suitable habitats shifted poleward for 20 out of 22 tuna stocks, based on their gravity centre (GC) and/or one of their distribution limits. On average, tuna habitat distribution limits have shifted poleward 6.5 km per decade in the northern hemisphere and 5.5 km per decade in the southern hemisphere. Larger tuna distribution shifts and changes in abundance are expected in the future, especially by the end-of-the-century (2080-2099). Temperate tunas (albacore, Atlantic bluefin, and southern bluefin) and the tropical bigeye tuna are expected to decline in the tropics and shift poleward. In contrast, skipjack and yellowfin tunas are projected to become more abundant in tropical areas as well as in most coastal countries' exclusive economic zones (EEZ). These results provide global information on the potential effects of climate change in tuna populations and can assist countries seeking to minimize these effects via adaptive management.

Terrestrial and marine perspectives on modeling organic matter degradation pathways.

Organic matter (OM) plays a major role in both terrestrial and oceanic biogeochemical cycles. The amount of carbon stored in these systems is far greater than that of carbon dioxide (CO2 ) in the atmosphere, and annual fluxes of CO2 from these pools to the atmosphere exceed those from fossil fuel combustion. Understanding the processes that determine the fate of detrital material is important for predicting the effects that climate change will have on feedbacks to the global carbon cycle. However, Earth System Models (ESMs) typically utilize very simple formulations of processes affecting the mineralization and storage of detrital OM. Recent changes in our view of the nature of this material and the factors controlling its transformation have yet to find their way into models. In this review, we highlight the current understanding of the role and cycling of detrital OM in terrestrial and marine systems and examine how this pool of material is represented in ESMs. We include a discussion of the different mineralization pathways available as organic matter moves from soils, through inland waters to coastal systems and ultimately into open ocean environments. We argue that there is strong commonality between aspects of OM transformation in both terrestrial and marine systems and that our respective scientific communities would benefit from closer collaboration.

Circulating PCSK9 levels are positively correlated with NMR-assessed atherogenic dyslipidaemia in patients with high cardiovascular risk.

The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene regulates cholesterol homoeostasis by accelerating low-density lipoprotein receptor (LDLR) degradation resulting in the decreased catabolism of low-density lipoprotein (LDL) leading to hypercholesterolaemia. PCSK9 has also been related to other metabolic risk factors such as triglycerides (TGs) and glucose levels and body mass index (BMI). Therefore, our aim was to study the relationship between the PCSK9 and the lipid and lipoprotein profile. We studied 267 diabetic and metabolic syndrome patients who were not receiving any lipid-lowering therapy. We measured circulating lipids, cholesterol in remnant lipoproteins (RLPc) and PCSK9 levels. A detailed lipoprotein profile was determined based on NMR. Plasma PCSK9 levels were significantly and positively correlated with TG (r=0.136, P=0.033), total cholesterol (r=0.219, P<0.001) and apoB (apolipoprotein B; r=0.226, P=0.006) circulating levels and with an atherogenic profile of lipoprotein subclasses. In further detail, circulating PCSK9 levels were positively correlated with large very-low density lipoprotein (VLDL) particles, (r=0.210, P=0.001) and with their remnants, the intermediate-density lipoprotein (IDL) particles (r=0.206, P=0.001); positively correlated with smaller LDL particles (for small LDL: r=0.224, P<0.001; for medium small LDL: r=0.235, P<0.001; and for very small LDL: r=0.220, P<0.001); and with high-density lipoprotein (HDL) particles (r=0.146, P<0.001), which is mainly explained by the PCSK9 correlation with the smallest HDL particles (r=0.130, P=0.037). In addition, circulating PCSK9 levels were positively correlated with the pro-atherogenic circulating RLPc levels (r=0.171, P=0.006). All of the correlations were adjusted by age, gender and BMI. PCSK9 levels are significantly and positively correlated with atherogenic lipoproteins such as large VLDL, IDL, the smallest LDL, the smallest HDL particles and RLPc levels.

Parallel evolution of circulating FABP4 and NT-proBNP in heart failure patients.

BACKGROUND: Circulating adipocyte fatty acid-binding protein (FABP4) levels are considered to be a link between obesity, insulin resistance, diabetes, and cardiovascular (CV) diseases. In vitro, FABP4 has exhibited cardiodepressant activity by suppressing cardiomyocyte contraction. We have explored the relationship between FABP4 and the N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP) as a clinical parameter of heart failure (HF). METHODS: We included 179 stable HF patients who were referred to a specialized HF unit, 108 of whom were prospectively followed for up to 6 months. A group of 163 non-HF patients attending a CV risk unit was used as the non-HF control group for the FABP4 comparisons. RESULTS: In the HF patients, FABP4 and NT-proBNP were assayed, along with a clinical and functional assessment of the heart at baseline and after 6 months of specialized monitoring. The FABP4 levels were higher in the patients with HF than in the non-HF high CV risk control group (p<0.001). The FABP4 levels were associated with the NT-proBNP levels in patients with HF (r=0.601, p<0.001), and this association was stronger in the diabetic patients. FABP4 was also associated with heart rate and the results of the 6-minute walk test. After the follow-up period, FABP4 decreased in parallel to NT-proBNP and to the clinical parameters of HF. CONCLUSIONS: FABP4 is associated with the clinical manifestations and biomarkers of HF. It exhibits a parallel evolution with the circulating levels of NT-proBNP in HF patients.

Fatty acid-binding protein 4 impairs the insulin-dependent nitric oxide pathway in vascular endothelial cells.

BACKGROUND: Recent studies have shown that fatty acid-binding protein 4 (FABP4) plasma levels are associated with impaired endothelial function in type 2 diabetes (T2D). In this work, we analysed the effect of FABP4 on the insulin-mediated nitric oxide (NO) production by endothelial cells in vitro. METHODS: In human umbilical vascular endothelial cells (HUVECs), we measured the effects of FABP4 on the insulin-mediated endothelial nitric oxide synthase (eNOS) expression and activation and on NO production. We also explored the impact of exogenous FABP4 on the insulin-signalling pathway (insulin receptor substrate 1 (IRS1) and Akt). RESULTS: We found that eNOS expression and activation and NO production are significantly inhibited by exogenous FABP4 in HUVECs. FABP4 induced an alteration of the insulin-mediated eNOS pathway by inhibiting IRS1 and Akt activation. These results suggest that FABP4 induces endothelial dysfunction by inhibiting the activation of the insulin-signalling pathway resulting in decreased eNOS activation and NO production. CONCLUSION: These findings provide a mechanistic linkage between FABP4 and impaired endothelial function in diabetes, which leads to an increased cardiovascular risk.

Fatty acid-binding protein-4 plasma levels are associated to metabolic abnormalities and response to therapy in girls and young women with androgen excess.

OBJECTIVE: To assess the usefulness of circulating fatty acid-binding protein 4 (FABP4) as a predictive marker of long-term therapeutic outcome in girls with ovarian androgen excess and a history of precocious pubarche (PP) and low birth weight (LBW) and in young women with polycystic ovary syndrome (PCOS). METHODS: We included 97 patients. Thirty-nine had a history of LBW-PP and were randomized to remain untreated (n = 13) or to receive metformin (n = 26). PCOS women (n = 58) received low-dose flutamide-metformin plus an oral contraceptive. Auxology, androgens, glucose, insulin, homeostasis model assessment (HOMA)-insulin resistance (IR), lipid profile, FABP4, and body composition (by dual-energy X-ray absorptiometry) were assessed at baseline and after 2 years. RESULTS: At baseline, FABP4 was associated with anthropometric measurements and fat body mass (all P < 0.05). FABP4 levels increased less after follow-up in the PP-treated girls (P < 0.05); in the PCOS patients, basal FABP4 levels were inversely associated with changes in systolic blood pressure, HOMA-IR, and total fat mass (all P < 0.05). Body mass index-standard deviation scores was the main independent predictor of FABP4 variations (33%, P < 0.001). CONCLUSION: FABP4 is a strong clinical biomarker of adiposity, IR, and the presence of the components of the metabolic syndrome in non-obese hyperandrogenic girls and young women; pretreatment FABP4 levels appear to predict therapeutic long-term response.

FABP4 plasma levels are increased in familial combined hyperlipidemia.

The lipid profile of familial combined hyperlipidemia (FCHL) shares some characteristics with atherogenic dyslipidemia seen in diabetes, metabolic syndrome, and obesity. Adipocyte fatty acid-binding protein 4 (FABP4) appears to be a determinant of atherogenic dyslipidemia. We examined relationships between FABP4 plasma concentrations, dyslipidemia, and metabolic variables in patients with FCHL. We studied 273 unrelated FCHL patients and 118 control subjects. FABP4 was higher in FCHL than controls, with mean levels of 21.8 (10.1) microg/l and 19.2 (9.2) microg/l, respectively (adjusted P= 0.012). In FCHL, FABP4 correlated to body mass index (BMI), waist circumference, insulin levels, and homeostasis model assessment (HOMA) index (all P< 0.05), but not to lipid levels, whereas in obese patients, FABP4 correlated to triglyceride levels (r = 0.303, P= 0.014) and very low density lipoprotein size (r = 0.502, P = 0.001), as determined by nuclear magnetic resonance. Associations of FABP4 with BMI and waist circumference, but not with insulin levels, persisted in this subgroup. Plasma FABP4 does not influence the lipid phenotype of FCHL. In a small subgroup of obese FCHL, FABP4 levels were associated with triglyceride-rich lipoproteins independent of insulin resistance. These results support a hyperlipidemic mechanism of FCHL different from similar metabolic conditions where fat mass is strongly related to FABP4 and hypertriglyceridemia.

Oxidized to non-oxidized lipoprotein ratios are associated with arteriosclerosis and the metabolic syndrome in diabetic patients.

BACKGROUND AND AIM: Type 2 diabetic patients have a greater prevalence of the metabolic syndrome, oxidative stress and accelerated atherosclerosis, compared to non-diabetics. We examined the association between biomarkers of lipid peroxidation and the presence of atherosclerosis and the metabolic syndrome in diabetic patients. METHODS AND RESULTS: We studied oxidized LDL (OxLDL), OxLDL/LDL, OxLDL/HDL, lipoperoxides, autoantibodies against OxLDL (OxLDL-Ab), diene formation of LDL (lag phase), vitamin E, vitamin E/cholesterol and PON1 polymorphisms (-108C>T, 55T>A, and 192A>G) in 166 non-smoking type 2 diabetic patients, 119 fulfilling the criteria for the metabolic syndrome, 73 with atherosclerosis and 93 without atherosclerosis. Patients with macrovascular disease had higher values of OxLDL/LDL (11%; P=0.016), OxLDL/HDL (18%; P=0.024) and OxLDL-Ab (12%; P=0.046). OxLDL/LDL and OxLDL/HDL were correlated with the number of components of the metabolic syndrome (P<0.001). PON1 polymorphisms were not associated to LDL oxidation markers, only PON1 (-108TT) was weakly associated with higher OxLDL-Ab concentrations (22%; P=0.040) in patients with atherosclerosis. CONCLUSION: OxLDL/LDL, OxLDL/HDL and OxLDL-Ab are the most useful clinical parameters of lipoprotein oxidation for discriminating the presence of macrovascular disease in diabetic patients. The presence of the metabolic syndrome in these patients is also associated with an increase in the oxidized lipoprotein ratios.

[Intraabdominal fat redistribution in long-term continuous positive airway pressure treatment in obstructive sleep apnea patients]. / Redistribución de grasa intraabdominal en el tratamiento a largo plazo con presión positiva continua de la vía aérea en los pacientes con síndrome de apnea-hipopnea durante el sueño.

BACKGROUND AND OBJECTIVE: Obesity is the main risk factor for obstructive sleep apnoea (OSA). The aim was to evaluate the long-term effect of continuous positive airway pressure (CPAP) on intraabdominal fat distribution in OSA patients. PATIENTS AND METHODS: Fifty OSA patients with and 35 without CPAP treatment criteria were followed-up for 2 years. Visceral and subcutaneous adipose tissue (VAT and SAT) and preaortic intraabdominal fat (PIF) were assessed by sonography. RESULTS: In the non CPAP treated group, SAT and VAT mean values didn't change, while a significantly PIF growth was observed (55.19 [23.44] vs. 63.45 [23.94] mm, P=.021). In the CPAP treated group, VAT and PIF mean were not changed, while SAT decreased significantly (11.29 [5.69] vs. 10.47 [5.71] mm, P=.012). CONCLUSIONS: Long-term CPAP treatment produces intraabdominal fat redistribution and is associated with an anthropometric profile of lower cardiovascular risk in OSA patients.

[Long-term effects of continuous positive airway pressure treatment on subclinical atherosclerosis in obstructive sleep apnoea syndrome]. / Efecto a largo plazo del tratamiento con presión positiva continua de la vía aérea sobre la arteriosclerosis subclínica en el síndrome de apnea-hipopnea durante el sueño.

BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) is associated with an increased risk of cardiovascular disease. Our objective was to evaluate subclinical atherosclerosis in OSA patients and the effect of continuous positive airway pressure (CPAP) treatment on carotid intima-media thickness (cIMT). PATIENTS AND METHOD: We included 125 patients with suspected OSA. After polysomnography, 107 patients were diagnosed with OSA; 58 of these met the criteria for CPAP treatment. cIMT was measured by ultrasonography at baseline in all patients and after 2 years of follow up in 50 patients on CPAP and 35 without CPAP treatment. RESULTS: The average cIMT was significantly thicker in OSA than in non-OSA patients (665±120 vs. 581±78µm, P=.005) and did not differ according to OSA severity. Atheromatous carotid plaque was more prevalent in OSA than non-OSA patients (48 vs. 2%, P=.004). Among OSA patients, the mean cIMT remained stable over time in the group without CPAP, whereas cIMT decreased markedly in the CPAP group (679±122 vs. 631±117µm, P<.0001). CONCLUSIONS: Increased cIMT was associated with presence of OSA, but not with its severity. Carotid ultrasound in OSA is a reliable marker of atherosclerosis. CPAP treatment with CPAP in OSA reduces cIMT and cardiovascular risk.

Circulating PCSK9 in patients with type 2 diabetes and related metabolic disorders.

BACKGROUND: PCSK9 is a pivotal molecule in the regulation of lipid metabolism. Previous studies have suggested that PCSK9 expression and its function in LDL receptor regulation could be altered in the context of diabetes. The aim was to assess PCSK9 plasma levels in patients with type 2 diabetes (T2DM) and other related metabolic disorders as well as its relation to the metabolomic profile generated by nuclear magnetic resonance (NMR) and glucose homeostasis. METHODS: There were recruited a total of 457 patients suffering from T2DM and other metabolic disorders (metabolic syndrome (MetS), obesity and atherogenic dyslipidaemia (AD) and other disorders). Anamnesis, anthropometry and physical examinations were conducted, and vascular and abdominal adiposity imaging were carried out. Biochemical studies were performed to determine PCSK9 plasma levels 6 weeks after lipid lowering drug wash-out in treated patients. A complete metabolomic lipid profile was also generated by NMR. The rs505151 and rs11591147 genetic variants of PCSK9 gene were identified in patients. RESULTS: The results showed that PCSK9 levels are increased in patients with T2DM and MetS (14% and 13%; p<0.005, respectively). Circulating PCSK9 levels were correlated with an atherogenic lipid profile and with insulin resistance parameters. PCSK9 levels were also positively associated with AD, as defined by lipoprotein particle number and size. The rs11591147 genetic variant resulted in lower levels of circulating PCSK9 and LDL cholesterol (LDL-C). CONCLUSIONS: PCSK9 plasma levels are increased in T2DM and MetS patients and are associated with LDL-C and other parameters of AD and glucose metabolism.

[Interaction of FABP4 with plasma membrane proteins of endothelial cells]. / Interacción de FABP4 con proteínas de membrana de células endoteliales.

INTRODUCTION: Fatty acid binding protein (FABP4) is an adipose tissue-secreted adipokine implicated in the regulation of the energetic metabolism and inflammation. High levels of circulating FABP4 have been described in people with obesity, atherogenic dyslipidemia, diabetes and metabolic syndrome. Recent studies have demonstrated that FABP4 could have a direct effect on peripheral tissues and, specifically, on vascular function. It is still unknown how the interaction between FABP4 and the endothelial cells is produced to prompt these effects on vascular function. The objective of this work is studying the interaction between FABP4 and the plasma membrane proteins of endothelial cells. METHODOLOGY: HUVEC cells were incubated with and without FABP4 (100 ng/ml) for 5 minutes. Immunolocalization of FABP4 was studied by confocal microscopy. The results showed that FABP4 colocalizates with CD31, a membrane protein marker. A strategy which combines 6XHistidine-tag FABP4 (FABP4-His), incubations with or without FABP4-His (100 ng/ml), formaldehyde cross-linking, cellular membrane protein extraction and western blot, was designed to study the FABP4 interactions with membrane proteins of HUVECs. RESULTS: The results showed different western blot profiles depending of the incubation with or without FABP4-His. The immunoblot revelead three covalent protein complexes of about 108, 77 and 33 kDa containing FAPB4 and its putative receptor. DISCUSSION: The existence of a specific binding protein complex able to bind FABP4 to endothelial cells is supported by these results. The obtained results will permit us advance in the molecular knowledge of FABP4 effects as well as use this protein and its receptor as therapeutic target to prevent cardiovascular.

Metabolomics reveals impaired maturation of HDL particles in adolescents with hyperinsulinaemic androgen excess.

Hyperinsulinaemic androgen excess (HIAE) in prepubertal and pubertal girls usually precedes a broader pathological phenotype in adulthood that is associated with anovulatory infertility, metabolic syndrome and type 2 diabetes. The metabolic derangements that determine these long-term health risks remain to be clarified. Here we use NMR and MS-based metabolomics to show that serum levels of methionine sulfoxide in HIAE girls are an indicator of the degree of oxidation of methionine-148 residue in apolipoprotein-A1. Oxidation of apo-A1 in methionine-148, in turn, leads to an impaired maturation of high-density lipoproteins (HDL) that is reflected in a decline of large HDL particles. Notably, such metabolic alterations occur in the absence of impaired glucose tolerance, hyperglycemia and hypertriglyceridemia, and were partially restored after 18 months of treatment with a low-dose combination of pioglitazone, metformin and flutamide.

Remarkable quantitative and qualitative differences in HDL after niacin or fenofibrate therapy in type 2 diabetic patients.

HDL-increasing drugs such as fenofibrate and niacin have failed to decrease the cardiovascular risk in patients with type 2 diabetes. Drug-mediated quantitative and qualitative HDL modifications could be involved in these negative results. To evaluate the quantitative and qualitative effects of niacin and fenofibrate on HDL in patients with type 2 diabetes, a prospective, randomised controlled intervention trial was conducted. Thirty type 2 diabetic patients with low HDL were randomised to receive either fenofibrate (FFB) or niacin + laropiprant (ERN/LPR) as an add-on to simvastatin treatment for 12 weeks according to a crossover design. At the basal point and after each intervention period, physical examinations and comprehensive standard biochemical determinations and HDL metabolomics were performed. Thirty nondiabetic patients with normal HDL were used as a basal control group. ERN/LRP, but not FFB, significantly increased HDL cholesterol. Neither ERN/LRP nor FFB reversed the HDL particle size or particle number to normal. ERN/LRP increased apoA-I but not apoA-II, whereas FFB produced the opposite effect. FFB significantly increased Preß1-HDL, whereas ERN/LRP tended to lower Preß1-HDL. CETP and LCAT activities were significantly decreased only by ERN/LRP. PAF-AH activity in HDL and plasma decreased with the use of both agents. Despite their different actions on antioxidant parameters, none of the treatments induced detectable antioxidant improvements. ERN/LRP and FFB had strikingly different effects on HDL quantity and quality, as well as on HDL cholesterol concentrations. When prescribing HDL cholesterol increasing drugs, this differential action should be considered.

Cytotoxic effects of the lipid peroxidation product 2,4-decadienal in vascular smooth muscle cells.

It is well known that oxidized LDL can be cytotoxic to smooth muscle cells (SMC) and then contribute to the progression of atherosclerosis. Nevertheless, which oxidized compound and which mechanism are involved in cell death is still under study. In this work we have studied the role of two representative apolar aldehydes (hexanal and 2,4-decadienal (2,4-DDE)), derived from polyunsaturated fatty acids oxidation, on human SMC cytotoxicity. Cell cytotoxicity was assessed by means of lactate deshydrogenase (LDH) release, cell morphology and DNA fragmentation. Results showed that hexanal up to 50 microM for 24 h was not cytotoxic to cells. However, 2,4-DDE at 50 microM for 24 h induced a 48% LDH leakage. The observed cytotoxic effect of 2,4-DDE was not due to a programmed cell death as no DNA ladder was detected. After aldehydes exposition a decreased expression of p53 and c-myc mRNA, genes involved in cell death regulation, was also demonstrated by RT-PCR. These observations suggest that 2,4-DDE may be the molecular cause of lipid oxidation cytotoxicity to human vascular SMC. By inducing cell necrosis in advanced stages, lipid oxidation may contribute to the cell debris core which is growing in the atherosclerotic lesion leading to a weakened and unstable plaque.

Unsaturated fatty acids and their oxidation products stimulate CD36 gene expression in human macrophages.

Fatty acids (FA) have been implicated in the control of expression of several atherosclerosis-related genes. Similarly, the CD36 receptor has recently been shown to play an important role in atherosclerosis and other pathologies. The aim of the present study was to evaluate the direct effect of FA and their oxidation products (aldehydes), on the expression of CD36 in both THP-1 macrophages and human monocyte-derived macrophages (HMDM). The FA tested included the saturated FA (SFA) lauric, myristic, palmitic and stearic acid; the monounsaturated FA oleic acid; and the unsaturated FA (UFA) linoleic, arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Aldehydes used were malondialdehyde (MDA), hexanal, 2,4-decadienal (DDE) and 4-hydroxynonenal (HNE). CD36 expression was measured by RT-PCR, Western blot and immunofluorescence. Incubation of THP-1 macrophages for 24 h with non-cytotoxic concentrations of UFA significantly increased CD36 mRNA expression. By contrast, exposure of THP-1 macrophages to SFA did not affect the levels of CD36 mRNA. Among all UFAs tested, EPA and DHA were the strongest inducers of CD36 mRNA levels, followed by oleic and linoleic acid. Incubation of HMDM with either oleic or linoleic acid significantly increased steady-state CD36 mRNA in a dose-dependent manner. Consistent with the increase of CD36 mRNA expression, incubation of THP-1 macrophages with oleic and linoleic acid for 24 h markedly increased CD36 protein expression. Treatment of THP-1 macrophages with MDA or hexanal for 24 h significantly increased CD36 mRNA expression in a dose dependent manner. In contrast, DDE and HNE significantly decreased this parameter. The data provide evidence for a direct regulatory effect of UFA on CD36 gene expression and support a role for aldehydes in the regulation of CD36 expression by FA.

Prevalence of atherogenic dyslipidemia in primary care patients at moderate-very high risk of cardiovascular disease. Cardiovascular risk perception.

INTRODUCTION: Atherogenic dyslipidemia is an important risk factor for cardiovascular disease. We aim to determine atherogenic dyslipidemia prevalence in primary care patients at moderate-very high cardiovascular risk and its associated cardiovascular risk perception in Spain. METHODS: This cross-sectional study included 1137 primary care patients. Patients had previous cardiovascular disease, diabetes mellitus, SCORE risk ≥ 3, severe hypertension or dyslipidemia. Atherogenic dyslipidemia was defined as low HDL-C (<40 mg/dL [males], <50 mg/dL [females]) and elevated triglycerides (≥ 150 mg/dL). A visual analog scale was used to define a perceived cardiovascular disease risk score. RESULTS: Mean age was 63.9 ± 9.7 years (64.6% males). The mean BMI was 29.1 ± 4.3 kg/m(2), and mean waist circumference 104.2 ± 12.7 cm (males), and 97.2 ± 14.0 cm (females). 29.4% were smokers, 76.4% had hypertension, 48.0% were diabetics, 24.7% had previous myocardial infarction, and 17.8% peripheral arterial disease. European guidelines classified 83.6% at very high cardiovascular risk. Recommended HDL-C levels were achieved by 50.1% of patients and 37.3% had triglycerides in the reference range. Target LDL-C was achieved by 8.8%. The overall atherogenic dyslipidemia prevalence was 27.1% (34.1% in diabetics). This prevalence in patients achieving target LDL-C was 21.4%. Cardiovascular risk perceived by patients was 4.3/10, while primary care physicians scored 5.7/10. CONCLUSIONS: When LDL-C levels are controlled, atherogenic dyslipidemia is more prevalent in those patients at highest cardiovascular risk and with diabetes. This highlights the importance of intervention strategies to prevent the residual vascular risk in this population. Both patients and physicians underestimated cardiovascular risk.

Akt and ERK/Nrf2 activation by PUFA oxidation-derived aldehydes upregulates FABP4 expression in human macrophages.

OBJECTIVE: In macrophages, adipocyte fatty acid-binding protein (FABP4) coordinates key events in oxidized LDL-induced foam cell formation, such as cholesterol trafficking and inflammatory responses. Nrf2 is a redox-sensitive transcription factor with antioxidant and anti-inflammatory properties. We investigated the involvement of the Nrf2 signaling pathway in FABP4-upregulation in response to aldehydes that are derived from polyunsaturated fatty acid (PUFA) oxidation. METHODS AND RESULTS: Using RT-PCR and western blotting, we found that the aldehyde 2,4-decadienal (2,4-DDE) produced a marked increase in FABP4 mRNA and protein levels. 2,4-DDE acts at the transcriptional level of FABP4 by promoting mRNA synthesis and prolonging the half-life of the de novo synthesized mRNA. 2,4-DDE consistently enhanced nuclear translocation of phosphorylated Nrf2, which was mediated by the activation of the Akt and ERK signaling pathways. A chromatin immunoprecipitation assay showed the in vivo binding of activated Nrf2 to a newly identified ARE site in the human FABP4 promoter. CONCLUSIONS: We propose an Akt and ERK/Nrf2-dependent FABP4 upregulation pathway in response to PUFA oxidation end-products in human macrophages. These results open a new avenue for putative therapeutic targets addressed to control atherogenesis.

Even low physical activity levels improve vascular function in overweight and obese postmenopausal women.

OBJECTIVE: Some individuals with cardiovascular risk are unable to achieve even the lower internationally recommended level of physical activity (PA). We aimed to study the impact of a lower-than-advised level of PA on small artery vascular function and oxidative stress in overweight and obese postmenopausal women. METHODS: Forty-seven overweight and obese postmenopausal women completed a 4-month program of 1-hour low-intensity PA for 2 days per week. Before and after the intervention, PA level (metabolic equivalent tasks/h/wk), endogenous antioxidant status (superoxide dismutase and erythrocyte lysate and glutathione peroxidase erythrocyte lysate concentrations, superoxide dismutase plasma and glutathione peroxidase plasma [GPXa] activities, and oxidized low-density lipoprotein), asymmetrical dimethylarginine concentrations, endothelial function by small artery reactive hyperemia index (saRHI), and resting heart rate (RHR) were assessed. RESULTS: After the intervention, a significant increase in GPXa and decreases in asymmetrical dimethylarginine concentrations and RHR (P < 0.001 for all) were observed. Increases in PA were positively associated with increases in saRHI (r = 0.330, P = 0.027) and GPXa (r = 0.299, P = 0.05) and a decrease in RHR (r = -0.297, P = 0.047). Multivariate analyses showed that the independent predictors of saRHI improvement were an increase in PA (ß = 2.63; 95% CI, 1.24-4.19; P = 0.019), a decrease in RHR (ß = 1.96; 95% CI, 1.01-5.03; P = 0.048), and an increase in GPXa (ß = 2.64; 95% CI, 1.18-5.08; P = 0.021). CONCLUSIONS: Even low-intensity PA improves antioxidant capacity, RHR, and saRHI in postmenopausal women. Advising postmenopausal women to increase their PA at any level seems warranted based on our preliminary and hypothesis-generating data.

Substituting non-HDL cholesterol with LDL as a guide for lipid-lowering therapy increases the number of patients with indication for therapy.

AIM: Our objective was to assess the number of patients with an indication for lipid-lowering therapy according to their non-HDL cholesterol (N-HDL-C) (>130 mg/dL) concentrations despite on-target LDL (≤100 mg/dL) values determined using ultracentrifugation (UC) or direct enzymatic methods (DM). METHODS: In 1590 patients we studied the lipid profile using standard biochemical methods and sequential UC (N = 637) or triglyceride (TG) independent DM (N = 953). The indications for lipid-lowering therapy were compared by evaluating the real LDL concentration or N-HDL-C concentration. RESULTS: The LDL/N-HDL-C correlation significantly decreased with increasing triglyceride concentrations: normal (r = 0.924, p < 0.001), 150-400 mg/dL (r = 0.825, p < 0.001) and higher than 400 mg/dL (r = 0.460, p < 0.001) (p < 0.001). The percentage of patients with an N-HDL-C concentration above the recommended level, despite having an LDL concentration that was on target, also increased significantly across the TG tertiles (3.1%, 15.6% and 57.%, respectively; p < 0.001). Of the patients with a TG level above 400 mg/dL and an LDL concentration that was on target, 86% had an N-HDL-C concentration above 130 mg/dL. Of the patients with a TG level above 400 and an N-HDL-C concentration qualifying for therapy, 40% had an LDL concentration that was on target. The ApoB concentration had a stronger concordance with the LDL concentration than N-HDL-C. CONCLUSIONS: Using the N-HDL-C concentration as a therapeutic target in hypertriglyceridemic patients almost doubled the number of patients requiring treatment. The ApoB concentration had a better association with LDL when determining the need for lipid-lowering therapy.