Peripheral blood levels of CXCL10 are a useful marker for diabetic polyneuropathy in subjects with type 2 diabetes.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a chronic complication of diabetes mellitus associated with high morbidity and mortality. Major risk factors for DPN include metabolic changes, duration of diabetes, nerve ischaemia and derangements in regeneration and nerve repair programmes. Chemokines have been previously implicated in the pathogenesis of various neuropathies and neuropathic pain processes. The aim of this pilot study was to evaluate the association between the plasma levels of chemokines (CXCL9, CXCL10 and CXCL11) in the presence of DPN in a cohort of type 2 diabetes (T2D) patients. MATERIALS AND METHODS: We studied 73 patients with T2D: 36 with DPN and 37 without DPN. DPN was established through the Semmes-Weinstein test (SW). Plasma levels of circulating chemokines CXCL9, CXCL10 and CXCL11 were determined using DuoSet ELISA kits (Abingdon, UK). RESULTS: We found that levels of CXCL10 were significantly higher in patients with DPN than amongst patients without DPN (57.6 ± 38.3 vs 38.1 ± 33.4 pg/mL, respectively; P = .034). Serum levels of chemokine CXCL9 were also higher amongst patients with DPN but did not reach a statistical significance (188.1 ± 72.7 and 150.4 ± 83.6 pg/mL, respectively, P = .06). CONCLUSIONS: Increased circulating levels of CXCL10 were associated with DPN in T2D patients, suggesting a role of this chemokine in the DPN. Determination of CXCL10 levels could be used as a marker for the early detection and implementation of therapeutic strategies in order to reverse and prevent the DPN.

Postprandial triglyceridaemia is modulated by insulin resistance but not by grade of obesity in abdominal and morbid obese subjects.

BACKGROUND: Obesity is associated with high cardiovascular risk. Postprandial lipidaemia has been associated with cardiovascular disease risk. Our aim was to identify whether anthropometric parameters, insulin resistance (IR) and/or fasting plasma triglycerides may determine postprandial changes in lipoprotein concentrations in abdominal and morbid obese subjects. METHODS: We have studied 20 non-diabetic, normolipidaemic subjects with abdominal obesity, 20 morbid obese subjects and 20 healthy individuals, that have similar age and gender. In all of them a standardised oral fat load test (OFLT) with unsaturated fat was performed. RESULTS: During the OFLT, the postprandial triglycerides response was significantly higher in subjects with abdominal obesity compared with morbid obese subjects (4 hours triglycerides pick value and AUC of triglycerides). Both obese groups showed significantly higher postprandial triglycerides response compared with healthy subjects. Dividing the obesity group according to the presence of IR, we found that IR was an important factor related with postprandial lipaemia but not BMI or waist circumference. In addition, postprandial glycaemia and insulinaemia significantly decreased in all studied subjects, being the highest decrease in morbid obese subjects and in subjects with IR. Postprandial triglyceridaemia significantly correlated with IR parameters and not with anthropometric parameters in AO and MO subjects. CONCLUSION: In subjects with AO and MO, postprandial triglycerides values are higher than healthy individuals and independently predicted by fasting IR parameters. Furthermore, unsaturated fat improved IR state.

Type 1 diabetic mellitus patients with increased atherosclerosis risk display decreased CDKN2A/2B/2BAS gene expression in leukocytes.

BACKGROUND: Type 1 diabetes mellitus (T1DM) patients display increased risk of cardiovascular disease (CVD) and are characterized by a diminished regulatory T (Treg) cell content or function. Previous studies have shown an association between decreased CDKN2A/2B/2BAS gene expression and enhanced CVD. In the present study the potential relationship between CDKN2A/2B/2BAS gene expression, immune cell dysfunction and increased cardiovascular risk in T1DM patients was explored. METHODS: A cross-sectional study was performed in 90 subjects divided into controls and T1DM patients. Circulating leukocyte subpopulations analysis by flow cytometry, expression studies on peripheral blood mononuclear cell by qPCR and western blot and correlation studies were performed in both groups of subjects. RESULTS: Analysis indicated that, consistent with the described T cell dysfunction, T1DM subjects showed decreased circulating CD4+CD25+CD127- Treg cells. In addition, T1DM subjects had lower mRNA levels of the transcription factors FOXP3 and RORC and lower levels of IL2 and IL6 which are involved in Treg and Th17 cell differentiation, respectively. T1DM patients also exhibited decreased mRNA levels of CDKN2A (variant 1 p16Ink4a), CDKN2A (p14Arf, variant 4), CDKN2B (p15Ink4b) and CDKN2BAS compared with controls. Notably, T1DM patients had augmented pro-atherogenic CD14++CD16+-monocytes, which predict cardiovascular acute events and enhanced common carotid intima-media thickness (CC-IMT). CONCLUSIONS: Decreased expression of CDKN2A/2B/2BAS in leukocytes associates with increased CC-IMT atherosclerosis surrogate marker and proatherogenic CD14++CD16+ monocytes in T1DM patients. These results suggest a potential role of CDKN2A/2B/2BAS genes in CVD risk in T1DM.

Upregulation of angiostatic chemokines IP-10/CXCL10 and I-TAC/CXCL11 in human obesity and their implication for adipose tissue angiogenesis.

BACKGROUND/AIMS: Impaired angiogenesis is linked to adipose tissue (AT) dysfunction, inflammation, and insulin resistance in human obesity. Chemokine (C-X-C motif) receptor. (CXCR3) ligands are important regulators of angiogenesis in different disease contexts such as cancer; however, their role in human morbid obesity is unknown. We investigated the role of the CXCR3 axis in AT angiogenesis in morbidly obese patients. SUBJECTS/METHODS: The study group comprised 50 morbidly obese patients (mean age 44 ± 1 years, body mass index 44 ± 1 kg/m2) who had undergone laparoscopic Roux-Y-gastric bypass surgery, and 25 age-matched non-obese control subjects. We measured the circulating levels of the CXCR3 ligands monokine induced by interferon-γ (MIG/CXCL9), interferon-γ inducible protein 10 (IP-10/CXCL10), and interferon-γ-inducible T-cell alpha chemoattractant (I-TAC/CXCL11) in all studied subjects. Additionally, the expression of CXCR3 ligands was analyzed in paired biopsies of subcutaneous and visceral AT obtained during the laparoscopic procedure in morbidly obese patients. Additionally, we explored the functional role of CXCR3 ligands on angiogenesis in AT from morbidly obese patients using an ex vivo assay. RESULTS: Plasma levels of CXCL10 and CXCL11 were significantly higher in morbidly obese patients than in controls (p < 0.01). In ex vivo assays, angiogenic growth was markedly lower in visceral AT than in subcutaneous AT (p < 0.05), which was related to significant tissue upregulation of CXCL10, CXCL11 and CXCR3 (p < 0.05). CXCL10 or CXCL11 inhibited AT angiogenesis (p < 0.05), and blockade of CXCR3 function significantly increased capillary sprouting in visceral fat deposits (p < 0.05). Western blot analysis showed that the p38 mitogen-activated protein kinase signaling pathway was implicated in the angiostatic effects of CXCR3 in AT. CONCLUSIONS: CXCL10 and CXCL11 may play. deleterious role in obesity as potential inhibitors of AT angiogenesis. Accordingly, pharmacological blockade of CXCR3 could represent. therapy to prevent AT dysfunction in obesity.

The GLP-1 analogue lixisenatide decreases atherosclerosis in insulin-resistant mice by modulating macrophage phenotype.

AIMS/HYPOTHESIS: Recent clinical studies indicate that glucagon-like peptide-1 (GLP-1) analogues prevent acute cardiovascular events in type 2 diabetes mellitus but their mechanisms remain unknown. In the present study, the impact of GLP-1 analogues and their potential underlying molecular mechanisms in insulin resistance and atherosclerosis are investigated. METHODS: Atherosclerosis development was evaluated in Apoe -/- Irs2 +/- mice, a mouse model of insulin resistance, the metabolic syndrome and atherosclerosis, treated with the GLP-1 analogues lixisenatide or liraglutide. In addition, studies in Apoe -/- Irs2 +/- mice and mouse-derived macrophages treated with lixisenatide were performed to investigate the potential inflammatory intracellular pathways. RESULTS: Treatment of Apoe -/- Irs2 +/- mice with either lixisenatide or liraglutide improved glucose metabolism and blood pressure but this was independent of body weight loss. Both drugs significantly decreased atheroma plaque size. Compared with vehicle-treated control mice, lixisenatide treatment generated more stable atheromas, with fewer inflammatory infiltrates, reduced necrotic cores and thicker fibrous caps. Lixisenatide-treated mice also displayed diminished IL-6 levels, proinflammatory Ly6Chigh monocytes and activated T cells. In vitro analysis showed that, in macrophages from Apoe -/- Irs2 +/- mice, lixisenatide reduced the secretion of the proinflammatory cytokine IL-6 accompanied by enhanced activation of signal transducer and activator of transcription (STAT) 3, which is a determinant for M2 macrophage differentiation. STAT1 activation, which is essential for M1 phenotype, was also diminished. Furthermore, atheromas from lixisenatide-treated mice showed higher arginase I content and decreased expression of inducible nitric oxide synthase, indicating the prevalence of the M2 phenotype within plaques. CONCLUSIONS/INTERPRETATION: Lixisenatide decreases atheroma plaque size and instability in Apoe -/- Irs2 +/- mice by reprogramming macrophages towards an M2 phenotype, which leads to reduced inflammation. This study identifies a critical role for this drug in macrophage polarisation inside plaques and provides experimental evidence supporting a novel mechanism of action for GLP-1 analogues in the reduction of cardiovascular risk associated with insulin resistance.

Altered Semmes-Weinstein monofilament test results are associated with oxidative stress markers in type 2 diabetic subjects.

BACKGROUND: Different lines of evidence suggest that oxidative stress (OS) is implicated in the pathogenesis of diabetic neuropathy. The Semmes-Weinstein monofilament (SWM) test is an efficient tool for evaluating diabetic polyneuropathy and diabetic foot. In this study, we analyzed the association between OS markers and altered SWM test results in type 2 diabetes (T2DM) patients. METHODS: Seventy T2DM patients were studied and 34 showed altered SWM results. The clinical and biochemical parameters were determined using standardized methods. Levels of oxidized glutathione (GSSG) and malondialdehyde (MDA) were measured in circulating mononuclear cells using high-performance liquid chromatography. RESULTS: We found that T2DM patients with altered SWM test results had significantly higher GSSG (3.53 ± 0.31 vs. 3.31 ± 0.35 mmol/ml, p < 0.05) and MDA (1.88 ± 0.16 vs. 1.75 ± 0.19 nmol/ml, p < 0.01) values compared to diabetic patients with normal SWM test outcomes. Moreover, altered SWM test results were independently related to age, glycosylated hemoglobin, and GSSG levels, but there was no association between OS markers and altered neuropathy sensitivity score (NSS) values. CONCLUSIONS: Alteration of the glutathione system and MDA values in T2DM patients are associated with loss of proprioceptive (pressure) sensitivity, but not with symptomatic polyneuropathy (as evaluated by NSS). This finding may be important for understanding how OS affects distal symmetric polyneuropathy in diabetic patients.

Increased thioredoxin levels are related to insulin resistance in familial combined hyperlipidaemia.

BACKGROUND: Thioredoxins (TRX) are major cellular protein disulphide reductases that are critical for redox regulation. Oxidative stress and inflammation play promoting roles in the genesis and progression of atherosclerosis, but until now scarce data are available considering the influence of TRX activity in familial combined hyperlipidaemia (FCH). Since FCH is associated with high risk of cardiovascular disease, the objective of the present study was to assess oxidative stress status in FCH patients, and evaluate the influence of insulin resistance (IR). MATERIALS AND METHODS: A cohort of 35 control subjects and 35 non-related FCH patients were included, all of them nondiabetic, normotensive and nonsmokers. We measured lipid profile, glucose and insulin levels in plasma, and markers of oxidative stress and inflammation such as oxidized glutathione (GSSG), reduced glutathione (GSH) and TRX. RESULTS: Familial combined hyperlipidaemia subjects showed significantly higher levels of GSSG, GSSG/GSH ratio and TRX than controls. In addition, FCH individuals with IR showed the worst profile of oxidative stress status compared to controls and FCH patients without IR (P < 0·01). TRX levels correlated with higher insulin resistance. CONCLUSION: Familial combined hyperlipidaemia patients showed increased TRX levels. TRX was positively correlated with IR. These data could partially explain the increased risk of cardiovascular events in primary dyslipidemic patients.

Relationships between obesity, glycemic control, and cardiovascular risk factors: a pooled analysis of cross-sectional data from Spanish patients with type 2 diabetes in the preinsulin stage.

BACKGROUND: Obesity is associated with the onset of type 2 diabetes mellitus (T2D), but reports conflict regarding the association between obesity and macrovascular complications. In this study, we investigated associations between cardiovascular risk factors and body mass index (BMI) and glycemic control in non-insulin-treated patients with T2D. METHODS: Authors gathered cross-sectional data from five observational studies performed in Spain. Generalized logit models were used to analyze the relationship between cardiovascular risk factors (independent variables) and 5 BMI strata (<25 kg/m2, 25 to <30 kg/m2, 30 to <35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2) and 5 glycated hemoglobin (HbA1c) strata (≤6.5%, >6.5-7%, >7-8%, >8-9%, >9%) (dependent outcomes). RESULTS: In total, data from 6442 patients were analyzed. Patients generally had mean values of investigated cardiovascular risk factors outside recommended thresholds. Younger patients had higher BMI, triglyceride levels and HbA1c than their older counterparts. Diastolic blood pressure, systolic blood pressure and triglyceride levels were directly correlated with BMI strata, whereas an inverse correlation was observed between BMI strata and high-density lipoprotein cholesterol (HDL-C) levels, patient age, and duration of T2D. Increased duration of T2D and total cholesterol levels, and decreased HDL-C levels were associated with a higher HbA1c category. BMI and HbA1c levels were not associated with each other. CONCLUSIONS: As insulin-naïve patients with T2D became more obese, cardiovascular risk factors became more pronounced. Higher BMI was associated with younger age and shorter duration of T2D, consistent with the notion that obesity at an early age may be key to the current T2D epidemic. Glycemic control was independent of BMI but associated with abnormal lipid levels. Further efforts should be done to improve modifiable cardiovascular risk factors.

Cardiovascular prevention in diabetes mellitus. Is it appropriate to speak of moderate or intermediate risk? / Prevención cardiovascular en la diabetes mellitus. ¿Es adecuado hablar de riesgo moderado o intermedio?

Diabetes, especially type 2, is considered a risk situation for atherosclerotic cardiovascular disease (ASCVD). Subjects with diabetes type 2 have a mortality rate due to ASCVD 3 times higher than that found in the general population, attributed to hyperglycemia and the frequent association of other cardiovascular risk factors, such as atherogenic dyslipidemia. Numerous scientific societies have established a risk classification for ASCVD in diabetes based on 3 degrees (moderate, high and very high). The objectives of dyslipidemia control are clearly defined and accepted, and vary depending on the previously established cardiovascular risk. In moderate or intermediate risk, the guidelines propose a less intensive intervention, maintaining LDL-C levels<100mg/dL and NO-HDL-C levels<130mg/dL, and waiting 10 years until reaching the high-risk category to initiate more intensive treatment. However, during the decade of follow-up recommended in the guidelines, cholesterol deposition in the arterial wall increases, facilitating the development of an unstable and inflammatory atheromatous plaque, and the development of ASCVD. Alternatively, diabetes could be considered from the outset to be a high-risk situation and the goal should be LDL-C<70mg/dL. Furthermore, maintaining LDL-C levels<70mg/dL contributes to reducing and stabilizing atheromatous plaque, avoiding or reducing mortality episodes due to ASCVD during those years of diabetes evolution. Should we maintain the proposed objectives in subjects with diabetes and moderate risk for a decade until reaching the high cardiovascular risk phase or, on the contrary, should we adopt a more intensive stance from the beginning seeking to reduce cardiovascular risk in the majority of patients with diabetes? Is it better to wait or prevent with effective therapeutic measures from the first moment?

Association of carotid atheroma plaque with IL-18 levels and with polymorphisms in the IL-18 receptor gene in a Mediterranean population. / Asociación de la placa de ateroma carotídea con los niveles plasmáticos de IL-18 y con polimorfismos en el gen del receptor de la IL-18 en la población mediterránea.

BACKGROUND: Atherosclerosis is an inflammatory disease. Interleukin 18 (IL-18) is an inflammatory molecule that has been linked to the development of atherosclerosis and cardiovascular disease. OBJECTIVE: To evaluate the possible relationship between plasma levels of IL-18 and the presence of atherosclerosis evaluated at the carotid level, as well as to analyze the possible modulation by different polymorphisms in a Mediterranean population. MATERIAL AND METHODS: Seven hundred and forty-six individuals from the metropolitan area of Valencia were included, recruited over a period of 2 years. Hydrocarbon and lipid metabolism parameters were determined using standard methodology and IL-18 using ELISA. In addition, carotid ultrasound was performed and the genotype of four SNPs related to the IL-18 signaling pathway was analyzed. RESULTS: Patients with higher plasma levels of IL-18 had other associated cardiovascular risk factors. Elevated IL-18 levels were significantly associated with higher carotid IMT and the presence of atheromatous plaques. The genotype with the A allele of the SNP rs2287037 was associated with a higher prevalence of carotid atheromatous plaque. On the contrary, the genotype with the C allele of the SNP rs2293224 was associated with a lower prevalence of atheromatous plaque. CONCLUSIONS: High levels of IL-18 were significantly associated with a higher carotid IMT and the presence of atheromatous plaques, which appear to be influenced by genetic factors, as evidenced by associations between SNPs in the IL-18 receptor gene and the presence of atheroma plaque.

Atherogenic dyslipidaemia in type 2 diabetes mellitus: The PREDISAT study.

Extremely variable prevalence rates of atherogenic dyslipidaemia (AD) in type 2 diabetes (T2DM) subjects have been reported. The primary aim was to assess AD prevalence in Spanish T2DM subjects. Secondary objectives were to evaluate the differential clinical characteristics between T2DM subjects with and without AD, to describe lipid profile evolution and use of lipid-lowering treatment in clinical practice by the Spanish Lipid Units. Data was obtained from the National Registry of Dyslipidaemias of the Spanish Atherosclerosis Society, from a multicentric sub-study focused on AD prevalence in T2DM subjects (PREDISAT study). The inclusion criteria were subjects diagnosed of T2DM with age ≥18 years old. A total of 385 T2DM subjects with a mean age of 61 years and 246 (64%) men were included. The mean follow-up was 22 ± 7.4 months. At baseline, 41.3% of the T2DM subjects presented AD, this percentage decreasing to 34.8% with therapeutic intervention. AD prevalence varied in different age groups and appeared to be more prevalent in younger T2DM subjects. Those with AD had a more atherogenic lipid profile at baseline, with higher total cholesterol, triglyceride and non-(high-density lipoprotein) HDL cholesterol levels at baseline, together with lower HDL cholesterol concentrations, without achieving lipid subfraction goals during follow-up. Although almost 90% of the AD subjects were under lipid-lowering treatment, most were receiving only one drug, being statins the most used treatmentA high AD prevalence in T2DM subjects was observed, being age a determinant factor, with a modest decline during follow-up. Although almost 90% of the AD subjects were under lipid-lowering drugs, most were only receiving monotherapy with statins.

Polymorphisms of the UCP2 gene are associated with body fat distribution and risk of abdominal obesity in Spanish population.

BACKGROUND: Increased accumulation of fat results from an imbalance between energy expenditure and intake, being modulated by different environmental and genetic factors. Uncoupling proteins (UCPs) are mitochondrial carrier proteins able to spend energy generating heat. Therefore, variations in these genes are good candidates as potential modulators of body fat accumulation. Our aim was to investigate the possible association of genetic variations of the gene codifying the UCP2 protein with obesity and fat distribution. DESIGN: We performed a cross-sectional study in 2367 individuals from two population-based studies from different regions of Spain. The Hortega Study included 1436 individuals (693 women) 21-85 years old, and the Pizarra Study included 931 individuals (584 women) 18-65 years old. We evaluated three polymorphisms of the UCP2 gene. RESULTS: The TT genotype of the rs660339 polymorphism and the AA genotype of the rs659366 polymorphism of the UCP2 gene were significantly associated with higher waist circumference in the Hortega Study. Furthermore, subjects carrying both genotypes (TT+AA) also showed higher central adiposity compared with other genotypes. This association was also present in the Pizarra Study. Moreover, in the pooled population, we found a stronger association with waist circumference. Even, we found association with BMI. Furthermore, rs659366 polymorphism was associated with the risk of abdominal obesity (P= 0·04: OR = 1·3; CI = 1·01-1·67). CONCLUSIONS: Polymorphisms of the UCP2 gene (rs660339 and rs659366) were associated with central obesity. This study shows association between the UCP2 gene and the susceptibility to obesity and body fat distribution in a south European population.

Plasma homocysteine levels are independently associated with the severity of peripheral polyneuropathy in type 2 diabetic subjects.

Peripheral polyneuropathy (PN) is a frequent complication of diabetes. However, mechanisms underlying the development of PN are multifactorial and not well understood. Our aim was to examine the association of plasma homocysteine (Hcy) with the prevalence and grade of peripheral PN in patients with type 2 diabetes (T2DM). We studied a cohort of 196 subjects with T2DM classified according to the grade of PN (Neuropathy Disability Score, NDS). Subjects with the highest grade of PN were older and had significantly increased levels of creatinine, microalbuminuria, HbA1c, and plasma Hcy compared to the other two groups. The differences in plasma Hcy values were maintained after correcting for confounding factors. Plasma Hcy, HbA1c, duration of diabetes, and age were predictors of the grade of PN. In conclusion, for each increase of 1 µmol in plasma Hcy there was a 23% increase of the risk of diabetic PN evaluated by NDS. Moreover, the grade of PN was predicted by plasma Hcy and HbA1c values, age and duration of diabetes. Further prospective studies should be conducted to confirm the association of plasma Hcy levels with the grade of PN in subjects with T2DM.

Beneficial effects of PCSK9 inhibition with alirocumab in familial hypercholesterolemia involve modulation of new immune players.

Familial hypercholesterolemia (FH) is associated with low-grade systemic inflammation, a key driver of premature atherosclerosis. We investigated the effects of inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) function on inflammatory state, endothelial dysfunction and cardiovascular outcomes in patients with FH. Fourteen patients with FH were evaluated before and 8 weeks after administration of a PCSK9 blocking monoclonal antibody (alirocumab, 150 mg/subcutaneous/14 days). In vivo and ex vivo analysis revealed that alirocumab blunted the attachment of leukocytes to TNFα-stimulated human umbilical arterial endothelial cells (HUAEC) and suppressed the activation of platelets and most leukocyte subsets, which was accompanied by the diminished expression of CX3CR1, CXCR6 and CCR2 on several leukocyte subpopulations. By contrast, T-regulatory cell activation was enhanced by alirocumab treatment, which also elevated anti-inflammatory IL-10 plasma levels and lowered circulating pro-inflammatory cytokines. Plasma levels of IFNγ positively correlated with levels of total and LDL-cholesterol, whereas circulating IL-10 levels negatively correlated with these key lipid parameters. In vitro analysis revealed that TNFα stimulation of HUAEC increased the expression of PCSK9, whereas endothelial PCSK9 silencing reduced TNFα-induced mononuclear cell adhesion mediated by Nox5 up-regulation and p38-MAPK/NFκB activation, concomitant with reduced SREBP2 expression. PCSK9 silencing also decreased endothelial CX3CL1 and CXCL16 expression and chemokine generation. In conclusion, PCSK9 inhibition impairs systemic inflammation and endothelial dysfunction by constraining leukocyte-endothelium interactions. PCSK9 blockade may constitute a new therapeutic approach to control the inflammatory state associated with FH, preventing further cardiovascular events in this cardiometabolic disorder.

Lipid metabolism and classification of hyperlipaemias. / Metabolismo lipídico y clasificación de las hiperlipemias.

This chapter summarises, and updates, lipid metabolism. Both pathways, exogenous metabolisms route via the chylomicrons, and the endogenous pathway of very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL). The reverse cholesterol metabolism will also be mentioned. It also includes the current classification of hyperlipidaemias or hyperlipoproteinaemias, with a reminder of the phenotype classification, and further developments of the aetiological classification. Both parts have updated references, with which knowledge of this vast subject can be expanded.

Oral Unsaturated Fat Load Impairs Postprandial Systemic Inflammation in Primary Hypercholesterolemia Patients.

Context: Primary hypercholesterolemia (PH) is a lipid disorder characterized by elevated levels of cholesterol and low-density lipoprotein (LDL). Low-grade systemic inflammation is associated with PH, which might explain the higher incidence of cardiovascular diseases in this setting. Objective: To evaluate the effect of an oral unsaturated fat load (OUFL) on different immune parameters and functional consequences in patients with PH in postprandial state. Design: A commercial liquid preparation of long-chain triglycerides (Supracal®; ω6/ω3 ratio >20/1, OUFL) was administered to 20 patients and 10 age-matched controls. Whole blood was collected before (fasting state) and 4 h after administration (postprandial state). Flow cytometry was employed to determine platelet and leukocyte activation, and the levels of circulating platelet-leukocyte aggregates. Soluble markers were determined by ELISA, and the parallel-plate flow chamber was employed to study leukocyte adhesion to the dysfunctional arterial endothelium. Results: The PH group had a lower percentage of activated platelets and circulating type 1 monocytes, and blunted neutrophil activation after the OUFL, accompanied by a significant increase in the percentage of regulatory T lymphocytes. In this group, the OUFL led to a significant impairment of leukocyte adhesion to the dysfunctional [tumor necrosis factor α (TNFα)-stimulated] endothelium and reduced the plasma levels of soluble P-selectin, platelet factor-4 (PF-4)/CXCL4, CXCL8, CCL2, CCL5, and TNFα. Conclusion: The OUFL has a beneficial impact on the pro-thrombotic and pro-inflammatory state of PH patients and might be a promising macronutrient approach to dampen the systemic inflammation associated with PH and the development of further cardiovascular events.

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.

[Global therapy of diabetic dyslipidemia: benefits and new therapeutic approaches]. / Tratamiento integral de la dislipidemia diabética: beneficios y nuevas alternativas terapéuticas.

Diabetic dyslipidemia, characterized by the lipid triad (elevated plasma triglycerides, low HDL cholesterol and predominance of small, dense LDL particles), is a significant contributor to the elevated cardiovascular risk of type 2 diabetic patients. Statin monotherapy has shown, in different prospective trials, significant reductions in cardiovascular events and mortality. However, the residual risk in these subjects remains elevated, probably due to the incomplete control of diabetic dyslipidemia. In this review we discuss the global therapeutic approach, underlying the need of combining statins with agents that more effective in reducing triglycerides and elevating HDL cholesterol, even in subjects whose LDL cholesterol values are at target. Available data supports that such combinations contribute to normalize the lipid profile with possible beneficial effects on the cardiovascular risk. Ongoing clinical trials, using different combinations and focusing on cardiovascular morbidity and mortality are also discussed. In our opinion, the future treatment of diabetic dyslipidemia will include the combination of statins and other hypolipidemic agents.

[Advances in cholesterol-lowering interventions]. / Avances en el tratamiento de la hipercolesterolemia.

Numerous epidemiological and prospective studies have shown a direct relationship between total cholesterol and low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (cardiovascular morbidity and mortality). In many intervention studies with more than 100,000 subjects, statins have shown a powerful and significant reduction of cardiovascular events and a decrease in cardiovascular and overall mortality, far superior to those produced by any other lipid-lowering group. Consequently statins are considered to be safe and well tolerated and are the first choice in the treatment of hypercholesterolemia and in cardiovascular disease prevention. If targets are not reached, other pharmacological groups must be associated (resins, nicotinic acid, ezetimibe, fibrates, etc.). Moreover, when hypercholesterolemia is associated with low concentrations of high-density lipoprotein (HDL)-cholesterol and high triglyceride levels, the association of statins with nicotinic acid, fibrates or omega-3 should be considered. Some questions remain to be answered: what LDL-C levels are desirable in secondary prevention? Which individuals might benefit from treatment in primary prevention? Which lipid-lowering drug is the most suitable to combine with statins and diminish cardiovascular risk in each situation? The present article reviews these important points.

Chronic kidney disease as a cardiovascular risk factor.

: Chronic kidney disease (CKD) is a public health threat with impact in cardiovascular risk. All forms of cardiovascular disease and mortality are more common in CKD. Treatment of cardiovascular risk factors, hypertension, dyslipidemia and diabetes is essential for cardiovascular and kidney protection. CKD is a marker of high or very high cardiovascular risk and its presence require early treatment and specific goals. Lifestyle is a pivotal factor, stopping smoking, reducing weight in the overweight or obese, starting regular physical exercise and healthy dietary pattern are recommended. Office BP should be lowered towards 130/80 mmHg or even lower if tolerated with sodium restriction and single pill combination, including angiotensin system blocker. Out-of-office BP monitoring, mainly 24-h assessment, is recommended. Diabetes requires treatment from the moment of diagnosis, but prediabetes benefits with lifestyle changes and metformin in patients stage 2 and 3a. iSGLT2 and GLP-1RA are initially recommended in T2D patients with high or very high cardiovascular risk. Concerning dyslipidemia, for patients in stage 4, LDL-C 55 mg/dl or less (1.4 mmol/l) and an LDL-C reduction of 50% or less from baseline is recommended. In stage 3, LDL-C goal is 70 mg/dl or less (1.8 mmol/l) and an LDL-C. reduction of at least 50% from baseline. Statins are the lipid-lowering therapy of choice with or without ezetimibe. Higher doses of statins are required as GFR declines. Available evidence suggests that combined PCSK9 inhibitors with maximally tolerated dose of statins may have an emerging role in treatment of dyslipidemia in CKD patients.